Abstract 810

The case study involves a unique family of six in Utah which has two female siblings affected with nesidioblastosis, and two pairs of unaffected siblings and parents. The parents were involved in a nonconsanguineous marriage without any known founder effect in their family pedigree. Both affected children were large for gestational age at birth and diagnosed within the first 3-4 days of life with persistent hyperinsulinemic hypoglycemia of infancy (nesidioblastosis). Both were treated initially with diazoxide and octreotide during their first two weeks; however, both required a 95% subtotal pancreatectomy during their second week of life. Both patients' hyperinsulinemic hypoglycemia subsequently normalized, albeit with continued need for high dose octreotide and diazoxide. Pathology results revealed the presence of diffuse pancreatic islet cell hyperplasia in the surgical specimens obtained from both patients. The oldest sibling is now 7.5 years old and has recently developed hypoinsulinemic hyperglycemia, requiring a daily regime of subcutaneous insulin for return to euglycemia.

Recent developments in characterizing the genetic basis for the autosomal recessive form of nesidioblastosis have localized two genes causing this disease to chromosome 11p15. Defects in these candidate genes, encoding the sulfonylurea receptor (SUR gene) and a KATP channel (Kir6.2 gene), were subsequently identified in kindreds with the autosomal recessive form of nesidioblastosis (Thomas, P. et al., (1995) Science 268, 426-429; Thomas, P. et al., (1996) Hum. Mol. Genet. 11, 1809-1812). Given the inheritance pattern noted in the above family with two affected siblings, it is very likely that this disease is inherited in an autosomal recessive manner.

Now that candidate genes have been identified for the autosomal recessive form of this disease, this information will allow us to perform a focused linkage analysis using highly informative markers from chromosome 11p15. The small family described above will be enrolled in a study with the null hypothesis directed at excluding linkage to chromosome 11p15. If linkage to chromosome 11p15 is not excluded, then mutational analysis studies (ie. single strand conformational polymorphism analysis, etc) will be performed directed against the candidate SUR and Kir6.2 genes. The overall goals of this study are to apply informative genetic linkage markers which ultimately may be help for this family in subsequent carrier status and/or prenatal diagnosis studies.