Expanded Clinical Spectrum in Hepatocyte Nuclear Factor 1B-Maturity-Onset Diabetes of the Young

• Published in: The journal of clinical endocrinology and metabolism Vol. 94; no. 7; pp. 2658 - 2664
• Main Authors: Raile, Klemens, Klopocki, Eva, Holder, Martin, Wessel, Theda, Galler, Angela, Deiss, Dorothee, Müller, Dominik, Riebel, Thomas, Horn, Denise, Maringa, Monika, Weber, Jürgen, Ullmann, Reinhard, Grüters, Annette
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.07.2009; Copyright by The Endocrine Society
• Subjects: Adolescent; Biological and medical sciences; Chromosome Deletion; Chromosomes, Human, Pair 17; Cohort Studies; Comparative Genomic Hybridization; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; DNA Mutational Analysis; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Hepatocyte Nuclear Factor 1-beta - analysis; Hepatocyte Nuclear Factor 1-beta - genetics; Humans; Male; Medical sciences; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Immunopathology; Maturity onset diabetes young; Obesity; Nutrition; Digestive system; Liver; Nutrition disorder; Autoimmune disease; Metabolic diseases; Genetic disease; Hepatocyte; Type 1 diabetes; Transcription factor; Expansion; Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2008-2189

Aims: HNF1B-maturity-onset diabetes of the young is caused by abnormalities in the HNF1B gene encoding the transcription factor HNF-1β. We aimed to investigate detailed clinical features and the type of HNF1B gene anomaly in five pediatric cases with HNF1B-MODY. Methods: From a cohort of 995 children and adolescents with diabetes, we analyzed the most frequent maturity-onset diabetes of the young genes (GCK, HNF1A, HNF4A) including HNF1B sequencing and deletion analysis by quantitative Multiplex-PCR of Short Fluorescent Fragments (QMPSF) if patients were islet autoantibody-negative and had one parent with diabetes or associated extrapancreatic features or detectable C-peptide outside honeymoon phase. Presence and size of disease-causing chromosomal rearrangements detected by QMPSF were further analyzed by array comparative genomic hybridization. Results: Overall, five patients had a heterozygous HNF1B deletion, presenting renal disease, elevated liver enzymes, and diabetes. Diabetes was characterized by insulin resistance and adolescent onset of hyperglycemia. Additionally, clinical features in some patients were pancreas dysplasia and exocrine insufficiency (two of five patients), genital defects (three of five), mental retardation (two of five), and eye abnormalities (coloboma, cataract in two of five). One case also had severe growth deficit combined with congenital cholestasis, and another case had common variable immune deficiency. All patients reported here had monoallelic loss of the entire HNF1B gene. Whole genome array comparative genomic hybridization confirmed a precurrent genomic deletion of approximately 1.3–1.7 Mb in size. Conclusion: The clinical data of our cases enlarge the wide spectrum of patients with HNF1B anomaly. The underlying molecular defect in all cases was a 1.3- to 1.7-Mb deletion, and paired, segmental duplications along with breakpoints were most likely involved in this recurrent chromosomal microdeletion. HNF1B-Maturity-onset diabetes of youth (MODY) has a broad clinical spectrum and heterozygous contiguous gene deletions, including HNF1B and 18 other known genes.