Triple-A syndrome

Triple-A syndrome

Triple-A syndrome or AAA syndrome is a rare autosomal recessive congenital disorder. In most cases, there is no family history of it. The syndrome was first identified by Jeremy Allgrove and colleagues in 1978, and since then just over 100 cases have been reported. The syndrome involves achalasia, addisonianism (adrenal insufficiency of primary type), and alacrima (insufficiency of tears). Alacrima is usually the earliest manifestation. It is a progressive disorder that can take years to develop the full-blown clinical picture.

Presentation

Individuals affected by AAA have adrenal insufficiency/Addison's disease due to ACTH resistance, alacrima (absence of tear secretion), and achalasia of the lower esophageal sphincter at the cardia which delays food going to the stomach and causes dilation of the thoracic esophagus. There may also be signs of autonomic dysfunction with AAA, such as pupillary abnormalities, abnormal sweating, orthostatic hypotension, and disturbances of the heart rate. Hypoglycemia is often mentioned as an early sign. The disorder has also been associated with mild mental retardation.

The syndrome is highly variable. Managed effectively, affected individuals can have a normal lifespan and bear children.

Cause

Triple-A syndrome is associated with mutations in the AAAS gene, which encodes a protein known as ALADIN. The ALADIN protein is a component of the nuclear pore complex, situated toward its cytoplasmic side. Mutant ALADIN remains mislocalized in the cytoplasm and causes selective failure of nuclear protein import and hypersensitivity to oxidative stress. Mutant ALADIN also causes decreased nuclear import of aprataxin, a repair protein for DNA single-strand breaks, and DNA ligase I. These decreases in DNA repair proteins may allow accumulation of DNA damages that trigger cell death.

Nucleoporin ALADIN participates in spindle assembly. ALADIN is employed in specific meiotic stages, including spindle assembly, and spindle positioning. Female mice homozygously null for ALADIN are sterile.

Diagnosis

Features of achalasia cardia include an absence of fundal gas shadow on plain x-ray, widened mediastinum, and an air-fluid level in the mediastinum. The gold standard investigation is a 24-hour manometry of the esophagus. It shows non-relaxation of the lower esophageal sphincter, increased tone of the esophageal sphincter, and an atonic esophagus. Bird-beak sign and rat-tail sign can be appreciated on a barium swallow.

Treatment

There is no definitive cure for this syndrome, as many of the mechanisms implicated have not been identified. Treatments address only some of the symptoms: artificial tear drops remedy the absence of tear secretion; achalasia can be treated with surgical intervention when needed; and corticosteroids, such as hydrocortisone, are prescribed to address adrenal insufficiency.

See also

• Achalasia
• Addisonianism
• Alacrima

External links

• Allgrove (AAA) Syndrome at eMedicine

• Online Mendelian Inheritance in Man (OMIM) 231550

Achalasia Addisonianism Alacrimia syndrome; Triple A syndrome at NIH's Office of Rare Diseases

Classification	ICD-10: E27.4 OMIM: 231550 DiseasesDB: 32088
External resources	eMedicine: ped/71 Orphanet: 869

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