Triple-A syndrome: Difference between revisions

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{{Infobox medical condition (new)
{{Short description|A rare autosomal recessive disorder}}
| name            = Triple A syndrome
{{Use dmy dates|date=October 2023}}
| synonyms        = '''Achalasia–addisonianism–alacrima syndrome'''<br>or '''Allgrove syndrome'''<ref name=omim>{{OMIM|231550}}</ref>
| image          = 1471-2415-4-7-1-l.jpg
| caption        = MRI of the brain of 12-year-old boy with triple-A syndrome<br> showing hypoplastic lacrimal glands (yellow arrows.)
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== Triple-A syndrome ==


'''Triple-A syndrome''' or '''AAA syndrome''' is a rare [[autosome|autosomal]] [[dominance (genetics)|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, and since then just over 100 cases have been reported. The syndrome involves [[achalasia]], [[Addison's disease|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.
'''Triple-A syndrome''', also known as '''Allgrove syndrome''', is a rare [[autosomal recessive]] disorder characterized by the triad of [[achalasia]], [[Addison's disease]], and [[alacrima]]. It is caused by mutations in the AAAS gene, which encodes the protein ALADIN, involved in nuclear pore complex function.


=== Presentation ===
==Signs and symptoms==
The hallmark features of Triple-A syndrome include:


Individuals affected by AAA have [[adrenal insufficiency]]/[[Addison's disease]] due to ACTH resistance, alacrima (absence of tear secretion), and [[achalasia]] of the lower [[esophagus|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, abnormal sweating, orthostatic hypotension, and disturbances of the heart rate. [[Hypoglycemia]] is often mentioned as an early sign. The disorder has also been associated with mild [[mental retardation]].
* '''Achalasia''': A condition where the lower esophageal sphincter fails to relax properly, leading to difficulty swallowing (dysphagia), regurgitation, and sometimes chest pain.
* '''Addison's disease''': A disorder of the [[adrenal glands]] leading to insufficient production of [[cortisol]] and [[aldosterone]], resulting in symptoms such as fatigue, muscle weakness, weight loss, low blood pressure, and hyperpigmentation.
* '''Alacrima''': A lack of tear production, which can lead to dry eyes and increased risk of eye infections.


The syndrome is highly variable. Managed effectively, affected individuals can have a normal lifespan and bear children.
Other symptoms may include [[neurological]] abnormalities, such as [[autonomic dysfunction]], [[peripheral neuropathy]], and [[cognitive impairment]].


=== Cause ===
==Genetics==
Triple-A syndrome is inherited in an [[autosomal recessive]] pattern, meaning that both copies of the gene in each cell have mutations. The AAAS gene is located on chromosome 12q13. Mutations in this gene disrupt the function of the ALADIN protein, affecting the nuclear pore complex and leading to the symptoms of the syndrome.


Triple-A syndrome is associated with mutations in the ''AAAS'' gene, which encodes a protein known as [[Aladin (protein)|ALADIN]]. The ''ALADIN'' protein is a component of the [[nuclear pore complex]], situated toward its cytoplasmic side. Mutant ALADIN remains mislocalized in the cytoplasm and causes selective failure of [[nuclear import|nuclear protein import]] and hypersensitivity to [[oxidative stress]]. Mutant ALADIN also causes decreased nuclear import of [[aprataxin]], a [[DNA repair|repair protein for DNA single-strand breaks]], and DNA [[LIG1|ligase I]]. These decreases in DNA repair proteins may allow accumulation of [[DNA damage (naturally occurring)|DNA damages]] that trigger cell death.
==Diagnosis==
Diagnosis of Triple-A syndrome is based on clinical evaluation, family history, and genetic testing to identify mutations in the AAAS gene. Additional tests may include esophageal manometry for achalasia, ACTH stimulation test for adrenal insufficiency, and Schirmer's test for alacrima.


[[Nucleoporin]] ALADIN participates in spindle assembly. ALADIN is employed in specific [[meiosis|meiotic stages]], including spindle assembly, and spindle positioning. Female mice homozygously null for ALADIN are sterile.
==Management==
Management of Triple-A syndrome is symptomatic and supportive. Treatment may include:


=== Diagnosis ===
* For achalasia: [[Pneumatic dilation]], [[Heller myotomy]], or [[botulinum toxin]] injections.
* For Addison's disease: Lifelong hormone replacement therapy with glucocorticoids and mineralocorticoids.
* For alacrima: Artificial tears and other measures to protect the eyes.


Features of achalasia cardia include an absence of fundal gas shadow on plain x-ray, widened mediastinum, and an air-fluid level in the mediastinum. The gold standard investigation is a 24-hour manometry of the esophagus. It shows non-relaxation of the lower esophageal sphincter, increased tone of the esophageal sphincter, and an atonic esophagus. Bird-beak sign and rat-tail sign can be appreciated on a barium swallow.
Regular monitoring and multidisciplinary care are essential to address the various aspects of the syndrome.


=== Treatment ===
==Prognosis==
The prognosis for individuals with Triple-A syndrome varies depending on the severity of symptoms and the effectiveness of treatment. With appropriate management, many individuals can lead relatively normal lives, although they may require ongoing medical care.


There is no definitive cure for this syndrome, as many of the mechanisms implicated have not been identified. Treatments address only some of the symptoms: artificial tear drops remedy the absence of tear secretion; achalasia can be treated with surgical intervention when needed; and corticosteroids, such as hydrocortisone, are prescribed to address adrenal insufficiency.
==Related pages==
* [[Achalasia]]
* [[Addison's disease]]
* [[Alacrima]]
* [[Autosomal recessive disorder]]


=== See also ===
==References==
{{Reflist}}


* [[Achalasia]]
==External links==
* [[Addison's disease|Addisonianism]]
* [https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=271 Orphanet: Triple A syndrome]
* [[lacrimation|Alacrima]]


[[Category:Genetic disorders]]
[[Category:Genetic disorders]]
[[Category:Rare diseases]]
[[Category:Rare diseases]]
[[Category:Syndromes]]
[[Category:Syndromes]]
== External links ==
 
*{{eMedicine|ped|71|Allgrove (AAA) Syndrome}}
[[File:1471-2415-4-7-1-l.jpg|thumb|right|Image related to Triple-A syndrome]]
*{{OMIM|231550||short}} {{RareDiseases|457|Achalasia Addisonianism Alacrimia syndrome; Triple A syndrome}}
{{Medical resources
|  DiseasesDB    =32088 
|  ICD10          = {{ICD10|E|27|4|e|27}}
|  ICD9          = 
|  ICDO          = 
|  OMIM          =231550 
|  MedlinePlus    = 
|  eMedicineSubj  =ped 
|  eMedicineTopic =71 
|  MeshID        = 
|  Orphanet      = 869
}}
{{stub}}
{{Nucleus diseases}}
[[Category:Autosomal recessive disorders]]
[[Category:Syndromes affecting the gastrointestinal tract]]
[[Category:Congenital disorders]]
[[Category:Rare syndromes]]
[[Category:Nucleus diseases]]
[[Category:Medical triads]]
[[Category:Syndromes affecting the eyes]]
[[Category:Syndromes affecting the endocrine system]]

Revision as of 15:47, 9 February 2025

A rare autosomal recessive disorder



Triple-A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by the triad of achalasia, Addison's disease, and alacrima. It is caused by mutations in the AAAS gene, which encodes the protein ALADIN, involved in nuclear pore complex function.

Signs and symptoms

The hallmark features of Triple-A syndrome include:

  • Achalasia: A condition where the lower esophageal sphincter fails to relax properly, leading to difficulty swallowing (dysphagia), regurgitation, and sometimes chest pain.
  • Addison's disease: A disorder of the adrenal glands leading to insufficient production of cortisol and aldosterone, resulting in symptoms such as fatigue, muscle weakness, weight loss, low blood pressure, and hyperpigmentation.
  • Alacrima: A lack of tear production, which can lead to dry eyes and increased risk of eye infections.

Other symptoms may include neurological abnormalities, such as autonomic dysfunction, peripheral neuropathy, and cognitive impairment.

Genetics

Triple-A syndrome is inherited in an autosomal recessive pattern, meaning that both copies of the gene in each cell have mutations. The AAAS gene is located on chromosome 12q13. Mutations in this gene disrupt the function of the ALADIN protein, affecting the nuclear pore complex and leading to the symptoms of the syndrome.

Diagnosis

Diagnosis of Triple-A syndrome is based on clinical evaluation, family history, and genetic testing to identify mutations in the AAAS gene. Additional tests may include esophageal manometry for achalasia, ACTH stimulation test for adrenal insufficiency, and Schirmer's test for alacrima.

Management

Management of Triple-A syndrome is symptomatic and supportive. Treatment may include:

  • For achalasia: Pneumatic dilation, Heller myotomy, or botulinum toxin injections.
  • For Addison's disease: Lifelong hormone replacement therapy with glucocorticoids and mineralocorticoids.
  • For alacrima: Artificial tears and other measures to protect the eyes.

Regular monitoring and multidisciplinary care are essential to address the various aspects of the syndrome.

Prognosis

The prognosis for individuals with Triple-A syndrome varies depending on the severity of symptoms and the effectiveness of treatment. With appropriate management, many individuals can lead relatively normal lives, although they may require ongoing medical care.

Related pages

References

<references group="" responsive="1"></references>


External links

Image related to Triple-A syndrome
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