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Triple A syndrome

Orpha number ORPHA869
Synonym(s) 2A syndrome
3A syndrome
4A syndrome
AAA syndrome
Achalasia - addisonianism - alacrima syndrome
Adrenal insufficiency - achalasia - alacrima
Allgrove syndrome
Double A syndrome
Quaternary A syndrome
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
Age of onset All ages
ICD-10
  • E27.4
ICD-O -
OMIM
UMLS
  • C0271742
  • C2931084
MeSH
  • C536008
  • C536009
MedDRA -

Summary

Triple A syndrome is a very rare multisystem disease characterized by adrenal insufficiency with isolated glucocorticoid deficiency, achalasia, alacrima, autonomic dysfunction and neurodegeneration.

Prevalence is unknown but less than 100 cases have been published since the first description in 1978.

The onset of Triple A syndrome varies between infancy and adulthood. When presenting in early childhood, alacrima and, possibly, achalasia are the indicative signs; in childhood and adolescence, onset is characterized by achalasia and adrenal insufficiency; while in adulthood, presentation is predominantly neurological with autonomous and polyneuropathic involvement. Alacrima, when present, is the first clinical sign, manifesting in the first months of life, but achalasia of the cardia, leading to dysphagia, is usually the first relevant symptom leading to diagnosis. Adrenal insufficiency may cause hypoglycemia and seizures. These three cardinal signs may not all be present, or be associated with autonomic dysfunction and other neurological features, leading to the ''double A'' or ''quaternary A'' denomination, respectively. Neurological manifestations are diverse: dysautonomia results in dyshidrosis and digestive, sexual, circulatory and urinary dysfunction; pyramidal syndrome and peripheral neuropathy lead to walking difficulties and sometimes to sensory deficit; and bulbar and facial deficiencies are responsible for velar insufficiency, tongue amyotrophy or paresis, orbicularis oris dysfunction and oropharyngeal dysphagia.

The disease is caused by mutations in the AAAS gene (12q13), coding for the ALADIN nuclear pore scaffolding protein.

Diagnosis is based on clinical examination and adrenal function testing. It can be confirmed by molecular testing.

Given that the presence of 2 among the 3 main clinical signs (achalasia, alacrima or adrenal insufficiency) is pathognomonic, differential diagnosis can be considered when only one clinical sign is observed, for example at the onset of the disease. Differential diagnosis thus includes other causes of adrenal insufficiency, achalasia or alacrima such as frequent forms of congenital adrenal hyperplasia (easily excluded with dosage of adrenal hormones precursors), and rare peripheral forms of congenital adrenal insufficiency or adrenoleukodystrophy, which might be associated with neurological features.

Triple-A syndrome has an autosomal recessive mode of inheritance, thus causing a 25% recurrence risk for parents with an affected child.

Treatment for Triple A syndrome includes hydrocortisone substitutive therapy, esophageal dilatation or myotomy of the lower esophageal sphincter and artificial tear drops. Management of neurological features is symptomatic.

If untreated, triple A syndrome may have a high morbidity and prognosis can be severe. The appropriate management of the disease ameliorates the prognosis significantly.

Expert reviewer(s)

  • Pr Marc NICOLINO

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