UNRAVELLING THE MYSTERY

A CASE OF ATYPICAL DIABETES WITH HEPATIC AND RENAL CLUES TO HNF1B DEFICIENCY

Abstract

INTRODUCTION/BACKGROUND
Hepatocyte nuclear factor 1β (HNF1B) deficiency associated with MODY-5 is increasingly recognised as a multifaceted syndrome with diverse manifestations. We present a suspected case initially misdiagnosed as type 1 diabetes with autoimmune hepatitis.

CASE
A 14-year-old male with learning disability was admitted for insulin initiation when he presented with osmotic symptoms with hyperglycaemia and ketonuria. He reported no family history of diabetes. HbA1c was 18.5% and LFTs were deranged (AST 74, ALT 209 and ALP 451 IU/L). He has some dysmorphic facial features. Despite good glycemic control on intensive insulin therapy, his liver enzymes remained elevated (8–17x ULN) with normal ferritin, ceruloplasmin and viral panel. Abdominal ultrasound showed normal liver and spleen but detected bilateral medullary nephrocalcinosis. The liver biopsy showed mild periportal hepatitis. He was treated for autoimmune hepatitis with prednisolone and azathioprine. Subsequent investigations revealed negative diabetes (anti-GAD, ICA, IA2), hepatic (ANA, smooth muscle, LC1, LKM and mitochondrial) autoantibodies and normal serum immunoglobulins. The absence of diabetes-related autoantibodies, coupled with multisystem involvement (pancreas, liver, kidney, neurocognitive and dysmorphism), raised the suspicion of HNF1B mutation. Although genetic confirmation was not feasible, further investigation with elevated C peptide (1652 pmol/L) and persistent hypomagnesemia (0.4 to 0.55 mmol/L) further substantiated this hypothesis. Immunotherapy was withheld. He remained well with fluctuating liver function on follow-up 5 years since the initial presentation.

CONCLUSION
This case underscores the diagnostic complexity of HNF1B deficiency, a rare monogenic diabetes subtype accounting for ~6% of MODY. Despite an autosomal dominant inheritance pattern, de-novo mutation accounts for 50% of cases. Lack of family history does not preclude the diagnosis. Diagnostic clues include multisystem involvement, which is rarely found in other MODY subtypes. Hypomagnesemia is another common feature. Early recognition is essential for individualised management, avoidance of mismanagement, monitoring for other organ involvement or complications and genetic counselling.