title: Two patients with an identical novel mutation in the AAAS gene and similar phenotype of triple A (Allgrove) syndrome.
abstract: BACKGROUND
  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 12q13. 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.618delC, p.Ser207fs) in the AAAS gene.
  
  
  CONCLUSIONS
  Recent 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.Ser207fs mutation in the AAAS gene.
authors.affiliation: Division of Endocrinology and Diabetes, Department of Internal Medicine, Cantonal Hospital St. Gallen, Switzerland. ina.krull@bluewin.ch
authors.forename: I
authors.initials: I
authors.lastname: Krull
authors.forename: M
authors.initials: M
authors.lastname: M-Woelfle
authors.forename: K
authors.initials: K
authors.lastname: Bärlocher
authors.forename: K
authors.initials: K
authors.lastname: Koehler
authors.forename: A
authors.initials: A
authors.lastname: Huebner
authors.forename: M
authors.initials: M
authors.lastname: Brändle
mesh_terms: D000309:Adrenal Insufficiency / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D000328:Adult; D001483:Base Sequence; D002404:Catheterization; D004931:Esophageal Achalasia / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D049630:Esophageal Sphincter, Lower; D005091:Exons; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D022022:Nuclear Pore / Q000235:genetics; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: C416506:AAAS protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D006854:Hydrocortisone