Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing's 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 activating mutation in the stimulatory G-protein (Gs alpha) was detected. The patient presented at 3 months of age with Cushingoid features, poor linear growth, and elevated liver enzymes. Plasma ACTH and dexamethasone suppression test results were consistent with ACTH-independent Cushing's syndrome, and a subsequent adrenalectomy revealed bilateral adrenocorticonodular hyperplasia. Asymptomatic lesions consistent with fibrous dysplasia were later detected on bone scan. Genomic DNA was extracted from adrenal, liver, and blood and amplified by polymerase chain reaction with Gs alpha exon 8 primers. Using allele-specific oligonucleotide hybridization, the DNA was probed for known Gs alpha-activating mutations. A point mutation coding for an arginine to cysteine substitution at codon 201 of exon 8 was detected in genomic DNA from this infant's adrenal, liver, and leukocytes. The mutation was detected in nodular adrenal tissue, but was essentially absent in normal adrenal tissue. Activating mutations in the Gs alpha gene have previously been described in GH-secreting tumors, thyroid adenomas, and the McCune-Albright syndrome and are probably involved in the pathogenesis of adrenocorticonodular hyperplasia in this infant with Cushing's syndrome.