#5283 HNF1β MUTATIONS AND ASSOCIATED PHENOTYPES – WHAT TO LOOK FOR?

Abstract

Abstract Background and Aims Hepatocyte nuclear factor 1β (HNF1β)-associated disorder is a rare entity that may present with a wide range of clinical phenotypes. Genetic transmission is autosomal dominant, penetrance is incomplete, and expression is variable, which can contribute to different clinical presentations, raising difficulties to reach the diagnosis. The most common findings are renal cysts, responsible for kidney function decline, as well as diabetes mellitus, among other possible organs’ manifestations such as the pancreas, liver, brain and parathyroid gland. The disease arises through monoallelic single nucleotide deleterious variants (SNVs) or whole-gene deletions, in the chromosome 17q12. Method Retrospective analysis of patients with HNF1β-associated disease followed in pediatric nephrology unit, throughout the last 10 years (2013-2022), in our pediatric tertiary center. Data regarding demographic variables, along with family history, relevant clinical information and genetic variants were collected from electronical clinical files. Results A total of 6 patients were followed in our centre, mostly males (n = 5). Regarding age at diagnosis, two patients were diagnosed prenatally, owing to positive familial history and renal cysts, while for the other 4 patients (de novo mutations) the age at diagnosis ranged from one to 13 years-old (yo). Five patients presented with renal cysts, while the other patient presented with unilateral urinary tract dilation. Only one patient presented with diabetes mellitus. Regarding other possible comorbidities, two patients presented with neurodevelopmental disorders and one with hypertension. At presentation, 3 patients had chronic kidney disease stage 3. The mean decrease in glomerular filtration rate was 1.44 ml/min/year (according to Schwartz “bedside” formula). Creatinine levels almost doubled in 3 of the patients since referral (adolescents currently with 1.5-2 mg/dL), while remaining in the normal range in the other patients. Two patients presented with low grade proteinuria during follow-up (max protein/creatinine ratio 0.36 g/g). Values of calcium, transaminases and uric acid were normal in all patients. Familial history of kidney disease, namely cysts or chronic kidney disease, was positive in 3 patients. In terms of genetic transmission, 3 patients had SNVs, while the other 3 presented with larger deletions in chromosome 17q12. Conclusion In conclusion, in these patients, a high degree of suspicion is needed for diagnosis, owing to the rarity of the disease and heterogeneity of its manifestations. A multidisciplinary approach and genetic counseling are determinant for disease management. Families of the affected individuals should be tested, even if asymptomatic, to determine if the HNF1β variant was inherited or occurred de novo. Given the small number of patients, it would be important to widen the sample through a multicentric study.