A Rare Case of HNF1B and NR3C1 Genetic Mutations Leading to Severe Electrolyte Derangements and Impaired Glucose Control

Introduction: HNF1B plays a crucial role in the development the kidney/liver/pancreas by regulating gene expression. HNF1B gene mutations cause structural kidney defects and electrolyte abnormalities. Non-renal consequences, notably MODY type 5, are also noted. Our case describes a patient incorrectly diagnosed with type 1 diabetes but was found to have a pathogenic HNF1B mutation and a likely pathogenic NR3C1 mutation, both contributing to her hyperglycemia, as well as hallmark features of ADTKD. Case Description: 37-year-old female with insulin-dependent diabetes, autonomic neuropathy, hypomagnesemia, hypokalemia, hypophosphatemia, and cachexia presented with worsening fatigue and CKD. She was wheelchair bound, hypotensive, and cachectic. She denied PPI/laxative/diuretic use; denied family history of kidney disease. K 2.6 mmol/L, Cl 93 mmol/L, CO2 37 mmol/L, BUN 12 mg/dL, Cr 0.7 mg/dL, eGFR 114 mL/min/1.73m^2 [CKD Epi 2021; likely an overestimate of actual GFR given cachexia], Mg 1.1 mg/dL, Phos 1.9 mg/dL, Albumin 3.1 g/dL, HbA1c 15.9. Urinalysis - pH 6.3 and absent dipstick proteinuria. UACR 321 mg/g and UPCR 1987 mg/g [tubular proteinuria]. Kidney USG: B/L kidneys 10.5 cm, normal echogenicity, and no kidney cysts. Targeted gene panel of blood revealed a pathogenic HNF1B whole gene deletion [heterozygous, AD inheritence] at chromosome 17q12 and likely pathogenic NR3C1 mutation at chromosome 5 [heterozygous, AD inheritence]. She requires frequent IV crystalloids, magnesium, and potassium replacement therapy. Genetic counselling was provided and she is being followed at the Rare Genetic Kidney Disease Clinic at UAB. Discussion: The case report explores the intricate relationship between HNF1 Beta mutation, potential tubulointerstitial nephritis, and MODY5 phenotype. HNF1B gene shows significant variability in mutation carriers, often without family history due to spontaneous mutations. Kidney involvement is common, with early manifestation and diverse phenotypes including electrolyte abnormalities. Pancreatic involvement is also notable. Our patient has a HNF1B 17q12 genetic variant that has been observed at a frequency of < 0.014% of the general population. Not much is known regarding NR3C1 mutations. We highlight the importance of genetic testing and counselling in tailoring individualized treatment.