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Bhattacharya S, Fernandez CJ, Kamrul-Hasan ABM, Pappachan JM. Monogenic diabetes: An evidence-based clinical approach. World J Diabetes 2025; 16:104787. [DOI: 10.4239/wjd.v16.i5.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/11/2025] [Indexed: 04/25/2025] Open
Abstract
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. GCK-MODY, a common subtype, manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy. In contrast, mutations in HNF4A, HNF1A, and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel (KCNJ11 or ABCC8) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
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Affiliation(s)
| | - Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
| | | | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, Greater Manchester, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
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Świeca A, Franaszczyk M, Maryniak A, Lipiński P, Płoski R, Szczałuba K. Maternal Uniparental Isodisomy of Chromosome 6: A Novel Case of Teratoma and Autism Spectrum Disorder with a Diagnostic and Management Framework. Genes (Basel) 2025; 16:434. [PMID: 40282394 PMCID: PMC12026494 DOI: 10.3390/genes16040434] [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: 02/24/2025] [Revised: 03/28/2025] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Uniparental disomy (UPD) is the inheritance of both copies of a chromosome from a single parent, leading to distinct genetic conditions. Maternal UPD of chromosome 6 (UPD(6)mat) is extremely rare, with few molecularly confirmed cases reported. METHODS We report a prematurely born female with isodisomic UPD(6)mat, presenting with intrauterine growth restriction (IUGR), developmental delay, autism spectrum disorder, dysmorphic features, and a sacrococcygeal teratoma. In addition, we reviewed 24 confirmed UPD(6)mat cases to assess clinical patterns in prenatal findings, birth outcomes, and postnatal features. RESULTS Trio whole-exome sequencing revealed complete isodisomy of chromosome 6 and a de novo heterozygous DIAPH2 variant of uncertain significance. In the literature review, IUGR was present in 87% of cases, with most individuals born small for gestational age and preterm. Failure to thrive and neurodevelopmental issues were also frequent. While the exact molecular basis remains unknown, imprinting disturbances-similar to those in UPD(6)pat-and cryptic trisomy 6 mosaicism, particularly in heterodisomy, are the most likely mechanisms. No specific gene or consistent epigenetic abnormality has been identified. CONCLUSIONS This study aims to enhance the understanding of the genetic and phenotypic spectrum of UPD(6)mat, improving diagnostic and management approaches for this ultra-rare genetic disorder. We propose a detailed list of clinical assessments and tests to be performed following the detection of maternal uniparental disomy of chromosome 6.
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Affiliation(s)
- Aleksandra Świeca
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland
| | - Maria Franaszczyk
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland
| | | | - Patryk Lipiński
- Institute of Clinical Sciences, Maria Skłodowska-Curie Medical Academy, 00-136 Warsaw, Poland
- Department of Pediatrics, Bielański Hospital, 01-809 Warsaw, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland
| | - Krzysztof Szczałuba
- Department of Medical Genetics, Medical University of Warsaw, 02-106 Warsaw, Poland
- Center of Excellence for Rare and Undiagnosed Disorders, Medical University of Warsaw, 02-106 Warsaw, Poland
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McCullough ME, Letourneau-Freiberg LR, Bowden TL, Kandasamy B, Ray A, Wroblewski K, del Gaudio D, Mackay DJG, Philipson LH, Greeley SAW. Clinical Characteristics and Remission Monitoring of 6q24-Related Transient Neonatal Diabetes. Pediatr Diabetes 2024; 2024:3624339. [PMID: 40302951 PMCID: PMC12020819 DOI: 10.1155/pedi/3624339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/24/2024] [Accepted: 11/09/2024] [Indexed: 05/02/2025] Open
Abstract
Introduction: Transient neonatal diabetes mellitus (TNDM) is a heterogeneous subtype of neonatal diabetes that usually presents within the first days or weeks of life, spontaneously remits in infancy, but can recur in childhood or adolescence as a permanent form of diabetes. Approximately 70% of TNDM cases are due to overexpression of genes at chromosome 6q24 (6q24-TNDM) caused by one of three potential mechanisms: paternal uniparental disomy (pUPD6), paternal duplication, or hypomethylation of the maternal allele. Our aim was to further elucidate the clinical characteristics of a relatively large group of individuals with this rare condition. Methods: Participants with a genetically confirmed diagnosis of 6q24-TNDM were identified through the University of Chicago Monogenic Diabetes Registry. Some participants had testing done on a clinical basis, with the remainder having received research-based genetic testing. Clinical information was extracted from survey responses and medical records. Results: There were 33 participants with 6q24-TNDM (58% were male). Eight (24%) had hypomethylation of the maternal allele, seven (21%) had paternal duplication, 17 (52%) had pUPD6, and one individual had 6q24 hypomethylation of unknown etiology. The median age of initial diabetes presentation was 2 days (n = 33). Remission occurred at a median age of 3 months (n = 28). The median age of relapse was 14 years (range 12-31 years, n = 9). The majority (71%) of participants were born small for gestational age and 32% of participants were born before 37 weeks gestation. The most common extra-pancreatic features were umbilical hernia (22%, n = 6/27), macroglossia (56%, n = 15/27), and speech pathologies (36%, n = 10/28). No significant differences in clinical characteristics were identified across the three genetic etiologies (pUPD6, paternal duplication, maternal hypomethylation). Conclusions: Clinical characteristics were not different across underlying genetic mechanism groups, suggesting that genetic testing is required to definitively determine the mechanism and diagnosis of 6q24-TNDM. Clarification of the specific underlying mechanism is strongly encouraged to clarify recurrence risk, but whether these subcategories may have other clinically relevant differences remains to be elucidated. Early assessment for speech therapy should be considered for this patient population. We recommend that patients in remission be equipped to check blood glucose levels as needed, such as during illness, and should continue seeing a diabetes provider at least occasionally, especially around the time of puberty and thereafter.
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Affiliation(s)
- Michael E. McCullough
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | - Lisa R. Letourneau-Freiberg
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | - Tiana L. Bowden
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | - Balamurugan Kandasamy
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | - Angela Ray
- Department of Hospital Medicine, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Kristen Wroblewski
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois, USA
| | - Daniela del Gaudio
- Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
| | | | - Louis H. Philipson
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | - Siri Atma W. Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
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Hassan D, Allen DB, Chen M. Successful Transition to Sulfonylurea for Relapsed Monogenic Diabetes Due to Rare 6q23.3 Duplication. JCEM CASE REPORTS 2024; 2:luae180. [PMID: 39416272 PMCID: PMC11482010 DOI: 10.1210/jcemcr/luae180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Indexed: 10/19/2024]
Abstract
Transient neonatal diabetes mellitus (TNDM) due to 6q duplication usually presents in the first 4 months of life, resolves before 18 months of life, and recurs in adolescence or adulthood. Insulin is the first-line treatment for chromosome 6-related neonatal diabetes in infancy. While there is no ideal treatment for patients with relapsed TNDM, residual β-cell function after remission of neonatal diabetes indicates a potential role for insulin secretagogues. Patients with 6q24 duplication have been successfully transitioned from insulin to sulfonylureas (SUs) in adolescence. We present the first report to our knowledge of TNDM secondary to a rare 6q23.3 duplication for which reemergence of diabetes was successfully transitioned from insulin to SU treatment. The successful transition to SU improved glycemic control, cost-effectiveness, and overall quality of life, while decreasing occurrence of hypoglycemia.
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Affiliation(s)
- Doha Hassan
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA
| | - David B Allen
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA
| | - Melinda Chen
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA
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Serbis A, Kantza E, Siomou E, Galli-Tsinopoulou A, Kanaka-Gantenbein C, Tigas S. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes. Int J Mol Sci 2024; 25:10501. [PMID: 39408828 PMCID: PMC11476815 DOI: 10.3390/ijms251910501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Evanthia Kantza
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Ekaterini Siomou
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Diabetes and Metabolism and Aghia Sophia ENDO-ERN Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, Medical School, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stelios Tigas
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
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Emfietzoglou R, Muscogiuri G, Tsilingiris D, Kounatidis D, Stratigou T, Vallianou N, Karampela I, Basdra EK, Dalamaga M. Macroglossia in endocrine and metabolic disorders: current evidence, perspectives and challenges. Minerva Endocrinol (Torino) 2024; 49:335-350. [PMID: 39081187 DOI: 10.23736/s2724-6507.24.04219-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2024]
Abstract
Macroglossia is an uncommon condition characterized by chronic, painless and abnormal enlargement of the tongue. A multitude of medical conditions can cause macroglossia. Major endocrine and metabolic disorders associated with macroglossia include genetic, congenital and acquired conditions, such as mucopolysaccharidoses; acquired and congenital hypothyroidism and myxedema; transient neonatal diabetes mellitus; acromegaly and amyloidosis. Macroglossia is often associated (~57-60%) with all types of mucopolysaccharidoses, particularly type I (Hurler syndrome) and type II (Hunter syndrome), being a prominent feature of the disorder. It may also occur in patients with acquired and congenital hypothyroidism and myxedema, being a common sign of congenital hypothyroidism with an approximate prevalence of 12-25% at the time of diagnosis. Macroglossia is a predominant oral finding in subjects with transient neonatal diabetes mellitus (~44%), acromegaly (54-69%) and amyloidosis (10-25%), particularly AL amyloidosis (20-40%) whereas is considered a hallmark of the disease. Secondary to macroglossia various disturbances may occur, such as difficulty in speech or eating, orthodontic anomalies or even more serious conditions including upper airway obstruction or obstructive sleep apnea. Until now, no comprehensive review has been conducted focusing on macroglossia in endocrine and metabolic disorders. The objective of this review is to summarize literature on the etiology and epidemiology of macroglossia in major endocrine and metabolic disorders. It highlights key aspects such as pathophysiology, clinical presentation, diagnostic evaluation, management and prognosis of macroglossia in the context of endocrine and metabolic disorders.
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Affiliation(s)
- Rodopi Emfietzoglou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Private Dental Practice, Voula Attikis, Greece
| | - Giovanna Muscogiuri
- Unit of Endocrinology, Diabetology, and Andrology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Centro Italiano per la Cura e il Benessere del Paziente con Obesità (C.I.B.O.), Unit of Endocrinology, Diabetology, and Andrology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Cattedra Unesco "Educazione alla Salute e allo Sviluppo Sostenibile", University of Naples Federico II, Naples, Italy
| | - Dimitrios Tsilingiris
- Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitrios Kounatidis
- Second Department of Internal Medicine, Hippokration General Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodora Stratigou
- Department of Endocrinology, Evangelismos General Hospital, Athens, Greece
| | - Natalia Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, Athens, Greece
| | - Irene Karampela
- Second Department of Critical Care, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Efthimia K Basdra
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece -
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Mackay DJG, Gazdagh G, Monk D, Brioude F, Giabicani E, Krzyzewska IM, Kalish JM, Maas SM, Kagami M, Beygo J, Kahre T, Tenorio-Castano J, Ambrozaitytė L, Burnytė B, Cerrato F, Davies JH, Ferrero GB, Fjodorova O, Manero-Azua A, Pereda A, Russo S, Tannorella P, Temple KI, Õunap K, Riccio A, de Nanclares GP, Maher ER, Lapunzina P, Netchine I, Eggermann T, Bliek J, Tümer Z. Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis. Clin Epigenetics 2024; 16:99. [PMID: 39090763 PMCID: PMC11295890 DOI: 10.1186/s13148-024-01713-y] [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: 04/25/2024] [Accepted: 07/24/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. METHODS A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. RESULTS In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. CONCLUSIONS MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.
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Affiliation(s)
| | - Gabriella Gazdagh
- Faculty of Medicine, University of Southampton, Southampton, UK
- Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK
| | - David Monk
- Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK
| | - Frederic Brioude
- Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
| | - Eloise Giabicani
- Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
| | - Izabela M Krzyzewska
- Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jennifer M Kalish
- Division of Human Genetics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
- Departments of Pediatrics and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Saskia M Maas
- Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Masayo Kagami
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Jasmin Beygo
- Institut Für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Tiina Kahre
- Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
- Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
| | - Jair Tenorio-Castano
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
- Institute of Medical and Molecular Genetics, INGEMM-Idipaz, Madrid, Spain
| | - Laima Ambrozaitytė
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Birutė Burnytė
- Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Flavia Cerrato
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy
| | - Justin H Davies
- Faculty of Medicine, University of Southampton, Southampton, UK
- Regional Centre for Paediatric Endocrinology, Faculty of Medicine, Southampton Children's Hospital, University of Southampton, Southampton, UK
| | - Giovanni Battista Ferrero
- Department of Clinical and Biological Science, School of Medicine, Centre for Hemoglobinopathies, AOU San Luigi Gonzaga, University of Turin, Turin, Italy
| | - Olga Fjodorova
- Department of Laboratory Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
| | - Africa Manero-Azua
- Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
| | - Arrate Pereda
- Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
| | - Silvia Russo
- IRCCS Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy
| | - Pierpaola Tannorella
- IRCCS Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy
| | - Karen I Temple
- Faculty of Medicine, University of Southampton, Southampton, UK
- Wessex Clinical Genetics Service, Princess Anne Hospital, University Hospital Southampton NHS Trust, Southampton, UK
| | - Katrin Õunap
- Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia
| | - Andrea Riccio
- Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy
- Institute of Genetics and Biophysics (IGB),"Adriano Buzzati-Traverso", Consiglio Nazionale Delle Ricerche (CNR), Naples, Italy
| | - Guiomar Perez de Nanclares
- Rare Diseases Research Group, Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Araba, Spain
| | - Eamonn R Maher
- Aston Medical School, Aston University, Birmingham, UK
- Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
- Institute of Medical and Molecular Genetics, INGEMM-Idipaz, Madrid, Spain
| | - Irène Netchine
- Centre de Recherche Saint Antoine, Endocrinologie Moléculaire et Pathologies d'empreinte, INSERMSorbonne Université, Hôpital Armand TrousseauAPHP, 75012, Paris, France
| | - Thomas Eggermann
- Institute for Human Genetics and Genome Medicine. Faculty of Medicine, RWTH University Aachen, Aachen, Germany
| | - Jet Bliek
- Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Zeynep Tümer
- Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Tarasiewicz M, Pietrzykowska A, Włodarczyk J, Seget S, Gadzalska K, Jakiel P, Skoczylas S, Jarosz-Chobot P, Borowiec M. Transient Neonatal Diabetes Mellitus with an Unknown Cause in a 1-Month-Old Infant: A Case Report. Healthcare (Basel) 2024; 12:1257. [PMID: 38998792 PMCID: PMC11241581 DOI: 10.3390/healthcare12131257] [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: 04/30/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes characterized by hyperglycemia that remits during infancy with a tendency to recur in later life. This case report presents the history of a male infant with transient neonatal diabetes mellitus. The patient was treated with a continuous subcutaneous insulin infusion (CSII) and a continuous glucose monitoring (CGM) system until the age of 2 months, when the normoglycemia connected with a withdrawal of treatment was noted. The genetic test results excluded the majority of known mutations related to TNDM. This case report focuses on various genetic mutations and the clinical features connected with them that cause TNDM and highlights the difficulties in the diagnostic and therapeutic processes of this disease. CSII and CGM systems seem to be a safe and effective treatment option in TNDM and may be used in the therapy.
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Affiliation(s)
- Mateusz Tarasiewicz
- Department of Children’s Diabetology and Pediatrics, Medical University of Silesia, 40-055 Katowice, Poland
| | - Anna Pietrzykowska
- Department of Children’s Diabetology and Pediatrics, Medical University of Silesia, 40-055 Katowice, Poland
| | - Julia Włodarczyk
- Department of Children’s Diabetology and Pediatrics, Medical University of Silesia, 40-055 Katowice, Poland
| | - Sebastian Seget
- Department of Children’s Diabetology and Pediatrics, Medical University of Silesia, 40-055 Katowice, Poland
| | - Karolina Gadzalska
- Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland
| | - Paulina Jakiel
- Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland
| | - Sebastian Skoczylas
- Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland
| | - Przemysława Jarosz-Chobot
- Department of Children’s Diabetology and Pediatrics, Medical University of Silesia, 40-055 Katowice, Poland
| | - Maciej Borowiec
- Department of Clinical Genetics, Medical University of Lodz, 90-419 Lodz, Poland
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9
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Eggermann T. Human Reproduction and Disturbed Genomic Imprinting. Genes (Basel) 2024; 15:163. [PMID: 38397153 PMCID: PMC10888310 DOI: 10.3390/genes15020163] [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: 01/02/2024] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/25/2024] Open
Abstract
Genomic imprinting is a specific mode of gene regulation which particularly accounts for the factors involved in development. Its disturbance affects the fetus, the course of pregnancy and even the health of the mother. In children, aberrant imprinting signatures are associated with imprinting disorders (ImpDis). These alterations also affect the function of the placenta, which has consequences for the course of the pregnancy. The molecular causes of ImpDis comprise changes at the DNA level and methylation disturbances (imprinting defects/ImpDefs), and there is an increasing number of reports of both pathogenic fetal and maternal DNA variants causing ImpDefs. These ImpDefs can be inherited, but prediction of the pregnancy complications caused is difficult, as they can cause miscarriages, aneuploidies, health issues for the mother and ImpDis in the child. Due to the complexity of imprinting regulation, each pregnancy or patient with suspected altered genomic imprinting requires a specific workup to identify the precise molecular cause and also careful clinical documentation. This review will cover the current knowledge on the molecular causes of aberrant imprinting signatures and illustrate the need to identify this basis as the prerequisite for personalized genetic and reproductive counselling of families.
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Affiliation(s)
- Thomas Eggermann
- Institute for Human Genetics and Genomic Medicine, Medical Faculty, RWTH University Aachen, Pauwelsstr. 3, D-52074 Aachen, Germany
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10
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Gunes SO, Calisici E, Arslan M, Akin O, Karagol BS. Transient Neonatal Diabetes Mellitus and Seizure with an Unknown Etiology. J Pediatr Genet 2023; 12:242-245. [PMID: 37575648 PMCID: PMC10421686 DOI: 10.1055/s-0041-1727175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 02/11/2021] [Indexed: 10/21/2022]
Abstract
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.
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Affiliation(s)
- Sevinc Odabasi Gunes
- Department of Pediatric Endocrinology, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Türkiye
| | - Erhan Calisici
- Department of Neonatology, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Türkiye
| | - Mutluay Arslan
- Department of Pediatric Neurology, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Türkiye
| | - Onur Akin
- Department of Pediatric Endocrinology, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Türkiye
| | - Belma Saygili Karagol
- Department of Neonatology, Gulhane Training and Research Hospital, University of Health Sciences, Ankara, Türkiye
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11
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Chisnoiu T, Balasa AL, Mihai L, Lupu A, Frecus CE, Ion I, Andrusca A, Pantazi AC, Nicolae M, Lupu VV, Ionescu C, Mihai CM, Cambrea SC. Continuous Glucose Monitoring in Transient Neonatal Diabetes Mellitus-2 Case Reports and Literature Review. Diagnostics (Basel) 2023; 13:2271. [PMID: 37443665 DOI: 10.3390/diagnostics13132271] [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: 04/25/2023] [Revised: 06/03/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Neonatal diabetes mellitus is a rare genetic disease that affects 1 in 90,000 live births. The start of the disease is often before the baby is 6 months old, with rare cases of onset between 6 months and 1 year. It is characterized by low or absent insulin levels in the blood, leading to severe hyperglycemia in the patient, which requires temporary insulin therapy in around 50% of cases or permanent insulin therapy in other cases. Two major processes involved in diabetes mellitus are a deformed pancreas with altered insulin-secreting cell development and/or survival or faulty functioning of the existing pancreatic beta cell. We will discuss the cases of two preterm girls with neonatal diabetes mellitus in this research. In addition to reviewing the literature on the topic, we examined the different mutations, patient care, and clinical outcomes both before and after insulin treatment.
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Affiliation(s)
- Tatiana Chisnoiu
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Adriana Luminita Balasa
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Larisia Mihai
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Ancuta Lupu
- Pediatrics, "Grigore T. Popa", Department of Mother and Child Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Corina Elena Frecus
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Irina Ion
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Antonio Andrusca
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Alexandru Cosmin Pantazi
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Maria Nicolae
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Vasile Valeriu Lupu
- Pediatrics, "Grigore T. Popa", Department of Mother and Child Medicine, University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Constantin Ionescu
- Department 1 Preclinical, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
| | - Cristina Maria Mihai
- Department of Pediatrics, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
- Pediatrics, County Clinical Emergency Hospital of Constanta, 900591 Constanta, Romania
| | - Simona Claudia Cambrea
- Department of Infectious Diseases, Faculty of General Medicine, "Ovidius" University, 900470 Constanta, Romania
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12
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Mackay D, Bliek J, Kagami M, Tenorio-Castano J, Pereda A, Brioude F, Netchine I, Papingi D, de Franco E, Lever M, Sillibourne J, Lombardi P, Gaston V, Tauber M, Diene G, Bieth E, Fernandez L, Nevado J, Tümer Z, Riccio A, Maher ER, Beygo J, Tannorella P, Russo S, de Nanclares GP, Temple IK, Ogata T, Lapunzina P, Eggermann T. First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders. Clin Epigenetics 2022; 14:143. [PMID: 36345041 DOI: 10.1186/s13148-022-01358-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 10/17/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses.
Results
We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver–Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith–Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories.
Conclusions
Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
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13
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Lannoo L, van Straaten K, Breckpot J, Brison N, De Catte L, Dimitriadou E, Legius E, Peeters H, Parijs I, Tsuiko O, Vancoillie L, Vermeesch JR, Van Buggenhout G, Van Den Bogaert K, Van Calsteren K, Devriendt K. Rare autosomal trisomies detected by non-invasive prenatal testing: an overview of current knowledge. Eur J Hum Genet 2022; 30:1323-1330. [PMID: 35896702 PMCID: PMC9712527 DOI: 10.1038/s41431-022-01147-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/15/2022] [Accepted: 06/30/2022] [Indexed: 12/16/2022] Open
Abstract
Non-invasive prenatal testing has been introduced for the detection of Trisomy 13, 18, and 21. Using genome-wide screening also other "rare" autosomal trisomies (RATs) can be detected with a frequency about half the frequency of the common trisomies in the large population-based studies. Large prospective studies and clear clinical guidelines are lacking to provide adequate counseling and management to those who are confronted with a RAT as a healthcare professional or patient. In this review we reviewed the current knowledge of the most common RATs. We compiled clinical relevant parameters such as incidence, meiotic or mitotic origin, the risk of fetal (mosaic) aneuploidy, clinical manifestations of fetal mosaicism for a RAT, the effect of confined placental mosaicism on placental function and the risk of uniparental disomy (UPD). Finally, we identified gaps in the knowledge on RATs and highlight areas of future research. This overview may serve as a first guide for prenatal management for each of these RATs.
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Affiliation(s)
- Lore Lannoo
- Department of Obstetrics and Gynaecology, Division Woman and Child, University Hospitals Leuven, Leuven, Belgium
| | | | - Jeroen Breckpot
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Nathalie Brison
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Luc De Catte
- Department of Obstetrics and Gynaecology, Division Woman and Child, University Hospitals Leuven, Leuven, Belgium
| | | | - Eric Legius
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Hilde Peeters
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Ilse Parijs
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Olga Tsuiko
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | - Leen Vancoillie
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium
| | | | | | | | - Kristel Van Calsteren
- Department of Obstetrics and Gynaecology, Division Woman and Child, University Hospitals Leuven, Leuven, Belgium
| | - Koenraad Devriendt
- Department of Human Genetics, University Hospitals Leuven, Leuven, Belgium.
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14
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Colclough K, van Heugten R, Patel K. An update on the diagnosis and management of monogenic diabetes. PRACTICAL DIABETES 2022. [DOI: 10.1002/pdi.2410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust Exeter UK
| | - Rachel van Heugten
- Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust Exeter UK
| | - Kashyap Patel
- Institute of Biomedical and Clinical Science University of Exeter Medical School Exeter UK
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15
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Kontbay T, Atar M, Demirbilek H. Long-term follow-up of transient neonatal diabetes mellitus due to a novel homozygous c.7734C>T (p.R228C) mutation in ZFP57 gene: relapse at prepubertal age. J Pediatr Endocrinol Metab 2022; 35:695-698. [PMID: 35218690 DOI: 10.1515/jpem-2021-0538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 01/30/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes present within the first six months of life. NDM can be transient (TNdM) or permanent (PNDM). About 70% of TNDM cases have abnormalities in the imprinted region of chromosome 6q24. In TNDM, diabetes remits at infancy whilst may relapse later in life. Chromosome 6q24 related TNDM usually relapses at the pubertal period, while in some cases, relapse occurs earlier. It has been reported that these cases can respond to sulfonylurea treatment, while more evidence and experience are needed. CASE PRESENTATION Herein, we reported relapse of diabetes at prepubertal age and its response to sulphonylurea therapy in a case with TNDM due to a homozygous c.7734C>T (p.R228C) variant in the ZFP57 gene. CONCLUSIONS A response to the sulphonylurea monotherapy seems not optimal for relapsed TNDM due to chromosome 6q24 abnormalities.
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Affiliation(s)
- Tuğba Kontbay
- Şanlıurfa Training and Research Hospital, Şanlıurfa, Turkey
| | - Müge Atar
- Şanlıurfa Training and Research Hospital, Şanlıurfa, Turkey
| | - Hüseyin Demirbilek
- Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine, Ankara, Turkey
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16
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Cai M, Lin N, Su L, Wu X, Xie X, Xu S, Fu X, Xu L, Huang H. Fetal growth restriction: associated genetic etiology and pregnancy outcomes in a tertiary referral center. J Transl Med 2022; 20:168. [PMID: 35397568 PMCID: PMC8994287 DOI: 10.1186/s12967-022-03373-z] [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: 01/05/2022] [Accepted: 03/29/2022] [Indexed: 11/29/2022] Open
Abstract
Background The etiology of fetal growth restriction (FGR) is complex and currently, there is a paucity of research about the genetic etiology of fetal growth restriction. We investigated the genetic associations and pregnancy outcomes in cases of fetal growth restriction. Methods A retrospective analysis of 210 pregnant women with fetal growth restriction was performed using karyotype analysis and single nucleotide polymorphism arrays (SNP-array). The differences in pathogenic copy number variation (CNV) detected by the two methods were compared. At the same time, the fetuses were divided into three groups: isolated FGR (n = 117), FGR with ultrasonographic soft markers (n = 48), and FGR with ultrasonographic structural anomalies (n = 45). Further, the differences in pathogenic copy number variations were compared among the groups. Results The total detection rate of pathogenic CNVs was 12.4% (26/210). Pathogenic copy number variation was detected in 14 cases (6.7%, 14/210) by karyotype analysis. Furthermore, 25 cases (11.9%, 25/210) with pathogenic CNVs were detected using the SNP-array evaluation method. The difference in the pathogenic CNV detection rate between the two methods was statistically significant. The result of the karyotype analysis and SNP-array evaluation was inconsistent for 13 cases with pathogenic CNV. The rate of detecting pathogenic CNVs in fetuses with isolated FGR, FGR combined with ultrasonographic soft markers, and FGR combined with ultrasonographic structural malformations was 6.0, 10.4, and 31.1%, respectively, with significant differences among the groups. During the follow-up, 35 pregnancies were terminated, two abortions occurred, and 13 cases were lost to follow-up. Of the 160 deliveries, nine fetuses had adverse pregnancy outcomes, and the remaining 151 had normal postnatal growth and developmental assessments. Conclusions Early diagnosis and timely genomic testing for fetal growth restriction can aid in its perinatal prognosis and subsequent intervention. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03373-z.
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17
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Barbetti F, Rapini N, Schiaffini R, Bizzarri C, Cianfarani S. The application of precision medicine in monogenic diabetes. Expert Rev Endocrinol Metab 2022; 17:111-129. [PMID: 35230204 DOI: 10.1080/17446651.2022.2035216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/25/2022] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Monogenic diabetes, a form of diabetes mellitus, is caused by a mutation in a single gene and may account for 1-2% of all clinical forms of diabetes. To date, more than 40 loci have been associated with either isolated or syndromic monogenic diabetes. AREAS COVERED While the request of a genetic test is mandatory for cases with diabetes onset in the first 6 months of life, a decision may be difficult for childhood or adolescent diabetes. In an effort to assist the clinician in this task, we have grouped monogenic diabetes genes according to the age of onset (or incidental discovery) of hyperglycemia and described the additional clinical features found in syndromic diabetes. The therapeutic options available are reviewed. EXPERT OPINION Technical improvements in DNA sequencing allow for rapid, simultaneous analysis of all genes involved in monogenic diabetes, progressively shrinking the area of unsolved cases. However, the complexity of the analysis of genetic data requires close cooperation between the geneticist and the diabetologist, who should play a proactive role by providing a detailed clinical phenotype that might match a specific disease gene.
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Affiliation(s)
- Fabrizio Barbetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Novella Rapini
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Riccardo Schiaffini
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Carla Bizzarri
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Stefano Cianfarani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
- Department of Women's and Children Health, Karolisnska Institute and University Hospital, Sweden
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18
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Laver TW, De Franco E, Johnson MB, Patel KA, Ellard S, Weedon MN, Flanagan SE, Wakeling MN. SavvyCNV: Genome-wide CNV calling from off-target reads. PLoS Comput Biol 2022; 18:e1009940. [PMID: 35294448 PMCID: PMC8959187 DOI: 10.1371/journal.pcbi.1009940] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 03/28/2022] [Accepted: 02/19/2022] [Indexed: 12/04/2022] Open
Abstract
Identifying copy number variants (CNVs) can provide diagnoses to patients and provide important biological insights into human health and disease. Current exome and targeted sequencing approaches cannot detect clinically and biologically-relevant CNVs outside their target area. We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide. Up to 70% of sequencing reads from exome and targeted sequencing fall outside the targeted regions. We have developed a new tool, SavvyCNV, to exploit this 'free data' to call CNVs across the genome. We benchmarked SavvyCNV against five state-of-the-art CNV callers using truth sets generated from genome sequencing data and Multiplex Ligation-dependent Probe Amplification assays. SavvyCNV called CNVs with high precision and recall, outperforming the five other tools at calling CNVs genome-wide, using off-target or on-target reads from targeted panel and exome sequencing. We then applied SavvyCNV to clinical samples sequenced using a targeted panel and were able to call previously undetected clinically-relevant CNVs, highlighting the utility of this tool within the diagnostic setting. SavvyCNV outperforms existing tools for calling CNVs from off-target reads. It can call CNVs genome-wide from targeted panel and exome data, increasing the utility and diagnostic yield of these tests. SavvyCNV is freely available at https://github.com/rdemolgen/SavvySuite.
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Affiliation(s)
- Thomas W. Laver
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Elisa De Franco
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Matthew B. Johnson
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Kashyap A. Patel
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Sian Ellard
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Michael N. Weedon
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Sarah E. Flanagan
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
| | - Matthew N. Wakeling
- Institute of Biomedical & Clinical Science, University of Exeter, Exeter, United Kingdom
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19
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Hammoud B, Greeley SAW. Growth and development in monogenic forms of neonatal diabetes. Curr Opin Endocrinol Diabetes Obes 2022; 29:65-77. [PMID: 34864759 PMCID: PMC11056188 DOI: 10.1097/med.0000000000000699] [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] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Neonatal diabetes mellitus (NDM) is a rare disorder in which 80-85% of infants diagnosed under 6 months of age will be found to have an underlying monogenic cause. This review will summarize what is known about growth and neurodevelopmental difficulties among individuals with various forms of NDM. RECENT FINDINGS Patients with NDM often have intrauterine growth restriction and/or low birth weight because of insulin deficiency in utero and the severity and likelihood of ongoing growth concerns after birth depends on the specific cause. A growing list of rare recessive causes of NDM are associated with neurodevelopmental and/or growth problems that can either be related to direct gene effects on brain development, or may be related to a variety of co-morbidities. The most common form of NDM results in spectrum of neurological disability due to expression of mutated KATP channels throughout the brain. SUMMARY Monogenic causes of neonatal diabetes are characterized by variable degree of restriction of growth in utero because of deficiency of insulin that depends on the specific gene cause. Many forms also include a spectrum of neurodevelopmental disability because of mutation-related effects on brain development. Longer term study is needed to clarify longitudinal effects on growth into adulthood.
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Affiliation(s)
- Batoul Hammoud
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
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20
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Bartolomé A. Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction. Int J Mol Sci 2022; 23:501. [PMID: 35008927 PMCID: PMC8745644 DOI: 10.3390/ijms23010501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/27/2021] [Accepted: 12/29/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.
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Affiliation(s)
- Alberto Bartolomé
- Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, 28029 Madrid, Spain
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21
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Fukuda Y, Ishii A, Kamasaki H, Fusagawa S, Terada K, Igarashi L, Kobayashi M, Suzuki S, Tsugawa T. Long-term sensor-augmented pump therapy for neonatal diabetes mellitus: a case series. Clin Pediatr Endocrinol 2022; 31:178-184. [PMID: 35928380 PMCID: PMC9297173 DOI: 10.1297/cpe.2022-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 04/12/2022] [Indexed: 11/04/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is a rare metabolic disorder that is mainly present in
the first 6 months of life and necessitates insulin treatment. Sensor-augmented pump (SAP)
therapy has been widely used in children with type 1 diabetes mellitus, but its use in
patients with NDM is limited. We report three patients with NDM who received SAP therapy
using the MiniMed™ 640G system starting in the neonatal period. Two patients were treated
for 3 months, and one patient continued treatment up to an age of 22 mo. The MiniMed 640G
system can automatically suspend insulin delivery (SmartGuard™ Technology) to avoid
hypoglycemia when the sensor glucose level is predicted to approach the predefined
threshold. We suggest that SmartGuard Technology is particularly useful for infants in
whom hypoglycemia cannot be identified. The MiniMed 640G system automatically records the
trends of sensor glucose levels and the total daily dose of insulin, which can make the
management more accurate and reduce the family’s effort. SAP therapy for patients with NDM
automatically prevents severe hypoglycemia and is useful for long-term management;
however, attention should be paid to its application.
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Affiliation(s)
- Yuya Fukuda
- Department of Pediatrics, Steel Memorial Muroran Hospital, Muroran, Japan
| | - Akira Ishii
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hotaka Kamasaki
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shintaro Fusagawa
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kojiro Terada
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Lisa Igarashi
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masaki Kobayashi
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Shigeru Suzuki
- Department of Pediatrics, Asahikawa Medical University, Asahikawa, Japan
| | - Takeshi Tsugawa
- Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
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22
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Maia N, Nabais Sá MJ, Melo-Pires M, de Brouwer APM, Jorge P. Intellectual disability genomics: current state, pitfalls and future challenges. BMC Genomics 2021; 22:909. [PMID: 34930158 PMCID: PMC8686650 DOI: 10.1186/s12864-021-08227-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 12/02/2021] [Indexed: 12/18/2022] Open
Abstract
Intellectual disability (ID) can be caused by non-genetic and genetic factors, the latter being responsible for more than 1700 ID-related disorders. The broad ID phenotypic and genetic heterogeneity, as well as the difficulty in the establishment of the inheritance pattern, often result in a delay in the diagnosis. It has become apparent that massive parallel sequencing can overcome these difficulties. In this review we address: (i) ID genetic aetiology, (ii) clinical/medical settings testing, (iii) massive parallel sequencing, (iv) variant filtering and prioritization, (v) variant classification guidelines and functional studies, and (vi) ID diagnostic yield. Furthermore, the need for a constant update of the methodologies and functional tests, is essential. Thus, international collaborations, to gather expertise, data and resources through multidisciplinary contributions, are fundamental to keep track of the fast progress in ID gene discovery.
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Affiliation(s)
- Nuno Maia
- Centro de Genética Médica Jacinto de Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal.
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), and ITR - Laboratory for Integrative and Translational Research in Population Health, University of Porto, Porto, Portugal.
| | - Maria João Nabais Sá
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), and ITR - Laboratory for Integrative and Translational Research in Population Health, University of Porto, Porto, Portugal
| | - Manuel Melo-Pires
- Serviço de Neuropatologia, Centro Hospitalar e Universitário do Porto (CHUPorto), Porto, Portugal
| | - Arjan P M de Brouwer
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands
| | - Paula Jorge
- Centro de Genética Médica Jacinto de Magalhães (CGM), Centro Hospitalar Universitário do Porto (CHUPorto), Porto, Portugal
- Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), and ITR - Laboratory for Integrative and Translational Research in Population Health, University of Porto, Porto, Portugal
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23
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Kang E, Chung LY, Kim YJ, Oh KE, Rhie YJ. Monogenic diabetes mellitus and clinical implications of genetic diagnosis. PRECISION AND FUTURE MEDICINE 2021. [DOI: 10.23838/pfm.2021.00100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Monogenic diabetes mellitus, which is diabetes caused by a defect in a single gene that is associated with β cell function or insulin action, accounts for 1% to 6% of all pediatric diabetes cases. Accurate diagnosis is important, as the effective treatment differs according to genetic etiology in some types of monogenic diabetes: high-dose sulfonylurea treatment in neonatal diabetes caused by activating mutations in KCNJ11 or ABCC8; low-dose sulfonylurea treatment in HNF1A/HNF4A-diabetes; and no treatment in GCK diabetes. Monogenic diabetes should be suspected by clinicians for certain combinations of clinical features and laboratory results, and approximately 80% of monogenic diabetes cases are misdiagnosed as type 1 diabetes or type 2 diabetes. Here, we outline the types of monogenic diabetes and the clinical implications of genetic diagnosis.
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24
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Transient Neonatal Diabetes Mellitus with the Rare Association of Nonsuppurative Sialadenitis and Genetic Defects in 6q24. Case Rep Pediatr 2021; 2021:5901898. [PMID: 34422424 PMCID: PMC8376448 DOI: 10.1155/2021/5901898] [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: 05/28/2021] [Accepted: 08/04/2021] [Indexed: 11/17/2022] Open
Abstract
Background Transient neonatal diabetes mellitus (TNDM) is the most common cause of diabetes in the first week of life, with an overall incidence of 1 in 90,000 to 160,000 live births. TNDM occurs soon after birth and undergoes spontaneous remission during infancy; however, it may relapse to a permanent form of diabetes mellitus in childhood or adolescence. We report a case of TNDM due to hypomethylation on chromosome 6q24, associated with a rare clinical finding of nonsuppurative submandibular sialadenitis managed by subcutaneous insulin, and who underwent remission by three months of age. Case Presentation. We report a male neonate of Arab ancestry delivered by caesarean section at 37 weeks of gestation. He had intrauterine growth retardation with a birth weight of 2.099 kg. He presented with hyperglycemia on the first day of life, which was managed with parenteral insulin infusion. Blood glucose control was initially difficult to achieve due to difficulties in preparing such small doses of insulin and the significant variations in blood glucose concentrations, without ketosis. Blood tests revealed low serum insulin and C-peptide levels. Genetic analysis revealed multiple loci hypomethylation of the PLAGL1/HYMAI-DMR in the TNDM region in chromosome 6q24 and two pathogenic heterozygous variants in the ZFP57 gene. Segregation analysis showed that both parents were heterozygous carriers of familial ZFP57 variants. The clinical course was associated with bilateral nonsuppurative sialadenitis, which is extremely rare among newborns. Conclusion Sialadenitis is a well-known phenomenon that is rarely diagnosed in neonates. To the best of our knowledge, this is the first case report to describe the exceedingly rare association of nonsuppurative submandibular sialadenitis in a neonate with TNDM due to multiple loci hypomethylation of the PLAGL1/HYMAI-DMR in the TNDM region in 6q24 and heterozygous pathogenic variants in the ZFP57 gene.
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25
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Erfolgreiche Sulfonylharnstoffbehandlung eines transienten neonatalen Diabetes. DIABETOLOGE 2021. [DOI: 10.1007/s11428-021-00794-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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26
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Eggermann T, Davies JH, Tauber M, van den Akker E, Hokken-Koelega A, Johansson G, Netchine I. Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network. Genes (Basel) 2021; 12:genes12040585. [PMID: 33920525 PMCID: PMC8073901 DOI: 10.3390/genes12040585] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023] Open
Abstract
Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.
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Affiliation(s)
- Thomas Eggermann
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, 52062 Aachen, Germany
- Correspondence: ; Tel.: +49-241-8088008; Fax: +49-241-8082394
| | - Justin H. Davies
- Department of Paediatric Endocrinology, University Hospital Southampton, Southampton SO16 6YD, UK;
| | - Maithé Tauber
- Research centre of rare diseases PRADORT, Childrens Hospital, CHU Toulouse, Toulouse Institute of Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291-CNRS UMR5051-Tolouse III University, 31062 Toulouse, France;
| | - Erica van den Akker
- Erasmus University Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands;
| | - Anita Hokken-Koelega
- Erasmus University Medical Center, Pediatrics, Subdivision of Endocrinology, 3015 GD Rotterdam, The Netherlands;
| | - Gudmundur Johansson
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Department of Endocrinology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden;
| | - Irène Netchine
- Medical Faculty, AP-HP, Armand Trousseau Hospital-Functional Endocrine Research Unit, INSERM, Research Centre Saint-Antoine, Sorbonne University, 75012 Paris, France;
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27
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Zhang H, Colclough K, Gloyn AL, Pollin TI. Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest 2021; 131:142244. [PMID: 33529164 PMCID: PMC7843214 DOI: 10.1172/jci142244] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
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Affiliation(s)
- Haichen Zhang
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Anna L. Gloyn
- Department of Pediatrics, Division of Endocrinology, and,Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, California, USA
| | - Toni I. Pollin
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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28
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Novel Variant in PLAG1 in a Familial Case with Silver-Russell Syndrome Suspicion. Genes (Basel) 2020; 11:genes11121461. [PMID: 33291420 PMCID: PMC7762056 DOI: 10.3390/genes11121461] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 12/01/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023] Open
Abstract
Silver-Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver-Russell syndrome.
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29
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Severe Dental Disease as a Presenting Sign of Relapsed 6q24-Related Transient Neonatal Diabetes Mellitus. Case Rep Endocrinol 2020; 2020:8828516. [PMID: 33274084 PMCID: PMC7683122 DOI: 10.1155/2020/8828516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/05/2020] [Accepted: 10/28/2020] [Indexed: 11/24/2022] Open
Abstract
Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes that presents in infancy and is characterized by intrauterine growth restriction and hyperglycemia without ketones on urinalysis. Patients are treated with insulin until remission, usually within the first year. Relapse to a permanent state may occur later in life, with a mean age of 14 years. The most common cause of TNDM is a chromosome 6q24 mutation that affects pancreatic β-cell function. Reports of relapse have been limited. We describe a case of an adolescent female with TNDM due to 6q24 hypomethylation who relapsed at 15 years of age with severe dental disease as the presenting sign.
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30
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Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics. Genes (Basel) 2020; 11:genes11121454. [PMID: 33287348 PMCID: PMC7761756 DOI: 10.3390/genes11121454] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022] Open
Abstract
Prenatal detection of uniparental disomy (UPD) is a methodological challenge, and a positive testing result requires comprehensive considerations on the clinical consequences as well as ethical issues. Whereas prenatal testing for UPD in families which are prone to UPD formation (e.g., in case of chromosomal variants, imprinting disorders) is often embedded in genetic counselling, the incidental identification of UPD is often more difficult to manage. With the increasing application of high-resolution test systems enabling the identification of UPD, an increase in pregnancies with incidental detection of UPD can be expected. This paper will cover the current knowledge on uniparental disomies, their clinical consequences with focus on prenatal testing, genetic aspects and predispositions, genetic counselling, as well as methods (conventional tests and high-throughput assays).
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31
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Riddle MC, Philipson LH, Rich SS, Carlsson A, Franks PW, Greeley SAW, Nolan JJ, Pearson ER, Zeitler PS, Hattersley AT. Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care 2020; 43:3117-3128. [PMID: 33560999 PMCID: PMC8162450 DOI: 10.2337/dci20-0065] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023]
Abstract
Individualization of therapy based on a person's specific type of diabetes is one key element of a "precision medicine" approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of Diabetes Care convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.
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Affiliation(s)
- Matthew C Riddle
- Division of Endocrinology, Diabetes, & Clinical Nutrition, Oregon Health & Science University, Portland, OR
| | - Louis H Philipson
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.,Kovler Diabetes Center, The University of Chicago, Chicago, IL
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA
| | - Annelie Carlsson
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Lund, Sweden
| | - Paul W Franks
- Harvard T.H. Chan School of Public Health, Boston, MA.,Lund University Diabetes Center, Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Siri Atma W Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL.,Kovler Diabetes Center, The University of Chicago, Chicago, IL
| | - John J Nolan
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Ewan R Pearson
- Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, Scotland, U.K
| | - Philip S Zeitler
- Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO
| | - Andrew T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
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32
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Elbracht M, Binder G, Hiort O, Kiewert C, Kratz C, Eggermann T. Clinical spectrum and management of imprinting disorders. MED GENET-BERLIN 2020. [DOI: 10.1515/medgen-2020-2044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Imprinting disorders are exceptional within the group of monogenic syndromes. They are associated with molecular changes affecting imprinted regions and usually do not follow the rules of Mendelian inheritance. They account for a relevant proportion of congenital disorders, especially within the syndromal growth entities with endocrine, neurological, and skeletal characteristics. In patients with imprinting disorders and accelerated growth, significant tumor risks have to be considered. The number of known imprinting disorders increases with the identification of new regions in which parentally imprinted genes are located. Imprinting disorders are caused by genomic pathogenic variants affecting imprinted genes, as well as by aberrant imprinting marks (epimutations) in the patients themselves. Additionally, maternal effect mutations have recently been identified that trigger secondary epimutations in the offspring. These maternal effect mutations explain not only imprinting disorders in their children, but also recurrent reproductive failure in the families. This review aims to provide an overview of the recent findings in 13 well-known imprinting disorders relating to clinical diagnosis, management and counseling.
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Affiliation(s)
- Miriam Elbracht
- Institute of Human Genetics, Medical Faculty , RWTH Aachen University , Pauwelsstr. 30 , Aachen , Germany
| | - Gerhard Binder
- Pädiatrische Endokrinologie, Universitätsklinik für Kinder- und Jugendmedizin , Universitätsklinikum Tübingen , Tübingen , Germany
| | - Olaf Hiort
- Department of Paediatrics and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes , University of Lübeck , Lübeck , Germany
| | - Cordula Kiewert
- Pediatric Endocrinology and Diabetology , Children’s University Hospital Essen , Essen , Germany
| | - Christian Kratz
- Department of Pediatric Hematology and Oncology , Hannover Medical School , Hannover , Germany
| | - Thomas Eggermann
- Institute of Human Genetics, Medical Faculty , RWTH Aachen University , Pauwelsstr. 30 , Aachen , Germany
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33
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Abstract
Neonatal diabetes (ND) appears during the first months of life and is caused by a single gene mutation. It is heterogenous and very different compared to other forms of multi-factorial or polygenic diabetes. Clinically, this form is extremely severe, however, early genetic diagnosis is pivotal for successful therapy. A large palette of genes is demonstrated to be a cause of ND, however, the mechanisms of permanent hyperglycemia are different. This review will give an overview of more frequent genetic mutations causing ND, including the function of the mutated genes and the specific therapy for certain sub-forms.
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Affiliation(s)
- M Kocova
- Medical Faculty, University Cyril and Methodius, Skopje, Republic of Macedonia
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34
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Uchida N, Ohnishi T, Kojima T, Takahashi T, Makita Y, Fukami M, Shibata H, Hasegawa T, Ishii T. Relapsing 6q24-related transient neonatal diabetes mellitus with insulin resistance: A case report. Clin Pediatr Endocrinol 2020; 29:179-182. [PMID: 33088017 PMCID: PMC7534527 DOI: 10.1297/cpe.29.179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/06/2020] [Indexed: 11/06/2022] Open
Abstract
The overexpression of imprinted genes on chromosome 6q24 causes 6q24-related transient
neonatal diabetes mellitus (6q24-TNDM). Most cases of 6q24-TNDM show transient diabetes
mellitus (DM) during the neonatal period, followed by relapse after puberty. These two
courses of DM are both characterized by insulin insufficiency. However, there has been no
previously reported case of 6q24-TNDM with insulin resistance at relapse. We report the
case of a 10-yr-old Japanese girl with relapsing 6q24-TNDM. In the neonatal period, she
had hyperglycemia and was treated with insulin injection until 2 mo of age. After several
years of remission of DM, her HbA1c level increased to 7.4% at 10 yr of age. Homeostasis
model assessment of insulin resistance (HOMA-IR) score was high at 6.2. After starting
metformin therapy, her glycemic control improved along with normalization of HOMA-IR
score. Using microsatellite marker analysis on the 6q24 region and array comparative
genome hybridization, we diagnosed her with 6q24-TNDM due to paternally inherited
duplication of 6q24. These data indicate that patients with 6q24-TNDM can develop
relapsing DM with insulin resistance.
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Affiliation(s)
- Noboru Uchida
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Takuma Ohnishi
- Division of Infectious Diseases and Immunology, Saitama Children's Medical Center, Saitama, Japan
| | - Takuro Kojima
- Division of Pediatric Cardiology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Tsutomu Takahashi
- Department of Pediatrics, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan
| | - Yoshio Makita
- Education Center, Asahikawa Medical University, Asahikawa, Japan
| | - Maki Fukami
- Department of Molecular Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Hironori Shibata
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Tomonobu Hasegawa
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
| | - Tomohiro Ishii
- Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
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35
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Cao L, He Y, Huang Q, Zhang Y, Deng P, Du W, Hua Z, Zhu M, Wei H. Clinical features and partial proportional molecular genetics in neonatal diabetes mellitus: a retrospective analysis in southwestern China. Endocrine 2020; 69:53-62. [PMID: 32279225 DOI: 10.1007/s12020-020-02279-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 03/23/2020] [Indexed: 01/29/2023]
Abstract
PURPOSE To explore the relationship of phenotype and genotype of neonatal diabetes mellitus (NDM) in southwestern China. METHODS Sixteen cases of NDM admitted to Children's Hospital of Chongqing Medical University from May 2009 to May 2019 were included in this study. The clinical features of the included infants were retrospectively analyzed. Peripheral blood samples of the patients and their parents were collected for mutation detection. RESULTS Among the 16 cases of NDM, 8 cases were permanent neonatal diabetes mellitus (PNDM) (including 3 clinical syndromes), and 3 cases were transient neonatal diabetes mellitus (TNDM). Mutation detection was performed in six cases. The mutation genes and their loci were FOXP3 p.V408M, KCNJ11 p.C166Y, ABCC8 p.S830P, KCNJ11 p.I182T, KCNJ11 p.G334D, and ZFP57 p.R125X,412. ABCC8 p.S830P was the new found pathogenic site of gene mutation. According to the clinical features and follow-up results, one case was diagnosed as IPEX syndrome, two as DEND syndrome, two as simple PNDM, and one as TNDM. All the TNDM could spontaneously alleviate and then insulin was withdrawn. In PNDM, 75% of those with KATP channel gene mutation could be completely or partially converted to oral sulfonylureas treatment, however, the rest cases needed lifelong insulin replacement therapy. CONCLUSION The clinical manifestations and treatment regimens of patients with NDM vary according to the type of gene mutation. Even the same mutant genotype has differences in phenotype and response to treatment.
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Affiliation(s)
- Luying Cao
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Yi He
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Qinrong Huang
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Department of Rehabilitation, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Yu Zhang
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Pinglan Deng
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Weixia Du
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Ziyu Hua
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Min Zhu
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China
- Department of Endocrinology, Children's Hospital of Chongqing Medical University, Chongqing, PR China
| | - Hong Wei
- Department of Neonatology, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
- Ministry of Education Key Laboratory of Child Development and Disorders; National Clinical Research Center for Child Health and Disorders; China International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
- Chongqing Key Laboratory of Pediatrics, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
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36
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Nicolaides NC, Kanaka-Gantenbein C, Papadopoulou-Marketou N, Sertedaki A, Chrousos GP, Papassotiriou I. Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus. Crit Rev Clin Lab Sci 2020; 57:522-531. [PMID: 32356495 DOI: 10.1080/10408363.2020.1752141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
In the era of precision medicine, the tremendous progress in next-generation sequencing technologies has allowed the identification of an ever-increasing number of genes associated with known Mendelian disorders. Neonatal diabetes mellitus is a rare, genetically heterogeneous endocrine disorder diagnosed before 6 months of age. It may occur alone or in the context of genetic syndromes. Neonatal diabetes mellitus has been linked with genetic defects in at least 26 genes to date. Novel mutations in these disease-causing genes are being reported, giving us a better knowledge of the molecular events that occur upon insulin biosynthesis and secretion from the pancreatic β-cell. Of great importance, some of the identified genes encode proteins that can be therapeutically targeted by drugs per os, leading to transitioning from insulin to sulfonylureas. In this review, we provide an overview of pancreatic β-cell physiology, present the clinical manifestations and the genetic causes of the different forms of neonatal diabetes, and discuss the application of next-generation sequencing methods in the diagnosis and therapeutic management of neonatal diabetes and on research in this area.
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Affiliation(s)
- Nicolas C Nicolaides
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Nektaria Papadopoulou-Marketou
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Amalia Sertedaki
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - George P Chrousos
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece.,IFCC Emerging Technologies Division, Emerging Technologies in Pediatric Laboratory Medicine (C-ETPLM), Milano, Italy
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37
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Gore RH, Nikita ME, Newton PG, Carter RG, Reyes-Bautista J, Greene CL. Duplication 6q24: More Than Just Diabetes. J Endocr Soc 2020; 4:bvaa027. [PMID: 32373772 PMCID: PMC7185952 DOI: 10.1210/jendso/bvaa027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 04/24/2020] [Indexed: 11/19/2022] Open
Abstract
Chromosome 6q24-related transient neonatal diabetes mellitus is characterized by intrauterine growth restriction and low birth weight, with neonatal hyperglycemia resolving by 18 months and an increased risk for type 2 diabetes in adulthood. Molecularly, it is caused by overexpression of the 6q24 imprinted chromosomal region due to a duplication, uniparental disomy, or abnormal methylation. Conventional testing for this condition analyzes methylation patterns at the 6q24 locus but does not evaluate for the presence of other surrounding chromosomal abnormalities. We report a female with a history of neonatal hyperglycemia due to a paternally inherited duplication at chromosomal location 6q24. She subsequently presented to the pediatric genetics clinic at 15 months of age with developmental delay and abnormal balance. Microarray analysis identified a larger 14 Mb chromosomal duplication from 6q24 to 6q25.2, consistent with a diagnosis of duplication 6q syndrome. This case highlights the clinical importance of pursuing further genetic evaluation in patients diagnosed with chromosome 6q24-related neonatal hyperglycemia via targeted methylation-specific multiplex ligation-dependent probe amplification analysis identifying a duplication in this region. Early identification and intervention can improve developmental outcomes for patients with larger chromosome 6q duplications.
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Affiliation(s)
- Rachel H Gore
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Maria Eleni Nikita
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Paula G Newton
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Rebecca G Carter
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jeanine Reyes-Bautista
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
| | - Carol L Greene
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
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38
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Iwata N, Asui R, Mizumoto H, Hata D. Management of a case of transient neonatal diabetes mellitus using continuous glucose monitoring. Clin Pediatr Endocrinol 2020; 29:77-80. [PMID: 32313376 PMCID: PMC7160458 DOI: 10.1297/cpe.29.77] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/03/2020] [Indexed: 11/18/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is a very rare disorder and its diagnosis can be
challenging especially in mild and transient cases. Herein, we describe a 2.4-kg female
infant born at 38 wk of gestation who showed hyperglycemia (388 mg/dL) on Day 1.
Intermittent blood sampling showed glucose concentrations of 100–150 mg/dL on Day 2–5.
However, continuous glucose monitoring (CGM) from Day 7 revealed hyperglycemia (> 200
mg/dL) after every feeding. The patient required low-dose (0.1–0.2 U/kg/d) insulin therapy
for a short period (7 d). During the treatment, hypoglycemic (< 50 mg/dL) events were
not detected by real- time CGM. Follow-up CGM from Day 32 showed normoglycemia for 3 full
days; therefore, we ascertained that the diabetes had been transient. Later genetic
analysis revealed an abnormal methylation pattern on chromosome 6q24, which is the most
frequent cause of transient NDM. Most cases of 6q24-related NDM relapse after puberty,
implying that long term follow up is required. We speculate that the NDM in this case
might not have been diagnosed without CGM. This report highlights the usefulness of CGM
for the initial diagnosis, monitoring during insulin therapy, and confirmation of
improvement in patients with transient NDM.
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Affiliation(s)
- Naoya Iwata
- Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Risa Asui
- Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Hiroshi Mizumoto
- Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Daisuke Hata
- Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
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39
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A Triplication of 6q24 and Meconium Pseudocyst: A Case Report. Neonatal Netw 2020; 38:329-335. [PMID: 31712397 DOI: 10.1891/0730-0832.38.6.329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2019] [Indexed: 11/25/2022]
Abstract
With the rise in genetic screening both pre- and postnatally, new variances in genes are being recognized. Some are of unknown significance, while other known genetic expressions have obvious phenotypical expressions. Transient neonatal diabetes mellitus is a result of the duplication of chromosome 6q24, but little is known about the phenotypic expression of a triplication of chromosome 6q24. This case study presents an infant with a postnatally diagnosed triplication of chromosome 6q24, meconium pseudocyst, and multiple congenital anomalies with unknown genetic significance.
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40
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DNA Methylation in the Diagnosis of Monogenic Diseases. Genes (Basel) 2020; 11:genes11040355. [PMID: 32224912 PMCID: PMC7231024 DOI: 10.3390/genes11040355] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/13/2020] [Accepted: 03/24/2020] [Indexed: 02/08/2023] Open
Abstract
DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.
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41
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Elbracht M, Mackay D, Begemann M, Kagan KO, Eggermann T. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. Hum Reprod Update 2020; 26:197-213. [DOI: 10.1093/humupd/dmz045] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 11/07/2019] [Accepted: 11/15/2019] [Indexed: 12/19/2022] Open
Abstract
Abstract
BACKGROUND
Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes.
OBJECTIVE AND RATIONALE
This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine.
SEARCH METHODS
Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms ‘multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction’ were used in various combinations.
OUTCOMES
A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders.
WIDER IMPLICATIONS
Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.
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Affiliation(s)
- Miriam Elbracht
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Deborah Mackay
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Matthias Begemann
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Karl Oliver Kagan
- Obstetrics and Gynaecology, University Hospital of Tübingen, Tübingen, Germany
| | - Thomas Eggermann
- Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany
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42
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Habeb AM, Deeb A, Elbarbary N, Beshyah SA. Diagnosis and management of neonatal diabetes mellitus: A survey of physicians' perceptions and practices in ASPED countries. Diabetes Res Clin Pract 2020; 159:107975. [PMID: 31830516 DOI: 10.1016/j.diabres.2019.107975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 12/03/2019] [Indexed: 11/27/2022]
Abstract
AIM To ascertain the awareness and practice of neonatal diabetes mellitus (NDM) among paediatricians in Arab countries. METHODS An online questionnaire was distributed to physicians associated with the Arab Society for Paediatric Endocrinology and Diabetes (ASPED). RESULTS We received 126 replies, from 16 countries. All except one classified the survey's case scenario as NDM and 94% agreed that NDM patients should have detailed assessment to identify extra-pancreatic features. Although 92% felt that genetic testing is necessary, only 72% requesting them routinely and 32% unaware of the availability of free genetic testing. Insulin is considered the initial therapy for 93% and 80% diluted insulin to deliver accurate doses. Basal-bolus regimen was preferred by 36% and similar percentage used insulin pump. The remaining 28% favour long acting insulin alone. Oral sulfonylureas would be tried empirically by 34% and 69% would do so if genetic testing is unavailable. Whilst 70% have no local NDM management guidelines, 41% are unaware of any international guidelines. CONCLUSIONS The ASPED surveyed clinicians have good awareness of NDM diagnosis with marked variation in their practice raising the need to establish management guideline for the condition. The survey highlights areas to focus on in developing consensus and educational activities.
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MESH Headings
- Arabs/psychology
- Arabs/statistics & numerical data
- Cross-Sectional Studies
- Diabetes Mellitus/congenital
- Diabetes Mellitus/diagnosis
- Diabetes Mellitus/therapy
- Female
- Genetic Testing/statistics & numerical data
- Health Knowledge, Attitudes, Practice
- Humans
- Infant, Newborn
- Infant, Newborn, Diseases/diagnosis
- Infant, Newborn, Diseases/therapy
- Insulin/classification
- Insulin/therapeutic use
- Insulin Infusion Systems/statistics & numerical data
- Male
- Middle East/epidemiology
- Perception
- Physicians/psychology
- Physicians/statistics & numerical data
- Practice Patterns, Physicians'/statistics & numerical data
- Societies, Medical/organization & administration
- Societies, Medical/standards
- Surveys and Questionnaires
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Affiliation(s)
- Abdelhadi M Habeb
- Prince Mohammed bin Abdulaziz Hospital for National Guard, Madinah, Saudi Arabia.
| | - Asma Deeb
- Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, United Arab Emirates
| | | | - Salem A Beshyah
- Mediclinic Abu Dhabi, United Arab Emirates; Dubai Medical College, Dubai, United Arab Emirates
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43
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Shidler KL, Letourneau LR, Novak LM. Uncommon Presentations of Diabetes: Zebras in the Herd. Clin Diabetes 2020; 38:78-92. [PMID: 31975755 PMCID: PMC6969666 DOI: 10.2337/cd19-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The majority of patients with diabetes are diagnosed as having either type 1 or type 2 diabetes. However, when encountered in clinical practice, some patients may not match the classic diagnostic criteria or expected clinical presentation for either type of the disease. Latent autoimmune, ketosis-prone, and monogenic diabetes are nonclassical forms of diabetes that are often misdiagnosed as either type 1 or type 2 diabetes. Recognizing the distinguishing clinical characteristics and understanding the diagnostic criteria for each will lead to appropriate treatment, facilitate personalized medicine, and improve patient outcomes.
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Affiliation(s)
- Karen L. Shidler
- North Central Indiana Area Health Education Center, Rochester, IN
| | | | - Lucia M. Novak
- Riverside Diabetes Center, Riverside Medical Associates, Riverdale, MD
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44
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Beltrand J, Busiah K, Vaivre-Douret L, Fauret AL, Berdugo M, Cavé H, Polak M. Neonatal Diabetes Mellitus. Front Pediatr 2020; 8:540718. [PMID: 33102403 PMCID: PMC7554616 DOI: 10.3389/fped.2020.540718] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
Neonatal Diabetes (ND) mellitus is a rare genetic disease (1 in 90,000 live births). It is defined by the presence of severe hyperglycaemia associated with insufficient or no circulating insulin, occurring mainly before 6 months of age and rarely between 6 months and 1 year. Such hyperglycaemia requires either transient treatment with insulin in about half of cases, or permanent insulin treatment. The disease is explained by two major groups of mechanism: malformation of the pancreas with altered insulin-secreting cells development/survival or abnormal function of the existing pancreatic β cell. The most frequent genetic causes of neonatal diabetes mellitus with abnormal β cell function are abnormalities of the 6q24 locus and mutations of the ABCC8 or KCNJ11 genes coding for the potassium channel in the pancreatic β cell. Other genes are associated with pancreas malformation or insufficient β cells development or destruction of β cells. Clinically, compared to patients with an ABCC8 or KCNJ11 mutation, patients with a 6q24 abnormality have lower birth weight and height, are younger at diagnosis and remission, and have a higher malformation frequency. Patients with an ABCC8 or KCNJ11 mutation have neurological and neuropsychological disorders in all those tested carefully. Up to 86% of patients who go into remission have recurrent diabetes when they reach puberty, with no difference due to the genetic origin. All these results reinforce the importance of prolonged follow-up by a multidisciplinary pediatric team, and later doctors specializing in adult medicine. 90% of the patients with an ABCC8 or KCNJ11 mutation as well as those with 6q24 anomalies are amenable to a successful switch from insulin injection to oral sulfonylureas.
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Affiliation(s)
- Jacques Beltrand
- Paediatric Endocrinology, Gynaecology and Diabetology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France.,Faculty of Medicine, Université de Paris, Paris, France.,INSERM U1016, Cochin Institute, Paris, France
| | - Kanetee Busiah
- Paediatric Endocrinology, Gynaecology and Diabetology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France.,Paediatric Endocrinology, Diabetology and Obesity Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Laurence Vaivre-Douret
- Paediatric Endocrinology, Gynaecology and Diabetology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France.,Faculty of Medicine, Université de Paris, Paris, France.,Inserm UMR-1018-CESP, Necker-Enfants Malades University Hospital Paedopsychiatry Department, Cochin University Hospital Paediatrics Department, Institut Universitaire de France, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
| | - Anne Laure Fauret
- Genetics Department, Robert-Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Marianne Berdugo
- Faculty of Medicine, Université de Paris, Paris, France.,INSERM U1138, Cordeliers Research Centre, Paris, France
| | - Hélène Cavé
- Faculty of Medicine, Université de Paris, Paris, France.,Genetics Department, Robert-Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Michel Polak
- Paediatric Endocrinology, Gynaecology and Diabetology, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France.,Faculty of Medicine, Université de Paris, Paris, France.,INSERM U1016, Cochin Institute, Paris, France
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45
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Abstract
Monogenic diabetes affects approximately 120,000 people in the United States but continues to be misdiagnosed. Within the pediatric population, 1% to 3% of diabetes is monogenic, and early diagnosis and genetically targeted management of congenital diabetes and maturity onset diabetes of the young (MODY) can have a tremendous impact on future health outcomes and quality of life. In some of the more common monogenic diabetes types, patients can switch from insulin therapy to sulfonylureas or even discontinue glucose-lowering therapy with stable glycemic control. Advancements in the field have identified tools and resources to aid in distinguishing patients likely to have monogenic diabetes from the more common forms of type 1 and type 2 diabetes. However, genetic testing with accurate interpretation of results is necessary to confirm a diagnosis and direct treatment selection and disease management. This article discusses challenges and opportunities in monogenic diabetes in the pediatric population. [Pediatr Ann. 2019;48(8):e319-e325.].
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46
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Novak A, Bowman P, Kraljevic I, Tripolski M, Houghton JAL, De Franco E, Shepherd MH, Skrabic V, Patel KA. Transient Neonatal Diabetes: An Etiologic Clue for the Adult Diabetologist. Can J Diabetes 2019; 44:128-130. [PMID: 31255515 PMCID: PMC7049895 DOI: 10.1016/j.jcjd.2019.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 04/26/2019] [Accepted: 05/01/2019] [Indexed: 12/02/2022]
Affiliation(s)
- Anela Novak
- Section of Endocrinology, Department of Internal Medicine, University Hospital Split, Split, Croatia
| | - Pamela Bowman
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
| | - Ivana Kraljevic
- Department of Endocrinology, Department of Internal Medicine, University Hospital Zagreb, Zagreb, Croatia
| | - Marija Tripolski
- Section of Endocrinology, Department of Internal Medicine, University Hospital Osijek, Osijek, Croatia
| | - Jayne A L Houghton
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
| | - Elisa De Franco
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
| | - Maggie H Shepherd
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom; Exeter NIHR Clinical Research Facility, Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom
| | - Veselin Skrabic
- Section of Neuroendocrinology, Department of Pediatrics, University Hospital Split, Split, Croatia
| | - Kashyap A Patel
- The Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom.
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47
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Transient neonatal diabetes mellitus caused by a novel mutation in the ABCC8 gene. JOURNAL OF SURGERY AND MEDICINE 2019. [DOI: 10.28982/josam.515839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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48
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Touati A, Errea-Dorronsoro J, Nouri S, Halleb Y, Pereda A, Mahdhaoui N, Ghith A, Saad A, Perez de Nanclares G, H'mida Ben Brahim D. Transient neonatal diabetes mellitus and hypomethylation at additional imprinted loci: novel ZFP57 mutation and review on the literature. Acta Diabetol 2019; 56:301-307. [PMID: 30315371 DOI: 10.1007/s00592-018-1239-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 09/29/2018] [Indexed: 11/28/2022]
Abstract
AIM 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is a rare imprinting disorder characterized by uncontrolled hyperglycemia during the first 6 months of life. The molecular etiology of 6q24-TNDM is attributable to overexpression of the paternally inherited PLAGL1 and HYMAI genes located on the 6q24 locus. One of these major defects is maternal loss of methylation (LOM) at 6q24. In addition, approximately 50% of TNDM patients that present LOM at 6q24 can also display hypomethylation at additional imprinted loci (multilocus imprinting disturbances, MLID). Interestingly, the majority of these patients carry mutations in the ZFP57 gene, a transcription factor required for the adequate maintenance of methylation during early embryonic development. METHODS Methylation analysis of 6q24 and additional imprinted loci was carried out by MS-MLPA in a Tunisian male patient with clinical diagnosis of TNMD. For the same patient, mutation analysis of the ZFP57 gene was conducted by direct Sanger sequencing. RESULTS We report a novel nonsense mutation (c.373C > T; p.R125*; ENST00000376883.1) at the ZFP57 gene causing TNDM-MLID and describe detailed phenotype/epigenotype analysis of TNMD patients carrying ZFP57 mutations. CONCLUSION We provide additional support to the role of ZFP57 as a genetic determinant cause of MLID in patients with TNMD.
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Affiliation(s)
- Ameni Touati
- Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- High Institute of Biotechnology, Monastir University, Monastir, Tunisia
| | - Javier Errea-Dorronsoro
- Molecular (Epi)Genetic Lab, BioAraba National Health Institute, OSI Araba University Hospital, 01009, Vitoria-Gasteiz, Alava, Spain
| | - Sonia Nouri
- Department of Neonatology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- Faculty of Medicine, Sousse University, Sousse, Tunisia
| | - Yosra Halleb
- Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- Faculty of Medicine, Sousse University, Sousse, Tunisia
| | - Arrate Pereda
- Molecular (Epi)Genetic Lab, BioAraba National Health Institute, OSI Araba University Hospital, 01009, Vitoria-Gasteiz, Alava, Spain
| | - Nabiha Mahdhaoui
- Department of Neonatology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- Faculty of Medicine, Sousse University, Sousse, Tunisia
| | - Aida Ghith
- Department of Neonatology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- Faculty of Medicine, Sousse University, Sousse, Tunisia
| | - Ali Saad
- Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia
- Faculty of Medicine, Sousse University, Sousse, Tunisia
| | - Guiomar Perez de Nanclares
- Molecular (Epi)Genetic Lab, BioAraba National Health Institute, OSI Araba University Hospital, 01009, Vitoria-Gasteiz, Alava, Spain
| | - Dorra H'mida Ben Brahim
- Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia.
- Faculty of Medicine, Sousse University, Sousse, Tunisia.
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Abstract
In addition to the common types of diabetes mellitus, two major monogenic diabetes forms exist. Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic, autosomal dominant diseases. MODY accounts for 1-2% of all diabetes cases, and it is not just underdiagnosed but often misdiagnosed to type 1 or type 2 diabetes. More than a dozen MODY genes have been identified to date, and their molecular classification is of great importance in the correct treatment decision and in the judgment of the prognosis. The most prevalent subtypes are HNF1A, GCK, and HNF4A. Genetic testing for MODY has changed recently due to the technological advancements, as contrary to the sequential testing performed in the past, nowadays all MODY genes can be tested simultaneously by next-generation sequencing. The other major group of monogenic diabetes is neonatal diabetes mellitus which can be transient or permanent, and often the diabetes is a part of a syndrome. It is a severe monogenic disease appearing in the first 6 months of life. The hyperglycemia usually requires insulin. There are two forms, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). In TNDM, the diabetes usually reverts within several months but might relapse later in life. The incidence of NDM is 1:100,000-1:400,000 live births, and PNDM accounts for half of the cases. Most commonly, neonatal diabetes is caused by mutations in KCNJ11 and ABCC8 genes encoding the ATP-dependent potassium channel of the β cell. Neonatal diabetes has experienced a quick and successful transition into the clinical practice since the discovery of the molecular background. In case of both genetic diabetes groups, recent guidelines recommend genetic testing.
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Affiliation(s)
- Zsolt Gaál
- 4th Department of Medicine, Jósa András Teaching Hospital, Nyíregyháza, Hungary
| | - István Balogh
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Abstract
PURPOSE OF REVIEW Great strides have recently been made in elucidating the role of genetic sequence variation in diabetes pathogenesis. Increasingly, studies are focusing on other factors that may contribute to the pathogenesis of diabetes, such as epigenetics, a term "traditionally" encompassing changes to the DNA that do not alter sequence and are heritable (primary methylation and histone modification) but often expanded to include microRNAs. This review summarizes latest findings on the role of epigenetics in diabetes pathogenesis. RECENT FINDINGS Recent studies illustrate roles for methylation changes, histone modification, imprinting, and microRNAs across several diabetes types and complications. Notably, methylation changes in the human leukocyte antigen (HLA) region have been found to precede the development of type 1 diabetes. In type 2 diabetes, lifestyle factors appear to interact with epigenetic mechanisms in pathogenesis. Emerging technologies have allowed increasingly comprehensive descriptive analysis of the role of epigenetic mechanisms in diabetes pathogenesis which have yielded meaningful insights into effects on expression of relevant genes. These findings have the potential to inform future development of predictive testing to enable primary prevention and further work to uncover the complex pathogenesis of diabetes.
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Affiliation(s)
- Haichen Zhang
- Department of Medicine, Division of Endocrinology, Diabetes and Nutrition Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, 670 West Baltimore Street, Room 4040, Baltimore, MD, 21201, USA
| | - Toni I Pollin
- Department of Medicine, Division of Endocrinology, Diabetes and Nutrition Program for Personalized and Genomic Medicine, Department of Epidemiology and Public Health, University of Maryland School of Medicine, 670 West Baltimore Street, Room 4040, Baltimore, MD, 21201, USA.
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