Insulinomatosis And Diabetes Mellitus

A number sign (#) is used with this entry because of evidence that insulinomatosis and diabetes mellitus syndrome (INSDM) is caused by heterozygous mutation in the MAFA gene (610303) on chromosome 8q24.

Description

Insulinomatosis and diabetes mellitus syndrome is an autosomal dominant disorder in which affected individuals within a family present with either hyperinsulinemic hypoglycemia secondary to pancreatic neuroendocrine tumors, or a noninsulin-dependent form of diabetes mellitus. A few affected individuals show only impaired glucose tolerance. Some patients also exhibit congenital cataract and/or congenital glaucoma (Iacovazzo et al., 2018).

Clinical Features

Tragl and Mayr (1977) described a Yugoslavian father and daughter with multiple beta-cell adenomas of the pancreas. The father and daughter, who came to medical attention at age 38 years and 28 years, respectively, each underwent several pancreatic surgeries to remove insulinomas, but hypoglycemia always recurred; ultimately they were successfully treated with diazoxide and diet. The daughter had a 6-year-old son who had no abnormality of the endocrine system or indication of hyperinsulinism. The father's brother and 2 of the brother's children had diabetes mellitus. The authors suggested that an autosomal dominant gene is responsible for either one or the other trait by determining 'an abnormal sensitivity of the beta-cells.'

Iacovazzo et al. (2018) studied 25 affected individuals from 2 unrelated white Caucasian families with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, 1 of which (family 2) was the Yugoslavian family originally reported by Tragl and Mayr (1977). Insulinomatosis was present in 10 patients, and 15 patients had a form of noninsulin-dependent DM resembling maturity-onset diabetes of the young (MODY); in addition, there were 2 family members with glucose intolerance. Diagnosis generally occurred between the third and fifth decades of life, although 2 individuals with DM were diagnosed in the second decade of life. In family 1, 4 patients with DM also exhibited congenital cataract and/or glaucoma. In individuals with hyperinsulinemic hypoglycemia who underwent surgery, histopathology revealed the presence of multifocal well-differentiated neuroendocrine tumors, including microadenomas and macrotumors, with a trabecular tissue architecture. The number of lesions was variable; the authors noted that the affected Yugoslavian daughter was reported to have had over 100 lesions in a surgical specimen (Anlauf et al., 2009). All tumors in these patients expressed insulin, and immunostaining for other pancreatic hormones was negative; local or distant metastases were not observed. All 6 patients who underwent surgery had persistent or recurrent disease.

Inheritance

Tragl and Mayr (1977) reported a 4-generation Yugoslavian family in which beta-cell adenomatosis or diabetes mellitus segregated as autosomal dominant traits.

Molecular Genetics

In a large white Caucasian family with insulinomatosis and diabetes mellitus, Iacovazzo et al. (2018) performed exome sequencing and identified a heterozygous missense mutation in the MAFA gene (S64F; 610303.0001) that segregated with disease and was not found in public variant databases. Targeted sequencing of MAFA in a Yugoslavian family with INSDM that was originally reported by Tragl and Mayr (1977) identified the same heterozygous S64F mutation in affected individuals. Haplotype analysis suggested that the mutation arose on separate alleles in the 2 families.