HNF1B-MODY: Clinical and Diagnostic Insights from a Case Report of Frequently Misdiagnosed Monogenic Diabetes

Introduction

Maturity-onset diabetes of the young (MODY) is a monogenic diabetes mellitus with autosomal dominant inheritance (onset <40 years), representing 1-5% of European and 2% of Indian diabetes cases. However, genetic confirmation rates remain low (10.9–13%) due to overlapping features with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM),^1,2 emphasizing the need for precise diagnostic criteria.³

HNF1B-MODY (MODY5) is rare (<5% of MODY cases) and presents with renal cysts, diabetes (Renal cysts and diabetes (RCAD) syndrome), pancreatic atrophy, and genital/liver abnormalities. Unlike HNF1A-/HNF4A-MODY, HNF1B-MODY patients often require early insulin therapy due to a poor response to sulfonylureas (SU), which can lead to misdiagnosis as T1DM.

Diagnostic confusion extends to polycystic kidney disease (PKD): while autosomal dominant polycystic kidney disease (ADPKD) shows progressive adult-onset renal cysts and autosomal recessive polycystic kidney disease (ARPKD) presents with childhood hepatic-renal involvement, HNF1B-MODY features stable renal changes with predominant β-cell dysfunction. We present a case of HNF1B-MODY initially misdiagnosed T1DM with PKD, highlighting the diagnostic challenges.

Case Report

A 13-year-old male presented with poorly controlled DM, recurrent leg pain and decreased appetite. He was diagnosed with ARPKD, based on multiple renal cysts detected in childhood, and T1DM due to young onset, lean phenotype, and insulin requirement, despite negative autoantibodies. A history of failure to thrive was evident since early childhood. His medications included insulin, sodium bicarbonate syrup, and vitamin D.

On examination, he had a weight and height of 30.6 kg and 142 cm respectively, with a BMI of 15.2 kg/m². Laboratory tests showed severe hyperglycemia (FBG 320 mg/dL, PPBG 437 mg/dL, HbA1C 11.5/dL), hypomagnesemia (1.1 mg/dL), and elevated liver enzymes (AST 46.46 IU/L, ALT 72.96 IU/L) with normal bilirubin. His C-peptide levels were detectable (fasting: 1.22 ng/mL, random: 2.68 ng/mL) despite the presumed T1DM diagnosis.

Abdominal ultrasonography showed pancreatic atrophy with bilateral small renal cortical cysts (largest cyst on right kidney- 11 x 10 mm in mid pole and on left kidney- 7 x 8 mm in lower pole). The ECG showed sinus tachycardia. Renal function, lipid profile, and thyroid function tests were normal. Given these findings, HNF1B-MODY was deemed the likely diagnosis, prompting genetic analysis. Targeted next-generation sequencing identified a pathogenic heterozygous HNF1B variant (c.544+1G>A) affecting the GT donor splice site, causing exon 2 skipping, leading to HNF1B protein haploinsufficiency and RCAD phenotype.

His mother, aged 51, was diagnosed with DM at age 13 and was long managed as T1DM. Renal cysts were found during routine ultrasonography at 30, attributed to ADPKD. Her BMI was 19 kg/m², with a random C-peptide of 1.2 ng/mL after 38 years of DM, excluding T1DM. Her history included anemia, hypertension, stage III CKD, and cardiovascular complications, including coronary artery disease (CAD) with regional wall motion abnormalities and moderate mitral regurgitation. Her first child had died at 6 months from kidney failure, and the second of hepatic encephalopathy at 18 days. Genetic testing revealed the same HNF1B variant. Family pedigree analysis [Figure 1] revealed autosomal dominant transmission, with multiple affected members exhibiting early-onset DM, renal manifestations, and cardiovascular involvement, suggesting that they may carry the mutation.

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Figure 1:

Pedigree chart depicting familial history of HNF1B-MODY and associated comorbidities.

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Treatment was focused on continuous glucose monitoring with insulin optimization, correcting hypomagnesaemia, exocrine pancreatic enzyme supplementation, multidisciplinary care, regular complication surveillance, and genetic counseling for at-risk family members.

Discussion

Misdiagnosing patients with T1DM and PKD highlights challenges in recognizing HNF1B-MODY. This case highlights the importance of physician education and the inclusion of MODY subtypes in diabetes guidelines to ensure diagnosis.

The triad of pancreatic atrophy, renal cysts, and early-onset DM is a signature for HNF1B-MODY. Additional features include detectable C-peptide, hypomagnesemia (present in 84.6% of HNF1B-MODY patients),⁴ and elevated liver enzymes (from impaired hepatic gene regulation). These features, when combined, should prompt genetic testing and a review of family history.

A systematic approach, incorporating pedigree analysis, is crucial for atypical DM. Autosomal dominant inheritance, with DM and renal disease occurring across generations, supported the diagnosis of HNF1B-MODY. Unilateral transmission of renal abnormalities excluded ARPKD. Low birth weight and growth retardation supported HNF1B-MODY, as mutations cause insulin deficiency. Unlike progressive ADPKD, patients showed stable cystic changes.

Management challenges arise from distinct pathophysiology. Patients respond poorly to SU due to hepatic insulin resistance and β-cell toxicity, and insulin remains primary treatment. SGLT-2 inhibitors could help correct hypomagnesemia,⁵ while imeglimin shows promise with cardio-renal protective effects.⁶ Multidisciplinary care is essential while avoiding nephrotoxic and hepatotoxic agents. This case highlights the importance of HNF1B-MODY awareness. Recognizing hallmark features enables accurate diagnosis, tailored therapy, and family screening.