Two patients with an identical novel mutation in the AAAS gene and similar phenotype of triple A (Allgrove) syndrome.

[triple a syndrome]

Triple A syndrome , also known as Allgrove syndrome , is a rare autosomal recessive disorder characterized by three cardinal symptoms : adrenal insufficiency due to ACTH insensitivity , achalasia and alacrima . Various progressive neurological abnormalities and skin changes have been described in association with the syndrome . The disease is caused by mutation in the AAAS gene on chromosome 12 q 13 . AAAS encodes a protein named ALADIN which is part of the nuclear pore complex (NPC ). The mislocalization of mutated ALADIN proteins in the cytoplasm and /or the nucleus results in an impaired protein function . Phenotypes of previously reported patients with triple A syndrome varied within and between affected families so that no genotype-phenotype could be established .Genetic analysis was performed in two unrelated patients , their parents and one sister . AAAS coding sequences including exon-intron boundaries were amplified and sequenced using an ABI 3100 sequencing machine .We present two unrelated Swiss patients with triple A syndrome demonstrating similar phenotypic characteristics . Both showed a progression of the disease presenting with adrenal insufficiency and alacrima in early childhood . At the age between 30 -40 years they developed symptomatic achalasia . The pattern and severity of progressive neurological and autonomic dysfunction was comparable . In both patients molecular genetic analysis revealed an identical novel homozygous mutation (c .618 delC , p .Ser 207 fs ) in the AAAS gene .R ecent genotype /phenotype studies showed a marked inter- and intrafamiliar variability in triple A syndrome . Here we present a rather tight genotype /phenotype correlation in two unrelated patients carrying the identical novel p .Ser 207 fs mutation in the AAAS gene .