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1
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Kushimo OA, Sokunbi OJ, Ibe F, Adekolade AS. Noonan Syndrome Associated with a Patent Foramen Ovale. Niger Postgrad Med J 2025; 32:74-76. [PMID: 40091476 DOI: 10.4103/npmj.npmj_294_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 01/23/2025] [Indexed: 03/19/2025]
Abstract
Noonan syndrome is a genetic disorder characterised by abnormalities of the facial, musculoskeletal and cardiovascular systems. Pulmonary stenosis is the most common abnormality seen. We describe a 48-year-old male with clinical features of Noonan syndrome, and severe pulmonary stenosis with cyanosis. A long-standing history of effort intolerance was noted since childhood. The cause of cyanosis was unclear since an initial echo did not reveal an obvious shunt by Doppler imaging. An agitated saline contrast study performed confirmed a patent foramen ovale (PFO) with right to left shunting. PFO should be suspected and screened for in patients with Noonan syndrome and unexplained cyanosis.
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Affiliation(s)
| | | | - Festus Ibe
- Department of Medicine, Lagos University Teaching Hospital, Lagos, Nigeria
| | - Ayodeji S Adekolade
- Cardiology Unit, Department of Medicine, Lagos University Teaching Hospital, Lagos, Nigeria
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Martinez-Mayer J, Vishnopolska S, Perticarari C, Iglesias Garcia L, Hackbartt M, Martinez M, Zaiat J, Jacome-Alvarado A, Braslavsky D, Keselman A, Bergadá I, Marino R, Ramírez P, Pérez Garrido N, Ciaccio M, Di Palma MI, Belgorosky A, Forclaz MV, Benzrihen G, D'Amato S, Cirigliano ML, Miras M, Paez Nuñez A, Castro L, Mallea-Gil MS, Ballarino C, Latorre-Villacorta L, Casiello AC, Hernandez C, Figueroa V, Alonso G, Morin A, Guntsche Z, Lee H, Lee E, Song Y, Marti MA, Perez-Millan MI. Exome Sequencing Has a High Diagnostic Rate in Sporadic Congenital Hypopituitarism and Reveals Novel Candidate Genes. J Clin Endocrinol Metab 2024; 109:3196-3210. [PMID: 38717911 DOI: 10.1210/clinem/dgae320] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/22/2024] [Accepted: 05/06/2024] [Indexed: 06/23/2024]
Abstract
CONTEXT The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction, with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported. OBJECTIVE We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina. METHODS We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date. RESULTS Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes with high loss-of-function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (eg, PTPN6, ARID5B). CONCLUSION Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.
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Affiliation(s)
- Julian Martinez-Mayer
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Sebastian Vishnopolska
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Catalina Perticarari
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Lucia Iglesias Garcia
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Martina Hackbartt
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Marcela Martinez
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, C1428EHA, Ciudad de Buenos Aires, Argentina
| | - Jonathan Zaiat
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, C1428EHA, Ciudad de Buenos Aires, Argentina
| | - Andrea Jacome-Alvarado
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
| | - Debora Braslavsky
- Centro de Investigaciones "Dr. Cesar Bergadá" (CEDIE)-CONICET-FEI-División Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina
| | - Ana Keselman
- Centro de Investigaciones "Dr. Cesar Bergadá" (CEDIE)-CONICET-FEI-División Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina
| | - Ignacio Bergadá
- Centro de Investigaciones "Dr. Cesar Bergadá" (CEDIE)-CONICET-FEI-División Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina
| | - Roxana Marino
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Pablo Ramírez
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Natalia Pérez Garrido
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Marta Ciaccio
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Maria Isabel Di Palma
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Alicia Belgorosky
- Servicio de Endocrinología-CONICET, Hospital de Pediatría Prof. Dr. J. P. Garrahan, C1245AAM, Buenos Aires, Argentina
| | - Maria Veronica Forclaz
- Servicio de Endocrinología Pediátrica, Hospital Nacional Profesor Alejandro Posadas, 1684, Buenos Aires, Argentina
| | - Gabriela Benzrihen
- Servicio de Endocrinología Pediátrica, Hospital Nacional Profesor Alejandro Posadas, 1684, Buenos Aires, Argentina
| | - Silvia D'Amato
- Servicio de Endocrinología Pediátrica, Hospital Nacional Profesor Alejandro Posadas, 1684, Buenos Aires, Argentina
| | - Maria Lujan Cirigliano
- Servicio de Endocrinología Pediátrica, Hospital Nacional Profesor Alejandro Posadas, 1684, Buenos Aires, Argentina
| | - Mirta Miras
- Hospital De Niños de la Santísima Trinidad, CP5000, Córdoba, Argentina
- Centro Privado de Endocrinologia Infanto Juvenil Crecer, CP5000, Cordoba, Argentina
| | - Alejandra Paez Nuñez
- Centro Privado de Endocrinologia Infanto Juvenil Crecer, CP5000, Cordoba, Argentina
| | - Laura Castro
- Hospital De Niños de la Santísima Trinidad, CP5000, Córdoba, Argentina
| | | | - Carolina Ballarino
- Servicio de Endocrinología, Hospital Militar Central, C1426BOS, Buenos Aires, Argentina
| | | | - Ana Clara Casiello
- Servicio de Endocrinología, Hospital General de Niños Pedro de Elizalde, C1270AAN, Buenos Aires, Argentina
| | - Claudia Hernandez
- Servicio de Endocrinología, Hospital General de Niños Pedro de Elizalde, C1270AAN, Buenos Aires, Argentina
| | - Veronica Figueroa
- Servicio de Endocrinología, Hospital General de Niños Pedro de Elizalde, C1270AAN, Buenos Aires, Argentina
| | - Guillermo Alonso
- Sección Endocrinología Pediátrica, Hospital Italiano, C1199ABB, Buenos Aires, Argentina
| | - Analia Morin
- Sala de Endocrinología, Hospital de Niños Sor Maria Ludovica de La Plata, B1904, La Plata, Argentina
| | | | - Hane Lee
- 3Billion Inc., 14th, 416 Teheran-ro, Gangnam-gu, Seoul, South Korea
| | - Eugene Lee
- 3Billion Inc., 14th, 416 Teheran-ro, Gangnam-gu, Seoul, South Korea
| | - Yongjun Song
- 3Billion Inc., 14th, 416 Teheran-ro, Gangnam-gu, Seoul, South Korea
| | - Marcelo Adrian Marti
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, C1428EHA, Ciudad de Buenos Aires, Argentina
| | - Maria Ines Perez-Millan
- Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428EHA, Buenos Aires, Argentina
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Patir MG, Guven ESG, Albayrak M, Guven S. Comparison of Cerebral Blood Circulation of Fetuses with Congenital Heart Disease with Healthy Fetuses. J Med Ultrasound 2024; 32:329-333. [PMID: 39801541 PMCID: PMC11717079 DOI: 10.4103/jmu.jmu_66_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/13/2023] [Accepted: 10/26/2023] [Indexed: 01/16/2025] Open
Abstract
Background The effect of congenital cardiac malformation on fetal cerebral circulation has not been well known. This study aimed to compare the cerebral blood circulation of fetuses with congenital heart disease (CHD) with healthy fetuses. Methods This prospective cohort study included 37 pregnant women who presented to the gynecology and obstetrics department of department of Farabi Hospital, Faculty of Medicine, Karadeniz Technical University for anomaly screening in the second trimester. The women were divided into two groups as those with fetuses having CHD and healthy fetuses. Middle cerebral artery (MCA), peak systolic velocity (PSV), pulsatility index (PI), resistivity index (RI), systole/diastole (S/D) ratio, and MCA transverse section diameter (mm) were recorded for each fetus. Results The most common CHDs were truncus arteriosus and hypoplastic left heart syndrome. The mean MCA PSV, resistivity index, and MDCA vessel diameter values were statistically significantly higher in the study group compared with fetuses without CHDs. The mean PI and systole/diastole ratio were statistically significantly lower in the study group than in the control group. Conclusion This study reported that MCA PSV, RI, and vessel diameter were significantly higher and the S/D ratio and PI were significantly lower in fetuses with CHD compared to the healthy fetuses.
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Affiliation(s)
- Muserref Gamze Patir
- Department of Obstetrics and Gynecology, Faculty of Medicine, Karadeniz Technical University, Ortahisar, Trabzon, Turkey
| | - Emine Seda Guvendag Guven
- Department of Obstetrics and Gynecology, Faculty of Medicine, Karadeniz Technical University, Ortahisar, Trabzon, Turkey
| | - Mehmet Albayrak
- Department of Obstetrics and Gynecology, Faculty of Medicine, Karadeniz Technical University, Ortahisar, Trabzon, Turkey
| | - Suleyman Guven
- Department of Obstetrics and Gynecology, Faculty of Medicine, Karadeniz Technical University, Ortahisar, Trabzon, Turkey
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Faienza MF, Meliota G, Mentino D, Ficarella R, Gentile M, Vairo U, D’amato G. Cardiac Phenotype and Gene Mutations in RASopathies. Genes (Basel) 2024; 15:1015. [PMID: 39202376 PMCID: PMC11353738 DOI: 10.3390/genes15081015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/23/2024] [Accepted: 07/30/2024] [Indexed: 09/03/2024] Open
Abstract
Cardiac involvement is a major feature of RASopathies, a group of phenotypically overlapping syndromes caused by germline mutations in genes encoding components of the RAS/MAPK (mitogen-activated protein kinase) signaling pathway. In particular, Noonan syndrome (NS) is associated with a wide spectrum of cardiac pathologies ranging from congenital heart disease (CHD), present in approximately 80% of patients, to hypertrophic cardiomyopathy (HCM), observed in approximately 20% of patients. Genotype-cardiac phenotype correlations are frequently described, and they are useful indicators in predicting the prognosis concerning cardiac disease over the lifetime. The aim of this review is to clarify the molecular mechanisms underlying the development of cardiac diseases associated particularly with NS, and to discuss the main morphological and clinical characteristics of the two most frequent cardiac disorders, namely pulmonary valve stenosis (PVS) and HCM. We will also report the genotype-phenotype correlation and its implications for prognosis and treatment. Knowing the molecular mechanisms responsible for the genotype-phenotype correlation is key to developing possible targeted therapies. We will briefly address the first experiences of targeted HCM treatment using RAS/MAPK pathway inhibitors.
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Affiliation(s)
- Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giovanni Meliota
- Department of Pediatric Cardiology, Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy; (G.M.); (U.V.)
| | - Donatella Mentino
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Romina Ficarella
- U.O.C. Laboratorio di Genetica Medica, PO Di Venere-ASL Bari, 70012 Bari, Italy; (R.F.); (M.G.)
| | - Mattia Gentile
- U.O.C. Laboratorio di Genetica Medica, PO Di Venere-ASL Bari, 70012 Bari, Italy; (R.F.); (M.G.)
| | - Ugo Vairo
- Department of Pediatric Cardiology, Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy; (G.M.); (U.V.)
| | - Gabriele D’amato
- Neonatal Intensive Care Unit, Di Venere Hospital, 70012 Bari, Italy;
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van Vlimmeren AE, Voleti R, Chartier CA, Jiang Z, Karandur D, Humphries PA, Lo WL, Shah NH. The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain. Proc Natl Acad Sci U S A 2024; 121:e2407159121. [PMID: 39012820 PMCID: PMC11287265 DOI: 10.1073/pnas.2407159121] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/19/2024] [Indexed: 07/18/2024] Open
Abstract
Mutations in the tyrosine phosphatase Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting autoinhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8 to 10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine-binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.
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Affiliation(s)
- Anne E. van Vlimmeren
- Department of Chemistry, Columbia University, New York, NY10027
- Department of Biological Sciences, Columbia University, New York, NY10027
| | - Rashmi Voleti
- Department of Chemistry, Columbia University, New York, NY10027
| | | | - Ziyuan Jiang
- Department of Chemistry, Columbia University, New York, NY10027
| | - Deepti Karandur
- Department of Biochemistry, Vanderbilt University, Nashville, TN37232
| | - Preston A. Humphries
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Wan-Lin Lo
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT84112
| | - Neel H. Shah
- Department of Chemistry, Columbia University, New York, NY10027
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Yang D, Jian Z, Tang C, Chen Z, Zhou Z, Zheng L, Peng X. Zebrafish Congenital Heart Disease Models: Opportunities and Challenges. Int J Mol Sci 2024; 25:5943. [PMID: 38892128 PMCID: PMC11172925 DOI: 10.3390/ijms25115943] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/18/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
Congenital heart defects (CHDs) are common human birth defects. Genetic mutations potentially cause the exhibition of various pathological phenotypes associated with CHDs, occurring alone or as part of certain syndromes. Zebrafish, a model organism with a strong molecular conservation similar to humans, is commonly used in studies on cardiovascular diseases owing to its advantageous features, such as a similarity to human electrophysiology, transparent embryos and larvae for observation, and suitability for forward and reverse genetics technology, to create various economical and easily controlled zebrafish CHD models. In this review, we outline the pros and cons of zebrafish CHD models created by genetic mutations associated with single defects and syndromes and the underlying pathogenic mechanism of CHDs discovered in these models. The challenges of zebrafish CHD models generated through gene editing are also discussed, since the cardiac phenotypes resulting from a single-candidate pathological gene mutation in zebrafish might not mirror the corresponding human phenotypes. The comprehensive review of these zebrafish CHD models will facilitate the understanding of the pathogenic mechanisms of CHDs and offer new opportunities for their treatments and intervention strategies.
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Orsolini F, Pignata L, Baldinotti F, Romano S, Tonacchera M, Canale D. Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature. Front Endocrinol (Lausanne) 2024; 15:1354699. [PMID: 38689733 PMCID: PMC11059086 DOI: 10.3389/fendo.2024.1354699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/22/2024] [Indexed: 05/02/2024] Open
Abstract
Noonan syndrome (NS) is a genetic disorder characterized by multiple congenital defects caused by mutations in the RAS/mitogen-activated protein kinase pathway. Male fertility has been reported to be impaired in NS, but only a few studies have focused on fertility status in NS patients and underlying mechanisms are still incompletely understood. We describe the case of a 35-year-old man who underwent an andrological evaluation due to erectile dysfunction and severe oligospermia. A syndromic facial appearance and reduced testis size were present on clinical examination. Hormonal evaluation showed normal total testosterone level, high FSH level, and low-normal AMH and inhibin B, compatible with primary Sertoli cell dysfunction. Genetic analysis demonstrated the pathogenetic heterozygous variant c.742G>A, p.(Gly248Arg) of the LZTR1 gene (NM_006767.3). This case report provides increased knowledge on primary gonadal dysfunction in men with NS and enriches the clinical spectrum of NS from a rare variant in the novel gene LZTR1.
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Affiliation(s)
- Francesca Orsolini
- Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy
| | - Luisa Pignata
- Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy
| | - Fulvia Baldinotti
- Department of Laboratory Medicine, Section of Molecular Genetics, Pisa University Hospital, Pisa, Italy
| | - Silvia Romano
- Departmental Section of Medical Genetics, Pisa University Hospital, Pisa, Italy
| | - Massimo Tonacchera
- Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy
| | - Domenico Canale
- Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy
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van Vlimmeren AE, Voleti R, Chartier CA, Jiang Z, Karandur D, Humphries PA, Lo WL, Shah NH. The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.10.548257. [PMID: 37502916 PMCID: PMC10369915 DOI: 10.1101/2023.07.10.548257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Mutations in the tyrosine phosphatase SHP2 are associated with a variety of human diseases. Most mutations in SHP2 increase its basal catalytic activity by disrupting auto-inhibitory interactions between its phosphatase domain and N-terminal SH2 (phosphotyrosine recognition) domain. By contrast, some disease-associated mutations located in the ligand-binding pockets of the N- or C-terminal SH2 domains do not increase basal activity and likely exert their pathogenicity through alternative mechanisms. We lack a molecular understanding of how these SH2 mutations impact SHP2 structure, activity, and signaling. Here, we characterize five SHP2 SH2 domain ligand-binding pocket mutants through a combination of high-throughput biochemical screens, biophysical and biochemical measurements, and molecular dynamics simulations. We show that, while some of these mutations alter binding affinity to phosphorylation sites, the T42A mutation in the N-SH2 domain is unique in that it also substantially alters ligand-binding specificity, despite being 8-10 Å from the specificity-determining region of the SH2 domain. This mutation exerts its effect on sequence specificity by remodeling the phosphotyrosine binding pocket, altering the mode of engagement of both the phosphotyrosine and surrounding residues on the ligand. The functional consequence of this altered specificity is that the T42A mutant has biased sensitivity toward a subset of activating ligands and enhances downstream signaling. Our study highlights an example of a nuanced mechanism of action for a disease-associated mutation, characterized by a change in protein-protein interaction specificity that alters enzyme activation.
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Affiliation(s)
- Anne E. van Vlimmeren
- Department of Chemistry, Columbia University, New York, NY 10027
- Department of Biological Sciences, Columbia University, New York, NY 10027
| | - Rashmi Voleti
- Department of Chemistry, Columbia University, New York, NY 10027
| | | | - Ziyuan Jiang
- Department of Chemistry, Columbia University, New York, NY 10027
| | - Deepti Karandur
- Department of Biochemistry, Vanderbilt University, Nashville, TN 37232
| | - Preston A. Humphries
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Wan-Lin Lo
- Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112
| | - Neel H. Shah
- Department of Chemistry, Columbia University, New York, NY 10027
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Sivakumar K, Jain G. Is There a Role for Alcohol Septal Ablation in Young Patients with Medically Refractory Hypertrophic Obstructive Cardiomyopathy? Pediatr Cardiol 2024; 45:648-659. [PMID: 36995405 DOI: 10.1007/s00246-023-03145-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/11/2023] [Indexed: 03/31/2023]
Abstract
Surgical myectomy is recommended for symptomatic hypertrophic obstructive cardiomyopathy (HOCM) after optimal pharmacological therapy. Percutaneous transluminal septal myocardial ablation (PTSMA) is reserved for high-risk adults. Symptomatic patients below 25 years underwent either surgery or PTSMA after heart-team discussion and informed consent. Echocardiography assessed gradients in surgical group. PTSMA group underwent invasive transseptal hemodynamic assessment, selective coronary angiography and super-selective cannulation of septal perforators using microcatheters. Contrast echocardiography through the microcatheter identified the myocardial target for PTSMA. Hemodynamic and electrocardiographic monitoring guided alcohol injection. Both groups were continued on beta-blockers. Symptoms, echocardiographic gradients and Brain natriuretic peptide (NTproBNP) measurements were assessed on follow-up. Twelve patients aged 5-23 years (11-98 kg) formed the study group. Indications for PTSMA in 8 patients included abnormal mitral valve anatomy warranting replacement (n = 3), Jehovah's witness (n = 2), severe neurodevelopmental and growth retardation (n = 1) and refusal of surgery (n = 2). PTSMA targeted first perforator (n = 5), second perforator (n = 2) and anomalous septal artery from left main trunk (n = 1). Outflow gradient reduced from 92.5 ± 19.7 to 33.1 ± 13.5 mmHg. At a median follow-up of 38 months (range 3-120 weeks), the peak instantaneous echocardiographic gradient was 32 ± 16.5 mmHg. Gradient reduced in four surgical patients from 86.5 ± 16.3 mmHg to 42 ± 14.7 mm Hg. All patients were in NYHA class I/II on follow-up. The mean NTproBNP in PTSMA group reduced from 6084 ± 3628 pg/ml to 3081 ± 2019 pg/ml; it was 1396 and 1795 pg/ml in surgery. PTSMA may be considered in medically refractory high-risk young patients. It relieves symptoms and reduces gradient. Though surgery is preferred in young patients, PTSMA may have a role in selected patients.
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Affiliation(s)
- Kothandam Sivakumar
- Department of Pediatric Cardiology, Institute of Cardio Vascular Diseases, Madras Medical Mission, 4A, Dr J J Nagar, Mogappair, Chennai, 600089, India.
| | - Gaurav Jain
- Department of Pediatric Cardiology, Institute of Cardio Vascular Diseases, Madras Medical Mission, 4A, Dr J J Nagar, Mogappair, Chennai, 600089, India
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De Schepper J, Thomas M, Huysentruyt K, Becker M, Boros E, Casteels K, Chivu O, De Waele K, Dotremont H, Lysy PA, Massa G, Parent AS, Rochtus A, Gies I. Near Adult Height and Body Mass Index Changes in Growth Hormone Treated Short Children with Noonan Syndrome: The Belgian Experience. Horm Res Paediatr 2024; 98:193-205. [PMID: 38432193 DOI: 10.1159/000538034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/23/2024] [Indexed: 03/05/2024] Open
Abstract
INTRODUCTION A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity, and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods: Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no-mutation group). RESULTS After a median (P10; P90) duration of 5.4 (2.2; 10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.1; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype, and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (β = 0.90, p < 0.001), mid-parental height SDS (β = 0.27; p = 0.005), birth weight SDS (β = 0.15; p = 0.051), age at start (β = 0.07; p = 0.032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p < 0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. CONCLUSION Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.
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Affiliation(s)
- Jean De Schepper
- Division of Pediatric Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Muriel Thomas
- The BElgian and Luxembourg Society for PEdiatric Endocrinology and Diabetology (BELSPEED), Brussels, Belgium
| | - Koen Huysentruyt
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
- Division of Pediatric Gastroenterology and Nutrition, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Marianne Becker
- Department of Pediatric Endocrinology and Diabetology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
| | - Emese Boros
- Pediatric Endocrinology Unit, Hôpital Universitaire de Bruxelles (HUB)- Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université libre de Bruxelles (ULB), Brussels, Belgium
| | - Kristina Casteels
- Department of Pediatrics, Universitair Ziekenhuis Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Olimpia Chivu
- Department of Pediatrics, Clinique CHC MontLégia, Liège, Belgium
| | - Kathleen De Waele
- Department of Pediatrics, Universitair Ziekenhuis Gent, Gent, Belgium
| | - Hilde Dotremont
- Department of Pediatric Endocrinology and Diabetology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
| | - Philippe A Lysy
- Service of Specialized Pediatrics, Pediatric Endocrinology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Guy Massa
- Department of Pediatrics, Jessa Ziekenhuis, Hasselt, Belgium
| | | | - Anne Rochtus
- Department of Pediatrics, Universitair Ziekenhuis Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Inge Gies
- Division of Pediatric Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Research Unit GRON, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium
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Prapa M, Ho SY. Human Genetics of Semilunar Valve and Aortic Arch Anomalies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:761-775. [PMID: 38884747 DOI: 10.1007/978-3-031-44087-8_45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Lesions of the semilunar valve and the aortic arch can occur either in isolation or as part of well-described clinical syndromes. The polygenic cause of calcific aortic valve disease will be discussed including the key role of NOTCH1 mutations. In addition, the complex trait of bicuspid aortic valve disease will be outlined, both in sporadic/familial cases and in the context of associated syndromes, such as Alagille, Williams, and Kabuki syndromes. Aortic arch abnormalities particularly coarctation of the aorta and interrupted aortic arch, including their association with syndromes such as Turner and 22q11 deletion, respectively, are also discussed. Finally, the genetic basis of congenital pulmonary valve stenosis is summarized, with particular note to Ras-/mitogen-activated protein kinase (Ras/MAPK) pathway syndromes and other less common associations, such as Holt-Oram syndrome.
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Affiliation(s)
- Matina Prapa
- Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK.
| | - Siew Yen Ho
- Cardiac Morphology, Royal Brompton & Harefield Hospitals, London, UK
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12
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Dorn C, Perrot A, Grunert M, Rickert-Sperling S. Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1441:629-644. [PMID: 38884738 DOI: 10.1007/978-3-031-44087-8_36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2024]
Abstract
Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.
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Affiliation(s)
- Cornelia Dorn
- Cardiovascular Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Andreas Perrot
- Cardiovascular Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Marcel Grunert
- Cardiovascular Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
- DiNAQOR AG, Schlieren, Switzerland
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13
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Yi JS, Perla S, Bennett AM. An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies. Cardiovasc Drugs Ther 2023; 37:1193-1204. [PMID: 35156148 PMCID: PMC11726350 DOI: 10.1007/s10557-022-07324-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2022] [Indexed: 12/14/2022]
Abstract
The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.
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Affiliation(s)
- Jae-Sung Yi
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA
| | - Sravan Perla
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA
| | - Anton M Bennett
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA.
- Yale Center for Molecular and Systems Metabolism, Yale University, New Haven, CT, 06520, USA.
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14
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Tsatsopoulou A, Protonotarios I, Xylouri Z, Papagiannis I, Anastasakis A, Germanakis I, Patrianakos A, Nyktari E, Gavras C, Papadopoulos G, Meditskou S, Lazarou E, Miliou A, Lazaros G. Cardiomyopathies in children: An overview. Hellenic J Cardiol 2023; 72:43-56. [PMID: 36870438 DOI: 10.1016/j.hjc.2023.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.
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Affiliation(s)
- Adalena Tsatsopoulou
- General Paediatrics and Clinical Research, Private Clinic, Naxos, Greece; Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece; Unit of Inherited and Rare Cardiovascular Diseases, Onassis Cardiac Surgery Centre, Athens, Greece; Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Protonotarios
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK
| | - Zafeirenia Xylouri
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK
| | - Ioannis Papagiannis
- Department of Paediatric Cardiology and Adult Congenital Heart Disease, Onassis Cardiac Surgery Centre, Athens, Greece
| | - Aris Anastasakis
- Unit of Inherited and Rare Cardiovascular Diseases, Onassis Cardiac Surgery Centre, Athens, Greece
| | - Ioannis Germanakis
- Department of Paediatrics, University Hospital Heraklion, School of Medicine, University of Crete, Heraklion, Greece
| | | | | | | | | | - Soultana Meditskou
- Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Emilia Lazarou
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Antigoni Miliou
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - George Lazaros
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece.
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Yang W, Wang Y, Sirajuddin A, He J, Wu W, Sun X, Zhuang B, Li S, Xu J, Zhou D, Zhao S, Lu M. Multimodality Imaging in Noonan Syndrome: Case Series of Young Children. Radiol Cardiothorac Imaging 2023; 5:e220218. [PMID: 36860839 PMCID: PMC9969215 DOI: 10.1148/ryct.220218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 01/04/2023] [Accepted: 01/18/2023] [Indexed: 02/25/2023]
Abstract
Noonan syndrome (NS) is an autosomal dominant disorder characterized by distinctive facial anomalies, growth failure, and a wide spectrum of cardiac abnormalities. Here, the clinical presentation, multimodality imaging characteristics, and management in a case series of four patients with NS are presented. Multimodality imaging showed frequently biventricular hypertrophy accompanied by biventricular outflow tract obstruction and pulmonary stenosis, similar late gadolinium enhancement pattern, and elevation of native T1 and extracellular volume, which may serve as multimodality imaging features in NS to aid in patient diagnosis and treatment. Keywords: Pediatrics, Echocardiography, MR Imaging, Cardiac Supplemental material is available for this article. © RSNA, 2023.
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16
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Delogu AB, Limongelli G, Versacci P, Adorisio R, Kaski JP, Blandino R, Maiolo S, Monda E, Putotto C, De Rosa G, Chatfield KC, Gelb BD, Calcagni G. The heart in RASopathies. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:440-451. [PMID: 36408797 DOI: 10.1002/ajmg.c.32014] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/11/2022] [Accepted: 11/03/2022] [Indexed: 11/22/2022]
Abstract
The cardiovascular phenotype associated with RASopathies has expanded far beyond the original descriptions of pulmonary valve stenosis by Dr Jaqueline Noonan in 1968 and hypertrophic cardiomyopathy by Hirsch et al. in 1975. Because of the common underlying RAS/MAPK pathway dysregulation, RASopathy syndromes usually present with a typical spectrum of overlapping cardiovascular anomalies, although less common cardiac defects can occur. The identification of the causative genetic variants has enabled the recognition of specific correlations between genotype and cardiac phenotype. Characterization and understanding of genotype-phenotype associations is not only important for counseling a family of an infant with a new diagnosis of a RASopathy condition but is also critical for their clinical prognosis with respect to cardiac disease, neurodevelopment and other organ system involvement over the lifetime of the patient. This review will focus on the cardiac manifestations of the most common RASopathy syndromes, the relationship between cardiac defects and causal genetic variation, the contribution of cardiovascular abnormalities to morbidity and mortality and the most relevant follow-up issues for patients affected by RAS/MAPK pathway diseases, with respect to cardiac clinical outcomes and management, in children and in the adult population.
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Affiliation(s)
- Angelica Bibiana Delogu
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giuseppe Limongelli
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Monaldi Hospital, Naples, Italy
- European Reference Network for rare, low-prevalence, or complex disease of the heart (ERN GUARD-Heart), University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy. Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Paolo Versacci
- Pediatric Cardiology Unit, Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Rachele Adorisio
- European Reference Network for rare, low-prevalence, or complex disease of the heart (ERN GUARD-Heart), University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy. Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Cardiac Surgery, Cardiology, Heart and Lung Transplantation, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Juan Pablo Kaski
- Centre for Pediatric Inherited and Rare Cardiovascular Disease, University College London Institute of Cardiovascular Science, London, UK
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK
| | | | - Stella Maiolo
- European Reference Network for rare, low-prevalence, or complex disease of the heart (ERN GUARD-Heart), University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy. Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Pediatric Cardiology Unit, Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
- Department of Cardiac Surgery, Cardiology, Heart and Lung Transplantation, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Emanuele Monda
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Monaldi Hospital, Naples, Italy
- European Reference Network for rare, low-prevalence, or complex disease of the heart (ERN GUARD-Heart), University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy. Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Carolina Putotto
- Pediatric Cardiology Unit, Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Rome, Italy
| | - Gabriella De Rosa
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Kathryn C Chatfield
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Bruce D Gelb
- Mindich Child Health and Development Institute and the Departments of Pediatrics and Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Giulio Calcagni
- European Reference Network for rare, low-prevalence, or complex disease of the heart (ERN GUARD-Heart), University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy. Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Cardiac Surgery, Cardiology, Heart and Lung Transplantation, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
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Shehade-Awwad N, Yeshayahu Y, Pinhas-Hamiel O, Katz U. Differences in severity of cardiovascular anomalies in children with Noonan syndrome based on the causative gene. Front Pediatr 2022; 10:946071. [PMID: 36160796 PMCID: PMC9492920 DOI: 10.3389/fped.2022.946071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Noonan syndrome (NS) is a genetic syndrome, characterized by various dysmorphic features, cardiac anomalies, short stature, and developmental delay. NS is a leading cause of cardiovascular anomalies. The syndrome results from dysregulation in the RAS-MAPK pathway and is related to the RASopathy family syndromes. Pathogenic variants in more than 20 related genes have been identified in association with NS, and several genotype-phenotype correlations were suggested. The specific severity of the same cardiovascular anomalies has not been described as linked to a specific causative gene. METHODS For this retrospective, single-center study, data retrieved from medical charts of a multidisciplinary NS clinic included genetic diagnosis, cardiac malformations, the need for intervention, demographics, and prenatal diagnosis. We analyzed molecular genetics and the severity of cardiac malformations. RESULTS The cohort comprised 74 children with NS. Consistent with previous studies, pathogenic variants in PTPN11 were the most common (62%). Cardiovascular anomalies presented in 57%; pulmonary stenosis (PS) was the most common (about 79% of anomalies). In children with pathogenic variants in PTPN11, PS tended to be more severe and required intervention in 53%, compared to 25% of children with PS and a variant in other genes. CONCLUSION This first Israeli cohort of NS showed similar rates of cardiac malformations and genetic breakdown as previously published. Variants in PTPN11 were prone to a higher risk for severe PS that requires intervention. This finding may assist in genetic counseling and cardiac treatment decisions, and stresses the importance of genetic in addition to clinical diagnosis of NS.
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Affiliation(s)
| | - Yonatan Yeshayahu
- Pediatrics Department, Samson Assuta Ashdod Hospital, Ashdod, Israel
- Noonan Multidisciplinary Clinic, Pediatric Endocrinology and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
- Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel
| | - Orit Pinhas-Hamiel
- Noonan Multidisciplinary Clinic, Pediatric Endocrinology and Diabetes Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Uriel Katz
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Pediatric Heart Institute, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel
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Hagino M, Ota C, Onoki T, Iwasawa S. Male infant with Noonan syndrome with RAF-1 gene mutation who survived hypertrophic cardiomyopathy-induced fatal heart failure and uncontrollable arrhythmias. BMJ Case Rep 2022; 15:15/9/e250342. [PMID: 36171012 PMCID: PMC9528629 DOI: 10.1136/bcr-2022-250342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Noonan syndrome (NS) is a congenital disease with characteristic facial features as well as heart disease, short stature and thoracic abnormalities. More than eighty per cent of patients with NS show several cardiac disorders including pulmonary valvular stenosis, hypertrophic cardiomyopathy (HCM) and/or atrial septal defects. HCM is a serious cardiac comorbidity in patients with NS, especially in those who are diagnosed within 6 months of age with congestive heart failure. Arrhythmia with or without HCM in NS is a rare comorbidity with a complicated clinical course and poor prognosis. In this manuscript, we present the case of a male infant with NS with RAF1 gene mutation, who showed various types of arrhythmias. He developed life-threatening heart failure and uncontrollable arrhythmias. We attempted several antiarrhythmic agents and finally controlled the arrhythmias to establish a normal sinus rhythm with a combination of amiodarone and flecainide.
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Affiliation(s)
- Mao Hagino
- Department of Paediatrics, Tohoku University Hospital, Sendai, Japan
| | - Chiharu Ota
- Department of Paediatrics, Tohoku University Hospital, Sendai, Japan
| | - Takehiko Onoki
- Department of Paediatrics, Tohoku University Hospital, Sendai, Japan
| | - Shinya Iwasawa
- Department of Paediatrics, Tohoku University Hospital, Sendai, Japan
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Sun L, Xie YM, Wang SS, Zhang ZW. Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome. Front Genet 2022; 13:915129. [PMID: 35770001 PMCID: PMC9234298 DOI: 10.3389/fgene.2022.915129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/23/2022] [Indexed: 11/20/2022] Open
Abstract
Background: Common cardiac abnormalities in Noonan syndrome (NS) include congenital heart diseases (CHD), pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Molecular diagnoses are enabling earlier and more precise diagnosis of patients who have a subtle or atypical presentation. The aims of this study were to investigate genotype-phenotype associations with respect to Noonan syndrome (NS)-associated cardiac abnormalities and catheter or surgery-based interventions conditions. Methods: From January 2019 to December 2021, 22 children with a confirmed molecular diagnosis of NS combined with cardiovascular abnormalities were consecutively enrolled into the current study. A comprehensive review was carried out of echocardiography and electrocardiogram results, second-generation whole-exome sequencing results and catheter or surgery-based interventions conditions. Results: The main manifestations of electrocardiogram abnormalities were QTc prolongation, abnormal Q wave in the precordial lead and limb lead, right ventricular hypertrophy and left or right deviation of the electrical axis. The most commonly detected abnormality was pulmonary valve dysplasia with stenosis, seen in 15 (68.2%) patients, followed by atrial septal defect in 11 (50%) patients. Seven genes (RAF1, RIT1, SOS1, PTPN11, BRAF, SOS2, and LZTR1) were found to contain disease-associated variants. The most commonly observed genetic mutations were PTPN11 (27%) and RAF1 (27%). Each genotype was associated with specific phenotypic findings. RIT1, SOS1, PTPN11, and SOS2 had common echocardiography features characterized by pulmonary valve stenosis, while RAF1 was characterized by HCM. Interestingly, patients with BRAF mutations were not only characterized by HCM, but also by pulmonary valve stenosis. In the cohort there was only one patient carrying a LZTR1 mutation characterized by left ventricle globose dilation. Ten cases underwent catheter or surgery-based interventions. All the operations had immediate results and high success rates. However, some of the cases had adverse outcomes during extended follow-up. Based on the genotype-phenotype associations observed during follow-up, BRAF and RAF1 genotypes seem to be poor prognostic factors, and multiple interventions may be required for NS patients with severe pulmonary stenosis or myectomy for HCM. Conclusions: The identification of causal genes in NS patients has enabled the evaluation of genotype-cardiac phenotype relationships and prognosis of the disease. This may be beneficial for the development of therapeutic approaches.
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Leoni C, Blandino R, Delogu AB, De Rosa G, Onesimo R, Verusio V, Marino MV, Lanza GA, Rigante D, Tartaglia M, Zampino G. Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review. Am J Med Genet A 2022; 188:431-445. [PMID: 34643321 DOI: 10.1002/ajmg.a.62529] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/11/2021] [Accepted: 09/21/2021] [Indexed: 11/07/2022]
Abstract
Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype- phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single-center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid-shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.
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Affiliation(s)
- Chiara Leoni
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Rita Blandino
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Angelica Bibiana Delogu
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gabriella De Rosa
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Roberta Onesimo
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Valeria Verusio
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Maria Vittoria Marino
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gaetano Antonio Lanza
- Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCSS, Rome, Italy
| | - Donato Rigante
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Giuseppe Zampino
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
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21
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Romano A, Kaski JP, Dahlgren J, Kelepouris N, Pietropoli A, Rohrer TR, Polak M. Cardiovascular safety of growth hormone treatment in Noonan syndrome: real-world evidence. Endocr Connect 2022; 11:e210549. [PMID: 34939937 PMCID: PMC8859970 DOI: 10.1530/ec-21-0549] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 11/08/2022]
Abstract
Objective The study aims to assess the cardiovascular safety of growth hormone (GH) treatment in patients with Noonan syndrome (NS) in clinical practice. Design The study design involves two observational, multicentre studies (NordiNet® IOS and the ANSWER Program) evaluating the long-term effectiveness and safety of GH in >38,000 paediatric patients, of which 421 had NS. Methods Serious adverse events, serious adverse reactions (SARs) and non-serious adverse reactions (NSARs) were reported by the treating physicians. Cardiovascular comorbidities at baseline and throughout the studies were also recorded. Results The safety analysis set comprised 412 children with NS (29.1% females), with a mean (s.d.) baseline age of 9.29 (3.88) years, treated with an average GH dose of 0.047 (0.014) mg/kg/day during childhood. Cardiovascular comorbidities at baseline were reported in 48 (11.7%), most commonly pulmonary valve stenosis (PVS) and atrial septal defects. Overall, 22 (5.3%) patients experienced 34 safety events. The most common were the NSARs: headache (eight events in seven patients) and arthralgia (five events in three patients). Two SARs occurred in one patient (brain neoplasm and metastases to spine). No cardiovascular safety events were recorded in patients with NS. Five cardiovascular comorbidities in five patients were reported after initiation of GH treatment: three cases of unspecified cardiovascular disease, one ruptured abdominal aortic aneurysm and one PVS. Conclusions GH treatment had a favourable safety profile in patients with NS, including those with cardiovascular comorbidities. Prospective studies are warranted to systematically assess the safety of GH treatment in patients with NS and cardiovascular disease.
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Affiliation(s)
- Alicia Romano
- Department of Pediatrics, New York Medical College, Valhalla, New York, USA
| | - Juan Pablo Kaski
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital & UCL Institute of Cardiovascular Science, London, UK
| | - Jovanna Dahlgren
- Department of Paediatrics, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Nicky Kelepouris
- US Medical Affairs, Novo Nordisk Inc., Plainsboro, New Jersey, USA
| | - Alberto Pietropoli
- Global Medical Affairs, Novo Nordisk Health Care AG, Zurich, Switzerland
| | - Tilman R Rohrer
- Department of Pediatric Endocrinology, University Children’s Hospital, Saarland University Medical Center, Homburg, Germany
| | - Michel Polak
- Paediatric Endocrinology, Diabetology and Gynaecology Department, Hôpital Universitaire Necker Enfants-Malades, AP-HP, Université de Paris, Imagine Institute, Paris, France
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22
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Mohan P, Lemoine J, Trotter C, Rakova I, Billings P, Peacock S, Kao C, Wang Y, Xia F, Eng CM, Benn P. Clinical experience with non-invasive prenatal screening for single-gene disorders. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2022; 59:33-39. [PMID: 34358384 PMCID: PMC9302116 DOI: 10.1002/uog.23756] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/29/2021] [Accepted: 08/02/2021] [Indexed: 05/10/2023]
Abstract
OBJECTIVE To assess the performance of a non-invasive prenatal screening test (NIPT) for a panel of dominant single-gene disorders (SGD) with a combined population incidence of 1 in 600. METHODS Cell-free fetal DNA isolated from maternal plasma samples accessioned from 14 April 2017 to 27 November 2019 was analyzed by next-generation sequencing, targeting 30 genes, to look for pathogenic or likely pathogenic variants implicated in 25 dominant conditions. The conditions included Noonan spectrum disorders, skeletal disorders, craniosynostosis syndromes, Cornelia de Lange syndrome, Alagille syndrome, tuberous sclerosis, epileptic encephalopathy, SYNGAP1-related intellectual disability, CHARGE syndrome, Sotos syndrome and Rett syndrome. NIPT-SGD was made available as a clinical service to women with a singleton pregnancy at ≥ 9 weeks' gestation, with testing on maternal and paternal genomic DNA to assist in interpretation. A minimum of 4.5% fetal fraction was required for test interpretation. Variants identified in the mother were deemed inconclusive with respect to fetal carrier status. Confirmatory prenatal or postnatal diagnostic testing was recommended for all screen-positive patients and follow-up information was requested. The screen-positive rates with respect to the clinical indication for testing were evaluated. RESULTS A NIPT-SGD result was available for 2208 women, of which 125 (5.7%) were positive. Elevated test-positive rates were observed for referrals with a family history of a disorder on the panel (20/132 (15.2%)) or a primary indication of fetal long-bone abnormality (60/178 (33.7%)), fetal craniofacial abnormality (6/21 (28.6%)), fetal lymphatic abnormality (20/150 (13.3%)) or major fetal cardiac defect (4/31 (12.9%)). For paternal age ≥ 40 years as a sole risk factor, the test-positive rate was 2/912 (0.2%). Of the 125 positive cases, follow-up information was available for 67 (53.6%), with none classified as false-positive. No false-negative cases were identified. CONCLUSIONS NIPT can assist in the early detection of a set of SGD, particularly when either abnormal ultrasound findings or a family history is present. Additional clinical studies are needed to evaluate the optimal design of the gene panel, define target populations and assess patient acceptability. NIPT-SGD offers a safe and early prenatal screening option. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
| | | | | | | | | | | | | | - Y. Wang
- Baylor GeneticsHoustonTXUSA
- Baylor College of MedicineHoustonTXUSA
| | - F. Xia
- Baylor GeneticsHoustonTXUSA
- Baylor College of MedicineHoustonTXUSA
| | - C. M. Eng
- Baylor GeneticsHoustonTXUSA
- Baylor College of MedicineHoustonTXUSA
| | - P. Benn
- Department of Genetics and Genome SciencesUniversity of Connecticut Health CenterFarmingtonCTUSA
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23
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Lioncino M, Monda E, Verrillo F, Moscarella E, Calcagni G, Drago F, Marino B, Digilio MC, Putotto C, Calabrò P, Russo MG, Roberts AE, Gelb BD, Tartaglia M, Limongelli G. Hypertrophic Cardiomyopathy in RASopathies: Diagnosis, Clinical Characteristics, Prognostic Implications, and Management. Heart Fail Clin 2022; 18:19-29. [PMID: 34776080 PMCID: PMC9674037 DOI: 10.1016/j.hfc.2021.07.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.
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Affiliation(s)
- Michele Lioncino
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Emanuele Monda
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Federica Verrillo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Elisabetta Moscarella
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy
| | - Giulio Calcagni
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart;,Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital IRCSS, Rome, Italy
| | - Fabrizio Drago
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart;,Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital IRCSS, Rome, Italy
| | - Bruno Marino
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Maria Cristina Digilio
- Genetics and Rare Disease Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Carolina Putotto
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Paolo Calabrò
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy
| | - Maria Giovanna Russo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Department of Pediatric Cardiology, AORN dei Colli, Monaldi Hospital, Naples
| | - Amy E. Roberts
- Department of Cardiology, Children’s Hospital Boston, Boston, MA, USA
| | - Bruce D. Gelb
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marco Tartaglia
- Genetics and Rare Disease Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Giuseppe Limongelli
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy;,Corresponding author. Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples.
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24
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Jones VA, Patel PM, Valikodath T, Ashack KA. Dermatologic manifestations of pediatric cardiovascular diseases: Skin as a reflection of the heart. Pediatr Dermatol 2021; 38:1461-1474. [PMID: 34725847 DOI: 10.1111/pde.14841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cutaneous disease can often be an initial clue of an underlying cardiovascular disease. Many congenital conditions (ie, Noonan syndrome with multiple lentigines, Carney complex, and Fabry disease) and acquired conditions may present initially with specific cutaneous features that should prompt clinicians to conduct a full cardiac workup. Given the extensive number of conditions with both cardiovascular and cutaneous findings, this review will focus on diseases with cardiocutaneous pathology with hopes of raising clinician awareness of these associations to decrease morbidity and mortality, as several of these diseases often result in fatal outcomes.
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Affiliation(s)
- Virginia A Jones
- Department of Dermatology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Payal M Patel
- Department of Dermatology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Tom Valikodath
- Cincinnati Children's Hospital Medical Center Heart Institute, Cincinnati, Ohio, USA
| | - Kurt A Ashack
- Dermatology Associates of West Michigan, Grand Rapids, Michigan, USA
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25
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Wolf CM, Zenker M, Burkitt-Wright E, Edouard T, García-Miñaúr S, Lebl J, Shaikh G, Tartaglia M, Verloes A, Östman-Smith I. Management of cardiac aspects in children with Noonan syndrome - results from a European clinical practice survey among paediatric cardiologists. Eur J Med Genet 2021; 65:104372. [PMID: 34757052 DOI: 10.1016/j.ejmg.2021.104372] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 11/03/2022]
Abstract
BACKGROUND The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. CONCLUSIONS Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified.
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Affiliation(s)
- Cordula M Wolf
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Martin Zenker
- Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany
| | - Emma Burkitt-Wright
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust and University of Manchester, Manchester, UK
| | - Thomas Edouard
- Endocrine, Bone Diseases, And Genetics Unit, Children's Hospital, Toulouse University Hospital, RESTORE INSERM UMR1301, Toulouse, France
| | - Sixto García-Miñaúr
- Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz Research Institute (IdiPAZ), Hospital Universitario La Paz, Madrid, Spain
| | - Jan Lebl
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Guftar Shaikh
- Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, United Kingdom
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Alain Verloes
- Department of Genetics, APHP-Robert Debré University Hospital and Université de Paris Medical School, Paris, France
| | - Ingegerd Östman-Smith
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
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26
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Chen S, Chen L, Jiang Y, Xu H, Sun Y, Shi H, Li S, Zhang J, Yan J. Early Outcomes of Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy in Children With Noonan Syndrome. Semin Thorac Cardiovasc Surg 2021; 34:655-665. [PMID: 34324955 DOI: 10.1053/j.semtcvs.2021.07.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 07/22/2021] [Indexed: 12/26/2022]
Abstract
Noonan syndrome (NS) is a genetic syndrome causing obstructive hypertrophic cardiomyopathy (HCM) in infants. Studies of cardiac surgery in pediatric HCM patients with NS (NS-HCM) are lacking. We aim to characterize the early disease course of young NS-HCM patients before adolescence and assess their complications and survival condition after septal myectomy. Pediatric obstructive HCM patients who underwent septal myectomy at age 10 years or under were enrolled consecutively between 2009 and 2019. Ten patients with NS and 43 non-NS patients were enrolled in our study. NS-HCM patients were diagnosed at a younger age (5.00 ± 7.48 months vs. 18.73 ± 26.96 months) and more often had biventricular outflow tract obstruction (90.00% vs 30.23%). The surgical treatment can significantly reduce the pressure gradient of the outflow tract. More NS-HCM patients had biventricular reconstruction (70.00% vs 25.58%). The overall survival rates in all patients were 98.04% during 5-year follow-up, respectively. Complete heart block (CHB) was the most prevalent complication in patients with NS and tended to be more common than in non-NS patients (20% vs 7.32%). No sudden cardiac death (SCD) occurred in CHB patients who had pacemaker implantation. Biventricular reconstruction was the risk factor for CHB. Septal myectomy is safe and effective surgery to relieve obstruction in young age pediatric obstructive NS-HCM patients. Postoperative CHB is a common complication, especially in patients who underwent biventricular reconstruction. The implantation of pacemaker can protect CHB patients from SCD and improve their prognosis.
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Affiliation(s)
- Shi Chen
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liang Chen
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Jiang
- Department of Echocardiography, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China
| | - Haitao Xu
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yangxue Sun
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hao Shi
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shoujun Li
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jing Zhang
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Cardiac Surgery, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen, China.
| | - Jun Yan
- Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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27
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Calcagni G, Gagliostro G, Limongelli G, Unolt M, De Luca E, Digilio MC, Baban A, Albanese SB, Ferrero GB, Baldassarre G, Agnoletti G, Banaudi E, Marek J, Kaski JP, Tuo G, Marasini M, Cairello F, Madrigali A, Pacileo G, Russo MG, Milanesi O, Formigari R, Brighenti M, Ragni L, Donti A, Drago F, Dallapiccola B, Tartaglia M, Marino B, Versacci P. Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study. Birth Defects Res 2021; 112:725-731. [PMID: 32558384 DOI: 10.1002/bdr2.1670] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND RASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies. METHODS A retrospective, multicentric observational study (CArdiac Rasopathy NETwork-CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected. RESULTS Forty-five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow-up was 20.1 years (range 6.9-47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019. CONCLUSIONS Patients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.
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Affiliation(s)
- Giulio Calcagni
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Giulia Gagliostro
- Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy
| | | | - Marta Unolt
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Enrica De Luca
- Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy
| | - Maria C Digilio
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Anwar Baban
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Sonia B Albanese
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Giovanni B Ferrero
- Department of Pediatric and Public Health Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Giuseppina Baldassarre
- Department of Pediatric and Public Health Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Gabriella Agnoletti
- Department of Pediatric and Public Health Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Elena Banaudi
- Department of Pediatric and Public Health Sciences, Città della Salute e della Scienza, University of Turin, Turin, Italy
| | - Jan Marek
- Cardiorespiratory Unit, Great Ormond Street Hospital for Children, London, UK, UCL Institute of Cardiovascular Science, London, UK
| | - Juan P Kaski
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK, UCL Institute of Cardiovascular Science, London, UK
| | - Giulia Tuo
- Cardiovascular Department, Giannina Gaslini Institute, Genoa, Italy
| | | | | | - Andrea Madrigali
- Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy
| | - Giuseppe Pacileo
- Cardiologia SUN, Monaldi Hospital, II University of Naples, Naples, Italy
| | - Maria G Russo
- Cardiologia SUN, Monaldi Hospital, II University of Naples, Naples, Italy
| | - Ornella Milanesi
- Department of Woman and Child's Health, Pediatric Cardiology, University of Padova, Padua, Italy
| | - Roberto Formigari
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy.,Cardiology and Cardiac Surgery, Sant'Orsola Malpighi Hospital, Bologna, Italy
| | - Maurizio Brighenti
- Cardiology and Cardiac Surgery, Sant'Orsola Malpighi Hospital, Bologna, Italy
| | - Luca Ragni
- Cardiology and Cardiac Surgery, Sant'Orsola Malpighi Hospital, Bologna, Italy
| | - Andrea Donti
- Cardiology and Cardiac Surgery, Sant'Orsola Malpighi Hospital, Bologna, Italy
| | - Fabrizio Drago
- Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Bruno Dallapiccola
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy
| | - Bruno Marino
- Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy
| | - Paolo Versacci
- Pediatric Cardiology, Department of Pediatrics, Obstetrics and Gynecology, Sapienza University of Rome, Rome, Italy
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Calcagni G, Pugnaloni F, Digilio MC, Unolt M, Putotto C, Niceta M, Baban A, Piceci Sparascio F, Drago F, De Luca A, Tartaglia M, Marino B, Versacci P. Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights. Genes (Basel) 2021; 12:genes12071047. [PMID: 34356063 PMCID: PMC8307133 DOI: 10.3390/genes12071047] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 02/02/2023] Open
Abstract
Recent advances in understanding the genetic causes and anatomic subtypes of cardiac defects have revealed new links between genetic etiology, pathogenetic mechanisms and cardiac phenotypes. Although the same genetic background can result in different cardiac phenotypes, and similar phenotypes can be caused by different genetic causes, researchers’ effort to identify specific genotype–phenotype correlations remains crucial. In this review, we report on recent advances in the cardiac pathogenesis of three genetic diseases: Down syndrome, del22q11.2 deletion syndrome and Ellis–Van Creveld syndrome. In these conditions, the frequent and specific association with congenital heart defects and the recent characterization of the underlying molecular events contributing to pathogenesis provide significant examples of genotype–phenotype correlations. Defining these correlations is expected to improve diagnosis and patient stratification, and it has relevant implications for patient management and potential therapeutic options.
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Affiliation(s)
- Giulio Calcagni
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
- Correspondence: ; Tel.: +39-06-68594096
| | - Flaminia Pugnaloni
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Maria Cristina Digilio
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Marta Unolt
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Carolina Putotto
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Marcello Niceta
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Anwar Baban
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Francesca Piceci Sparascio
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (F.P.S.); (A.D.L.)
| | - Fabrizio Drago
- Department of Pediatric Cardiology and Cardiac Surgery, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.U.); (A.B.); (F.D.)
| | - Alessandro De Luca
- Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (F.P.S.); (A.D.L.)
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy; (M.C.D.); (M.N.); (M.T.)
| | - Bruno Marino
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
| | - Paolo Versacci
- Department of Pediatrics, Obstetrics and Gynecology, “Sapienza” University, 00161 Rome, Italy; (F.P.); (C.P.); (B.M.); (P.V.)
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29
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Regulation of the Small GTPase Ras and Its Relevance to Human Disease. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2021; 2262:19-43. [PMID: 33977469 DOI: 10.1007/978-1-0716-1190-6_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ras research has experienced a considerable boost in recent years, not least prompted by the Ras initiative launched by the NCI in 2013 ( https://www.cancer.gov/research/key-initiatives/ras ), accompanied and conditioned by a strongly reinvigorated determination within the Ras community to develop therapeutics attacking directly the Ras oncoproteins. As a member of the small G-protein superfamily, function and transforming activity of Ras all revolve about its GDP/GTP loading status. For one thing, the extent of GTP loading will determine the proportion of active Ras in the cell, with implications for intensity and quality of downstream signaling. But also the rate of nucleotide exchange, i.e., the Ras-GDP/GTP cycling rate, can have a major impact on Ras function, as illustrated perhaps most impressively by newly discovered fast-cycling oncogenic mutants of the Ras-related GTPase Rac1. Thus, while the last years have witnessed memorable new findings and technical developments in the Ras field, leading to an improved insight into many aspects of Ras biology, they have not jolted at the basics, but rather deepened our view of the fundamental regulatory principles of Ras activity control. In this brief review, we revisit the role and mechanisms of Ras nucleotide loading and its implications for cancer in the light of recent findings.
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Bagattoni S, Costi T, D'Alessandro G, Toni S, Gatto MR, Piana G. Craniofacial and occlusal features of children with Noonan syndrome. Am J Med Genet A 2021; 185:820-826. [PMID: 33438808 DOI: 10.1002/ajmg.a.62046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 09/08/2020] [Accepted: 12/12/2020] [Indexed: 11/06/2022]
Abstract
Craniofacial features of 12 children with Noonan syndrome (NS) were compared with age and gender matched healthy children. Dental history, panoramic radiograph, dental casts, and cephalometric measurements were assessed. The palatal height was significantly increased in the study group compared with the control group (p = .009; paired t-test). The palatal width was significantly reduced in the study group compared with the control group (p = .006; paired t-test). The mean SNB was reduced in the study group compared with the control group (p = .02; paired t-test) and the ANB increased (p = .009; paired t-test). The mean Sum (NSAr + SArGo + ArgoMe) angle and SN-GoMe were increased in the study group compared with the control group (respectively, p = .015 and p = .002; paired t-test). The cephalometric analysis assessed a retruded position of the mandible, skeletal class II characteristics, and a vertical growth pattern. The mandibular hyperdivergency was associated to a positive overbite.
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Affiliation(s)
- Simone Bagattoni
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Tommaso Costi
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giovanni D'Alessandro
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Sara Toni
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Maria Rosaria Gatto
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Gabriela Piana
- Unit of Special Needs Dentistry and Pediatric Dentistry, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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31
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Monda E, Rubino M, Lioncino M, Di Fraia F, Pacileo R, Verrillo F, Cirillo A, Caiazza M, Fusco A, Esposito A, Fimiani F, Palmiero G, Pacileo G, Calabrò P, Russo MG, Limongelli G. Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes. Front Pediatr 2021; 9:632293. [PMID: 33718303 PMCID: PMC7947260 DOI: 10.3389/fped.2021.632293] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 02/01/2021] [Indexed: 12/12/2022] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions. Despite its rare prevalence in pediatric age, HCM carries a relevant risk of mortality and morbidity in both infants and children. Pediatric HCM is a large heterogeneous group of disorders. Other than mutations in sarcomeric genes, which represent the most important cause of HCM in adults, childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally represent up to 35% of children with HCM. The age of presentation and the underlying etiology significantly impact the prognosis of children with HCM. Moreover, in recent years, different targeted approaches for non-sarcomeric etiologies of HCM have emerged. Therefore, the etiological diagnosis is a fundamental step in designing specific management and therapy in these subjects. The present review aims to provide an overview of the non-sarcomeric causes of HCM in children, focusing on the pathophysiology, clinical features, diagnosis, and treatment of these rare disorders.
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Affiliation(s)
- Emanuele Monda
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Marta Rubino
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Lioncino
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Francesco Di Fraia
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Roberta Pacileo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Federica Verrillo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Annapaola Cirillo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Martina Caiazza
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Adelaide Fusco
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Augusto Esposito
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fabio Fimiani
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Palmiero
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Pacileo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paolo Calabrò
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Maria Giovanna Russo
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giuseppe Limongelli
- Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.,Institute of Cardiovascular Sciences, University College of London and St. Bartholomew's Hospital, London, United Kingdom
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32
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Olariu IC, Popoiu A, Ardelean AM, Isac R, Steflea RM, Olariu T, Chirita-Emandi A, Stroescu R, Gafencu M, Doros G. Challenges in the Surgical Treatment of Atrioventricular Septal Defect in Children With and Without Down Syndrome in Romania-A Developing Country. Front Pediatr 2021; 9:612644. [PMID: 34307243 PMCID: PMC8292620 DOI: 10.3389/fped.2021.612644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 06/07/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Atrioventricular septal defect (AVSD) is a cardiac malformation that accounts for up to 5% of total congenital heart disease, occurring with high frequency in people with Down Syndrome (DS). We aimed to establish the surgical challenges and outcome of medical care in different types of AVSD in children with DS compared to those without DS (WDS). Methods: The study included 62 children (31 with DS) with AVSD, evaluated over a 5 year period. Results: Complete AVSD was observed in 49 (79%) children (27 with DS). Six children had partial AVSD (all WDS) and seven had intermediate types of AVSD (4 with DS). Eight children had unbalanced complete AVSD (1 DS). Median age at diagnosis and age at surgical intervention in complete AVSD was not significantly different in children with DS compared to those WDS (7.5 months vs. 8.6). Median age at surgical intervention for partial and transitional AVSDs was 10.5 months for DS and 17.8 months in those without DS. A large number of patients were not operated: 13/31 with DS and 8/31 WDS. Conclusion: The complete form of AVSD was more frequent in DS group, having worse prognosis, while unbalanced AVSD was observed predominantly in the group without DS. Children with DS required special attention due to increased risk of pulmonary hypertension. Late diagnosis was an important risk factor for poor prognosis, in the setting of suboptimal access to cardiac surgery for patients in Romania. Although post-surgery mortality was low, infant mortality before surgery remains high. Increased awareness is needed in order to provide early diagnosis of AVSD and enable optimal surgical treatment.
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Affiliation(s)
- Ioana-Cristina Olariu
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Anca Popoiu
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Andrada-Mara Ardelean
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Raluca Isac
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Ruxandra Maria Steflea
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania
| | - Tudor Olariu
- Department of Organic Chemistry, Faculty of Pharmacy, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Adela Chirita-Emandi
- Department of Microscopic Morphology Genetics Discipline, Center of Genomic Medicine Timisoara, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Regional Centre of Medical Genetics Timis, "Louis Turcanu" Emergency Hospital for Children Timisoara, Part of ERN ITHACA, Timisoara, Romania
| | - Ramona Stroescu
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Mihai Gafencu
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
| | - Gabriela Doros
- Department of Pediatrics, "Victor Babeş" University of Medicine and Pharmacy, Timisoara, Romania.,Department of Pediatrics, "Louis Turcanu" Emergency Hospital for Children, Timisoara, Romania
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Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. Nat Commun 2020; 11:4673. [PMID: 32938917 PMCID: PMC7495420 DOI: 10.1038/s41467-020-18483-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022] Open
Abstract
RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.
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Abstract
Congenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births and is a significant cause of birth defect-related mortality. The genetic mechanisms underlying the development of CHD are complex and remain incompletely understood. Known genetic causes include all classes of genetic variation including chromosomal aneuploidies, copy number variants, and rare and common single-nucleotide variants, which can be either de novo or inherited. Among patients with CHD, ∼8%-12% have a chromosomal abnormality or aneuploidy, between 3% and 25% have a copy number variation, and 3%-5% have a single-gene defect in an established CHD gene with higher likelihood of identifying a genetic cause in patients with nonisolated CHD. These genetic variants disrupt or alter genes that play an important role in normal cardiac development and in some cases have pleiotropic effects on other organs. This work reviews some of the most common genetic causes of CHD as well as what is currently known about the underlying mechanisms.
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Affiliation(s)
| | - Wendy K Chung
- Department of Pediatrics
- Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, USA
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35
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Noonan Syndrome in 12 -Year-Old Male: Case Report and Orthodontic Management of the Occlusion. BALKAN JOURNAL OF DENTAL MEDICINE 2020. [DOI: 10.2478/bjdm-2020-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Summary
Background/Aim: Noonan syndrome (NS) is an autosomal dominant disorder, caused by mutations on genes located on the long arm of chromosome 12. The condition has no sex or race predilection and its incidence is 1 per 1,000 – 2,500 live births. Individuals affected with Noonan syndrome have distinctive facial features, hypertelorism, short stature, congenital heart disease; mainly pulmonary stenosis and hypertrophic cardiomyopathy, chest deformities, variable learning disabilities and mental retardation. Orofacial findings in Noonan syndrome may be high-arched palate, micrognathia, dental malocclusion and articulation difficulties.
Case report: The present article reports on a male case of 12 years old, referred for treatment in the orthodontic office. Despite the difficulties of hyperactivity, the light mental delay and the gag reflex, the treatment was completed satisfactorily with fixed orthodontic appliances in 15 months. Both the patient and his parents were happy with the results. The patient is presently undergoing the retention period of this orthodontic treatment.
Conclusions: Despite the difficulties of treating a child with a genetic syndrome for his/her malocclusion, the reported case presented in this article proves that it is always worth trying for the benefit of the patient.
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Sahu S, Chaudhury S, Saldanha D. Noonan syndrome with somnambulism: A rare case report. Ind Psychiatry J 2020; 29:339-341. [PMID: 34158723 PMCID: PMC8188914 DOI: 10.4103/ipj.ipj_84_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 12/11/2020] [Indexed: 11/25/2022] Open
Abstract
Noonan syndrome is an autosomal dominant, genetic, multisystem disorder with a prevalence of 1 in 1000-2500 live births. Characteristic features of the condition include distinctive myopathic facial features, hypertelorism, short and broad nose, webbed neck, and low set ears. About 10% of the subjects have auditory defects due to sensorineural hearing loss. The patient also has short stature, chest deformity (superior pectus carinatum and inferior pectus excavatum), widely spaced nipples, and delayed puberty. A rare psychiatric manifestation of somnambulism and somniloquy in a case of Noonan syndrome is reported.
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Affiliation(s)
- Samiksha Sahu
- Department of Psychiatry, Dr. D Y Patil Medical College, Pune, Maharashtra, India
| | - Suprakash Chaudhury
- Department of Psychiatry, Dr. D Y Patil Medical College, Pune, Maharashtra, India
| | - Daniel Saldanha
- Department of Psychiatry, Dr. D Y Patil Medical College, Pune, Maharashtra, India
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37
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Agasthi P, Pujari SH, Tseng A, Graziano JN, Marcotte F, Majdalany D, Mookadam F, Hagler DJ, Arsanjani R. Management of adults with coarctation of aorta. World J Cardiol 2020; 12:167-191. [PMID: 32547712 PMCID: PMC7284000 DOI: 10.4330/wjc.v12.i5.167] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/21/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
Coarctation of the aorta (CoA) is a relatively common congenital cardiac defect often causing few symptoms and therefore can be challenging to diagnose. The hallmark finding on physical examination is upper extremity hypertension, and for this reason, CoA should be considered in any young hypertensive patient, justifying measurement of lower extremity blood pressure at least once in these individuals. The presence of a significant pressure gradient between the arms and legs is highly suggestive of the diagnosis. Early diagnosis and treatment are important as long-term data consistently demonstrate that patients with CoA have a reduced life expectancy and increased risk of cardiovascular complications. Surgical repair has traditionally been the mainstay of therapy for correction, although advances in endovascular technology with covered stents or stent grafts permit nonsurgical approaches for the management of older children and adults with native CoA and complications. Persistent hypertension and vascular dysfunction can lead to an increased risk of coronary disease, which, remains the greatest cause of long-term mortality. Thus, blood pressure control and periodic reassessment with transthoracic echocardiography and three-dimensional imaging (computed tomography or cardiac magnetic resonance) for should be performed regularly as cardiovascular complications may occur decades after the intervention.
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Affiliation(s)
- Pradyumna Agasthi
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States
| | - Sai Harika Pujari
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States
| | - Andrew Tseng
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, United States
| | - Joseph N Graziano
- Division of Cardiology, Phoenix Children's Hospital, Children's Heart Center, Phoenix, AZ 85016, United States
| | - Francois Marcotte
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States
| | - David Majdalany
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States
| | - Farouk Mookadam
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States
| | - Donald J Hagler
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, United States
| | - Reza Arsanjani
- Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States.
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Pugnaloni F, Digilio MC, Putotto C, De Luca E, Marino B, Versacci P. Genetics of atrioventricular canal defects. Ital J Pediatr 2020; 46:61. [PMID: 32404184 PMCID: PMC7222302 DOI: 10.1186/s13052-020-00825-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 05/03/2020] [Indexed: 12/11/2022] Open
Abstract
Atrioventricular canal defect (AVCD) represents a quite common congenital heart defect (CHD) accounting for 7.4% of all cardiac malformations. AVCD is a very heterogeneous malformation that can occur as a phenotypical cardiac aspect in the context of different genetic syndromes but also as an isolated, non-syndromic cardiac defect. AVCD has also been described in several pedigrees suggesting a pattern of familiar recurrence. Targeted Next Generation Sequencing (NGS) techniques are proved to be a powerful tool to establish the molecular heterogeneity of AVCD. Given the complexity of cardiac embryology, it is not surprising that multiple genes deeply implicated in cardiogenesis have been described mutated in patients with AVCD. This review attempts to examine the recent advances in understanding the molecular basis of this complex CHD in the setting of genetic syndromes or in non-syndromic patients.
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Affiliation(s)
- Flaminia Pugnaloni
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Maria Cristina Digilio
- Medical Genetics Unit, Bambino Gesù Children's Hospital and Research Institute, 00165, Rome, Italy
| | - Carolina Putotto
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Enrica De Luca
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Bruno Marino
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy
| | - Paolo Versacci
- Department of Pediatrics, Obstetrics and Gynecology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena, 324, 00161, Rome, Italy.
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Abduljawad EM, AlHarthi A, AlMatrafi SA, Hussain M, Shawli A, Waggass R. The Prevalence of Congenital Heart Diseases in Syndromic Children at King Khalid National Guard Hospital from 2005 to 2016. Cureus 2020; 12:e7891. [PMID: 32489745 PMCID: PMC7255536 DOI: 10.7759/cureus.7891] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 04/29/2020] [Indexed: 12/30/2022] Open
Abstract
Background Congenital heart diseases (CHDs) are abnormalities that present in the heart since birth and are one of the leading causes of infant mortality in the world. CHDs are more common among children with dysmorphic syndromes. The current study aims to estimate the prevalence of many CHDs in different dysmorphic syndromes. Methods This was a retrospective chart review study conducted on all dysmorphic syndrome patients who attended genetic clinics at King Khalid National Guard Hospital in King Abdulaziz Medical City (KAMC), Jeddah, Saudi Arabia from 2005 to 2016. Dysmorphic pediatric patients less than 14 years old who had genetic testing to confirm their diagnosis were included in the study. Patients who did not have any previous echocardiography were excluded. Results A total of 212 individuals (47% males and 53% females) were included. Eighty-five percent of Down syndrome patients had CHDs, and the most common CHD was an atrial septal defect (ASD) (51%). In patients with Turner syndrome, 45% of them had CHDs, and bicuspid aortic valve (BAV) (40%) was the most common defect. In DiGeorge syndrome, 81% of patients had CHDs, and ventricular septal defect (VSD) (41%) was the most common. In Williams syndrome, 83% of patients had CHDs. All patients with Noonan, Edwards, CHARGE (coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities), and Rubinstein-Taybi syndromes were found to have CHDs. In Patau syndrome and Joubert syndrome, 50% of patients in each had CHDs. Patients with Prader Willi syndrome had normal findings in the echocardiogram. Conclusion The highest prevalence of CHDs was found in Down syndrome. This study has a significant impact on the future of managing and directing the resources to improve the quality of life for syndromic patients. Further studies are needed to confirm these findings and to increase the local data in the field of CHDs in Saudi Arabia among syndromic patients.
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Affiliation(s)
- Elaf M Abduljawad
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
| | - Ahad AlHarthi
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
| | - Samah A AlMatrafi
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
| | - Mawaddah Hussain
- Medicine, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
| | - Aiman Shawli
- Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, SAU
| | - Rahaf Waggass
- Pediatric Cardiology, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
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40
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Athota JP, Bhat M, Nampoothiri S, Gowrishankar K, Narayanachar SG, Puttamallesh V, Farooque MO, Shetty S. Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC MEDICAL GENETICS 2020; 21:50. [PMID: 32164556 PMCID: PMC7068896 DOI: 10.1186/s12881-020-0986-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 02/25/2020] [Indexed: 02/08/2023]
Abstract
Background Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype–phenotype correlation. Methods Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. Results Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). Conclusion The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.
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Affiliation(s)
| | - Meenakshi Bhat
- Molecular Genetics, Centre for Human Genetics, Bengaluru, 560100, India.,Pediatric Genetics, Indira Gandhi Institute of Child Health, Bengaluru, 560029, India
| | - Sheela Nampoothiri
- Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre (AIMS), Kochi, 682041, India
| | | | | | | | | | - Swathi Shetty
- Molecular Genetics, Centre for Human Genetics, Bengaluru, 560100, India.
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Lutz JC, Nicot R, Schlund M, Schaefer E, Bornert F, Fioretti F, Ferri J. Dental and maxillofacial features of Noonan Syndrome: Case series of ten patients. J Craniomaxillofac Surg 2020; 48:242-250. [PMID: 32113883 DOI: 10.1016/j.jcms.2020.01.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 01/22/2020] [Accepted: 01/26/2020] [Indexed: 12/28/2022] Open
Abstract
Noonan syndrome (NS) is a relatively common congenital multiple-anomaly syndrome, resembling Turner syndrome, but without chromosomal anomaly. Besides the unusual facies, the maxillofacial and dental features of patients with NS are not well-summarized in the literature. The aim of this study was to describe these features and propose specific treatment guidelines for practitioners involved in oral and maxillofacial care. A retrospective multicentric study was conducted of 14 patients who were referred for NS screening. In total, 10 patients were found to carry a mutation involved in NS or NS-related disorders. Fifty percent of the mutations affected PTPN11. All patients presented with the typical extraoral features, such as macrocephaly, hypertelorism, ptosis, triangular face shape and ear dystrophy. Intraoral manifestations, including malocclusion (maxillary transversal deficiency, crossbite, anterior open-bite and class II malocclusion), dental anomalies (delayed eruption, agenesis and dystrophy, odontoma) and radiologic jaw lesions were identified in five out of 10 patients. These findings were searched in a review of the literature to obtain a comprehensive description of oral and maxillofacial features in patients with NS. The proposed treatment guidelines emphasize frequent coagulation anomalies that need to be considered prior to surgery. Early dental assessment and yearly follow-up with oral prophylaxis are recommended. Orthodontics and orthognathic surgery are also of primary importance in the management of NS patients.
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Affiliation(s)
- Jean-Christophe Lutz
- Oral and Maxillofacial Surgery Department, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg cedex, France; University of Strasbourg, Faculty of Medicine, 8 rue Kirschleger, 67000, Strasbourg, France; INSERM (French National Institute of Health and Medical Research), "Regenerative Nanomedicine" Laboratory, UMR 1260, Faculté de Médecine, FMTS, 67085, Strasbourg cedex, France.
| | - Romain Nicot
- Oral and Maxillofacial Surgery Department, Roger Salengro Hospital, Avenue du Professeur Emile Laine, 59037, Lille, France; Université Lille 2 Droit et Santé, 1 Pl. de Verdun, 59000, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Faculté de Pharmacie, 3, rue du Professeur Laguesse, BP83, 59006, Lille Cedex, France
| | - Matthias Schlund
- Oral and Maxillofacial Surgery Department, Roger Salengro Hospital, Avenue du Professeur Emile Laine, 59037, Lille, France; Université Lille 2 Droit et Santé, 1 Pl. de Verdun, 59000, Lille, France
| | - Elise Schaefer
- University of Strasbourg, Faculty of Medicine, 8 rue Kirschleger, 67000, Strasbourg, France; Medical Genetics Department, Strasbourg University Hospital, 1 avenue Molière, 67098, Strasbourg cedex, France
| | - Fabien Bornert
- INSERM (French National Institute of Health and Medical Research), "Regenerative Nanomedicine" Laboratory, UMR 1260, Faculté de Médecine, FMTS, 67085, Strasbourg cedex, France; Department of Dentistry / Oral Medicine and Oral Surgery, Strasbourg University Hospital, 1 Place de l'Hôpital, 67091, Strasbourg cedex, France; University of Strasbourg, Faculty of Dentistry, 8 rue Sainte Elisabeth, 67000, Strasbourg, France
| | - Florence Fioretti
- INSERM (French National Institute of Health and Medical Research), "Regenerative Nanomedicine" Laboratory, UMR 1260, Faculté de Médecine, FMTS, 67085, Strasbourg cedex, France; Department of Dentistry / Oral Medicine and Oral Surgery, Strasbourg University Hospital, 1 Place de l'Hôpital, 67091, Strasbourg cedex, France; University of Strasbourg, Faculty of Dentistry, 8 rue Sainte Elisabeth, 67000, Strasbourg, France
| | - Joël Ferri
- Oral and Maxillofacial Surgery Department, Roger Salengro Hospital, Avenue du Professeur Emile Laine, 59037, Lille, France; Université Lille 2 Droit et Santé, 1 Pl. de Verdun, 59000, Lille, France; INSERM U1008, Controlled Drug Delivery Systems and Biomaterials, Faculté de Pharmacie, 3, rue du Professeur Laguesse, BP83, 59006, Lille Cedex, France
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Linglart L, Gelb BD. Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2020; 184:73-80. [PMID: 32022400 DOI: 10.1002/ajmg.c.31765] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/06/2020] [Accepted: 01/09/2020] [Indexed: 11/10/2022]
Abstract
Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left-sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen-activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype-phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome-specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.
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Affiliation(s)
| | - Bruce D Gelb
- Mindich Child Health and Development Institute and the Departments of Pediatrics and Genetics & Genomic Sciences, the Icahn School of Medicine at Mount Sinai, New York, New York
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Unveiling the Molecular Basis of the Noonan Syndrome-Causing Mutation T42A of SHP2. Int J Mol Sci 2020; 21:ijms21020461. [PMID: 31936901 PMCID: PMC7013464 DOI: 10.3390/ijms21020461] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 11/30/2022] Open
Abstract
Noonan syndrome (NS) is a genetic disorder caused by the hyperactivation of the RAS-MAPK molecular pathway. About 50% of NS cases are caused by mutations affecting the SHP2 protein, a multi-domain phosphatase with a fundamental role in the regulation of the RAS-MAPK pathway. Most NS-causing mutations influence the stability of the inactive form of SHP2. However, one NS-causing mutation, namely T42A, occurs in the binding pocket of the N-SH2 domain of the protein. Here, we present a quantitative characterization of the effect of the T42A mutation on the binding of the N-terminal SH2 domain of SHP2 with a peptide mimicking Gab2, a fundamental interaction that triggers the activation of the phosphatase in the cellular environment. Our results show that whilst the T42A mutation does not affect the association rate constant with the ligand, it causes a dramatic increase of the affinity for Gab2. This effect is due to a remarkable decrease of the microscopic dissociation rate constant of over two orders of magnitudes. In an effort to investigate the molecular basis of the T42A mutation in causing Noonan syndrome, we also compare the experimental results with a more conservative variant, T42S. Our findings are discussed in the context of the structural data available on SHP2.
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Witman N, Zhou C, Grote Beverborg N, Sahara M, Chien KR. Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration. Semin Cell Dev Biol 2019; 100:29-51. [PMID: 31862220 DOI: 10.1016/j.semcdb.2019.10.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/13/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022]
Abstract
The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.
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Affiliation(s)
- Nevin Witman
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Chikai Zhou
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Niels Grote Beverborg
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Makoto Sahara
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Surgery, Yale University School of Medicine, CT, USA.
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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Lee CL, Tan LTHC, Lin HY, Hwu WL, Lee NC, Chien YH, Chuang CK, Wu MH, Wang JK, Chu SY, Lin JL, Lo FS, Su PH, Hsu CC, Ko YY, Chen MR, Chiu HC, Lin SP. Cardiac manifestations and gene mutations of patients with RASopathies in Taiwan. Am J Med Genet A 2019; 182:357-364. [PMID: 31837205 DOI: 10.1002/ajmg.a.61429] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 11/18/2019] [Accepted: 11/20/2019] [Indexed: 11/07/2022]
Abstract
RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.
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Affiliation(s)
- Chung-Lin Lee
- Department of Pediatrics, Mackay Memorial Hospital, Hsinchu, Taiwan
| | | | - Hsiang-Yu Lin
- Department of Pediatrics and Rare Disease Center, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.,Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.,Nursing and Management, Mackay Junior College of Medicine, Taipei, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Wuh-Liang Hwu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yin-Hsiu Chien
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Kuang Chuang
- Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.,College of Medicine, Fu-Jen Catholic University, Taipei, Taiwan
| | - Mei-Hwan Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Jou-Kou Wang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Shao-Yin Chu
- Department of Pediatrics, Buddhist Tzu-Chi General Hospital, Hualien, Taiwan
| | - Ju-Li Lin
- Department of Pediatrics, Chang-Gung Memorial Hospital, Taoyuan, Taiwan
| | - Fu-Sung Lo
- Department of Pediatrics, Chang-Gung Memorial Hospital, Taoyuan, Taiwan
| | - Pen-Hua Su
- Department of Pediatrics, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Chi Hsu
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yu-Yuan Ko
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ming-Ren Chen
- Pediatric Cardiology Department, Mackay Children's Hospital, Taipei, Taiwan
| | - Hui-Ching Chiu
- Department of Pediatrics and Rare Disease Center, Mackay Memorial Hospital, Taipei, Taiwan
| | - Shuan-Pei Lin
- Department of Pediatrics and Rare Disease Center, Mackay Memorial Hospital, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.,Division of Genetics and Metabolism, Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.,Department of Infant and Child Care, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
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Higgins EM, Bos JM, Dotzler SM, John Kim CS, Ackerman MJ. MRAS Variants Cause Cardiomyocyte Hypertrophy in Patient-Specific Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Additional Evidence for MRAS as a Definitive Noonan Syndrome-Susceptibility Gene. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019; 12:e002648. [PMID: 31638832 DOI: 10.1161/circgen.119.002648] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND MRAS was identified recently as a novel Noonan syndrome (NS)-susceptibility gene. Phenotypically, both patients with NS, harboring pathogenic MRAS variants, displayed severe cardiac hypertrophy. This study aimed to demonstrate both the necessity and sufficiency of a patient-specific variant (p.Gly23Val-MRAS) to cause NS through the generation and characterization of patient-specific, isogenic control, and disease modeled induced pluripotent stem cell (iPSC) lines. METHODS iPSCs were derived from a patient with a p.Gly23Val-MRAS variant to assess the effect of MRAS variants on pathogenesis of NS-associated cardiac hypertrophy. CRISPR/Cas9 gene editing was used to correct the pathogenic p.Gly23Val-MRAS variant in patient cells (isogenic control) and to introduce the pathogenic variant into unrelated control cells (disease modeled) to determine the necessity and sufficiency of the p.Gly23Val-MRAS variant to elicit the disease phenotype in iPSC-derived cardiomyocytes (iPSC-CMs). iPSC-CMs were analyzed by microscopy and immunofluroesence, single-cell RNAseq, Western blot, room temperature-quantitative polymerase chain reaction, and live-cell calcium imaging to define an in vitro phenotype of MRAS-mediated cardiac hypertrophy. RESULTS Compared with controls, both patient and disease modeled iPSC-CMs were significantly larger and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. Additionally, patient and disease modeled iPSC-CMs displayed impaired Ca2+ handling, including increased frequency of irregular Ca2+ transients and changes in Ca2+ handling kinetics. CONCLUSIONS p.Gly23Val-MRAS is both necessary and sufficient to elicit a cardiac hypertrophy phenotype in iPSC-CMs that includes increased cell size, changes in cardiac gene expression, and abnormal calcium handling-providing further evidence to establish the monogenetic pathogenicity of p.Gly23Val-MRAS in NS with cardiac hypertrophy.
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Affiliation(s)
- Erin M Higgins
- Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN
| | - J Martijn Bos
- Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN.,Department of Cardiovascular Medicine/Division of Heart Rhythm Services (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN
| | - Steven M Dotzler
- Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN.,Mayo Clinic Alix School of Medicine (S.M.D., M.J.A.), Mayo Clinic, Rochester, MN
| | - C S John Kim
- Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN
| | - Michael J Ackerman
- Mayo Clinic Graduate School of Biomedical Sciences, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (E.M.H., J.M.B., S.M.D., C.J.K., M.J.A.), Mayo Clinic, Rochester, MN.,Department of Cardiovascular Medicine/Division of Heart Rhythm Services (J.M.B., M.J.A.), Mayo Clinic, Rochester, MN.,Mayo Clinic Alix School of Medicine (S.M.D., M.J.A.), Mayo Clinic, Rochester, MN.,Department of Pediatrics/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN
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McCallen LM, Ameduri RK, Denfield SW, Dodd DA, Everitt MD, Johnson JN, Lee TM, Lin AE, Lohr JL, May LJ, Pierpont ME, Stevenson DA, Chatfield KC. Cardiac transplantation in children with Noonan syndrome. Pediatr Transplant 2019; 23:e13535. [PMID: 31259454 DOI: 10.1111/petr.13535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/04/2019] [Accepted: 06/06/2019] [Indexed: 11/30/2022]
Abstract
NS and related RAS/MAPK pathway (RASopathy) disorders are the leading genetic cause of HCM presenting in infancy. HCM is a major cause of morbidity and mortality in children with Noonan spectrum disorders, especially in the first year of life. Previously, there have been only isolated reports of heart transplantation as a treatment for heart failure in NS. We report on 18 patients with NS disorders who underwent heart transplantation at seven US pediatric heart transplant centers. All patients carried a NS diagnosis: 15 were diagnosed with NS and three with NSML. Sixteen of eighteen patients had comprehensive molecular genetic testing for RAS pathway mutations, with 15 having confirmed pathogenic mutations in PTPN11, RAF1, and RIT1 genes. Medical aspects of transplantation are reported as well as NS-specific medical issues. Twelve of eighteen patients described in this series were surviving at the time of data collection. Three patients died following transplantation prior to discharge from the hospital, and another three died post-discharge. Heart transplantation in NS may be a more frequent occurrence than is evident from the literature or registry data. A mortality rate of 33% is consistent with previous reports of patients with HCM transplanted in infancy and early childhood. Specific considerations may be important in evaluation of this population for heart transplant, including a potentially increased risk for malignancies as well as lymphatic, bleeding, and coagulopathy complications.
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Affiliation(s)
- Leslie M McCallen
- Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado
| | - Rebecca K Ameduri
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Susan W Denfield
- Department of Pediatrics, Baylor School of Medicine, Houston, Texas
| | - Debra A Dodd
- Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, Tennessee
| | - Melanie D Everitt
- Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado
| | | | - Teresa M Lee
- Department of Pediatrics, Columbia University, New York, New York
| | - Angela E Lin
- Medical Genetics, Massachusetts General Hospital for Children, Boston, Massachusetts
| | - Jamie L Lohr
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Lindsay J May
- Department of Pediatrics, University of Utah, Salt Lake City, Utah
| | - Mary Ella Pierpont
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - David A Stevenson
- Department of Pediatrics, Stanford University, Palo Alto, California
| | - Kathryn C Chatfield
- Department of Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado
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Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD, Hsu DT, Lin KY, Price JF, Wilkinson JD, Colan SD. Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association. Circulation 2019; 140:e9-e68. [PMID: 31132865 DOI: 10.1161/cir.0000000000000682] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute-funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
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Koh AL, Tan ES, Brett MS, Lai AHM, Jamuar SS, Ng I, Tan EC. The spectrum of genetic variants and phenotypic features of Southeast Asian patients with Noonan syndrome. Mol Genet Genomic Med 2019; 7:e00581. [PMID: 30784236 PMCID: PMC6465663 DOI: 10.1002/mgg3.581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 12/18/2018] [Accepted: 12/31/2018] [Indexed: 12/28/2022] Open
Abstract
Background Noonan syndrome (NS) is an autosomal dominant disorder that belongs to a group of developmental disorders called RASopathies with overlapping features and multiple causative genes. The aim of the study was to identify mutations underlying this disorder in patients from Southeast Asia and characterize their clinical presentations. Methods Patients were identified from the hospital's Genetics clinics after assessment by attending clinical geneticists. A targeted gene panel was used for next‐generation sequencing on genomic DNA extracted from the blood samples of 17 patients. Results Heterozygous missense variants were identified in 13 patients: eight were in PTPN11, three in SOS1, and one each in RIT1 and KRAS. All are known variants that have been reported in patients with NS. Of the 13 patients with identified variants, 10 had short stature, the most common feature for NS. Four of the eight patients with PTPN11 variants had atrial septal defect. Only two had pulmonary stenosis which is reported to be common for PTPN11 mutation carriers. Another two had hypertrophic cardiomyopathy, a feature which is negatively associated with PTPN11 mutations. Conclusions Our study provides the mutation and phenotypic spectrum of NS from a new population group. The molecular testing yield of 76% is similar to other studies and shows that the targeted panel approach is useful for identifying genetic mutations in NS which has multiple causative genes. The molecular basis for the phenotypes of the remaining patients remains unknown and would need to be uncovered via sequencing of additional genes or other investigative methods.
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Affiliation(s)
- Ai-Ling Koh
- Department of Paediatrics, KK Women's & Children's Hospital, Singapore
| | - Ee-Shien Tan
- Genetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, Singapore
| | - Maggie S Brett
- Research Laboratory, KK Women's & Children's Hospital, Singapore
| | - Angeline H M Lai
- Genetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, Singapore
| | - Saumya Shekhar Jamuar
- Genetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, Singapore
| | - Ivy Ng
- Genetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, Singapore
| | - Ene-Choo Tan
- Genetics Service, Department of Paediatrics, KK Women's & Children's Hospital, Singapore.,Paediatrics Academic Clinical Programme, SingHealth Duke-NUS Graduate Medical School, Singapore.,Research Laboratory, KK Women's & Children's Hospital, Singapore
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Anderson K, Cnota J, James J, Miller EM, Parrott A, Pilipenko V, Weaver KN, Shikany A. Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis. CONGENIT HEART DIS 2018; 14:264-273. [PMID: 30556322 DOI: 10.1111/chd.12721] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/09/2018] [Accepted: 10/25/2018] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To evaluate the prevalence of Noonan spectrum disorders (NSD) in a pediatric population with valvar pulmonary stenosis (vPS) and identify the clinical characteristics that differentiate those with NSD from those without NSD. DESIGN A retrospective chart review of 204 patients diagnosed with vPS between 9/1/2012 and 12/1/2016 at a pediatric medical center was performed. The quantitative features of vPS, genetic diagnosis information, and phenotypic characteristics of Noonan syndrome were collected. Chi-square test, Fisher's exact test, t test, Wilcoxon rank-sum test, and ANOVA were used for comparisons among the groups. Logistic regression was used to test for the association between the clinical characteristics and the presence of NSD. RESULTS Syndromic diagnoses were made in 10% of the children with vPS, with NSD accounting for 6%. Hypertrophic cardiomyopathy (P < .0001), short stature (P < .0001), developmental delay (P < .0001), ophthalmological abnormalities (P < .0001), pectus carinatum/excavatum (P = .01), neurological abnormalities (P = .022), and aortic stenosis (P = .031) were present more often in individuals with NSD compared to nonsyndromic vPS. A logistic regression analysis showed a 4.8-fold increase in odds for NSD for each additional characteristic (P < .0001). CONCLUSIONS At least 6% of the children with vPS have an underlying NSD. Individuals with vPS and NSD were significantly more likely to have additional features known to be associated with NSD than those with vPS without NSD. We conclude that vPS in the presence of one or more significant characteristics should prompt referral for genetic evaluation as a guide to ascertain patients at risk for NSD while optimizing the use of clinical genetics evaluation and potential genetic testing.
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Affiliation(s)
- Kailyn Anderson
- Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - James Cnota
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jeanne James
- Department of Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin.,Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Erin M Miller
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Ashley Parrott
- The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Valentina Pilipenko
- Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Kathryn Nicole Weaver
- Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Amy Shikany
- The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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