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, 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 (a failure of a ring of muscle fibers, such as a sphincter, to relax) 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, an abnormal reaction to intradermal histamine, abnormal sweating, orthostatic hypotension, and disturbances of the heart rate. Hypoglycemia (low blood sugar) 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 (ALacrima Achalasia aDrenal Insufficiency Neurologic disorder). In 2000, Huebner et al. mapped the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. Since inheritance and gene for the association is known, early diagnosis can allow genetic counseling.

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

Following features of achalasia cardia are seen. On plain x-ray an absence of fundal gas shadow, widened mediastinum and an air fluid level in mediastinum is also seen. The gold standard investigation is a 24 hours manometry of oesophagus. It shows non-relaxation of lower oesophageal sphincter, increased tone of oesophageal sphincter, atonic oesophagus. Bird-beak sign and rat-tail sign can be appreciated on barium swallow.

Treatment

There is no definitive cure for this syndrome, because many of the mechanisms implicated have not yet been identified.The only possible treatments address only some of the symptoms. Artificial tear drops are used to remedy the absence of tear secretion, achalasia, if needed, can be treated with surgical intervention and corticosteroids, such as hydrocortisone, are prescribed to solve the surrenal insufficiency.

See also

• Achalasia
• Addisonianism
• Alacrima