ESPE Abstracts

Introduction: HNF1B gene (OMIM*189907) encodes the transcription factor HNF1B, which is expressed early in embryogenesis, controls gene expression and is involved in multiple tissue and organ development. Mutations of HNF1B account for a complex disorder with multisystemic manifestations (Renal Cysts and Diabetes syndrome, OMIM #137920). Congenital urinary tract abnormalities and HNF1B MODY, a rare cause of diabetes mellitus (DM) (≤5% of MODY cases), are key phenotypic features. HNF1B MODY is a consequence of β-cell dysfunction in a setting of pancreatic hypoplasia and hepatic insulin resistance. Inheritance is autosomal dominant, with a high rate of de novo deletions (50%). This study aims to compare the cases of two adolescents diagnosed with HNF1B MODY with multisystem involvement.

Patients and Methods: The first patient was a 16-year-old adolescent from an immigrant shelter with family history of diabetes, who was hospitalized for diabetic ketoacidosis and was initially diagnosed with DM. Investigations revealed HbA1C:15.3%, normal c-peptide concentration, negative T1DM autoantibodies, impaired renal and hepatic function, hypomagnesemia, and dyslipidemia. Ultrasonography showed an atrophic pancreas and renal cysts. The second patient, a 14.3-year-old adolescent with a personal history of nephrectomy due to polycystic kidney, was investigated because of hyperglycemia. The OGTT was diagnostic of DM alongside with HbA1C:5.5%, borderline c-peptide concentration and negative T1DM autoantibodies and hypomagnesemia, hypertransaminasemia, hyperparathyroidism, and hyperuricemia. Imaging tests showed pancreatic hypoplasia and steatosis, hepatic fibrosis, and non-communicating hydrocele with cystic formation of the epididymis and normal bone density.

Results: The above phenotypical findings suggested HNF1B MODY. DNA was isolated from peripheral blood and genetic testing was undertaken. Sanger sequencing HNF1B gene did not reveal any single nucleotide variant and MLPA revealed heterozygous deletion of HNF1B gene in both patients. The first patient was treated with subcutaneous insulin but showed poor diabetic control and was lost to follow-up two years later. In the second case, an expectant management approach was adopted, including follow-up by a multidisciplinary team, lifestyle intervention and DM education, which led to glucose control at 12 months, postponed the need for insulin treatment and prevented the onset of diabetic ketoacidosis.

Conclusion: HNF1B MODY presents a heterogeneous and broad phenotype with multisystemic manifestations (extra-pancreatic and/or exocrine pancreas). The different diagnostic context of the two patients highlights the socioeconomic differences in access to preventive medicine and health services. These patients benefit from early diagnosis and require comprehensive follow-up to prevent and manage complications and comorbidities.