Diagnosis of hepatocellular adenoma in men before onset of diabetes in HNF1A‐MODY: Watch out for winkers

Abstract Hepatocyte nuclear factor 1A (HNF1A) maturity‐onset diabetes of the young (MODY) is a monogenetic, autosomal dominantly inherited form of diabetes. HNF1A‐MODY is associated with HNF1A‐inactivated hepatocellular adenoma (H‐HCA) formation. Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co‐occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus. Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA‐related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before. HNF1A‐MODY should be considered in (non‐)diabetic (male) patients with H‐HCA. We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A‐MODY patients.


| INTRODUC TI ON
Maturity-onset diabetes of the young (MODY) is a monogenic, autosomal dominant, non-ketotic form of diabetes mellitus (DM), representing genetic, metabolic and clinical heterogeneity. Because of a heterozygous germline mutation of the hepatocyte nuclear factor 1A (HNF1A) gene, HNF1A-MODY (formerly MODY3) is the most common subtype. HNF1A-MODY is associated with diabetes onset before the age of 25 years and gestational diabetes, and is treated best with sulfonylurea derivatives. [1][2][3] Transcription factor HNF1A interacts with DNA as a homodimer or heterodimer with HNF1B to regulate cellular function, including carbohydrate metabolism, lipid transport and detoxication, and is present in various organs of endodermal origin. 1 HNF1A is also an autosomal dominant inherited tumour suppressor gene. Somatic biallelic mutations of HNF1A are associated with hepatocellular adenoma (HCA) formation. 4,5 HCA are rare, benign liver tumours at risk for haemorrhage (15%) or malignant transformation to hepatocellular carcinoma (HCC, 5%). 5 HNF1A-inactivated HCA (H-HCA) are usually sporadic cases, which form 35% of HCA. 4,5 About a third of patients with H-HCA carry a HNF1A germline mutation in one allele, Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co-occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus.
Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA-related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before.
We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A-MODY patients.

K E Y W O R D S
hepatocellular adenoma, HNF1A-MODY, liver adenomatosis, treatment algorithm thereby causing H-HCA formation following a second, somatic mutation in the wild-type HNF1A allele. 4 Liver adenomatosis (LA) has first been described in the 1960s and has later been defined by the occurrence of 10 or more HCA. 6,7 It is a different entity from regular HCA, as it occurs more frequently in the presence of underlying liver disease such as HNF1A-MODY or glycogen storage disease. [8][9][10] The 2016 European guideline on benign liver tumours acknowledges the formation of HCA in metabolic disorders such as HNF1A-MODY, and recommends HCA resection in males, irrespective of size or concurring metabolic diagnosis. 11 Phenotype penetrance varies in families with identical HNF1A mutations, although MODY is typically diagnosed prior to H-HCA. 12

| MATERIAL S AND ME THODS
We report a family with a HNF1A germline mutation and high pen-

| RE SULTS
A 25-year-old man ( Figure 1A, III:2, index patient) without a medical history was presented with right hypochondriac ache.
Ultrasonography revealed two liver tumours, leading to referral to our centre. Serum alpha-foetoprotein, carcinoembryonic antigen and cancer antigen 19-9 levels were normal. Computed tomography (CT) revealed numerous, bi-lobar liver lesions with arterial enhancement and washout. Contrast-enhanced MRI could not differentiate between benignancy and malignancy ( Figure 1B). Histological and immunohistochemical analysis after percutaneous liver biopsy diagnosed HCA, but could not exclude well-differentiated HCC.
During laparotomy, an extensive, liver-wide spread of tumours, ranging in size from microscopic up to 40 mm was observed-preventing any tumour-free hepatic remnant ( Figure 1C Thereafter, all first-and second-degree family members were screened for mutations in the HNF1A gene ( Figure 1A). The mutation was maternally inherited ( Figure 1A, 2:II). Index patient's mother was diagnosed with DM at the age of 21. Aged 42 years, she underwent emergency laparotomy after spontaneous hepatic haemorrhage.
Histopathological analysis of intra-operative liver biopsies showed necrosis and steatotic hepatocytes. HCA was suspected, but un-

| D ISCUSS I ON
Our report describes a family with a HNF1A germline mutation and a high penetrance of HCA, varying from single HCA to LA.
Interestingly, both the index patient and also likely one of his sisters presented with HCA prior to DM. In one family member, index patient's mother, severe hepatic haemorrhage led to the diagnosis of HCA.
Haddouche et al have described the largest series of patients with a HNF1A germline mutation. 10 They report 87.5% of their cases demonstrating both DM and LA. 10 In seven of 30 HNF1A-MODY patients without DM, LA was revealed by screening. In addition, they report three patients who were diagnosed with HCA only after severe hepatic bleeding. 10 Barbier et al observed four cases of LA prior to DM in a family with a HNF1A germline mutation. 9 In two male patients, HCA was diagnosed by haemorrhage. 9 Malignant transformation from HCA to HCC is mostly observed in HCA carrying either an exon 3 b-catenin mutation, or in HCA occurring in males. 5,13 H-HCA is less known for this outcome, but should not be neglected completely. About 1.5% of all HCC carry a HNF1A mutation, and a HNF1A-MODY family with H-HCA-induced primary hepatic malignancies has been reported. 14,15 The expression of the diabetic phenotype of HNF1A-MODY is regulated by modifier genes. 16 Similar regulation by a currently unknown modifier gene could explain observations of LA prior to or after onset of diabetic symptoms. Our observed HNF1A germline mutation in the DNA-binding homeodomain (amino acids 198-281) in exon 4, c.815G>A (p.Arg272His) has previously been described. 17 The location of the mutation in the DNA-binding homeodomain could explain the high penetrance of HCA in the family described in this report.

CO N FLI C T O F I NTE R E S T
None of the authors declared conflict of interest.

AUTH O R CO NTR I B UTI O N S
All authors contributed to the drafting and revision of the manuscript. They interpreted the clinical information from their specialty and supervised the correct interpretation of results.