title: Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome.
abstract: The triple A syndrome (Allgrove syndrome, OMIM #231550) is caused by autosomal recessively inherited mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. This multisystemic disease is characterised by achalasia, alacrima, adrenal insufficiency and neurological impairment. We analyse long-term clinical follow-up and results of sequencing of the AAAS gene in eight patients with triple A syndrome aged from 2 to 35 years. At the time of diagnosis, all patients presented with alacrima, neurological dysfunction, dermatological abnormalities, seven of them with adrenal insufficiency and five of them with achalasia. Sequencing of the AAAS gene identified the p.S263P mutation in five of eight patients, supporting the hypothesis that this mutation is a founder mutation in Slavic population. One of the patients is homozygous for the p.S263P mutation, two are compound heterozygous for the p.S263P and the p.G14fs mutation, two are compound heterozygous for the p.S263Pro mutation and p.S296Y mutation, two are compound heterozygous for the p.G14fs and the p.Q387X mutations and one is homozygous for the p.Q387X mutation. In the course of the follow-up time of 4-29 years, progression of existing and appearance of new symptoms developed. Although severe, many of these symptoms presented in all six young adult patients are often overlooked or neglected: postural hypotension with blurred vision and syncope, hyposalivation resulting with complete edentulosis, talocrular contractures with permanent walking difficulties and erectile dysfunction in male patients. Triple A syndrome is a progressive debilitating disorder which may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment.
  
  
  CONCLUSIONS
  Long-term follow-up of patients with triple A syndrome revealed a variety of the clinical features involving many systems. Progressive natural course of the disease may seriously affect quality of life and even be life-threatening in patients with severe neurological impairment.
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University Hospital Centre Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia. drdumic@gmail.com
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dumic
authors.forename: Nina
authors.initials: N
authors.lastname: Barišic
authors.forename: Vesna
authors.initials: V
authors.lastname: Kusec
authors.forename: Katarina
authors.initials: K
authors.lastname: Stingl
authors.forename: Mate
authors.initials: M
authors.lastname: Skegro
authors.forename: Andrija
authors.initials: A
authors.lastname: Stanimirovic
authors.forename: Katrin
authors.initials: K
authors.lastname: Koehler
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D004931:Esophageal Achalasia / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D008297:Male; D010375:Pedigree