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Triple A Syndrome

Last updated April 24, 2018

Approved by: Krish Tangella MD, MBA, FCAP

Triple A Syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima (a reduced or absent ability to secrete tears).


What are the other Names for this Condition? (Also known as/Synonyms)

  • Achalasia Addisonianism Alacrimia syndrome
  • Alacrima-achalasia-adrenal insufficiency neurologic disorder
  • Addisonian achalasia syndrome

What is Triple A Syndrome? (Definition/Background Information)

  • Triple A Syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima (a reduced or absent ability to secrete tears)
  • Most people with triple A Syndrome have all three of these features, although some have only two. Several authors published descriptions of a more global autonomic disturbance associated with the original three characteristics, leading one author to suggest the name 4A syndrome (adrenal insufficiency, achalasia, alacrima, autonomic abnormalities)
  • Specific autonomic disturbances described in this syndrome include abnormal pupillary reflexes, poor heart rate variability, and orthostatic hypotension. Affected individuals may also have developmental delay, intellectual disability, speech problems, a small head size, muscle weakness, movement problems, peripheral neuropathy, and optic atrophy
  • Many of the neurological symptoms of triple A Syndrome worsen over time. Triple A Syndrome is caused by mutations in the AAAS gene and is inherited in an autosomal recessive pattern
  • Alacrimia is treated with artificial tears while achalasia may need surgery with either pneumatic dilatation or Heller's myotomy. Adrenal insufficiency is treated with glucocorticoid and if necessary mineralocorticoid replacement

(Source: Triple A Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Triple A Syndrome? (Age and Sex Distribution)

  • Triple A Syndrome is a rare congenital disorder. The age of onset of disease symptoms varies, and may occur at any age
  • Both males and females may be affected
  • Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Triple A Syndrome? (Predisposing Factors)

  • A positive family history may be an important risk factor, since Triple A Syndromes can be inherited
  • Currently, no other risk factors have been clearly identified for Triple A Syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Triple A Syndrome? (Etiology)

  • Mutations in the AAAS gene cause triple A Syndrome in many affected individuals
  • This gene provides instructions for making a protein called ALADIN, whose function is not well understood
  • Within cells, ALADIN is found in the nuclear envelope, the structure that surrounds the nucleus and separates it from the rest of the cell. Based on its location, ALADIN is thought to be involved in the movement of molecules into and out of the nucleus of the cell. Mutations in the AAAS gene prevent this protein from reaching its proper location in the cell, which may disrupt the movement of molecules
  • Researchers suspect that DNA repair proteins may be unable to enter the nucleus if ALADIN is missing from the nuclear envelope. DNA damage that is not repaired can cause the cell to become unstable and lead to cell death
  • Although the nervous system is particularly vulnerable to DNA damage, it remains unknown exactly how mutations in the AAAS gene lead to the signs and symptoms of triple A syndrome
  • Some individuals with triple A Syndrome do not have an identified mutation in the AAAS gene; in these individuals, the genetic cause of the disorder is unknown
  • Triple A syndrome is inherited in an autosomal recessive pattern 

(Source: Triple A Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive mode of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Triple A Syndrome?

The signs and symptoms of Triple A Syndrome may include:

Very frequently present symptoms in 80-99% of the cases:

  • Achalasia
  • Adrenal insufficiency
  • Generalized hyperpigmentation
  • Seizures

Occasionally present symptoms in 5-29% of the cases:

  • Anterior hypopituitarism
  • Ataxia
  • Developmental regression
  • Hyperreflexia
  • Iris coloboma
  • Microcephaly
  • Muscular hypotonia
  • Optic atrophy
  • Respiratory insufficiency
  • Sensorineural hearing impairment

In addition to the above-mentioned, the following signs and symptoms may be present in some affected individuals:

  • Abnormality of visual evoked potentials
  • Adrenocorticotropin receptor defect
  • Anisocoria
  • Babinski sign
  • Decreased circulating aldosterone level
  • Decreased circulating cortisol level
  • Dysarthria
  • Dysautonomia
  • Hyperpigmentation of the skin
  • Intellectual disability
  • Motor axonal neuropathy
  • Orthostatic hypotension
  • Palmoplantar hyperkeratosis

(Source: Triple A Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Triple A Syndrome Diagnosed?

Triple A Syndrome is diagnosed on the basis of the following information:

  • Complete physical examination
  • Thorough medical history evaluation
  • Assessment of signs and symptoms
  • Laboratory tests
  • Imaging studies
  • Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Triple A Syndrome?

The complications of Triple A Syndrome may include:

  • Severe weight loss
  • Extreme fatigue and dizziness, caused by untreated adrenal insufficiency
  • Risk of falls and injury due to seizures

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Triple A Syndrome Treated?

  • There is no cure for triple A Syndrome at this time; treatment typically focuses on managing individual signs and symptoms of the condition.
  • Glucocorticoid deficiency in individuals with known adrenal insufficiency (present with Addison disease) is typically treated by replacement of glucocorticoids. This may be important for avoiding an adrenal crisis and allowing for normal growth in children
  • In adult individuals, as well as those who have difficulty with compliance, replacing hydrocortisone with prednisone or dexamethasone is sometimes recommended. It is usually recommended that affected individuals wear a medical alert bracelet or necklace and carry the emergency medical information card supplied with it.
  • Achalasia is typically managed with surgical correction. Individuals may be monitored for pulmonary complications (due to reflux and aspiration). Gastric acid reduction therapy in individuals with reflux after surgical intervention is usually recommended
  • The symptoms in individuals with achalasia may be improved partially with pneumatic dilatation (also called balloon dilation). For those who remain symptomatic after this, other surgeries may be recommended.
  • Alacrima is typically managed by applying topical lubricants (such as artificial tears or ointments), and with punctal occlusion (a procedure used to close the tear ducts that drain tears from the eye)
  • The symptoms of alacrima typically improve with punctal occlusion. However, this procedure is usually only done when therapy with topical lubricants is unsuccessful

(Source: Triple A Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Triple A Syndrome be Prevented?

  • Triple A Syndrome may not be preventable, since it is a genetic disorder
  • Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
  • If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
  • Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
  • Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Triple A Syndrome? (Outcomes/Resolutions)

  • The prognosis of Triple A Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
  • Individuals with mild conditions have better prognosis than those with severe symptoms and complications
  • Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Triple A Syndrome:

Triple A Syndrome is also known by the following names:

  • AAA syndrome
  • AAA
  • Achalasia alacrima syndrome
  • Allgrove syndrome

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/

What are some Useful Resources for Additional Information?


References and Information Sources used for the Article:


Helpful Peer-Reviewed Medical Articles:


Reviewed and Approved by a member of the DoveMed Editorial Board
First uploaded: April 24, 2018
Last updated: April 24, 2018