Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism

The first child, a boy, of a consanguineous couple (first cousins) of Portuguese ancestry (Fig. 1) presented at birth with an increased weight and body length. He presented with hypoglycemic seizures during the first day of life. Repeated hypoglycemias (ranging from 1.7 to 2.3 mmol/l, reference range >2.7) were found during the 1st month, associated with high insulin levels (ranging from 5.5 to 18 mU/l, reference range <0.4 in hypoglycemia) consistent with the diagnosis of persistent neonatal hyperinsulinism. Medical treatment with diazoxide and somatostatin along with high-glucose dietary treatment failed to control hypoglycemia. A transhepatic pancreatic catheterization with venous sampling of glucose, insulin, and C-peptide, as previously described (17), revealed hypersecretion of insulin in the lower part of the pancreatic body. Via pancreatic surgery with a preoperative histological analysis, a focal lesion of 15 mm of diameter on the lower part of the pancreatic body was identified.

The second child, a girl, also suffered from neonatal hypoglycemic seizures. Treatment by diazoxide, nifedipin, and injection of somatostatin was not successful, and the child was infused with high doses of glucose (15 mg · kg⁻¹ · mn⁻¹) and continuous infusion of glucagon (2 mg/day). An ¹⁸F-fluoro-l-DOPA positron emission tomography study was performed, showing a diffuse uptake of the radiotracer in the pancreatic area, compatible with a diffuse form of hyperinsulinism.

A limited pancreatectomy fully cured the first child, who, now 6 years old, is healthy with no relapse of hypoglycemia. Loss of 11p15 heterozygosy of maternal origin was found in the lesion with positive proinsulin staining in β-cells (Fig. 1A) and absence of expression of the p57 protein (Fig. 1B). A paternally inherited heterozygous mutation of the ABCC8 gene (G228D) was also identified. The maternal genotype was not tested. As focal hyperinsulinism is sporadic, reassuring genetic counseling was given in another center.

On the second child, a near-total pancreatectomy was performed after a peroperative histological confirmation of the diffuse form (Fig. 1C), and the child developed signs of diabetes requiring insulin injections a few weeks after surgery. Moreover, the child acquired neurological impairment with psychomotor retardation due to repeated hypoglycemic seizures, with brain atrophy on the magnetic resonance imaging scan. Molecular analysis of the ABCC8 gene displayed a homozygous mutation identical to the one found in the first child at the heterozygous form. Both parents were found heterozygous for this mutation (Fig. 1).

We present here the first report on both focal (sporadic) and diffuse (familial) forms of hyperinsulinism occurring in the same family and showing well-characterized genetic patterns. In the first child, a paternally inherited ABCC8 mutation associated with a loss of the maternal wild-type chromosome in the pancreatic lesion was responsible for the focal lesion. Paternal and maternal mutations in the ABCC8 gene due to consanguinity were responsible for the recurrence of hyperinsulinism in the second child, with a diffuse pattern. Recent estimations from France, Japan, and the U.S. suggested that 40–65% of all hyperinsulinism patients have a focal form (20,21). Usually, genetic counseling in cases of focal hyperinsulinism is reassuring, as the paternally inherited ABCC8 mutation and the loss of the maternal 11p15 allele in the pancreatic cells are two independent genetic events. Indeed, loss of 11p15 heterozygosy may be regarded as the “second hit” according to Knudson's model, based on the paradigm of retinoblastoma (22), whereas the germline, inherited mutation may be regarded as the “first hit”. However, unlike mutations of genes involved in-cell growth or DNA repair, the germline ABCC8 mutation is not expected to trigger the “second hit,” unless by chance. Thus, the rate of somatic mutation (loss of 11p15 maternal allele) and, consequently, the risk of having another child with a focal form remains low. By contrast, in this consanguineous family, the risk of occurrence of a diffuse form of hyperinsulinism was 25%, as the risk for the offspring to be the carrier of a heterozygous mutation was 50%. The global risk for recurrence of hyperinsulinism in this family, focal or diffuse, was finally equal to the risk of relapse of a diffuse form.

In conclusion, this familial presentation confirms the possibility of the occurrence of focal hyperinsulinism in consanguineous families. Genetic counseling should be prudent in consanguineous families and should include molecular screening for both parents, regardless of the histological form of hyperinsulinism.