Primary hepatocellular adenoma due to biallelic HNF1A mutations and its co-occurrence with MODY 3: case-report and review of the literature

PURPOSE: Maturity-onset diabetes of the young type 3 (MODY 3) is a consequence of heterozygous germline mutations in HNF1A, and a subtype of hepatocellular adenoma (HCA) is caused by biallelic somatic HNF1A mutations; rare HCA may be related to MODY 3. This study aimed to investigate the cosegregation of HNF1A mutations with diabetes and HCA in two families. METHODS: Two patients suffering from HCA and diabetes were screened for HNF1A germline and somatic mutations using direct sequence analysis and methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay. Further, we screened eight relatives in the two independent families for diabetes, HCA and HNF1A variants. Additionally, we reviewed the literature concerning the phenotypes of MODY 3 and HCA at the background of HNF1A mutations. RESULTS: Here we reported two families (a total of six relatives) with two missense germline mutations of HNF1A identified initially using direct sequence analysis (c.686G>A in family A and c.526 + 1G>A in family B). Somatic deletion of the second allele of HNF1A was found in liver tumor tissues in both probands who were diagnosed with HCA. There are a total of ten cases of both MODY 3 and HCA phenotypes reported in the literature to date; incomplete penetrance for HCA was observed, and all the patients with HCA developed diabetes. The onset of diabetes and HCA was highly variable, the treatment of diabetes varied from diet to insulin, and the clinical expression of HCA ranged from silent to hemorrhage. Further, the severity of diabetes mellitus was not related to the occurrence of HCA. CONCLUSIONS: This study describes the association of HCA and MODY 3 at the background of HNF1A mutations and highlights the importance of screening for HCA in MODY 3 families to avoid the possibility of severe complications. Further, the current study indicated that there may be a special mutational spectrum of HNF1A correlated with HCA in MODY 3 families.