Context: CLAH, caused by mutations in steroidogenic acute regulatory protein (StAR) is most frequent in Japanese and Palestinians. We report eight Palestinians, from four unrelated families with CLAH.

Objective: To identify the mutation(s) in StAR, correlate genotype with phenotype, and to determine if the common mutation represents a founder mutation.

Patients and setting: Clinical, histopathological and molecular genetic characterization was performed in these eight patients.

Results: All affected individuals (3 XY, 5 XX) presented neonatally with undetectable adrenocortical hormones, and are responding to replacement therapy. Only two sisters had neurodevelopmental deficits. Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells. Significantly, already at 1y of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of StAR revealed homozygosity for c.201_202delCT mutation in all eight cases, causing premature termination of the StAR protein. This mutation was confirmed to be a founder mutation using both an intragenic microsatellite and several single nucleotide polymorphism markers. Screening of 100 normal Jerusalem-Palestinians detected no carriers of this mutation.

Conclusion: CLAH is rare in the general Palestinian population. In most Palestinian cases, a founder c.201_202delCT mutation in StAR is the cause. The observed early neonatal presentation may reflect the major StAR protein truncation caused by this mutation. A crucial role for StAR in the central nervous system was not supported with normal neurological examinations in 6/8 cases. Finally, we advocate early gonadectomy in XY CLAH cases given the early onset of neoplastic changes observed histologically.