Achalasia Addisonianism Alacrimia syndrome

Synonyms

7

Overview

It is a rare autosomal recessive congenital disorder. In most cases, there is no family history of it and only about 70 cases reported worldwide. It is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.

Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).

People with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.

People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.

Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.

Symptoms

  • Adrenal insufficiency
  • Adrenocorticotropic hormone resistance
  • Absent tears 
  • Autonomic dysfunction
  • Low blood sugar
  • Orthostatic hypotension
  • Heart rate changes
  • Short stature
  • Osteoporosis
  • Thickened skin on palms
  • Thickened skin on soles
  • Increased skin pigmentation
  • Dilated esophagus
  • Seizures
  • Impaired vision

Causes

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.

Treatment

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

Resources

Sources:

  • NIH
  • ghr.nlm.nih