Achalasia-Addisonianism-Alacrimia Syndrome (AAAS)
Achalasia-addisonianism-alacrimia syndrome (triple A syndrome) is an autosomal recessive disorder caused by pathogenic variants in AAAS. This gene encodes a protein thought to help move molecules into and out of the nucleus. Pathogenic variants in AAAS prevent the protein from localizing to the nuclear envelope leading to impaired transport of molecules. Alacrima, or the reduced ability to tear, typically manifests in early infancy followed by achalasia, a condition where the lower esophagus fails to relax preventing movement of food into the stomach. Achalasia can cause dysphagia (difficult swallowing), severe feeding difficulties, and hypoglycemic episodes. Addison disease, or adrenal insufficiency due to ACTH resistance, appears in childhood and may result in seizures, lethargy, weight loss, low blood pressure, and darkening of the skin. While most individuals experience all three conditions, some only exhibit two. A variety of other symptoms may also be present. These include peripheral neuropahy, muscle weakness, and neurological symptoms such as mild intellectual disability, dysarthria (unclear articulation of speech), ataxia (lack of muscle control of voluntary movements), and developmental delay. Dysautonomia can also lead to anisocoria and abnormal sweating. This condition exhibits variable expressivity, even between affected family members. Without treatment, individuals may die in infancy or childhood. However, proper management significantly improves the prognosis. No clear genotype-phenotype correlation has been established and the prevalence is unknown.
For information about carrier frequency and residual risk, please see the residual risk table.