ACTIVATING MUTATION IN THE STIMULATORY GUANINE-NUCLEOTIDE-BINDING PROTEIN IN AN INFANT WITH CUSHINGS-SYNDROME AND NODULAR ADRENAL-HYPERPLASIA

Cushing's syndrome in infancy is uncommon. In this report, we describe an infant with ACTH-independent Cushing's syndrome in which an activa ting mutation in the stimulatory G-protein (G(s alpha)) was detected. The patient presented at 3 months of age with Cushingoid features, poo r linear growth, and elevated liver enzymes. Plasma ACTH and dexametha sone suppression test results were consistent with ACTH-independent Cu shing's syndrome, and a subsequent adrenalectomy revealed bilateral ad renocorticonodular hyperplasia. Asymptomatic lesions consistent with f ibrous dysplasia were later detected on bone scan. Genomic DNA was ext racted from adrenal, liver, and blood and amplified by polymerase chai n reaction with G(s alpha) exon 8 primers. Using allele-specific oligo nucleotide hybridization, the DNA was probed for known G(s alpha)-acti vating mutations. A point mutation coding for an arginine to cysteine substitution at codon 201 of exon 8 was detected in genomic DNA from t his infant's adrenal, liver, and leukocytes. The mutation was detected in nodular adrenal tissue, but was essentially absent in normal adren al tissue. Activating mutations in the G(s alpha) gene have previously been described in GH-secreting tumors, thyroid adenomas, and the McCu ne-Albright syndrome and are probably involved in the pathogenesis of adrenocorticonodular hyperplasia in this infant with Cushing's syndrom e.