ACTIVATING MUTATION IN THE STIMULATORY G PROTEIN GENE IN AN INFANT WITH ADRFNOCORTICONODULAR DYSPLASIA

Abstract

Infantile Cushing's Syndrome is a rare condition caused by excess cortisol production. We describe an activating mutation in the gene coding for the stimulatory G protein (Gsalpha) in DNA from adrenal tissue in an infant with ACTH independent Cushing's Syndrome. Activating mutations in exons 8 and 9 of the Gsalpha gene have been associated with growth hormone secreting pituitary tumors and McCune-Albright syndrome. Specifically, point mutations coding for an arginine to cysteine or an arginine to histidine substitution at site 201 in exon 8 have been described.The patient in this study was Cushingoid in appearance with poor linear growth by 3 months of age. Evaluation revealed elevated serum cortisol despite low and high dose dexamethasone suppression and undetectable baseline ACTH levels (<3 pg/ml). He underwent bilateral adrenalectomy with subsequent steroid replacement. Adrenal histology revealed bilateral adrenalcortical dysplasia with nodular elements.Genomic DNA was extracted from adrenal tissue and amplified by PCR with primers for Gsalpha exon 8. Using allele specific oligonucleotide hybridization, the amplified DNA was probed for the presence of point mutations which correspond to the known mutations in exon 8. An oligonucleotide probe corresponding to the cysteine substitution at site 201 hybridized with amplified DNA from the patient's adrenal tissue. A “wild type” probe coding for arginine bound to both leukocyte DNA from a normal human control and patient DNA while the probe for the arginine to hisiidine mutation bound to neither patient nor control DNA.We conclude that the arginine to cysteine activating mutation in exon 8 of Gsalpha is present in the adrenal tissue of ihis infant with Cushing's Syndrome. This mutation may be involved in the pathogenesis of adrenocorticonodular dysplasia in some patient's with infantile Cushing's Syndrome.