UNIQUE PRESENTATION OF AN 8p DELETION IN A DISCORDANT TWIN WITH ATRIOVENTRICULAR CANAL DEFECT AND PROLONGED HYPOGLYCEMIA
Kumar P*, Elshershari H, Parashette KR, Ize-Ludlow D, Harris C
*Corresponding Author: Praveen Kumar, M.D., Department of Pediatrics, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60612, USA; Tel.: +312-850-0375; Fax: +312-413-0243; E-mail: praveenk@ uic.edu
page: 47

DISCUSSION

The first patient with an 8p deletion and congenital heart disease was reported in 1973 [4]. Such children frequently show congenital heart defects and a variable degree of mental retardation. In contrast, facial anomalies are subtle [5]. Congenital heart diseases which are phenotypically linked to chromosome 8p22-23 have a locus between D8S264 and D8S1827 [3], which is associated with GATA4, a zinc-finger transcription factor. Our patientís deleted locus was (D8S504-). In mouse embryos, this transcription factor is necessary for normal folding that later on gives rise to heart tube and pericardial cavity [6]. Therefore, GATA4 is required for development of all four chambers. GATA4 also interacts with TBX5 for normal development of cardiac septum [3]. Thus, an 8p deletion causes haploinsufficiency of GATA4 which is responsible for congenital heart diseases.

Hyperinsulinism during infancy causes transient or permanent hypoglycemia. Prematurity, intrauterine growth restriction and congestive heart failure may result in transient neonatal hypoglycemia without hyperinsulinemia. Perinatal asphyxia can result in hyperinsulinemic hypoglycemia, but it presents during the first days of life. There are several genetic causes of hyperinsulinemic hypoglycemia including mutations in the genes encoding the SUR1/Kir6.2 complex [7], glutamate dehydrogenase , glucokinase and 3-hydroxyacyl-CoA dehydrogenase, but in many cases the genetic etiology is unknown [8]. Laboratory diagnosis of hyperinsulinemic hypoglycemia of infancy is based on persistent hypoglycemia, inappropriately elevated plasma insulin concentration during hypoglycemia, low ketones and increased glycemic response to glucagon. Hoe et al. [9] reported 26 cases of prolonged neonatal hyperinsulinism where genetic etiology underlying glucose regulation was unknown and 95% neonates demonstrated good response to diazoxide. Our patient had late onset prolonged hypoglycemia with good response to diazoxide. The laboratory results confirmed non ketotic hypoglycemia with glycemic response to glucagon, inappropriate insulin levels during hypoglycemic episodes and low serum free fatty acid concentration. The response to glucagon and hyperinsulinism ruled out glycogen storage defects. In our patient, chromosome 8 locus D8S504- onwards is deleted. There are no known genes that regulate insulin secretion or action within this interval. One study has reported linkage of susceptibility to type 2 diabetes on indigenous Australians to the nearby marker D8S549 [10]. It is possible that a mutation vs. deletion in such a gene could cause opposite phenotypes, hyperinsulinemia vs. increased risk for Type 2 diabetes.




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