Triple A syndrome Symptoms, Causes and Treatment

Triple A syndrome, also called Allgrove syndrome, is an inherited condition that gets its name from three specific features: achalasia, adrenal insufficiency, and alacrima. Most people with triple A syndrome have all three of these features, although some have only two. 

Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that connects the throat to the stomach. Achalasia can lead to severe feeding difficulties, vomiting, and weight loss. Signs and symptoms of achalasia can appear at any time between the ages of 6 months and late adolescence.

Adrenal insufficiency occurs when the small hormone-producing glands on top of each kidney (adrenal glands) do not produce enough hormones. Features of adrenal insufficiency can include fatigue, loss of appetite, weight loss, low blood pressure, low blood glucose (hypoglycemia), and seizures.

The third major feature of triple A syndrome is alacrima. Tear secretion is reduced or completely absent in people with alacrima. This feature is often the first noticeable sign of triple A syndrome in affected infants.

Approximately one-third of all people with triple A syndrome also have dysfunction of the autonomic nervous system (dysautonomia). The autonomic nervous system regulates involuntary bodily processes, including digestion, blood pressure, and body temperature. People with triple A syndrome may experience abnormal sweating, changes in the production of saliva, difficulty regulating blood pressure and heart rate, unequal pupil size (anisocoria), and other problems.

Additional features of triple A syndrome can include cognitive abilities that decline over time. Affected individuals may also have muscle weakness, difficulty coordinating movements (ataxia), speech problems (dysarthria), short stature, and a small head size (microcephaly). Adults with triple A syndrome often have brittle bones that are prone to fracture (osteoporosis). Optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain, has also been found in affected individuals.

People with triple A syndrome may develop skin abnormalities, such as darkening of the skin and thickening of the outer layer of the skin (hyperkeratosis) on the palms of the hands and the soles of the feet. 

The symptoms of triple A syndrome typically develop gradually over a period of several years and can vary widely, even among members of the same family.

Triple A syndrome is a rare condition; it is estimated to affect 1 in 1 million individuals. However, it is likely that many people with this condition never receive a diagnosis.

Variants (also called mutations) in the AAAS gene cause triple A syndrome. This gene provides instructions for making a protein called ALADIN. ALADIN appears to be very active in the cells of the adrenal glands, brain, and digestive system. ALADIN is located in the nuclear envelope, which is the structure that surrounds the nucleus and separates it from the rest of the cell.  ALADIN helps determine which molecules can enter and exit the nucleus. 

The variants in the AAAS gene that are associated with triple A syndrome cause cells to produce a version of ALADIN that does not function properly. Researchers suspect that this change disrupts the communication and movement of molecules between the nucleus and the rest of the cell, which disrupts cellular processes such as growth, maturation, and repair. Exactly how variants in the AAAS gene lead to the specific signs and symptoms seen in people with triple A syndrome is unclear.

Some individuals with triple A syndrome do not appear to have a variant in the AAAS gene. In rare cases, variants in other genes have been found to cause signs and symptoms that are similar to those seen in people with triple A syndrome. Researchers are working to determine whether these gene variants cause triple A syndrome or a related condition.