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Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young
Klemens Raile1, Eva Klopocki, Martin Holder
1Department of Pediatric Endocrinology and Diabetes, Charité Campus Virchow, 13353 Berlin, Germany. klemens.raile@charite.de
Insights
HNF1B gene deletions cause maturity-onset diabetes of the young (MODY) in children, leading to diabetes, kidney issues, and liver problems. These deletions, often large, present a wide spectrum of clinical features in affected individuals.
Area of Science:
- Genetics
- Endocrinology
- Pediatrics
Background:
- Hepatocyte Nuclear Factor 1 Beta (HNF1B) gene mutations are a known cause of HNF1B-maturity-onset diabetes of the young (MODY).
- Understanding the specific genetic anomalies and associated clinical manifestations is crucial for accurate diagnosis and management of pediatric diabetes.
- Previous studies have identified various mutations in HNF1B, but detailed characterization of deletions and their phenotypic spectrum in children is less explored.
Purpose of the Study:
- To investigate the detailed clinical features of five pediatric cases with HNF1B-MODY.
- To identify the specific type of HNF1B gene anomaly, focusing on deletions, in these pediatric patients.
- To expand the understanding of the clinical spectrum associated with HNF1B gene deletions in a young population.
Main Methods:
- Analysis of a cohort of 995 children and adolescents with diabetes.
- Sequencing and deletion analysis of HNF1B and other common MODY genes (GCK, HNF1A, HNF4A) using quantitative Multiplex-PCR of Short Fluorescent Fragments (QMPSF).
- Array comparative genomic hybridization (aCGH) was employed to confirm and characterize the size of detected chromosomal rearrangements.
Main Results:
- Five pediatric patients were identified with heterozygous HNF1B deletions, all exhibiting monoallelic loss of the entire gene.
- Clinical presentations included diabetes (characterized by insulin resistance and adolescent onset), renal disease, and elevated liver enzymes.
- Additional features observed in some patients were pancreas dysplasia, exocrine insufficiency, genital defects, mental retardation, and eye abnormalities.
Conclusions:
- The study identified recurrent, large (1.3-1.7 Mb) deletions of the HNF1B gene as the underlying molecular defect in all five pediatric cases.
- These findings broaden the known clinical spectrum of HNF1B anomalies in children, highlighting the diverse phenotypes associated with these deletions.
- The recurrent nature of the microdeletion suggests a role for paired segmental duplications and breakpoints in its formation.
Aims:
HNF1B-maturity-onset diabetes of the young is caused by abnormalities in the HNF1B gene encoding the transcription factor HNF-1beta. 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.
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