Dual phenotype in a patient with adult-onset hyperinsulinism and diabetes caused by an activating MAFA variant

Context

The coexistence of diabetes and hyperinsulinemic hypoglycemia (HI) within a family is rare. Activating MAFA variants have been described in 3 families with this dual phenotype and are associated with sex-dependent clinical patterns.

Methods

We studied a family where members were affected by HI (n = 5), diabetes (n = 5), or both conditions (n = 1). Clinical, biochemical, and imaging data were collected. Genetic testing for variants in known monogenic diabetes and HI genes was performed in the proband, followed by cascade testing in available relatives. Pancreatic tissue was examined by immunohistochemistry and immunofluorescence.

Results

A heterozygous, p.(Ser64Phe) MAFA variant was identified in the male proband, who had presented with diabetes at 28 years and developed HI due to insulinomatosis 6 years later. The variant was confirmed in 5 relatives, 4 with HI and 1 with diabetes (including obligate heterozygotes). Among the 5 presenting with HI, 3 were female, whereas 4 of 6 presenting with diabetes were male, consistent with reported sex-dependent patterns.

Increased nuclear expression of the transcription factor MafA (MAFA) was detected by immunofluorescence in insulin-positive tumor regions compared to the adjacent islets, supporting a pathogenic role for the variant in beta-cell regulation.

Conclusion

We describe the fourth family with a pathogenic MAFA variant and the second individual with the dual phenotype of diabetes and HI. Our findings highlight challenges in clinical management of this condition and underscore the need to consider MAFA in cases of adult-onset HI or those with an atypical course of diabetes especially when there is family history.