Triple-A syndrome

Last updated
Triple A syndrome
Other namesAchalasia–addisonianism–alacrima syndrome or Allgrove syndrome [1]
1471-2415-4-7-1-l.jpg
MRI of the brain of 12-year-old boy with triple-A syndrome showing hypoplastic lacrimal glands (yellow arrows)
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Triple-A syndrome or AAA syndrome is a rare autosomal recessive congenital disorder. In most cases, there is no family history of AAA syndrome. [2] The syndrome was first identified by Jeremy Allgrove and colleagues in 1978; since then just over 100 cases have been reported. [3] The syndrome is called Triple-A due to the manifestation of the illness which includes achalasia (a dysfunction of the esophagus), addisonianism (adrenal insufficiency of primary type), and alacrima (insufficiency of tears). Alacrima is usually the earliest manifestation. [4] Neurodegeneration or atrophy of the nerve cells and autonomic dysfunction may be seen in the disorder; therefore, some have suggested the disorder be called 4A syndrome. [5] It is a progressive disorder that can take years to develop the full-blown clinical picture. [6] The disorder also has variability and heterogeneity in presentation. [7]

Contents

Presentation

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 in the lower part of the esophagus to relax) called the lower esophageal sphincter at the cardia (very upper portion of the stomach). The esophagus is the tube that carries food from the mouth to the stomach. Achalasia delays food going to the stomach and causes dilation of the thoracic esophagus. There may also be signs of autonomic dysfunction, such as pupillary abnormalities, an abnormal reaction to intradermal histamine, abnormal sweating, orthostatic hypotension (low blood pressure with standing), and disturbances of the heart rate. [8] Unexplained hypoglycemia (low blood sugar) is often mentioned as an early sign. [6] The disorder has also been associated with mild intellectual disability. [6] The syndrome is highly variable. However, one of the most common findings in all patients are the lack of tears. Lack of tears with crying is often mentioned in hindsight after the diagnosis has been made. [7] AAA syndrome may be diagnosed in early childhood or in adolescence. The disorder is typically managed by treating the symptoms with hormone replacement for adrenal insufficiency, lubricating drops for the eyes and managing low blood sugars. [9]

Cause

Triple-A syndrome is associated with mutations in the AAAS gene which encodes a protein known as ALADIN (ALacrima Achalasia adrenal Insufficiency Neurologic disorder). [10] [11] [12] In 2000, Huebner et al. mapped the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. [13] Since inheritance and gene for the association is known, early diagnosis can allow genetic counseling. [4] Furthermore, genotypic heterogeneity has also been documented suggesting that there may be other genes involved in this genetic disorder as well as unknown environmental factors that result in the phenotypic expression of the disease. [7]

ALADIN protein is a component of the nuclear pore complex, situated toward its cytoplasmic side. Mutant ALADIN remains mis-localized in the cytoplasm [14] and causes selective failure of nuclear protein import and hypersensitivity to oxidative stress. [15] Mutant ALADIN also causes decreased nuclear import of aprataxin, a repair protein for DNA single-strand breaks, and DNA ligase I. [15] These decreases in DNA repair proteins may allow accumulation of DNA damage that trigger cell death. [7]

Nucleoporin ALADIN participates in spindle assembly. ALADIN is employed in specific meiotic stages, including spindle assembly, and spindle positioning. [16] Female mice homozygously null for ALADIN are sterile. [16]

Diagnosis

The diagnosis of this condition involves examination by a health provider. Clinical signs may lead to the diagnosis such as the lack of tears and digestive issues, such as acid reflux disease in infancy as well as symptoms of adrenal insufficiency such as frequent bouts of low blood sugars are highly suggestive of the disorder. [7] [5] [9] Achalasia may be seen on plain X-rays and include an absence of fundal gas shadow, widened mediastinum and an air fluid level in mediastinum is also seen. The gold standard for confirming achalasia is a 24 hours manometry of oesophagus.This is a test that measures the pressure inside the esophagus. The test demonstrates non-relaxation of lower esophageal sphincter, increased tone of esophageal sphincter, atonic esophagus. Bird-beak sign and rat-tail sign can be appreciated on barium swallow. [17] [18] [19] Lack of tears or alacrima is caused by the lack of production of lacrimal glands or ducts and defects in the nerves of the lacrimal gland caused by a dysfunction in the autonomic nervous system. [20] The diagnosis is confirmed with genetic testing as well as clinical features. [9]

Treatment

There is no definitive cure for this syndrome because many of the mechanisms implicated have not yet been identified. The available treatments address only some of the symptoms. Lubricating drops and emulsions are used to remedy the absence of tear secretion. Achalasia can be treated with surgical intervention resulting in improved passage of food and drink into the stomach. Corticosteroids, such as hydrocortisone, are prescribed to solve the adrenal insufficiency. [21] Early diagnosis may prevent morbidity and improve growth in children due to early treatment of adrenal insufficiency. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Ehlers–Danlos syndromes</span> Group of genetic connective tissues disorders

Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders in the current classification, with the latest type discovered in 2018. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis.

<span class="mw-page-title-main">Esophageal achalasia</span> Rare, incurable, progressive motility disorder due to failure of esophogeal motor neurons

Esophageal achalasia, often referred to simply as achalasia, is a failure of smooth muscle fibers to relax, which can cause the lower esophageal sphincter to remain closed. Without a modifier, "achalasia" usually refers to achalasia of the esophagus. Achalasia can happen at various points along the gastrointestinal tract; achalasia of the rectum, for instance, may occur in Hirschsprung's disease. The lower esophageal sphincter is a muscle between the esophagus and stomach that opens when food comes in. It closes to avoid stomach acids from coming back up. A fully understood cause to the disease is unknown, as are factors that increase the risk of its appearance. Suggestions of a genetically transmittable form of achalasia exist, but this is neither fully understood, nor agreed upon.

An esophageal motility disorder (EMD) is any medical disorder resulting from dysfunction of the coordinated movement of esophagus, which causes dysphagia.

<span class="mw-page-title-main">Addison's disease</span> Endocrine disorder

Addison's disease, also known as primary adrenal insufficiency, is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands, causing adrenal insufficiency. Symptoms generally come on slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of the skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure, vomiting, lower back pain, and loss of consciousness. Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.

<span class="mw-page-title-main">Adrenal insufficiency</span> Medical condition

Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids, mineralocorticoids, and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. Deficiency of these hormones leads to symptoms ranging from abdominal pain, vomiting, muscle weakness and fatigue, low blood pressure, depression, mood and personality changes to organ failure and shock. Adrenal crisis may occur if a person having adrenal insufficiency experiences stresses, such as an accident, injury, surgery, or severe infection; this is a life-threatening medical condition resulting from severe deficiency of cortisol in the body. Death may quickly follow.

<span class="mw-page-title-main">Hyperandrogenism</span> Medical condition

Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.

<span class="mw-page-title-main">Fraser syndrome</span> Recessive genetic disorder involving eye and genital abnormalities

Fraser syndrome is an autosomal recessive congenital disorder, identified by several developmental anomalies. Fraser syndrome is named for the geneticist George R. Fraser, who first described the syndrome in 1962.

<span class="mw-page-title-main">Hermansky–Pudlak syndrome</span> Medical condition

Heřmanský–Pudlák syndrome is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism, bleeding problems due to a platelet abnormality, and storage of an abnormal fat-protein compound. It is thought to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.

<span class="mw-page-title-main">Adrenocorticotropic hormone deficiency</span> Medical condition

Adrenocorticotropic hormone deficiency is a rare disorder characterized by secondary adrenal insufficiency with minimal or no cortisol production and normal pituitary hormone secretion apart from ACTH. ACTH deficiency may be congenital or acquired, and its symptoms are clinically similar to those of glucocorticoid deficiency. Symptoms consist of weight loss, diminished appetite, muscle weakness, nausea, vomiting, and hypotension. Low blood sugar and hyponatremia are possible; however, blood potassium levels typically remain normal because affected patients are deficient in glucocorticoids rather than mineralocorticoids because of their intact renin-angiotensin-aldosterone system. ACTH may be undetectable in blood tests, and cortisol is abnormally low. Glucocorticoid replacement therapy is required. With the exception of stressful situations, some patients with mild or nearly asymptomatic disease may not require glucocorticoid replacement therapy. As of 2008 about two hundred cases have been described in the literature.

<span class="mw-page-title-main">Simpson–Golabi–Behmel syndrome</span> Congenital disorder

Simpson–Golabi–Behmel syndrome (SGBS), is a rare inherited congenital disorder that can cause craniofacial, skeletal, vascular, cardiac, and renal abnormalities. There is a high prevalence of cancer associated in those with sgbs which includes wilms tumors, neuroblastoma, tumors of the adrenal gland, liver, lungs and abdominal organs. The syndrome is inherited in an X-linked recessive manner. Females that possess one copy of the mutation are considered to be carriers of the syndrome but may still express varying degrees of the phenotype, suffering mild to severe malady. Males experience a higher likelihood of fetal death.

Esophageal dysphagia is a form of dysphagia where the underlying cause arises from the body of the esophagus, lower esophageal sphincter, or cardia of the stomach, usually due to mechanical causes or motility problems.

<span class="mw-page-title-main">Nutcracker esophagus</span> Medical condition

Nutcracker esophagus, jackhammer esophagus, or hypercontractile peristalsis, is a disorder of the movement of the esophagus characterized by contractions in the smooth muscle of the esophagus in a normal sequence but at an excessive amplitude or duration. Nutcracker esophagus is one of several motility disorders of the esophagus, including achalasia and diffuse esophageal spasm. It causes difficulty swallowing, or dysphagia, with both solid and liquid foods, and can cause significant chest pain; it may also be asymptomatic. Nutcracker esophagus can affect people of any age but is more common in the sixth and seventh decades of life.

<span class="mw-page-title-main">DAX1</span> Protein-coding gene in humans

DAX1 is a nuclear receptor protein that in humans is encoded by the NR0B1 gene. The NR0B1 gene is located on the short (p) arm of the X chromosome between bands Xp21.3 and Xp21.2, from base pair 30,082,120 to base pair 30,087,136.

<span class="mw-page-title-main">Aladin (protein)</span> Nuclear envelope protein

Aladin, also known as adracalin, is a nuclear envelope protein that in humans is encoded by the AAAS gene. It is named after the achalasia–addisonianism–alacrima syndrome which occurs when the gene is mutated.

<span class="mw-page-title-main">Adrenal crisis</span> Medical condition

Adrenal crisis, also known as Addisonian crisis or Acute adrenal insufficiency, is a serious, life-threatening complication of adrenal insufficiency. Hypotension, or hypovolemic shock, is the main symptom of adrenal crisis, other indications and symptoms include weakness, anorexia, nausea, vomiting, fever, fatigue, abnormal electrolytes, confusion, and coma. Laboratory testing may detect lymphocytosis, eosinophilia, hyponatremia, hyperkalemia, hypoglycemia, and on occasion, hypercalcemia.

<span class="mw-page-title-main">Autoimmune polyendocrine syndrome type 2</span> Medical condition

Autoimmune polyendocrine syndrome type 2, a form of autoimmune polyendocrine syndrome also known as APS-II, or PAS II, is the most common form of the polyglandular failure syndromes. PAS II is defined as the association between autoimmune Addison's disease and either autoimmune thyroid disease, type 1 diabetes, or both. It is heterogeneous and has not been linked to one gene. Rather, individuals are at a higher risk when they carry a particular human leukocyte antigen. APS-II affects women to a greater degree than men.

<span class="mw-page-title-main">Lujan–Fryns syndrome</span> Medical condition

Lujan–Fryns syndrome (LFS) is an X-linked genetic disorder that causes mild to moderate intellectual disability and features described as Marfanoid habitus, referring to a group of physical characteristics similar to those found in Marfan syndrome. These features include a tall, thin stature and long, slender limbs. LFS is also associated with psychopathology and behavioral abnormalities, and it exhibits a number of malformations affecting the brain and heart. The disorder is inherited in an X-linked dominant manner, and is attributed to a missense mutation in the MED12 gene. There is currently no treatment or therapy for the underlying MED12 malfunction, and the exact cause of the disorder remains unclear.

Alacrima refers to an abnormality in tear production that could mean reduced tear production or absent tear production. Because a lack of tears presents in only in a few rare disorders, it aids in diagnosis of these disorders, including Triple-A syndrome and NGLY1 deficiency.

<span class="mw-page-title-main">Achalasia microcephaly</span> Medical condition

Achalasia microcephaly syndrome is a rare condition whereby achalasia in the oesophagus manifests alongside microcephaly and mental retardation. This is a rare constellation of symptoms with a predicted familial trend.

Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia, is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.

References

  1. ↑ Online Mendelian Inheritance in Man (OMIM): 231550
  2. ↑ Dusek T, Korsic M, Koehler K, Perkovic Z, Huebner A, Korsic M (2006). "A novel AAAS gene mutation (p.R194X) in a patient with triple A syndrome". Hormone Research. 65 (4): 171–176. doi:10.1159/000092003. PMID   16543750. S2CID   36128858.
  3. ↑ Gazarian M, Cowell CT, Bonney M, Grigor WG (January 1995). "The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities". European Journal of Pediatrics. 154 (1): 18–23. doi:10.1007/BF01972967. PMID   7895750. S2CID   8904441.
  4. 1 2 Bharadia L, Kalla M, Sharma SK, Charan R, Gupta JB, Khan F (2005). "Triple A syndrome". Indian Journal of Gastroenterology. 24 (5): 217–218. PMID   16361769.
  5. 1 2 Tibussek D, Ghosh S, Huebner A, Schaper J, Mayatepek E, Koehler K (January 2018). ""Crying without tears" as an early diagnostic sign-post of triple A (Allgrove) syndrome: two case reports". BMC Pediatrics. 18 (1): 6. doi: 10.1186/s12887-017-0973-y . PMC   5769402 . PMID   29334914.
  6. 1 2 3 Prpic I, Huebner A, Persic M, Handschug K, Pavletic M (May 2003). "Triple A syndrome: genotype-phenotype assessment". Clinical Genetics. 63 (5): 415–417. doi: 10.1034/j.1399-0004.2003.00070.x . PMID   12752575. S2CID   19250948.
  7. 1 2 3 4 5 Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, et al. (September 2005). "Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005". Clinical Genetics. 68 (3): 215–221. doi:10.1111/j.1399-0004.2005.00482.x. PMID   16098009. S2CID   20404052.
  8. ↑ Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, et al. (September 2005). "Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005". Clinical Genetics. 68 (3): 215–221. doi:10.1111/j.1399-0004.2005.00482.x. PMID   16098009. S2CID   20404052.
  9. 1 2 3 4 "Triple A syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2022-04-20.
  10. ↑ Huebner A, Kaindl AM, Knobeloch KP, Petzold H, Mann P, Koehler K (November 2004). "The triple A syndrome is due to mutations in ALADIN, a novel member of the nuclear pore complex". Endocrine Research. 30 (4): 891–899. doi:10.1081/ERC-200044138. PMID   15666842. S2CID   31047487.
  11. ↑ Salmaggi A, Zirilli L, Pantaleoni C, De Joanna G, Del Sorbo F, Koehler K, et al. (2008). "Late-onset triple A syndrome: a risk of overlooked or delayed diagnosis and management". Hormone Research. 70 (6): 364–372. doi:10.1159/000161867. PMID   18953174. S2CID   8097415.
  12. ↑ "Triple A Syndrome". Genetics Home Reference. February 2010. Retrieved 10 May 2020.
  13. ↑ Huebner A, Yoon SJ, Ozkinay F, Hilscher C, Lee H, Clark AJ, Handschug K (November 2000). "Triple A syndrome--clinical aspects and molecular genetics". Endocrine Research. 26 (4): 751–759. doi:10.3109/07435800009048596. PMID   11196451. S2CID   42579320.
  14. ↑ Krumbholz M, Koehler K, Huebner A (April 2006). "Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation". Biochemistry and Cell Biology. 84 (2): 243–249. doi:10.1139/o05-198. PMID   16609705.
  15. 1 2 Hirano M, Furiya Y, Asai H, Yasui A, Ueno S (February 2006). "ALADINI482S causes selective failure of nuclear protein import and hypersensitivity to oxidative stress in triple A syndrome". Proceedings of the National Academy of Sciences of the United States of America. 103 (7): 2298–2303. Bibcode:2006PNAS..103.2298H. doi: 10.1073/pnas.0505598103 . PMC   1413683 . PMID   16467144.
  16. 1 2 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". Molecular Biology of the Cell. 28 (19): 2470–2478. doi:10.1091/mbc.E16-03-0158. PMC   5597320 . PMID   28768824.
  17. ↑ Wallace IR, Hunter SJ (August 2012). "AAA syndrome--adrenal insufficiency, alacrima and achalasia". QJM. 105 (8): 803–804. doi: 10.1093/qjmed/hcr145 . PMID   21865313.
  18. ↑ Gaiani F, Gismondi P, Minelli R, Casadio G, de'Angelis N, Fornaroli F, et al. (May 2020). "Case report of a familial triple: a syndrome and review of the literature". Medicine. 99 (22): e20474. doi: 10.1097/MD.0000000000020474 . PMID   32481456.
  19. ↑ Yadav P, Kumar D, Bohra GK, Garg MK (May 2020). "Triple A syndrome (Allgrove syndrome) - A journey from clinical symptoms to a syndrome". Journal of Family Medicine and Primary Care. 9 (5): 2531–2534. doi: 10.4103/jfmpc.jfmpc_237_20 . PMC   7380807 . PMID   32754538.
  20. ↑ Adams J, Schaaf CP (July 2018). "Diagnosis and genetics of alacrima". Clinical Genetics. 94 (1): 54–60. doi:10.1111/cge.13173. PMID   29120068. S2CID   32409479.
  21. ↑ Nicolino M (April 2013). "Triple A syndrome". Orphanet. Retrieved 31 August 2020.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.