Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome

Abstract

The triple A syndrome is a rare autosomal recessive disease that is characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal insufficiency, achalasia and alacrima. In most patients, neurological and dermatological abnormalities are associated features. We report on the first Bosnian patient with triple A syndrome. Endocrine investigation confirmed primary adrenal insufficiency at the age of 5.8 years. Two months later, achalasia was diagnosed, and in the presence of alacrima, the patient satisfies the diagnostic criteria of triple A syndrome. In addition, a large number of associated neurological and dermatological features were present in this patient. Moreover, he has dysmorphic facial features, which have not been previously described in triple A syndrome. Triple A syndrome was confirmed by molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The parents are both heterozygous carriers of the mutation. The affected twin brother unfortunately died from hypoglycaemic shock, despite a normal cortisol rise in an ACTH stimulation test. Further, triple A syndrome patients carrying the identical homozygous p.W84X mutation have to be studied to assess a genotype-phenotype relationship for this mutation.

Phenotype–genotype spectrum of AAA syndrome from Western India and systematic review of literature

“…Additionally, three papers describing summary statistics were excluded, as no clear information about phenotypic and genotypic characteristics of individual patients could be discerned. Finally, data of 133 index cases (cohort 2) from 68 publications were analyzed ( 4 , 5 , 6 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , ...…”

Achalasia: will genetic studies provide insights?

“…A variety of neurological and dermatological features, as well as occasional dysmorphic facial features, are also associated (Allgrove et al 1978;Prpic et al 2003). Since its initial description in 1978, more than 150 cases have been reported (Allgrove et al 1978;Toromanovic et al 2009). The triple A syndrome is caused by homozygous or compound heterozygous mutations in the AAAS gene on chromosome 12q13 (Tullio-Pelet et al 2000;Weber et al 1996), which encodes for the protein alacrima-achalasiaadrenal-insufficiency neurologic disorder (ALADIN).…”

“…Achalasia occurs in around 75% of patients with Allgrove syndrome and is its main presenting feature. The achalasia is usually diagnosed in infancy even when the remaining symptoms of triple A syndrome become clinically manifest at puberty or in adulthood (Gazarian et al 1995;Grant et al 1993;Houlden et al 2002;Prpic et al 2003;Salmaggi et al 2008;Toromanovic et al 2009). Although frameshift, stop codon, and other functionally significant mutations appear to be associated with a more severe phenotype (including an earlier age of onset), the type of mutation does not fully explain the observed variability, which must involve additional (possibly genetic) factors (Huebner et al 2002).…”

Diagnosis of Diseases of Steroid Hormone Production, Metabolism and Action

“…Neurologic problems may or may not be present. The achalasia−Addisonian−alacrima syndrome (AAA), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement (60). A gene for aladin on chromosome 12q3 is involved (61).…”