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Golden BM, Tucker SK, Carpenter M, Santi M, Viaene AN, Peranteau WH, Swanson JW, Bartlett SP, Taylor JA, Liao EC. Integration of Clinical, Radiographic, Histologic, and Molecular Findings to Diagnose Craniofacial Fibrous Dysplasia. J Craniofac Surg 2025:00001665-990000000-02668. [PMID: 40293126 DOI: 10.1097/scs.0000000000011431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Accepted: 04/01/2025] [Indexed: 04/30/2025] Open
Abstract
Fibrous dysplasia (FD) is a benign bone tumor consisting of fibrotic deposits interwoven with disorganized bone. Craniofacial FD is characterized by progressive expansile overgrowth resulting in facial disfigurement, vision loss, jaw disfunction, and pain. Diagnosis is often made by clinical presentation and suggestive radiographic findings, with histologic and genetic analyses recommended in questionable cases. However, genetic testing of the FD lesions can lead to false negatives, as lesions contain both normal and neoplastic cells. To explore the concordance between FD diagnostic tools, we evaluated clinical history, imaging, histology, and genetic testing of 6 cases. Six subjects presented with abnormal bony overgrowth and imaging suggestive of FD. Histologic examination of excised FD lesions revealed 4 cases with pathologic findings consistent with FD, 1 case diagnosed as juvenile psammomatoid ossifying fibroma (JPOF), and 1 with a vascular malformation. Given that somatic mosaicism underpins FD pathogenesis, targeted sequencing of the GNAS gene was performed from different tissue sources, including blood, bone lesion, and primary bone cell culture. GNAS pathogenic gene variants were detected in the lesion of all 6 cases, including the case demonstrating JPOF histologic features. The authors found the mutational burden of cells containing the pathogenic GNAS variant ranges from 35.8% to 46.8% in abnormal bone and 31.0% to 49.7% in cultured stromal cells. The variable correlation of the radiographic, histologic, and molecular diagnosis in this study highlights the clinical heterogeneity of FD and challenges in accurate diagnosis. By culturing primary stromal cells, the authors provide source material for somatic molecular diagnosis and future experiments.
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Affiliation(s)
- Brandi M Golden
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
| | - Scott K Tucker
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
| | - Marco Carpenter
- Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia
| | - Mariarita Santi
- Division of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Angela N Viaene
- Division of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
| | - William H Peranteau
- Division of General, Thoracic, and Fetal Surgery, Children's Hospital of Philadelphia
| | - Jordan W Swanson
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
| | - Scott P Bartlett
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
| | - Jesse A Taylor
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
| | - Eric C Liao
- Division of Plastic, Reconstructive, and Oral Surgery, Children's Hospital of Philadelphia
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Joy-Thomas A, Lalwani Z, Guajardo L, Valenza J, Fakhouri WD. The Role of Genetics in Human Oral Health: A Systematic-Narrative Review. Dent J (Basel) 2025; 13:133. [PMID: 40136761 PMCID: PMC11941287 DOI: 10.3390/dj13030133] [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: 11/13/2024] [Revised: 01/10/2025] [Accepted: 03/12/2025] [Indexed: 03/27/2025] Open
Abstract
Background/Objectives: An individual's genetic makeup influences their organ development, orofacial structures, and overall health. Though many studies have been conducted to determine the inheritance of oral diseases and conditions, there is a lack of comprehensive research classifying these disorders based on the genetic and environmental etiology. Methods: This systematic review aimed to analyze the existing body of literature using the PubMed and Cochrane databases and answer the following question: "What evidence exists supporting the role of genetic factors in oral conditions?" This systematic-narrative review methodically categorizes oral diseases and conditions based on their genetic or environmental linkages. Each classification is rigorously supported by the peer-reviewed articles and evidence strength, affirming the sufficient validity of the identified associations. Results: This study provides an overview of how genetics can influence oral health, from predisposition to susceptibility to various oral diseases, and the impact of genetic alterations on dental and oral conditions. Additionally, this study discusses the importance of understanding the interplay between genetic and environmental factors to improve oral health outcomes. An enhanced understanding of the impact of genetics on oral health will provide a better understanding of the implications of inherited or de novo genetic mutations and their potential interactions with environmental factors. Conclusions: The data collection and analysis indicate 25 oral conditions with strong genetic components and 2 with moderate genetic contributions (fibrous dysplasia and impacted teeth), while 14 oral conditions seem to have weak genetic contributions. Treatment planning that includes genetic testing and counseling as an approach of precision oral healthcare is encouraged to develop appropriate preventative and timely treatment plans to provide the effective management of patients' symptoms.
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Affiliation(s)
- Anita Joy-Thomas
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
| | - Zarna Lalwani
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
| | - Leticia Guajardo
- Department of Endodontics, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
| | - John Valenza
- Department of General Practice and Dental Public Health, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
| | - Walid D. Fakhouri
- Department of Diagnostic and Biomedical Sciences, Center for Craniofacial Research, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX 77054, USA;
- Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77054, USA
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Bergignat S, Chapurlat R, Nicolino M, Perge K. Clinical spectrum and uncommon features of McCune-Albright syndrome in children: a cohort study from a National Referral Center. Front Endocrinol (Lausanne) 2025; 16:1531765. [PMID: 40078582 PMCID: PMC11896858 DOI: 10.3389/fendo.2025.1531765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/03/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction McCune-Albright syndrome (MAS) is a rare disease caused by somatic gain-of-function variants in the GNAS gene that lead to constitutive activation of the G protein alpha subunit (Gsα). Pathologic consequences can involve several tissues. Fibrous dysplasia (FD), café-au-lait skin macules and hyperfunctioning endocrinopathies are classic manifestations. However, the phenotypic spectrum of MAS is considerably wider and more complex. Methods We performed a pediatric retrospective study from our National Referral Center between 2007 and 2021 to describe the clinical spectrum of MAS in children, with a focus on unusual or severe manifestations. Results and discussion A total of 33 children were included. Peripheral precocious puberty was the most frequent endocrinopathy, affecting 84,6% of girls and was the presenting feature for 57,6% of them. Thyroid involvement was also common, consisting in morphological abnormalities with or without slight hyperthyroidism. Thyroid nodules were typically benign, but one patient presented a follicular thyroid carcinoma. Cushing syndrome typically occurs in the neonatal period, but we observed an unusual case of hypercortisolism revealed in early infancy. FD was very common and manifested along a wide range of severity, from monostotic and asymptomatic lesion to polyostotic FD with pain, fractures, and compressive optic neuropathy. We described a locally aggressive FD involving sphenoid and maxillary bones which leaded a young female patient to death. Finally, we reported hepatic disorders, including a case of hepatocellular adenoma. In conclusion, MAS is a multisystemic disorder, with a variable combination of symptoms, and a broad range of severity. These uncommon abnormalities mostly occurred in patients with significant involvement of multiple other tissues.
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Affiliation(s)
- Solène Bergignat
- Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d’Endocrinologie Pédiatrique et Pédiatrie Générale, Bron, France
| | - Roland Chapurlat
- Faculté de Médecine Lyon-Est, Université Claude Bernard, Lyon, Lyon, France
- Hospices Civils de Lyon, Hôpital Edouard-Herriot, Service de rhumatologie, Lyon, France
- Centre National de Référence de la Dysplasie Fibreuse des Os, Hôpital E Herriot, Lyon, France
| | - Marc Nicolino
- Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d’Endocrinologie Pédiatrique et Pédiatrie Générale, Bron, France
- Faculté de Médecine Lyon-Est, Université Claude Bernard, Lyon, Lyon, France
| | - Kevin Perge
- Hospices Civils de Lyon, Hôpital Femme Mère Enfant, Service d’Endocrinologie Pédiatrique et Pédiatrie Générale, Bron, France
- Faculté de Médecine Lyon-Est, Université Claude Bernard, Lyon, Lyon, France
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Bouys L, Vaduva P, Jouinot A, Violon F, Vaczlavik A, Barat M, Charchar H, Chasseloup F, Kamilaris C, Espiard S, Haissaguerre M, Raverot G, Kroiss M, Berthon A, Perlemoine K, Tauveron I, Guignat L, Libé R, Groussin L, Assié G, Pasmant E, Reincke M, Borson-Chazot F, Ferrière A, Vantyghem MC, Stratakis CA, Kamenický P, Fragoso MCBV, Chansavang A, Ragazzon B, Bertherat J. KDM1A genetic alterations, a rare cause of primary bilateral macronodular adrenal hyperplasia, strongly associated with food-dependent Cushing's syndrome: results of its systematic germline screening in 301 index cases and genotype/phenotype correlation. Eur J Endocrinol 2025; 192:119-127. [PMID: 39921449 DOI: 10.1093/ejendo/lvaf016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 11/28/2024] [Accepted: 02/06/2025] [Indexed: 02/10/2025]
Abstract
OBJECTIVE ARMC5 is the most prevalent gene predisposing to primary bilateral macronodular adrenal hyperplasia (PBMAH), but germline KDM1A variants have been identified in the rare PBMAH associated with food-dependent Cushing's syndrome (FDCS). The purpose of this work was to assess the frequency of KDM1A variants in a large series of PBMAH patients. DESIGN A total of 301 consecutive PBMAH index cases from 8 international endocrinology departments were included. Clinical, biological, and imaging data were collected retrospectively. RESULTS Ten (3.3%) patients carried a germline KDM1A pathogenic or likely pathogenic variant, 60 (19.9%) carried a germline ARMC5 alteration, and 231 (76.8%) had no identified genetic predisposition. Food-dependent Cushing's syndrome was present in all patients with KDM1A variants and absent in the 2 other groups. KDM1A patients had a higher 24-h urinary free cortisol (3.0-fold upper limit of normal vs 1.36 for ARMC5 patients and 0.66 for wild-type patients, respectively, P = .0001). In accordance with FDCS pathophysiology, patients with KDM1A variants had a lower morning fasting plasma cortisol (192 nmol/L vs 407 and 428, respectively, P = .0003) and a higher midnight plasma cortisol (487 nmol/L vs 297 and 171.96, respectively, P = .0004). Morning/midnight plasma cortisol ratio below 0.65 holds 100% sensitivity and specificity for the detection of FDCS. All patients with KDM1A variants were women, vs 65% of ARMC5 patients and 67% of wild-type patients (P = .0337). CONCLUSIONS KDM1A germline pathogenic variants are rare in PBMAH and account for <5% of index cases. KDM1A seems constantly associated with FDCS, which can be evoked in front of a morning/midnight plasma cortisol ratio below 0.65.
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Affiliation(s)
- Lucas Bouys
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Patricia Vaduva
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Anne Jouinot
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Florian Violon
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
- Department of Pathology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Anna Vaczlavik
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Maxime Barat
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
- Department of Radiology, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Helaine Charchar
- Department of Endocrinology and Metabolism, University of São Paulo, 05403-010 São Paulo, Brazil
| | - Fanny Chasseloup
- Department of Endocrinology, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France
- Physiologie et Physiopathologie Endocriniennes, INSERM, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France
| | - Crystal Kamilaris
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892, United States
| | - Stéphanie Espiard
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, 59000 Lille, France
| | - Magalie Haissaguerre
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, 33600 Pessac, France
| | - Gérald Raverot
- Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
| | - Matthias Kroiss
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Annabel Berthon
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Karine Perlemoine
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Igor Tauveron
- Department of Endocrinology, CHU Clermont Ferrand, 63000 Clermont-Ferrand, France
| | - Laurence Guignat
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Rossella Libé
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Lionel Groussin
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Guillaume Assié
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Eric Pasmant
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
- Department of Genomic Medicine of Tumors and Cancers, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
| | - Françoise Borson-Chazot
- Department of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, 69500 Bron, France
| | - Amandine Ferrière
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Haut-Lévêque, CHU Bordeaux, 33600 Pessac, France
| | - Marie-Christine Vantyghem
- Department of Endocrinology, Diabetology, Metabolism and Nutrition, CHU Lille, Inserm U1190, 59000 Lille, France
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892, United States
- Institute of Molecular Biology and Biotechnology, FORTH & ELPEN, SA, 70013 Heraklion, Crete, Greece
| | - Peter Kamenický
- Department of Endocrinology, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, 94270 Le Kremlin-Bicêtre, France
- Physiologie et Physiopathologie Endocriniennes, INSERM, Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France
| | | | - Albain Chansavang
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
- Department of Genomic Medicine of Tumors and Cancers, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
| | - Bruno Ragazzon
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
| | - Jérôme Bertherat
- Department of Endocrinology and National Reference Center for Rare Adrenal Diseases, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France
- Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris-Cité, 75014 Paris, France
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Shen B, Fang Y, Dai Q, Xie Q, Wu W, Wang M. Whole Exome Sequencing as an Effective Molecular Diagnosis Tool for Craniofacial Fibrous Dysplasia with Ocular Complications. Curr Eye Res 2024; 49:996-1003. [PMID: 38708814 DOI: 10.1080/02713683.2024.2349634] [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: 03/19/2023] [Revised: 01/19/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE To summarize the clinical manifestations of craniofacial fibrous dysplasia (CFD) patients with ocular complications, and find effective methods to diagnose early. METHODS Nine CFD patients with ocular complications, and their parents were recruited in this study. All patients underwent ocular and systemic examinations. Bone lesions from all patients and peripheral blood from patients and their parents were collected for whole exome sequencing (WES). According to the screening for low-frequency deleterious variants, and bioinformatics variants prediction software, possible disease-causing variants were found in multiple CFD patients. The variants were validated by Sanger sequencing. Trio analysis was performed to verify the genetic patterns of CFD. RESULTS All patients were diagnosed with CFD, according to the clinical manifestations, classic radiographic appearance, and pathological biopsy. The main symptoms of the 9 CFD patients, included visual decline (9/9), craniofacial deformity (3/9) and strabismus (2/9), with few extraocular manifestations. The family backgrounds of all the CFD patients indicated that only the patient was affected, and their immediate family members were normal. GNAS variants were identified in all bone lesions from CFD patients, including two variant types: c.601C > T:p.R201C(6/9) and c.602G > A:p.R201H (3/9) in exon 8. The detection rate reached 100% by WES, but only 77.8% by Sanger sequencing. Interestingly, we found GNAS variants could not be detected in peripheral blood samples from CFD patients or their parents, and other potentially disease-causing gene variants related to CFD were not found. CONCLUSIONS For CFD patients with bone lesions involving the optic canal or sphenoid sinus regions, ocular symptoms should also be considered. Furthermore, we confirmed that CFD is not inherited, somatic variants in the GNAS gene are the main pathogenic gene causing CFD. Compared to the traditional methods in molecular genetic diagnosis of CFD, WES is more feasible and effective but limited in the type of samples.
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Affiliation(s)
- Bingyan Shen
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yenan Fang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Qin Dai
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Qiqi Xie
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wencan Wu
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Min Wang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
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Sigurðardóttir H, Ablondi M, Kristjansson T, Lindgren G, Eriksson S. Genetic diversity and signatures of selection in Icelandic horses and Exmoor ponies. BMC Genomics 2024; 25:772. [PMID: 39118059 PMCID: PMC11308356 DOI: 10.1186/s12864-024-10682-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND The Icelandic horse and Exmoor pony are ancient, native breeds, adapted to harsh environmental conditions and they have both undergone severe historic bottlenecks. However, in modern days, the selection pressures on these breeds differ substantially. The aim of this study was to assess genetic diversity in both breeds through expected (HE) and observed heterozygosity (HO) and effective population size (Ne). Furthermore, we aimed to identify runs of homozygosity (ROH) to estimate and compare genomic inbreeding and signatures of selection in the breeds. RESULTS HO was estimated at 0.34 and 0.33 in the Icelandic horse and Exmoor pony, respectively, aligning closely with HE of 0.34 for both breeds. Based on genomic data, the Ne for the last generation was calculated to be 125 individuals for Icelandic horses and 42 for Exmoor ponies. Genomic inbreeding coefficient (FROH) ranged from 0.08 to 0.20 for the Icelandic horse and 0.12 to 0.27 for the Exmoor pony, with the majority of inbreeding attributed to short ROHs in both breeds. Several ROH islands associated with performance were identified in the Icelandic horse, featuring target genes such as DMRT3, DOCK8, EDNRB, SLAIN1, and NEURL1. Shared ROH islands between both breeds were linked to metabolic processes (FOXO1), body size, and the immune system (CYRIB), while private ROH islands in Exmoor ponies were associated with coat colours (ASIP, TBX3, OCA2), immune system (LYG1, LYG2), and fertility (TEX14, SPO11, ADAM20). CONCLUSIONS Evaluations of genetic diversity and inbreeding reveal insights into the evolutionary trajectories of both breeds, highlighting the consequences of population bottlenecks. While the genetic diversity in the Icelandic horse is acceptable, a critically low genetic diversity was estimated for the Exmoor pony, which requires further validation. Identified signatures of selection highlight the differences in the use of the two breeds as well as their adaptive trait similarities. The results provide insight into genomic regions under selection pressure in a gaited performance horse breed and various adaptive traits in small-sized native horse breeds. This understanding contributes to preserving genetic diversity and population health in these equine populations.
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Affiliation(s)
- Heiðrún Sigurðardóttir
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden.
- Faculty of Agricultural Sciences, Agricultural University of Iceland, Hvanneyri, Borgarbyggð, 311, Iceland.
| | - Michela Ablondi
- Department of Veterinary Science, University of Parma, Parma, 43126, Italy
| | - Thorvaldur Kristjansson
- Faculty of Agricultural Sciences, Agricultural University of Iceland, Hvanneyri, Borgarbyggð, 311, Iceland
| | - Gabriella Lindgren
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden
- Center for Animal Breeding and Genetics, Department of Biosystems, KU Leuven, Leuven, 3001, Belgium
| | - Susanne Eriksson
- Department of Animal Biosciences, Swedish University of Agricultural Sciences, P.O. Box 7023, Uppsala, 75007, Sweden
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Li Z, Liu R, Liu P. McCune-Albright syndrome associated with pituitary adenoma: a clinicopathological study of ten cases and literature review. Br J Neurosurg 2024; 38:867-876. [PMID: 34632888 DOI: 10.1080/02688697.2021.1988512] [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: 12/13/2020] [Accepted: 09/28/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND McCune-Albright syndrome (MAS) is a rare genetic, non-inheritable disease and is characterized by fibrous dysplasia, hyperendocrinism, and café-au-lait macules. Pituitary adenomas could be concurrent with this syndrome but clinicopathological features and the surgical management of such disorders is unclear. METHODS We retrospectively reviewed ten MAS-associated pituitary adenoma patients with follow-up in Beijing Tiantan Hospital and analyzed their clinicohistological data, surgical strategies, neuro-imaging, genetic mutations, and prognosis. Moreover, a critical review of the English language literature was also conducted. RESULTS All of the ten MAS-associated adenoma patients underwent surgeries to remove the tumor (nine transsphenoidal approaches and one transcranial approach). None of these patients had a decompression of the optic canal. Notably, the growth hormone (GH), prolactin (PRL), and IGF-1 level had a significant reduction after the resection of the tumor while vision improvement was observed in most patients (6/7) with visual deficits. No tumor recurrence was observed during the follow-up from 16 to 150 months. The pathological examination showed a moderate Ki-67 LI (mean 1.19%, range from 0.1% to 3.3%) and the positive staining of Gsα and PKA C-beta. GNAS gene mutation (R201C) was detected in one patient. CONCLUSIONS Hormone excess (including GH and PRL) could be significantly reduced and the visual deficits are greatly improved after the surgery without the decompression of the optic canal. In addition, MAS-associated pituitary adenomas have a moderate expression of Ki-67 and positive expression of Gsα and PKA C-beta, indicating a mildly proliferative nature of these tumors and the possible linking between MAS and adenomas.
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Affiliation(s)
- Zhi Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Raynald Liu
- Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Pinan Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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McMillan KB, McMillan DC, Shariq O, Lohse C, Dy B, Lyden M, Arce K. Association of hyperparathyroidism and benign fibro-osseous jaw tumors: a 25-year retrospective study at Mayo Clinic. Oral Maxillofac Surg 2024; 28:723-728. [PMID: 37989891 DOI: 10.1007/s10006-023-01195-x] [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: 09/03/2023] [Accepted: 11/10/2023] [Indexed: 11/23/2023]
Abstract
PURPOSE The purpose of this study is to evaluate the association between hyperparathyroidism (PHPT), parathyroid hormone levels, and calcium levels in patients diagnosed with benign fibro-osseous lesions such as fibrous dysplasia (FD), ossifying fibroma (OF), central giant cell granulomas (GCG). METHODS This is a retrospective, single-center study from a sample of patients who underwent surgical treatment of FD, OF, and GCG at Mayo Clinic between 1996 and 2021. Patient demographics, history of PHPT, histopathological diagnosis, and relevant laboratory values such as parathyroid hormone (PTH), serum calcium, vitamin D, and alkaline phosphatase were collected. RESULTS Of the patients diagnosed with FD (n = 64), OF (n = 24), and GCG (n = 5), a diagnosis of PHPT was found in 2 patients (3.1%), 1 patient (4.2%), and 0 patients (0%), respectively. Elevated PTH levels (>65 pg/mL) were observed in 3 patients (4.7%) with FD, 1 patient (4.2%) with OF, and 1 patient (20%) with GCG. Mean (standard deviation) calcium levels were 9.3 (0.6) mg/dL in the FD group, 9.4 (0.5) mg/dL in the OF group, and 9.3 (0.6) mg/dL in the GCG group. Patients with fibro-osseous jaw tumors including FD, OF, and GCG may have increased risk of PHPT compared to the general population. CONCLUSION Patients with benign jaw tumors including FD, OF, and GCG may have increased risk of PHPT compared to the general population. Surgeons treating these benign tumors need to be cognizant of these findings, obtain appropriate laboratory studies, and incorporate multidisciplinary care including endocrinologists, endocrine surgeons, and maxillofacial surgeons.
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Affiliation(s)
- Kale B McMillan
- Division of Oral and Maxillofacial Surgery, Department of Surgery, Mayo Clinic and Mayo College of Medicine, Rochester, MN, USA.
| | - Dane C McMillan
- Division of Oral and Maxillofacial Surgery, Department of Surgery, Mayo Clinic and Mayo College of Medicine, Rochester, MN, USA
| | - Omair Shariq
- Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Christine Lohse
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Benzon Dy
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Melanie Lyden
- Division of Endocrine and Metabolic Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA
| | - Kevin Arce
- Division of Oral and Maxillofacial Surgery, Section of Head & Neck Oncologic Surgery and Reconstruction, Department of Surgery, Mayo Clinic and Mayo College of Medicine, Rochester, MN, USA
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9
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Ramírez-Rentería C, Hernández-Ramírez LC. Genetic diagnosis in acromegaly and gigantism: From research to clinical practice. Best Pract Res Clin Endocrinol Metab 2024; 38:101892. [PMID: 38521632 DOI: 10.1016/j.beem.2024.101892] [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] [Indexed: 03/25/2024]
Abstract
It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.
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Affiliation(s)
- Claudia Ramírez-Rentería
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Laura C Hernández-Ramírez
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México, e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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10
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Wittrien T, Ziegler A, Rühle A, Stomberg S, Meyer R, Bonneau D, Rodien P, Prunier-Mirebeau D, Coutant R, Behrends S. Heterozygous gain of function variant in GUCY1A2 may cause autonomous ovarian hyperfunction. Eur J Endocrinol 2024; 190:266-274. [PMID: 38578777 DOI: 10.1093/ejendo/lvae030] [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: 12/12/2023] [Revised: 03/01/2024] [Accepted: 03/07/2024] [Indexed: 04/07/2024]
Abstract
PURPOSE The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. METHODS An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/β1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. RESULTS The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. CONCLUSION Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.
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Affiliation(s)
- Theresa Wittrien
- Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, 38106 Braunschweig, Germany
| | - Alban Ziegler
- Department of Genetics, University Hospital of Angers, 49933 Angers, France
- Department of Genetics, CRMR AnDDI-Rares, University Hospital of Reims, 51092 Reims, France
| | - Anne Rühle
- Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, 38106 Braunschweig, Germany
| | - Svenja Stomberg
- Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, 38106 Braunschweig, Germany
| | - Ruben Meyer
- Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, 38106 Braunschweig, Germany
| | - Dominique Bonneau
- Department of Genetics, University Hospital of Angers, 49933 Angers, France
| | - Patrice Rodien
- Department of Endocrinology, Reference Center for Rare Thyroid and Hormone Receptor Diseases, University Hospital of Angers, 49933 Angers, France
| | - Delphine Prunier-Mirebeau
- Department of Biochemistry and Molecular Biology, University Hospital of Angers, 49933 Angers, France
| | - Régis Coutant
- Department of Pediatric Endocrinology, University Hospital, 49933 Angers, France
| | - Sönke Behrends
- Department of Pharmacology, Toxicology and Clinical Pharmacy, University of Braunschweig-Institute of Technology, 38106 Braunschweig, Germany
- Semmelweiss University Budapest, Asklepios Campus, 20099 Hamburg, Germany
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11
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Korkmaz I, Demirkilinc Biler E, Gokcen Simsek D, Palamar M. McCune-Albright Syndrome: Vision Loss and Strabismus as the Initial Symptoms in a Child. J Neuroophthalmol 2024; 44:e29-e31. [PMID: 36255094 DOI: 10.1097/wno.0000000000001729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Ilayda Korkmaz
- Departments of Ophthalmology (IK, EDB, MP) and Pediatric Endocrinology (DGS), Ege University, Izmir, Turkey
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12
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Wang H, Wang H, Liu H, Yang X, Meng Z, Cao Y. A young woman with atypical McCune-Albright syndrome and the difficult road to recovery: a case report. Front Surg 2024; 11:1326977. [PMID: 38371882 PMCID: PMC10869435 DOI: 10.3389/fsurg.2024.1326977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/22/2024] [Indexed: 02/20/2024] Open
Abstract
Background Fiber dysplasia is a complex condition that presents with various clinical manifestations, such as deformity, dysfunction, pathological fractures, and endocrine disorders. McCune-Albright syndrome (MAS) is a rare subtype of fiber dysplasia. This article reports a case of atypical McCune-Albright syndrome in a patient with a femoral neck fracture. Case presentation A patient with atypical McCune-Albright syndrome sustained a right femoral neck fracture and underwent multiple treatments, including total hip replacement, intravenous infusion of zoledronic acid, oral calcium supplementation, right supracondylar osteotomy, orthopedic surgery, plate and screw internal fixation for a left femoral shaft fracture, and removal of the right femoral plate. The patient also developed a submaxillary infection complicated by mandibular osteonecrosis. Conclusion Patients with MAS may experience rare complications as a result of their unique condition, regardless of whether they receive drug or surgical treatment. Therefore, personalized drug regimens and feasible surgical options are necessary.
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Affiliation(s)
| | | | | | | | | | - Yongping Cao
- Department of Orthopedics, Peking University First Hospital, Beijing, China
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13
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De Leo A, Ruscelli M, Maloberti T, Coluccelli S, Repaci A, de Biase D, Tallini G. Molecular pathology of endocrine gland tumors: genetic alterations and clinicopathologic relevance. Virchows Arch 2024; 484:289-319. [PMID: 38108848 PMCID: PMC10948534 DOI: 10.1007/s00428-023-03713-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 11/23/2023] [Accepted: 11/26/2023] [Indexed: 12/19/2023]
Abstract
Tumors of the endocrine glands are common. Knowledge of their molecular pathology has greatly advanced in the recent past. This review covers the main molecular alterations of tumors of the anterior pituitary, thyroid and parathyroid glands, adrenal cortex, and adrenal medulla and paraganglia. All endocrine gland tumors enjoy a robust correlation between genotype and phenotype. High-throughput molecular analysis demonstrates that endocrine gland tumors can be grouped into molecular groups that are relevant from both pathologic and clinical point of views. In this review, genetic alterations have been discussed and tabulated with respect to their molecular pathogenetic role and clinicopathologic implications, addressing the use of molecular biomarkers for the purpose of diagnosis and prognosis and predicting response to molecular therapy. Hereditary conditions that play a key role in determining predisposition to many types of endocrine tumors are also discussed.
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Affiliation(s)
- Antonio De Leo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Martina Ruscelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138, Bologna, Italy
| | - Thais Maloberti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Sara Coluccelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138, Bologna, Italy
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Andrea Repaci
- Division of Endocrinology and Diabetes Prevention and Care, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
| | - Dario de Biase
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Pharmacy and Biotechnology (FaBit), University of Bologna, 40126, Bologna, Italy
| | - Giovanni Tallini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138, Bologna, Italy.
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy.
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14
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Hatchett WJ, Brunetti M, Andersen K, Tandsæther MR, Lobmaier I, Lund-Iversen M, Lien-Dahl T, Micci F, Panagopoulos I. Genetic characterization of intramuscular myxomas. Pathol Oncol Res 2024; 30:1611553. [PMID: 38317844 PMCID: PMC10838995 DOI: 10.3389/pore.2024.1611553] [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: 10/16/2023] [Accepted: 01/10/2024] [Indexed: 02/07/2024]
Abstract
Introduction: Intramuscular myxomas are benign tumors that are challenging to diagnose, especially on core needle biopsies. Acquired chromosomal aberrations and pathogenic variants in codon 201 or codon 227 in GNAS complex locus gene (GNAS) have been reported in these tumors. Here we present our genetic findings in a series of 22 intramuscular myxomas. Materials and methods: The tumors were investigated for the presence of acquired chromosomal aberrations using G-banding and karyotyping. Pathogenic variants in codon 201 or codon 227 of GNAS were assessed using direct cycle Sanger sequencing and Ion AmpliSeq Cancer Hotspot Panel v2 methodologies. Results: Eleven tumors carried chromosomal abnormalities. Six tumors had numerical, four had structural, and one had both numerical and structural chromosomal aberrations. Gains of chromosomes 7 and 8 were the most common abnormalities being found in five and four tumors respectively. Pathogenic variants in GNAS were detected in 19 myxomas (86%) with both methodologies. The detected pathogenic variants were p.R201H in nine cases (seven with abnormal and two with normal karyotypes), p.R201C in five cases, all with normal karyotypes, p.R201S in three cases (two with abnormal and one with normal karyotype), p.R201G in one case with a normal karyotype, and p.Q227E in one case with a normal karyotype. Conclusion: Firstly, our data indicate a possible association between chromosomal abnormalities and GNAS pathogenic variants in intramuscular myxomas. Secondly, the presence of the rare pathogenic variants R201S, p.R201G and p.Q227E in 26% (5 out of 19) of myxomas with GNAS pathogenic variants shows that methodologies designed to detect only the common "hotspot" of p.R201C and p.R201H will give false negative results. Finally, a comparison between Ion AmpliSeq Cancer Hotspot Panel v2 and direct cycle Sanger sequencing showed that direct cycle Sanger sequencing provides a quick, reliable, and relatively cheap method to detect GNAS pathogenic variants, matching even the most cutting-edge sequencing methods.
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Affiliation(s)
- William John Hatchett
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Marta Brunetti
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kristin Andersen
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Maren Randi Tandsæther
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ingvild Lobmaier
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Marius Lund-Iversen
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Thomas Lien-Dahl
- Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Francesca Micci
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ioannis Panagopoulos
- Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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Perumal NL, Padidela R. Phosphate Homeostasis and Disorders of Phosphate Metabolism. Curr Pediatr Rev 2024; 20:412-425. [PMID: 36545737 DOI: 10.2174/1573396319666221221121350] [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: 03/23/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022]
Abstract
Phosphate is indispensable for human life and evolutionary changes over several millions of years have established tightly regulated mechanisms to ensure phosphate homeostasis. In this process, calcium and phosphate metabolism have come to be intricately linked together. Three hormones (PTH, FGF23 and Calcitriol) maintain the fine balance of calcium and phosphate metabolism through their actions at three sites (the gut, the kidneys and the skeleton). Disorders that disrupt this balance can have serious clinical consequences. Acute changes in serum phosphate levels can result in life threatening complications like respiratory failure and cardiac arrythmias. Chronic hypophosphataemia predominantly affects the musculoskeletal system and presents as impaired linear growth, rickets, osteomalacia and dental problems. Hyperphosphataemia is very common in the setting of chronic kidney disease and can be difficult to manage. A thorough understanding of calcium and phosphate homeostasis is essential to diagnose and treat conditions associated with hypo and hyperphosphataemia. In this review, we will discuss the calcium and phosphate metabolism, aetiologies and management of hypo and hyperphosphataemia.
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Affiliation(s)
| | - Raja Padidela
- Department of Endocrinology, Royal Manchester Children's Hospital, Manchester, United Kingdom
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16
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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17
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Torres-Morán M, Franco-Álvarez AL, Rebollar-Vega RG, Hernández-Ramírez LC. Hotspots of Somatic Genetic Variation in Pituitary Neuroendocrine Tumors. Cancers (Basel) 2023; 15:5685. [PMID: 38067388 PMCID: PMC10705109 DOI: 10.3390/cancers15235685] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 02/13/2025] Open
Abstract
The most common genetic drivers of pituitary neuroendocrine tumors (PitNETs) lie within mutational hotspots, which are genomic regions where variants tend to cluster. Some of these hotspot defects are unique to PitNETs, while others are associated with additional neoplasms. Hotspot variants in GNAS and USP8 are the most common genetic causes of acromegaly and Cushing's disease, respectively. Although it has been proposed that these genetic defects could define specific clinical phenotypes, results are highly variable among studies. In contrast, DICER1 hotspot variants are associated with a familial syndrome of cancer predisposition, and only exceptionally occur as somatic changes. A small number of non-USP8-driven corticotropinomas are due to somatic hotspot variants in USP48 or BRAF; the latter is a well-known mutational hotspot in cancer. Finally, somatic variants affecting a hotspot in SF3B1 have been associated with multiple cancers and, more recently, with prolactinomas. Since the associations of BRAF, USP48, and SF3B1 hotspot variants with PitNETs are very recent, their effects on clinical phenotypes are still unknown. Further research is required to fully define the role of these genetic defects as disease biomarkers and therapeutic targets.
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Affiliation(s)
| | | | | | - Laura C. Hernández-Ramírez
- Red de Apoyo a la Investigación, Coordinación de la Investigación Científica, Universidad Nacional Autónoma de México e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
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18
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Yang W, Zuo Y, Zhang N, Wang K, Zhang R, Chen Z, He Q. GNAS locus: bone related diseases and mouse models. Front Endocrinol (Lausanne) 2023; 14:1255864. [PMID: 37920253 PMCID: PMC10619756 DOI: 10.3389/fendo.2023.1255864] [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: 07/10/2023] [Accepted: 09/29/2023] [Indexed: 11/04/2023] Open
Abstract
GNASis a complex locus characterized by multiple transcripts and an imprinting effect. It orchestrates a variety of physiological processes via numerous signaling pathways. Human diseases associated with the GNAS gene encompass fibrous dysplasia (FD), Albright's Hereditary Osteodystrophy (AHO), parathyroid hormone(PTH) resistance, and Progressive Osseous Heteroplasia (POH), among others. To facilitate the study of the GNAS locus and its associated diseases, researchers have developed a range of mouse models. In this review, we will systematically explore the GNAS locus, its related signaling pathways, the bone diseases associated with it, and the mouse models pertinent to these bone diseases.
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Affiliation(s)
- Wan Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Yiyi Zuo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Nuo Zhang
- School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Kangning Wang
- School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Runze Zhang
- School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Ziyi Chen
- School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Qing He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
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19
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Fang W, Zhang Y, Chen L, Xie X. Neonatal cholestasis as the onset symptom of McCune-Albright syndrome: case reports and a literature review. Front Pediatr 2023; 11:1275162. [PMID: 37886236 PMCID: PMC10598585 DOI: 10.3389/fped.2023.1275162] [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: 08/09/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Aim This study aimed to summarize and show the characteristics and evolutionary process of neonatal cholestasis caused by McCune-Albright syndrome (MAS), as neonatal cholestasis may be the initial manifestation of MAS before other classic clinical features appear. Methods The clinical characteristics, treatment methods, and outcomes of three neonatal cholestasis cases caused by MAS in our center were retrospectively studied. In addition, all the reported cases of MAS combined with cholestasis were reviewed and summarized to show the cholestatic features in them. Results We have confirmed three MAS cases in our center, presenting onset symptoms of jaundice, pale stool, and neonatal cholestasis soon after birth. The cholestasis subsided spontaneously at around the sixth month. The literature review showed that the levels of total bilirubin, conjugated bilirubin, ALT, AST, and GGT in neonatal MAS cholestasis cases were 207 μmol/L (range 65-445 μmol/L), 162 μmol/L (range 46-412 μmol/L), 821 U/L (range 85-3,597 U/L), 532 U/L (range 127-3,633 U/L), and 244 U/L (range 79-3,800 U/L), respectively. Liver histology showed canalicular and hepatocellular cholestasis, giant hepatic cell transformation, and bile paucity. Extrahepatic manifestations such as café-au-lait pigmented skin lesions, Cushing's syndrome, hyperthyroidism, renal tubular dysfunction, and skeletal abnormalities could occur simultaneously when jaundice occurred. GNAS mutations had a high positive rate (83.3%-100%) in liver tissue with cholestasis. Neonatal cholestasis caused by MAS could be self-resolved, but hepatic lesions persist and have malignant potential. Conclusion MAS can be one of the causes of neonatal cholestasis, which may be the first manifestation of the disease. Extrahepatic coexisting symptoms of MAS and liver histology can help to distinguish MAS from other etiology of cholestasis. Detecting GNAS mutations in liver tissue may shorten diagnostic time and is of particular interest in the partial and atypical forms of MAS with neonatal cholestasis. Neonatal cholestasis in children with MAS can self-resolve, but liver dysfunction and malignant lesions persist.
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Affiliation(s)
- Weiyuan Fang
- Pediatric Liver Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Yanhui Zhang
- Infectious Disease Department, Qingdao Women and Children’s Hospital, Qingdao, China
| | - Lian Chen
- Department of Pathology, Children’s Hospital of Fudan University, Shanghai, China
| | - Xinbao Xie
- Pediatric Liver Center, Children’s Hospital of Fudan University, Shanghai, China
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20
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Mascioli I, Iapadre G, Ingrosso D, Donato GD, Giannini C, Salpietro V, Chiarelli F, Farello G. Brain and eye involvement in McCune-Albright Syndrome: clinical and translational insights. Front Endocrinol (Lausanne) 2023; 14:1092252. [PMID: 37274327 PMCID: PMC10235602 DOI: 10.3389/fendo.2023.1092252] [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: 03/01/2023] [Accepted: 05/10/2023] [Indexed: 06/06/2023] Open
Abstract
McCune-Albright Syndrome (MAS) is a rare mosaic (post-zygotic) genetic disorder presenting with a broad continuum clinical spectrum. MAS arises from somatic, activating mutations in the GNAS gene, which induces a dysregulated Gsα-protein signaling in several tissues and an increased production of intracellular cyclic adenosine monophosphate (cAMP). Overall, MAS is a rare disorder affecting less than 1/100,000 children and, for this reason, data establishing genotype-phenotype correlations remain limited. Affected individuals clinically present with a variable combination of fibrous dysplasia of bone (FD), extra-skeletal manifestations (including cafeí-au-lait spots) and precocious puberty which might also be associated to broad hyperfunctioning endocrinopathies, and also gastrointestinal and cardiological involvement. Central nervous system (CNS) and eye involvement in MAS are among the less frequently described complications and remain largely uncharacterized. These rare complications mainly include neurodevelopmental abnormalities (e.g., delayed motor development, cognitive and language impairment), CNS anomalies (e.g., Chiari malformation type I) and a wide array of ophthalmological abnormalities often associated with vision loss. The pathophysiological mechanisms underlying abnormal neurological development have not been yet fully elucidated. The proposed mechanisms include a deleterious impact of chronically dysregulated Gsα-protein signaling on neurological function, or a secondary (damaging) effect of (antenatal and/or early postnatal) hypercortisolism on early pre- and post-natal CNS development. In this Review, we summarize the main neurological and ophthalmological features eventually associated with the MAS spectrum, also providing a detailed overview of the potential pathophysiological mechanisms underlying these clinical complications.
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Affiliation(s)
- Ilaria Mascioli
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | - Giulia Iapadre
- Department of Pediatrics, University of L’Aquila, L’Aquila, Italy
| | | | - Giulio Di Donato
- Department of Pediatrics, University of L’Aquila, L’Aquila, Italy
| | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | | | | | - Giovanni Farello
- Department of Pediatrics, University of L’Aquila, L’Aquila, Italy
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21
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Nicolaides NC, Kontou M, Vasilakis IA, Binou M, Lykopoulou E, Kanaka-Gantenbein C. McCune-Albright Syndrome: A Case Report and Review of Literature. Int J Mol Sci 2023; 24:ijms24108464. [PMID: 37239810 DOI: 10.3390/ijms24108464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 04/18/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
McCune-Albright syndrome (MAS) is a rare sporadic condition defined by the classic triad of fibrous dysplasia of bone, café au lait skin macules, and hyperfunctioning endocrinopathies. The molecular basis of MAS has been ascribed to the post-zygotic somatic gain-of-function mutations in the GNAS gene, which encodes the alpha subunit of G proteins, leading to constitutive activation of several G Protein-Coupled Receptors (GPCRs). The co-occurrence of two of the above-mentioned cardinal clinical manifestations sets the diagnosis at the clinical level. In this case report, we describe a 27-month-old girl who presented with gonadotropin-independent precocious puberty secondary to an estrogen-secreting ovarian cyst, a café au lait skin macule and growth hormone, and prolactin excess, and we provide an updated review of the scientific literature on the clinical features, diagnostic work-up, and therapeutic management of MAS.
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Affiliation(s)
- Nicolas C Nicolaides
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
- Reference Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
| | - Maria Kontou
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
| | - Ioannis-Anargyros Vasilakis
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
- Reference Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
| | - Maria Binou
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
- Reference Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
| | - Evangelia Lykopoulou
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
| | - Christina Kanaka-Gantenbein
- First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
- Reference Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, 11527 Athens, Greece
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22
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Roszko KL, Guthrie L, Li X, Collins MT, de Castro LF, Boyce AM. Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome. J Bone Miner Res 2023; 38:443-450. [PMID: 36593655 DOI: 10.1002/jbmr.4766] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/20/2022] [Accepted: 12/29/2022] [Indexed: 01/04/2023]
Abstract
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
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Affiliation(s)
- Kelly L Roszko
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Lori Guthrie
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Xiaobai Li
- Biostatistics and Clinical Epidemiology Service, NIH Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Michael T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Luis F de Castro
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
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23
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Xing Z, Tao G, Pan W, Wu D, Pan T, Wan L, Ma X, Wang Y. Case report: Surgical treatment of McCune-Albright syndrome with hyperthyroidism and retrosternal goiter: A case report and literature review. Front Surg 2023; 9:921427. [PMID: 36684307 PMCID: PMC9852710 DOI: 10.3389/fsurg.2022.921427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 11/28/2022] [Indexed: 01/07/2023] Open
Abstract
Introduction McCune-Albright syndrome (MAS) is a low-incidence syndrome consisting of the clinical triad of fibrous structural dysplasia of bone, endocrine disease, and skin pigmentation. Thyroid dysfunction is the second most common endocrine dysregulation in MAS. However, there are no treatment guidelines for MAS complicated with hyperthyroidism. Notably, no case of MAS complicated with retrosternal goiter and hyperthyroidism has been reported to our knowledge. Case presentation We report a 27-year-old man with MAS who developed the typical triad of bone fibrous dysplasia, skin pigmentation and hyperthyroidism, complaining of recent fast-growing neck mass and difficulty in breathing. Hyperthyrodism was under control by Thiamazole, and computed tomography showed an enlarged thyroid extending retrosternally. We performed a total thyroidectomy on the patient. At the 1-year follow-up, the patient's dyspnea, hyperthyroidism, and bone pain were all significantly alleviated. Review We searched the literature for previous case reports concerning MAS patients complicated with thyroid dysregulation. A total of 17 articles and 22 patients were identified to form our database. Among them, 9 studies clearly mentioned surgical intervention in 11 patients, and prognoses were also reported. Surgery was the most common intervention chosen and indicated a satisfactory prognosis. Conclusion We report a rare case of MAS patient complicated with retrosternal goiter and hyperthyroidism. Our review provides an overview of MAS cases requiring interventions on thyroid function, and total thyroidectomy should be a proper treatment for these patients.
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Affiliation(s)
- Zhiwei Xing
- Graduate School, Wannan Medical College, Wuhu, China,Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Gongshuai Tao
- Graduate School, Wannan Medical College, Wuhu, China,Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Wanwan Pan
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Delin Wu
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Tingting Pan
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Lingfeng Wan
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaopeng Ma
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China,Correspondence: Xiaopeng Ma Yangyi Wang
| | - Yangyi Wang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China,Correspondence: Xiaopeng Ma Yangyi Wang
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24
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Bertherat J, Bourdeau I, Bouys L, Chasseloup F, Kamenicky P, Lacroix A. Clinical, pathophysiologic, genetic and therapeutic progress in Primary Bilateral Macronodular Adrenal Hyperplasia. Endocr Rev 2022:6957368. [PMID: 36548967 DOI: 10.1210/endrev/bnac034] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 10/07/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022]
Abstract
Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome, but may represent up to one third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G-protein coupled receptors aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation, led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20-25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by GIP-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over or down-regulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and co-morbidities assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses taking in account co-morbidities. It previously relied on bilateral adrenalectomy; however recent studies tend to favor unilateral adrenalectomy, or less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.
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Affiliation(s)
- Jerôme Bertherat
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Cochin Hospital, Assistance Publique Hôpitaux de Paris, 24 rue du Fg St Jacques, Paris 75014, France
| | - Isabelle Bourdeau
- Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
| | - Lucas Bouys
- Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Cochin Hospital, Assistance Publique Hôpitaux de Paris, 24 rue du Fg St Jacques, Paris 75014, France
| | - Fanny Chasseloup
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, 94276 Le Kremlin-Bicêtre, France
| | - Peter Kamenicky
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, 94276 Le Kremlin-Bicêtre, France
| | - André Lacroix
- Division of Endocrinology, Department of Medicine and Research Center, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada
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25
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Abstract
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.
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Affiliation(s)
- Xinming Liu
- Department of Endocrinology and Metabolism, The First Hospital of Jilin
University, Changchun, China
| | - Siwen Zhang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin
University, Changchun, China
| | - Yunran Guo
- Department of Endocrinology and Metabolism, The First Hospital of Jilin
University, Changchun, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin
University, Changchun, China
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin
University, Changchun, China
- Correspondence Dr. Guixia Wang The First Hospital of Jilin
UniversityDepartment of Endocrinology and
MetabolismNO.1 Xinmin
Street130021
ChangchunChina+86 431
8878-2078+86 431 8878-6066
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26
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Xue J, Jia K, Li T, Zhang J, An J. GNAS mutation analysis assists in differentiating chronic diffuse sclerosing osteomyelitis from fibrous dysplasia in the jaw. Mod Pathol 2022; 35:1334-1340. [PMID: 35672467 DOI: 10.1038/s41379-022-01103-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/23/2022] [Accepted: 05/03/2022] [Indexed: 11/10/2022]
Abstract
Chronic diffuse sclerosing osteomyelitis of the mandible (DSOM) and fibrous dysplasia (FD) are distinct lesions with overlapping clinicopathological features that complicate their diagnosis. This study aimed to evaluate the efficacy of GNAS mutation analysis in differentiating between these two conditions. DNA samples from patients with DSOM (n = 35) and FD (n = 29) were collected to analyze the presence of GNAS mutations in exons 8 and 9, the two previously reported hotspot regions, using polymerase chain reaction and direct sequencing. Twenty-four of 29 patients (83%) with FD showed missense mutations in codon 201 in exon 8, whereas no mutation was detected in exon 9. No mutations were found in any of the 35 cases with DSOM. We also identified one case with an uncertain diagnosis due to overlapping clinicopathological features of DSOM and FD. A Q227H mutation was detected in this case, that confirmed the diagnosis of FD. Taken together, the findings indicate that mutational analysis of the GNAS is a reliable approach to differentiate between DSOM and FD of the jaw.
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Affiliation(s)
- Jiang Xue
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Avenue Zhongguancun, Haidian District, Beijing, 100081, PR China.,National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, PR China.,Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, 100081, PR China
| | - Kuankuan Jia
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, PR China.,Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 South Avenue Zhongguancun, Haidian District, Beijing, 100081, PR China
| | - Tiejun Li
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Avenue Zhongguancun, Haidian District, Beijing, 100081, PR China.,National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, PR China.,Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, 100081, PR China
| | - Jianyun Zhang
- Department of Oral Pathology, Peking University School and Hospital of Stomatology, 22 South Avenue Zhongguancun, Haidian District, Beijing, 100081, PR China. .,National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, PR China. .,Research Unit of Precision Pathologic Diagnosis in Tumors of the Oral and Maxillofacial Regions, Chinese Academy of Medical Sciences (2019RU034), Beijing, 100081, PR China.
| | - Jingang An
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, PR China. .,Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 South Avenue Zhongguancun, Haidian District, Beijing, 100081, PR China.
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27
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Costa-Barbosa FA, Giorgi RB, Kater CE. Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized? ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2022; 66:895-907. [PMID: 35929903 PMCID: PMC10118774 DOI: 10.20945/2359-3997000000507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.
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28
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McCune-Albright Syndrome in Infant with Growth Hormone Excess. Genes (Basel) 2022; 13:genes13081345. [PMID: 36011254 PMCID: PMC9407244 DOI: 10.3390/genes13081345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/20/2022] [Accepted: 07/23/2022] [Indexed: 12/10/2022] Open
Abstract
Background: McCune-Albright is a rare syndrome, caused by mutation of the GNAS1 gene, and is characterized by an appearance of multiple endocrinopathies, most commonly premature puberty, polyostotic fibrous dysplasia and skin changes called cafe au lait macules. Case report: We present the case of a patient who is, to the best of our knowledge and after extensive review of literature, the youngest McCune-Albright syndrome patient with growth hormone excess, diagnosed at 8.9 months of age. An extensive diagnostic procedure was done upon the diagnosis. Hormonal assessment was performed and all hormone levels were within reference range, and an additional oral glucose suppression that noted the presence of growth hormone excess. Magnetic resonance imaging of the pituitary gland did not detect a tumor process. The genetic analysis of the GNAS1 gene from skin punch biopsy came back negative. Octreotide was administered as therapy for growth hormone excess at 9.8 months. After the introduction of therapy, we noted a decrease in growth rate from 29.38 to 16.6 cm/year. Conclusion: This case report emphasizes the lack of available data on treatment of growth hormone excess and follow-up in pediatric population and the need for further research.
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29
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Barakizou H, Gannouni S, Kamoun T, Mehdi M, Amary F, Huma Z, Todeschini AL, Veitia R, Donaldson M. Precocious Pseudo-puberty in a Two-year-old Girl, Presenting with Bilateral Ovarian Enlargement and Progressing to Unilateral Juvenile Granulosa Cell Tumour. J Clin Res Pediatr Endocrinol 2022; 14:107-113. [PMID: 33849266 PMCID: PMC8900080 DOI: 10.4274/jcrpe.galenos.2021.2021.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Ovarian causes of precocious pseudo-puberty (PPP) include McCune-Albright syndrome (MAS) and juvenile granulosa cell tumour (JGCT). We describe a case of PPP in which bilateral ovarian enlargement with multiple cysts progressed to unilateral JGCT. A girl aged 2.17 years presented with three months of breast development, and rapid growth. Examination showed tall stature, height +2.6 standard deviations, Tanner stage B3P2A1. A single café au lait patch was noted. Bone age was advanced at 5 years. Pelvic ultrasound showed bilaterally enlarged ovaries (estimated volumes 76 mL on the left, 139 mL on the right), each containing multiple cysts. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) values before/after gonadotrophin administration were 0.43/0.18 and <0.1/<0.1 mUI/mL, serum estradiol 130 pg/mL, (prepubertal range <20 pg/mL). PPP of ovarian origin was diagnosed, and tamoxifen 20 mg daily started. However, after only seven weeks height velocity escalated and breast development increased to B3-4 with menorrhagia. Basal/stimulated LH and FSH were still suppressed at 0.13/0.25 and <0.1/<0.1 mUI/mL and, serum estradiol 184 pg/mL. Repeat imaging now showed normal right ovary (volume 1.8 mL) and a large left-sided vascular solid/cystic ovarian tumour which was excised (weight 850 g). Histology showed JGCT, International Federation of Gynecology and Obstetrics stage IA. DNA from tumour tissue showed no mutation in GNAS, exon 3 of AKT1 (which contains a mutational hotspot) or FOXL2. The observation that bilateral ovarian activity progressed to unilateral development of JGCT in this patient is novel. This case highlights current uncertainties in the ontology of JGCT, and its possible relationship with MAS.
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Affiliation(s)
- Hager Barakizou
- Military Hospital of Tunis, Clinic of Pediatric, Tunis, Tunisia
| | - Souha Gannouni
- Military Hospital of Tunis, Clinic of Pediatric, Tunis, Tunisia
| | - Thouraya Kamoun
- Centre Hospitalo-Universitaire, Department of Pediatric, Sfax, Tunisia
| | - Muhammed Mehdi
- Glan Clwyd Hospital, Clinic of Pathology, Rhyl, United Kingdom
| | - Fernanda Amary
- Royal National Orthopaedic Hospital, London, United Kingdom
| | - Zilla Huma
- Royal National Orthopaedic Hospital, London, United Kingdom
| | - Anne-Laure Todeschini
- Université Paris-Saclay, Institut de Biologie François Jacob, Gif-sur-Yvette, France
| | - Reiner Veitia
- Université Paris-Saclay, Institut de Biologie François Jacob, Gif-sur-Yvette, France
| | - Malcolm Donaldson
- Glasgow University School of Medicine, Glasgow, United Kingdom,* Address for Correspondence: Section of Child Health, Royal Hospital for Children, Glasgow, United Kingdom Phone: +44 141 4515841 E-mail:
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30
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Shi D, Motamed M, Mejía-Benítez A, Li L, Lin E, Budhram D, Kaur Y, Meyre D. Genetic syndromes with diabetes: A systematic review. Obes Rev 2021; 22:e13303. [PMID: 34268868 DOI: 10.1111/obr.13303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 01/19/2023]
Abstract
Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.
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Affiliation(s)
- Daniel Shi
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Mehras Motamed
- Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Aurora Mejía-Benítez
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Leon Li
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ethan Lin
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dalton Budhram
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Yuvreet Kaur
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, France.,Faculty of Medicine of Nancy INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, France
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Marks BE, Sugrue R, Bourgeois W, Frazier AL, Voss SD, Laufer MR, Gordon CM, Cohen LE. Juvenile Granulosa Cell Tumor as the Presenting Feature of McCune-Albright Syndrome. J Endocr Soc 2021; 5:bvab098. [PMID: 34286167 PMCID: PMC8282215 DOI: 10.1210/jendso/bvab098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Indexed: 12/01/2022] Open
Abstract
Introduction GNAS mutations have been reported in both McCune-Albright syndrome (MAS) and juvenile granulosa cell tumors (JGCT) but have never been reported simultaneously in the same patient. Case Presentation A 15-year-old girl developed secondary oligomenorrhea. Laboratory studies revealed suppressed gonadotropin levels with markedly elevated estradiol and inhibin B levels. Pelvic ultrasound showed a 12-cm heterogeneous right adnexal mass; pelvic magnetic resonance imaging to further characterize the mass displayed heterogeneous bilateral femoral bone lesions initially concerning for metastatic disease. Positron emission tomography/computed tomography showed minimal 18F-fluorodeoxyglucose (FDG) uptake in the pelvic mass but unexpectedly revealed FDG uptake throughout the skeleton, concerning for polyostotic fibrous dysplasia in the context of MAS. The adnexal mass was excised and pathology confirmed a JGCT. The patient’s affected bone and JGCT tissue revealed the same pathogenic GNAS p.R201C mutation, while her peripheral blood contained wild-type arginine at codon 201. Conclusion This mutation has been previously reported in cases of MAS and JGCT but never simultaneously in the same patient. This demonstration of a GNAS mutation underlying both JGCT and MAS in the same patient raises questions about appropriate surveillance for patients with these conditions.
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Affiliation(s)
- Brynn E Marks
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.,Division of Endocrinology, Children's National Hospital, Washington, DC, USA
| | - Ronan Sugrue
- Division of Gynecology, Boston Children's Hospital, Boston, MA, USA
| | - Wallace Bourgeois
- Cancer and Blood Disorders Center, Dana-Farber/Boston Children's, Boston, MA, USA
| | - A Lindsay Frazier
- Cancer and Blood Disorders Center, Dana-Farber/Boston Children's, Boston, MA, USA
| | - Stephan D Voss
- Department of Radiology, Boston Children's Hospital, Boston, MA, USA
| | - Marc R Laufer
- Division of Gynecology, Boston Children's Hospital, Boston, MA, USA
| | - Catherine M Gordon
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.,Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Laurie E Cohen
- Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.,Cancer and Blood Disorders Center, Dana-Farber/Boston Children's, Boston, MA, USA
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32
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Exertional pain in the thigh: test yourself question and answer. Skeletal Radiol 2021; 50:1047-1049. [PMID: 33123742 DOI: 10.1007/s00256-020-03571-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Zhadina M, Roszko KL, Geels RES, de Castro LF, Collins MT, Boyce AM. Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome. J Clin Endocrinol Metab 2021; 106:1482-1490. [PMID: 33512531 PMCID: PMC8522305 DOI: 10.1210/clinem/dgab053] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Indexed: 02/07/2023]
Abstract
CONTEXT Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood. OBJECTIVE This work aimed 1) to determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort. METHODS This retrospective cross-sectional analysis measured the correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data. RESULTS Sixty-one individuals were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two patients (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the 2 groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a nonsignificant association of cancer with the R201H variant. CONCLUSION There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for the future development of targeted therapies.
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Affiliation(s)
- Maria Zhadina
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kelly L Roszko
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Raya E S Geels
- Department of Medicine, Division of Endocrinology, Centre for Bone Quality, Leiden University Medical Centre, ZA Leiden, the Netherlands
| | - Luis F de Castro
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Michael T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Alison M Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland , USA
- Correspondence: Alison Boyce, MD, Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, 30 Convent Dr, Bldg 30, Rm 228, MSC 4320, Bethesda, MD 20892, USA.
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Satomura Y, Bessho K, Kitaoka T, Takeyari S, Ohata Y, Kubota T, Ozono K. Neonatal cholestasis can be the first symptom of McCune–Albright syndrome: A case report. World J Clin Pediatr 2021; 10:7-14. [PMID: 33758748 PMCID: PMC7958557 DOI: 10.5409/wjcp.v10.i2.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/22/2021] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND McCune–Albright syndrome (MAS) is caused by postzygotic somatic mutations of the GNAS gene. It is characterized by the clinical triad of fibrous dysplasia, café-au-lait skin spots, and endocrinological dysfunction. Myriad complications in MAS, including hepatobiliary manifestations, are also reported.
CASE SUMMARY This is a case of a 4-year-old boy who presented with MAS with neonatal cholestasis. He was suspected to have Alagille syndrome due to neonatal cholestasis with intrahepatic bile duct paucity in liver biopsy, peripheral pulmonary artery stenosis, and renal tubular dysfunction. By the age of 2 years, his cholestatic liver injury gradually improved, but he had repeated left femoral fractures. He did not exhibit endocrinological abnormality or café-au-lait skin spots. However, MAS was suspected due to fibrous dysplasia at the age of 4 years. No mutation was identified in the GNAS gene in the DNA isolated from the peripheral blood, but an activating point mutation (c.601C>T, p.Arg201Cys) was observed in the DNA extracted from the affected bone tissue and that extracted from the formalin-fixed paraffin-embedded liver tissue, which was obtained at the age of 1 mo.
CONCLUSION MAS should be considered as a differential diagnosis for transient cholestasis in infancy.
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Affiliation(s)
- Yoshinori Satomura
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Kazuhiko Bessho
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Taichi Kitaoka
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Shinji Takeyari
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yasuhisa Ohata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Takuo Kubota
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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35
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Rosenfield RL, Cooke DW, Radovick S. Puberty in the Female and Its Disorders. SPERLING PEDIATRIC ENDOCRINOLOGY 2021:528-626. [DOI: 10.1016/b978-0-323-62520-3.00016-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Jia K, Li X, An J, Zhang Y. Comparing Clinical and Radiographic Characteristics of Chronic Diffuse Sclerosing Osteomyelitis and Craniofacial Fibrous Dysplasia in the Mandible. J Oral Maxillofac Surg 2020; 79:1053-1061. [PMID: 33345814 DOI: 10.1016/j.joms.2020.11.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 11/17/2020] [Accepted: 11/17/2020] [Indexed: 01/19/2023]
Abstract
PURPOSE Differential diagnosis of chronic diffuse sclerosing osteomyelitis of the mandible (DSOM) and craniofacial fibrous dysplasia (CFD) involving the mandible is challenging. The purpose of this study was to explore the differences of the clinical and radiographic characteristics between these 2 conditions. PATIENTS AND METHODS In this retrospective cross-sectional, blinded, comparative study, clinical and imaging data of patients with DSOM and CFD at the Peking University Hospital of Stomatology from 2012 to 2018 were retrieved. Clinical characteristics, mainly pain, swelling, and trismus, and radiographic findings, including sclerosis, lysis, and subperiosteal bone formation, were evaluated. The t test, χ2 test, and Fisher-Freeman-Halton test were used to determine differences. RESULTS Thirty-seven patients with DSOM and 32 patients with CFD were included (mean ages, 24.2 and 28.4 years, respectively); both groups showed a female predilection. DSOM (91.9%) and CFD (84.4%) were mainly unilateral. Patients with DSOM mainly presented with pain (94.6%), soft-tissue swelling (100.0%), and trismus (54.1%), whereas those with CFD did not experience pain (90.6%) and showed bone enlargement (87.5%) without trismus (6.3%). Panoramic radiographs and computed tomography scans of patients with DSOM showed subperiosteal bone formation, cortex lysis, and poorly demarcated cortex, whereas those patients with CFD mainly showed moderate-to-severe bone expansion, well-demarcated cortex, and tooth and mandibular canal displacement. CONCLUSIONS These findings emphasize the importance of clinical and radiographic features in differentiating between DSOM and CFD. Pain, soft-tissue or bone-tissue swelling, subperiosteal bone formation, clarity of the boundary of the cortex and medulla, and continuity of the cortical bone are key points facilitating differentiation.
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Affiliation(s)
- Kuankuan Jia
- Resident, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Xiaoli Li
- Resident, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Jingang An
- Associate Professor, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.
| | - Yi Zhang
- Professor, Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
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37
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Sweeney K, Kaban LB. Natural History and Progression of Craniofacial Fibrous Dysplasia: A Retrospective Evaluation of 114 Patients From Massachusetts General Hospital. J Oral Maxillofac Surg 2020; 78:1966-1980. [DOI: 10.1016/j.joms.2020.05.036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/23/2020] [Accepted: 05/23/2020] [Indexed: 12/16/2022]
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38
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Dejkhamron P, Ittiwut C, TangNgam H, Sunkonkit K, Natesirinilkul R, Suphapeetiporn K, Shotelersuk V. A Novel GNAS Mutation Causing Isolated Infantile Cushing's Syndrome. Horm Res Paediatr 2020; 92:196-202. [PMID: 31362300 DOI: 10.1159/000501169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 05/26/2019] [Indexed: 01/30/2023] Open
Abstract
Infantile Cushing's syndrome is potentially found as part of McCune-Albright syndrome (MAS) which is caused by postzygotic somatic mutations of the GNAS gene. MAS is typically characterized by a triad of polyostotic fibrous dysplasia, café-au-lait skin pigmentation, and precocious puberty or other endocrine hyperfunction. Here, we describe a 2-month-old female infant with features of Cushing's syndrome without café au lait spots, polyostotic fibrous dysplasia, and clinical evidence of other endocrine hyperfunction. Investigations demonstrated adrenocorticotropic hormone-independent Cushing's syndrome with bilateral adrenal gland enlargement. Whole-exome sequencing of leukocytes identified a de novo heterozygous novel missense mutation (c.521G>A, p.Cys174Tyr) in the GNAS gene. The patient experienced clinical improvement of Cushing's syndrome during ketoconazole treatment. Her clinical course was complicated by Pneumocystis jiroveci pneumonia. She also had shortened activated partial thromboplastin time indicating a hypercoagulable state and resulting in pulmonary embolism. She eventually manifested gonadotropin-independent precocious puberty at the age of 13 months after ketoco-nazole was discontinued. This patient demonstrated that Cushing syndrome can be the presenting sign of MAS in infancy. A high index of suspicion followed by genetic analysis is essential in order to establish a diagnosis.
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Affiliation(s)
- Prapai Dejkhamron
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Chupong Ittiwut
- Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
| | | | - Kanokkarn Sunkonkit
- Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | | | - Kanya Suphapeetiporn
- Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand, .,Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand,
| | - Vorasuk Shotelersuk
- Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
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39
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de Castro LF, Ovejero D, Boyce AM. DIAGNOSIS OF ENDOCRINE DISEASE: Mosaic disorders of FGF23 excess: Fibrous dysplasia/McCune-Albright syndrome and cutaneous skeletal hypophosphatemia syndrome. Eur J Endocrinol 2020; 182:R83-R99. [PMID: 32069220 PMCID: PMC7104564 DOI: 10.1530/eje-19-0969] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/17/2020] [Indexed: 12/11/2022]
Abstract
Fibrous dysplasia/McCune-Albright Syndrome (FD/MAS), arising from gain-of-function mutations in Gαs, and cutaneous skeletal hypophosphatemia syndrome (CSHS), arising from gain-of-function mutations in the Ras/MAPK pathway, are strikingly complex, mosaic diseases with overlapping phenotypes. Both disorders are defined by mosaic skin and bone involvement, and both are complicated by increased FGF23 production. These similarities have frequently led to mis-diagnoses, primarily in patients with CSHS who are often assumed to have FD/MAS. The intriguing similarities in skeletal involvement in these genetically distinct disorders have led to novel insights into FGF23 physiology, making an understanding of FD/MAS and CSHS relevant to both clinicians and researchers interested in bone and endocrine disorders. This review will give an overview of FD/MAS and CSHS, focusing on the roles of mosaicism and FGF23 in the pathogenesis and clinical presentation of these disorders.
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Affiliation(s)
- Luis F de Castro
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Diana Ovejero
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
- Musculoskeletal Research Unit, Hospital del Mar Institute of Medical Investigation (IMIM), Barcelona, Spain
- National Research Council, Institute of Clinical Physiology, Lecce, Italy
| | - Alison M Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
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40
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Daussac A, Barat P, Servant N, Yacoub M, Missonier S, Lavran F, Gaspari L, Sultan C, Paris F. Testotoxicosis without Testicular Mass: Revealed by Peripheral Precocious Puberty and Confirmed by Somatic LHCGR Gene Mutation. Endocr Res 2020; 45:32-40. [PMID: 31394950 DOI: 10.1080/07435800.2019.1645163] [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] [Indexed: 10/26/2022]
Abstract
Purpose: Testotoxicosis is an autosomal dominant form of limited gonadotropin-independent precocious puberty in boys. It is caused by a heterozygous constitutively activating mutation of the LHCGR gene encoding the luteinizing/hormone receptor (LHR). Some twenty mutations of the LHCGR gene have been reported. Most of them are constitutive mutations isolated from blood leukocyte DNA, although others are somatic, found only in testicular tumoural tissue. In all the previously reported cases of these somatic mutations, the tumour, whether a nodular Leydig cell adenoma or hyperplasia, was easily visible on testicular ultrasonography. The aim of this study was to describe an unusual presentation of a patient with the clinical and hormonal characteristics of testotoxicosis but no well-circumscribed lesion at testicular ultrasonography.Materials and Methods: Molecular analysis of the LHCGR gene was performed by direct sequencing of DNA extracted from peripheral leucocytes and testicular biopsy.Results: Molecular analysis didn't find any LHR mutation in blood, whereas it revealed for the first time a somatic D578H mutation in testicular tissue despite no evidence of a nodular aspect at testis ultrasonography.Conclusions: This observation underlines the need to look for a somatic LHCGR gene mutation from the testicular biopsies of all boys with testotoxicosis with no constitutive LHCGR gene mutation identified from blood DNA, even in the absence of circumscribed testicular lesion at ultrasonography. In addition, based on the known link between LHR mutations and testicular tumourigenesis, yearly ultrasound monitoring of the testes should be considered for these patients.
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Affiliation(s)
- A Daussac
- Département de Pédiatrie, Endocrinologie Pédiatrique, CHU de Bordeaux, Bordeaux, France
| | - P Barat
- Département de Pédiatrie, Endocrinologie Pédiatrique, CHU de Bordeaux, Bordeaux, France
- Département de Pédiatrie, Centre d'Investigation Clinique (CIC 0005), CHU de Bordeaux, Bordeaux, France
| | - N Servant
- Département d'Hormonologie (Développement et Reproduction), CHU de Montpellier, Hôpital Lapeyronie, Université de Montpellier, Montpellier, France
| | - M Yacoub
- Unité d'Anatomo cytopathologie, CHU de Bordeaux, Bordeaux, France
| | - S Missonier
- Unité de Radiologie pédiatrique, CHU de Bordeaux, Bordeaux, France
| | - F Lavran
- Unité de Chirurgie viscérale pédiatrique, CHU de Bordeaux, Bordeaux, France
| | - L Gaspari
- Unité d'Endocrinologie-Gynécologie Pédiatriques, Département de Pédiatrie, CHU de Montpellier, Hôpital Arnaud de Villeneuve, Université Montpellier 1, Montpellier, France
| | - C Sultan
- Département d'Hormonologie (Développement et Reproduction), CHU de Montpellier, Hôpital Lapeyronie, Université de Montpellier, Montpellier, France
- Unité d'Endocrinologie-Gynécologie Pédiatriques, Département de Pédiatrie, CHU de Montpellier, Hôpital Arnaud de Villeneuve, Université Montpellier 1, Montpellier, France
| | - F Paris
- Département d'Hormonologie (Développement et Reproduction), CHU de Montpellier, Hôpital Lapeyronie, Université de Montpellier, Montpellier, France
- Unité d'Endocrinologie-Gynécologie Pédiatriques, Département de Pédiatrie, CHU de Montpellier, Hôpital Arnaud de Villeneuve, Université Montpellier 1, Montpellier, France
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Tufano M, Ciofi D, Amendolea A, Stagi S. Auxological and Endocrinological Features in Children With McCune Albright Syndrome: A Review. Front Endocrinol (Lausanne) 2020; 11:522. [PMID: 32849305 PMCID: PMC7417367 DOI: 10.3389/fendo.2020.00522] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 06/26/2020] [Indexed: 01/09/2023] Open
Abstract
McCune-Albright syndrome is a rare and challenging congenital sporadic disease involving the skin and skeletal and endocrine systems with a prevalence ranges from one in 100,000 to 1,000,000. In addition to the classical triad of fibrous dysplasia of bone, café au lait pigmented skin lesions and precocious puberty, other multiple endocrinological features, including hyperthyroidism, growth hormone excess, hypercortisolism, and hypophosphatemic rickets, have been reported. A brief review of the syndrome in children is here reported.
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Affiliation(s)
- Maria Tufano
- Pediatric Unit, Mugello Hospital, Borgo San Lorenzo, Florence, Italy
| | - Daniele Ciofi
- Health Sciences Department, University of Florence, Anna Meyer Children's University Hospital, Florence, Italy
| | | | - Stefano Stagi
- Health Sciences Department, University of Florence, Anna Meyer Children's University Hospital, Florence, Italy
- *Correspondence: Stefano Stagi
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42
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McNulty SN, Evenson MJ, Corliss MM, Love-Gregory LD, Schroeder MC, Cao Y, Lee YS, Drolet BA, Neidich JA, Cottrell CE, Heusel JW. Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort. Am J Hum Genet 2019; 105:734-746. [PMID: 31585106 DOI: 10.1016/j.ajhg.2019.09.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/27/2019] [Indexed: 01/01/2023] Open
Abstract
Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
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Elli FM, de Sanctis L, Bergallo M, Maffini MA, Pirelli A, Galliano I, Bordogna P, Arosio M, Mantovani G. Improved Molecular Diagnosis of McCune-Albright Syndrome and Bone Fibrous Dysplasia by Digital PCR. Front Genet 2019; 10:862. [PMID: 31620168 PMCID: PMC6760069 DOI: 10.3389/fgene.2019.00862] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 08/19/2019] [Indexed: 12/26/2022] Open
Abstract
McCune-Albright syndrome (MAS) is a rare congenital disorder characterized by the association of endocrine and nonendocrine anomalies caused by somatic activating variants of GNAS. The mosaic state of variants makes the clinical presentation extremely heterogeneous depending on involved tissues. Biological samples bearing a low level of mosaicism frequently lead to false-negative results with an underestimation of causative molecular alterations, and the analysis of biopsies is often needed to obtain a molecular diagnosis. To date, no reliable analytical method for the noninvasive testing of blood is available. This study was aimed at validating a novel and highly sensitive technique, the digital PCR (dPCR), to increase the detection rate of GNAS alterations in patients with a clinical suspicion of MAS and, in particular, in blood. We screened different tissues (blood, bone, cutis, ovary, and ovarian cyst) collected from 54 MAS patients by different technical approaches. Considering blood, Sanger was unable to detect mutations, the allele-specific PCR and the co-amplification at lower denaturation temperature had a 9.1% and 18.1% detection rate, respectively, whereas the dPCR reached a 37.8% detection rate. In conclusion, the dPCR resulted in a cost-effective, reliable, and rapid method allowing the selective amplification of low-frequency variants and able to improve GNAS mutant allele detection, especially in the blood.
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Affiliation(s)
- Francesca Marta Elli
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Luisa de Sanctis
- Department of Public Health and Pediatric Sciences, University of Torino, Regina Margherita Children's Hospital-AOU Cittàdella Salute e dellaScienza, Torino, Italy
| | - Massimiliano Bergallo
- Department of Public Health and Pediatric Sciences, University of Torino, Regina Margherita Children's Hospital-AOU Cittàdella Salute e dellaScienza, Torino, Italy
| | - Maria Antonia Maffini
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Arianna Pirelli
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Ilaria Galliano
- Department of Public Health and Pediatric Sciences, University of Torino, Regina Margherita Children's Hospital-AOU Cittàdella Salute e dellaScienza, Torino, Italy
| | - Paolo Bordogna
- Endocrinology Unit, Fondazione IRCCS Ca' GrandaOspedale Maggiore Policlinico, Milan, Italy
| | - Maura Arosio
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.,Endocrinology Unit, Fondazione IRCCS Ca' GrandaOspedale Maggiore Policlinico, Milan, Italy
| | - Giovanna Mantovani
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.,Endocrinology Unit, Fondazione IRCCS Ca' GrandaOspedale Maggiore Policlinico, Milan, Italy
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Javaid MK, Boyce A, Appelman-Dijkstra N, Ong J, Defabianis P, Offiah A, Arundel P, Shaw N, Pos VD, Underhil A, Portero D, Heral L, Heegaard AM, Masi L, Monsell F, Stanton R, Dijkstra PDS, Brandi ML, Chapurlat R, Hamdy NAT, Collins MT. Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis 2019; 14:139. [PMID: 31196103 PMCID: PMC6567644 DOI: 10.1186/s13023-019-1102-9] [Citation(s) in RCA: 143] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 05/21/2019] [Indexed: 02/07/2023] Open
Abstract
Fibrous Dysplasia / McCune Albright syndrome (FD/MAS) represents a wide spectrum of diseases due to somatic gain-of-function mutations of the GNAS gene. The mutation leads to overactivity in the target tissues and to a wide phenotype of clinical features that vary in severity and age of onset. The rarity of the disease and its variable presentation to multiple specialities often leads to misdiagnosis and inappropriate variability in investigations and treatments. To address this, our international consortium of clinicians, researchers, and patients’ advocates has developed pragmatic clinical guidelines for best clinical practice for the definition, diagnosis, staging, treatment and monitoring for FD/MAS to empower patients and support clinical teams in both general and specialised healthcare settings. With the lack of strong evidence to inform care, the guidelines were developed based on review of published literature, long-standing extensive experience of authors, input from other healthcare professionals involved in the care of FD/MAS patients and feedback from patients and patient groups across the globe. This has led to the formulation of a set of statements to inform healthcare professionals, patients, their families, carers and patient groups of the best practice of care. It is anticipated the implementation of these recommendations will lead to improvement in the care of patients with FD/MAS internationally.
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Affiliation(s)
- Muhammad Kassim Javaid
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
| | - Alison Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
| | - Natasha Appelman-Dijkstra
- Department of Medicine, Division of Endocrinology & Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Juling Ong
- Department of Plastic Surgery, Craniofacial Centre, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | | | - Amaka Offiah
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Paul Arundel
- Metabolic Bone Team, Sheffield Children's Hospital, Sheffield, UK
| | - Nick Shaw
- Endocrine Department, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Valter Dal Pos
- European Association of Friends of McCune-Albright Syndrome (TO), Turino, Italy
| | - Ann Underhil
- Fibrous Dysplasia Support Society, Birmingham, UK
| | | | - Lisa Heral
- Fibrous Dysplasia Foundation, Grandville, USA
| | - Anne-Marie Heegaard
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Laura Masi
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Fergal Monsell
- Paediatric Orthopaedic and Trauma Surgery, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Robert Stanton
- Department of Orthopaedic Surgery, Nemours Children's Hospital, Orlando, Florida, USA
| | | | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | | | - Neveen Agnes Therese Hamdy
- Department of Medicine, Division of Endocrinology & Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Terrence Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, Bethesda, MD, USA
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Traversari M, Serrangeli MC, Catalano G, Petrella E, Piciucchi S, Feletti F, Oxilia G, Cristiani E, Vazzana A, Sorrentino R, De Fanti S, Luiselli D, Calcagnile L, Saragoni L, Feeney RNM, Gruppioni G, Cilli E, Benazzi S. Multi-analytic study of a probable case of fibrous dysplasia (FD) from certosa monumental cemetery (Bologna, Italy). INTERNATIONAL JOURNAL OF PALEOPATHOLOGY 2019; 25:1-8. [PMID: 30913508 DOI: 10.1016/j.ijpp.2019.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 03/08/2019] [Accepted: 03/08/2019] [Indexed: 06/09/2023]
Abstract
OBJECTIVE To evaluate, via a multidisciplinary approach, a distinctive paleopathological condition believed to be fibrous dysplasia, found on a 19th/20th century skeleton from Certosa Monumental Cemetery, Bologna, Italy. MATERIALS A skeletonized cranium and mandible recovered from an ossuary in 2014. METHODS Pathological alterations were analysed by radiological examination, dental macrowear, histopathological and genetic analyses. RESULT The skeleton is believed to be an adult male. Differential diagnoses include Paget's disease, McCune-Albright syndrome, osteochondroma and osteosarcoma. The radiographic findings, along with the solitary nature of the lesions, are strong evidence for the diagnosis of fibrous dysplasia (FD). Genetic analysis further revealed a frequency of ˜1% of mutant alleles with the R201C substitution, one of the post-zygotic activating mutation frequently associated with FD. CONCLUSIONS The multi-analytical method employed suggests a diagnosis of monostotic form of FD. The diagnostic design incorporates multiple lines of evidence, including macroscopic, histopathological, and genetic analyses. SIGNIFICANCE Through the use of a multi-analytic approach, robust diagnoses can be offered. This case serves as one of the oldest examples of FD from an historical context. The genetic mutation detected, associated with FD, has not been previously reported in historical/ancient samples.
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Affiliation(s)
- Mirko Traversari
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy.
| | - Maria Cristina Serrangeli
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy; UCD School of Medicine, Health Science Centre, University College Dublin, Belfield, Dublin 4, Ireland
| | - Giulio Catalano
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Enrico Petrella
- Department of Radiology, AUSL Romagna, Morgagni-Pierantoni city hospital, via Carlo Forlanini 34, 47121, Forlì, Italy
| | - Sara Piciucchi
- Department of Radiology, AUSL Romagna, Morgagni-Pierantoni city hospital, via Carlo Forlanini 34, 47121, Forlì, Italy
| | - Francesco Feletti
- Department of Diagnostic Imaging Ausl Romagna, Santa Maria delle Croci Hospital, Viale Randi, 5, 48121 Ravenna, Italy
| | - Gregorio Oxilia
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Emanuela Cristiani
- Department of Oral and Maxillofacial Sciences, School of Dentistry, Sapienza University of Rome, Via Caserta, 6, 00161 Rome
| | - Antonino Vazzana
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Rita Sorrentino
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy; Department of Biological, Geological and Environmental Sciences, University of Bologna, via Selmi 3, Bologna, Italy
| | - Sara De Fanti
- Department of Biological, Geological and Environmental Sciences, University of Bologna, via Selmi 3, Bologna, Italy
| | - Donata Luiselli
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Lucio Calcagnile
- CEDAD - CEnter for DAting and Diagnostics Department of Mathematics and Physics "Ennio De Giorgi", University of Salento and INFN-National Institute for Nuclear Physics, Via Monteroni, 73100, Lecce, Italy
| | - Luca Saragoni
- Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni city hospital, via Carlo Forlanini 34, 47121, Forlì, Italy
| | - Robin N M Feeney
- UCD School of Medicine, Health Science Centre, University College Dublin, Belfield, Dublin 4, Ireland
| | - Giorgio Gruppioni
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Elisabetta Cilli
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy
| | - Stefano Benazzi
- Department of Cultural Heritage, University of Bologna, via degli Ariani 1, 48121, Ravenna, Italy; Department of Human Evolution, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, 04103, Leipzig, Germany
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46
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Hartley I, Zhadina M, Collins MT, Boyce AM. Fibrous Dysplasia of Bone and McCune-Albright Syndrome: A Bench to Bedside Review. Calcif Tissue Int 2019; 104:517-529. [PMID: 31037426 PMCID: PMC6541017 DOI: 10.1007/s00223-019-00550-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
Abstract
Fibrous dysplasia is an uncommon mosaic disorder in which bone is replaced by structurally unsound fibro-osseous tissue. It is caused by the sporadic post-zygotic activating mutations in GNAS, resulting in dysregulated GαS-protein signaling in affected tissues. This manifests on a broad clinical spectrum ranging from insignificant solitary lesions to severe disease with deformities, fractures, functional impairment, and pain. Fibrous dysplasia may present in isolation or in association with hyperfunctioning endocrinopathies and café-au-lait macules, known as McCune-Albright Syndrome. This review summarizes the current understanding of pathophysiology in fibrous dysplasia, describes key pre-clinical and clinical investigations, and details the current approach to diagnosis and management.
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Affiliation(s)
- Iris Hartley
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30 Room 228 MSC 4320, Bethesda, MD, 20892, USA
- Interinstitute Endocrine Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Maria Zhadina
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30 Room 228 MSC 4320, Bethesda, MD, 20892, USA
- Pediatric Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA
| | - Micheal T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30 Room 228 MSC 4320, Bethesda, MD, 20892, USA
| | - Alison M Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30 Room 228 MSC 4320, Bethesda, MD, 20892, USA.
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Coles N, Comeau I, Munoz T, Harrington J, Mendoza-Londono R, Schulze A, Kives S, Kamath BM, Hamilton J. Severe Neonatal Cholestasis as an Early Presentation of McCune-Albright Syndrome. J Clin Res Pediatr Endocrinol 2019; 11:100-103. [PMID: 29991465 PMCID: PMC6398189 DOI: 10.4274/jcrpe.galenos.2018.2018.0110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
McCune-Albright syndrome (MAS) is a rare genetic disorder characterized by café-au-lait macules, polyostotic fibrous dysplasia and multiple endocrinopathies. Liver involvement, although described, is a rare complication. We review the case of a child with MAS whose initial presentation was characterized by severe neonatal cholestasis. The case demonstrates a severe phenotype of persistent cholestasis in MAS requiring liver transplantation. This phenotype has been previously considered to be a more benign feature. This case highlights the importance of consideration of MAS as an uncommon but important cause of neonatal cholestasis. Early diagnosis may allow for prompt recognition and treatment of other endocrinopathies.
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Affiliation(s)
- Nicole Coles
- University of Toronto, Hospital for Sick Children, Clinic of Endocrinology, Toronto, Canada
| | - Ian Comeau
- Montreal Children’s Hospital, Clinic of Adolescent Medicine and Paediatric Gynaecology, Montreal, Canada
| | - Tatiana Munoz
- University of Toronto, Hospital for Sick Children, Clinic of Clinical and Metabolic Genetics, Toronto, Canada
| | - Jennifer Harrington
- University of Toronto, Hospital for Sick Children, Clinic of Endocrinology, Toronto, Canada
| | - Roberto Mendoza-Londono
- University of Toronto, Hospital for Sick Children, Clinic of Clinical and Metabolic Genetics, Toronto, Canada
| | - Andreas Schulze
- University of Toronto, Hospital for Sick Children, Clinic of Clinical and Metabolic Genetics, Toronto, Canada
| | - Sari Kives
- University of Toronto, Hospital for Sick Children, Clinic of Paediatric Gynaecology, Toronto, Canada
| | - Binita M. Kamath
- University of Toronto, Hospital for Sick Children, Clinic of Gastroenterology, Hepatology and Nutrition, Toronto, Canada
| | - Jill Hamilton
- University of Toronto, Hospital for Sick Children, Clinic of Endocrinology, Toronto, Canada,* Address for Correspondence: University of Toronto, Hospital for Sick Children, Clinic of Endocrinology, Toronto, Canada Phone: +4168135115 E-mail:
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Pepe S, Korbonits M, Iacovazzo D. Germline and mosaic mutations causing pituitary tumours: genetic and molecular aspects. J Endocrinol 2019; 240:R21-R45. [PMID: 30530903 DOI: 10.1530/joe-18-0446] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 11/07/2018] [Indexed: 12/24/2022]
Abstract
While 95% of pituitary adenomas arise sporadically without a known inheritable predisposing mutation, in about 5% of the cases they can arise in a familial setting, either isolated (familial isolated pituitary adenoma or FIPA) or as part of a syndrome. FIPA is caused, in 15-30% of all kindreds, by inactivating mutations in the AIP gene, encoding a co-chaperone with a vast array of interacting partners and causing most commonly growth hormone excess. While the mechanisms linking AIP with pituitary tumorigenesis have not been fully understood, they are likely to involve several pathways, including the cAMP-dependent protein kinase A pathway via defective G inhibitory protein signalling or altered interaction with phosphodiesterases. The cAMP pathway is also affected by other conditions predisposing to pituitary tumours, including X-linked acrogigantism caused by duplications of the GPR101 gene, encoding an orphan G stimulatory protein-coupled receptor. Activating mosaic mutations in the GNAS gene, coding for the Gα stimulatory protein, cause McCune-Albright syndrome, while inactivating mutations in the regulatory type 1α subunit of protein kinase A represent the most frequent genetic cause of Carney complex, a syndromic condition with multi-organ manifestations also involving the pituitary gland. In this review, we discuss the genetic and molecular aspects of isolated and syndromic familial pituitary adenomas due to germline or mosaic mutations, including those secondary to AIP and GPR101 mutations, multiple endocrine neoplasia type 1 and 4, Carney complex, McCune-Albright syndrome, DICER1 syndrome and mutations in the SDHx genes underlying the association of familial paragangliomas and phaeochromocytomas with pituitary adenomas.
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Affiliation(s)
- Sara Pepe
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
- Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Donato Iacovazzo
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
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Romanet P, Philibert P, Fina F, Cuny T, Roche C, Ouafik L, Paris F, Reynaud R, Barlier A. Using Digital Droplet Polymerase Chain Reaction to Detect the Mosaic GNAS Mutations in Whole Blood DNA or Circulating Cell-Free DNA in Fibrous Dysplasia and McCune-Albright Syndrome. J Pediatr 2019; 205:281-285.e4. [PMID: 30442414 DOI: 10.1016/j.jpeds.2018.09.070] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/10/2018] [Accepted: 09/28/2018] [Indexed: 12/21/2022]
Abstract
The GNAS postzygotic mosaic activating mutations involved in fibrous dysplasia and McCune-Albright syndrome (MAS) are not detectable in leukocytes by Sanger sequencing. Digital droplet polymerase chain reaction detects GNAS mutations in 7 of 12 patients (58.3%) suspected to have fibrous dysplasia/MAS from whole blood DNA, and in 4 of 5 patients (80%) from circulating cell-free DNA.
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Affiliation(s)
- Pauline Romanet
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital de la Conception, Laboratory of Molecular Biology, Marseille, France.
| | - Pascal Philibert
- Département de Biochimie et Hormonologie, Hôpital Lapeyronie, CHU Montpellier and Institut de Génétique Humaine, UMR 9002 CNRS-Université de Montpellier, France
| | - Frédéric Fina
- APHM, Unit of Technology Development, Laboratory of Medical Biology, Marseille, France
| | - Thomas Cuny
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital de la Conception, Department of Endocrinology APHM, Marseille, France
| | - Catherine Roche
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital de la Conception, Laboratory of Molecular Biology, Marseille, France
| | - L'houcine Ouafik
- Marseille Univ, APHM, CNRS, INP UMR7259, Department of Biologic Oncology, Marseille, France
| | - Françoise Paris
- CHU Montpellier, Molecular Biology Department, Montpellier; endocrinologie pédiatrique CHU Arnaud de Villeneuve Montpellier, France
| | - Rachel Reynaud
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital La Timone Enfants, Pediatric Department, Marseille, France
| | - Anne Barlier
- Aix Marseille Univ, APHM, INSERM, MMG, Hôpital de la Conception, Laboratory of Molecular Biology, Marseille, France
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Sakaguchi C, Ashida K, Kohashi K, Ohe K, Fujii Y, Yano S, Matsuda Y, Sakamoto S, Sakamoto R, Oda Y, Nomura M, Ogawa Y. A case of autonomous cortisol secretion in a patient with subclinical Cushing's syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone. BMC Endocr Disord 2019; 19:13. [PMID: 30670014 PMCID: PMC6343241 DOI: 10.1186/s12902-019-0345-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 01/16/2019] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Increased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing's syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS). CASE PRESENTATION A 65-year-old woman was diagnosed with subclinical Cushing's syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated. CONCLUSIONS This patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing's syndrome.
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Affiliation(s)
- Chihiro Sakaguchi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenji Ashida
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume-city, Fukuoka, 830-0011 Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenji Ohe
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
| | - Yoichi Fujii
- Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seiichi Yano
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yayoi Matsuda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Sakamoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryuichi Sakamoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Nomura
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume-city, Fukuoka, 830-0011 Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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