|Triple A syndrome|
|MRI of the brain of 12-year-old boy with triple-A syndrome showing hypoplastic lacrimal glands (yellow arrows.)|
Triple-A syndrome or AAA syndrome, also known as achalasia-addisonianism-alacrima syndrome or Allgrove 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. 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.
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 and genetics
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. Mutant ALADIN 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.
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.
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- Online Mendelian Inheritance in Man (OMIM) 231550
- Dusek, Tina; Korsic, Marta; Koehler, Katrin; Perkovic, Zdravko; Huebner, Angela; Korsic, Mirko (2006). "A Novel AAAS Gene Mutation (p.R194X) in a Patient with Triple A Syndrome". Hormone Research. 65 (4): 171&ndash, 176. doi:10.1159/000092003. PMID 16543750.
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- Huebner, Angela; Kaindl, A.M.; Knobeloch, K.P.; Petzold, H.; Mann, P.; Koehler, K. (2004). "The Triple A Syndrome Is Due to Mutations in Aladin, a Novel Member of the Nuclear Pore Complex". Endocrine Research. 30 (4): 891&ndash, 899. doi:10.1081/ERC-200044138. PMID 15666842.
- Salmaggi A, Zirilli L, Pantaleoni C, et al. (2008). "Late-onset triple A syndrome: a risk of overlooked or delayed diagnosis and management". Horm. Res. 70 (6): 364&ndash, 372. doi:10.1159/000161867. PMID 18953174.
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- Carvalhal S, Stevense M, Koehler K, Naumann R, Huebner A, Jessberger R, Griffis ER (September 2017). "ALADIN is required for the production of fertile mouse oocytes". Mol. Biol. Cell. 28 (19): 2470–2478. doi:10.1091/mbc.E16-03-0158. PMC 5597320. PMID 28768824.
- Allgrove (AAA) Syndrome at eMedicine
- OMIM: 231550 Achalasia Addisonianism Alacrimia syndrome; Triple A syndrome at NIH's Office of Rare Diseases