Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia

Congenital lipoid adrenal hyperplasia (lipoid CAH), the most severe form of CAH, is caused by mutations in the steroidogenic acute regulatory protein (StAR). Lipoid CAH is common among the Japanese, Korean, and Palestinian Ar ab populations, but is rare elsewhere. We describe six patients with lipoid CAH: four Japanese, one Palestinian, and one Guatemalan Native American. A ll had classical clinical presentations of normal female external genitalia in both genetic sexes, with severe glucocorticoid and mineralocorticoid de ficiency presenting in the first month of life. Quite atypically, one patie nt had small adrenal glands shown by computed tomographic scanning. The StA R genes were characterized in all six patients. Three of the Japanese patie nts were compound heterozygotes for the common Japanese mutation Q258X in a ssociation with three different novel frameshift mutations: the fourth Japa nese patient was homozygous for the mutation R182L, which is common among P alestinian patients but has not been described previously in a Japanese pat ient. Our Palestinian and Native American patients were each homozygous for novel frameshift mutations. Thus we have found five new frameshift mutatio ns, but no new amino acid replacement (missense) mutations. This would be c onsistent with the view that only a small number of residues in the StAR pr otein are crucial for biological activity. The tomographic finding of small adrenals in a patient with genetically proven lipoid CAH due to a StAR mut ation suggests a substantially broader spectrum of clinical findings in thi s disease than has been appreciated previously.