Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young.
OBJECTIVE
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.


CONCLUSIONS
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.
Raile
Klemens
K
Department of Pediatric Endocrinology and Diabetes, Charité Campus Virchow, 13353 Berlin, Germany. klemens.raile@charite.de
Klopocki
Eva
E
Holder
Martin
M
Wessel
Theda
T
Galler
Angela
A
Deiss
Dorothee
D
Müller
Dominik
D
Riebel
Thomas
T
Horn
Denise
D
Maringa
Monika
M
Weber
Jürgen
J
Ullmann
Reinhard
R
Grüters
Annette
A
D000293:Adolescent; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000032:analysis / Q000235:genetics*; D006801:Humans; D008297:Male
D051539:Hepatocyte Nuclear Factor 1-beta