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{{Infobox medical condition (new)
{{SI}}
| name            = Triple A syndrome
{{Infobox medical condition
| synonyms        = '''Achalasia–addisonianism–alacrima syndrome'''<br>or '''Allgrove syndrome'''<ref name=omim>{{OMIM|231550}}</ref>
| name            = Triple-A syndrome
| image          = 1471-2415-4-7-1-l.jpg
| image          = [[File:1471-2415-4-7-1-l.jpg|alt=Image of a patient with Triple-A syndrome]]
| caption        = MRI of the brain of 12-year-old boy with triple-A syndrome<br> showing hypoplastic lacrimal glands (yellow arrows.)
| caption        = A patient with Triple-A syndrome
| pronounce      =
| synonyms        = [[Allgrove syndrome]], [[AAA syndrome]]
| field          =
| pronounce      =  
| symptoms        =
| specialty      = [[Endocrinology]], [[Neurology]], [[Genetics]]
| complications  =
| symptoms        = [[Achalasia]], [[Adrenal insufficiency]], [[Alacrima]]
| onset          =
| onset          = Childhood
| duration        =
| duration        = Lifelong
| types          =
| causes          = Mutations in the [[AAAS gene]]
| causes          =
| risks          =  
| risks          =
| diagnosis      = Clinical evaluation, genetic testing
| diagnosis      =
| differential    = [[Addison's disease]], [[Esophageal motility disorder]]
| differential    =
| prevention      = None
| prevention      =
| treatment      = [[Hormone replacement therapy]], [[Botulinum toxin]] for achalasia
| treatment      =
| medication      = [[Glucocorticoids]], [[Mineralocorticoids]]
| medication      =
| prognosis      = Variable, depends on severity and management
| prognosis      =
| frequency      = Rare
| frequency      =
| deaths          =  
| deaths          =
}}
}}
== Triple-A syndrome ==
{{Short description|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]], [[adrenal insufficiency]], and [[alacrima]]. The condition is caused by mutations in the AAAS gene, which encodes the protein ALADIN, involved in nuclear pore complex function.
'''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.
==Signs and symptoms==
 
The hallmark features of Triple-A syndrome include:
=== Presentation ===
* '''Achalasia''': A condition where the lower esophageal sphincter fails to relax properly, leading to difficulty swallowing (dysphagia), regurgitation, and sometimes chest pain.
 
* '''Adrenal insufficiency''': This results from the underproduction of adrenal hormones, particularly cortisol, leading to symptoms such as fatigue, muscle weakness, weight loss, low blood pressure, and hyperpigmentation of the skin.
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]].
* '''Alacrima''': A lack of tear production, which can lead to dry eyes and increased risk of eye infections.
 
Additional symptoms may include neurological abnormalities, such as peripheral neuropathy, autonomic dysfunction, and cognitive impairment.
The syndrome is highly variable. Managed effectively, affected individuals can have a normal lifespan and bear children.
==Genetics==
 
Triple-A syndrome is inherited in an [[autosomal recessive]] pattern, meaning that an individual must inherit two copies of the mutated gene, one from each parent, to be affected. The AAAS gene is located on chromosome 12q13, and mutations in this gene disrupt the function of the ALADIN protein, affecting cellular processes.
=== Cause ===
==Diagnosis==
 
Diagnosis of Triple-A syndrome is based on clinical evaluation, family history, and genetic testing. The presence of the characteristic triad of symptoms often prompts further investigation. Genetic testing can confirm mutations in the AAAS gene.
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.
==Management==
 
Management of Triple-A syndrome is symptomatic and supportive. Treatment may include:
[[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.
* Hormone replacement therapy for adrenal insufficiency, typically with glucocorticoids and mineralocorticoids.
 
* Surgical or endoscopic intervention for achalasia, such as pneumatic dilation or Heller myotomy.
=== Diagnosis ===
* Artificial tears and other measures to manage alacrima and protect the eyes.
 
==Prognosis==
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.
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.
 
==See also==
=== Treatment ===
 
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.
 
=== See also ===
 
* [[Achalasia]]
* [[Achalasia]]
* [[Addison's disease|Addisonianism]]
* [[Adrenal insufficiency]]
* [[lacrimation|Alacrima]]
* [[Autosomal recessive disorder]]
 
[[Category:Genetic disorders]]
[[Category:Genetic disorders]]
[[Category:Rare diseases]]
[[Category:Rare diseases]]
[[Category:Syndromes]]
== External links ==
*{{eMedicine|ped|71|Allgrove (AAA) 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]]

Latest revision as of 19:21, 8 April 2025

Editor-In-Chief: Prab R Tumpati, MD
Obesity, Sleep & Internal medicine
Founder, WikiMD Wellnesspedia &
W8MD medical weight loss NYC and sleep center NYC

Triple-A syndrome
Image of a patient with Triple-A syndrome
Synonyms Allgrove syndrome, AAA syndrome
Pronounce
Specialty Endocrinology, Neurology, Genetics
Symptoms Achalasia, Adrenal insufficiency, Alacrima
Complications N/A
Onset Childhood
Duration Lifelong
Types N/A
Causes Mutations in the AAAS gene
Risks
Diagnosis Clinical evaluation, genetic testing
Differential diagnosis Addison's disease, Esophageal motility disorder
Prevention None
Treatment Hormone replacement therapy, Botulinum toxin for achalasia
Medication Glucocorticoids, Mineralocorticoids
Prognosis Variable, depends on severity and management
Frequency Rare
Deaths


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, adrenal insufficiency, and alacrima. The condition is caused by mutations in the AAAS gene, which encodes the protein ALADIN, involved in nuclear pore complex function.

Signs and symptoms[edit]

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.
  • Adrenal insufficiency: This results from the underproduction of adrenal hormones, particularly cortisol, leading to symptoms such as fatigue, muscle weakness, weight loss, low blood pressure, and hyperpigmentation of the skin.
  • Alacrima: A lack of tear production, which can lead to dry eyes and increased risk of eye infections.

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

Genetics[edit]

Triple-A syndrome is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the mutated gene, one from each parent, to be affected. The AAAS gene is located on chromosome 12q13, and mutations in this gene disrupt the function of the ALADIN protein, affecting cellular processes.

Diagnosis[edit]

Diagnosis of Triple-A syndrome is based on clinical evaluation, family history, and genetic testing. The presence of the characteristic triad of symptoms often prompts further investigation. Genetic testing can confirm mutations in the AAAS gene.

Management[edit]

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

  • Hormone replacement therapy for adrenal insufficiency, typically with glucocorticoids and mineralocorticoids.
  • Surgical or endoscopic intervention for achalasia, such as pneumatic dilation or Heller myotomy.
  • Artificial tears and other measures to manage alacrima and protect the eyes.

Prognosis[edit]

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.

See also[edit]

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