Achalasia-Addisonianism-Alacrima Syndrome

Alternative Names

  • AAAS
  • Triple-A Syndrome
  • Alacrima-Achalasia-Adrenal Insufficiency Neurologic Disorder
  • Glucocorticoid Deficiency and Achalasia
  • Allgrove Syndrome
  • Addisonian-Achalasia Syndrome
  • Hypoadrenalism with Achalasia
  • Alacrima-Achalasia-Addisonianism
  • ACTH-Resistant Adrenal Insufficiency, Achalasia and Alacrima
  • Achalasia-Alacrima Syndrome

Associated Genes

AAAS Gene
Back to search Result
WHO-ICD-10 version:2010

Mental and behavioural disorders

Schizophrenia, schizotypal and delusional disorders

OMIM Number

231550

Mode of Inheritance

Autosomal recessive

Gene Map Locus

12q13.13

Description

Allgrove syndrome, also known as Triple A syndrome, is a rare autosomal recessive disease with recurrence risk of 25% for families with affected children. With an early age of onset, roughly 70 cases has been reported worldwide. The disease is distinguished through a triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia, and alacrima.

Triple-A syndrome is thought to occur due to mutations in the AAAS gene located on chromosome 12q13.

Epidemiology in the Arab World

View Map

Other Reports

Algeria

Using linkage analysis in 12, mostly consanguineous, families with triple-A syndrome and originating from North Africa (five families from Algeria, and two families from Tunisia), Hadj-Rabia et al. (2000) confirmed that the disease locus maps to 12q13 (maximum lod score = 10.89 at marker D12S1604) and suggest that triple A is probably a genetically homogeneous disorder in patients of North African ancestry. Analysis of markers at five contiguous loci showed that most of the triple-A chromosomes were derived from a single founder chromosome, and Hadj-Rabia et al. (2000) speculated that the triple-A mutation was due to an ancient Arabian founder effect that occurred before migration to North Africa.

Tullio-Pelet et al. (2000) carried out fine-mapping based on linkage disequilibrium in 10 North African inbred families with triple-A-syndrome (including: 7 families with 10 affected individuals from Algeria, and 3 families with 5 affected individuals from Tunisia). Most of these families were consanguineous except one Algerian and one Tunisian family. Tullio-Pelet et al. (2000) identified a short ancestral haplotype on 12q13 (less than 1 cM), sequenced a BAC contig encompassing the triple-A minimal region, and identified a novel gene designated AAAS, encoding a 547-amino acid protein, called aladin, that was mutant in affected individuals. Nine of the 10 families from North African ancestry carrying allele 5 at the D12S1604 locus were found to have the same splice site mutation (IVS14+1G>A), and Tullio-Pelet et al. (2000) calculated that this founder mutation first occurred more than 2,400 years ago. Two unrelated Tunisian patients from two of the families with the founder mutation had achalasia and alacrima without adrenal insufficiency, while each of their sibs had all three disease features. Tullio-Pelet et al. (2000) suggested that other unlinked genes or environmental factors may modify the expression of the mutant genotype. The remaining Algerian family was found to have nonsense mutation in exon 9 of the AAAS gene (1024C>T; R312X). The predicted product of AAAS, Aladin (for 'alacrima-achalasia-adrenal insufficiency neurologic disorder') belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in the triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures pointed to a role in the normal development of the peripheral and central nervous systems.

 

Kuwait

El-Rayyes et al. (1991) described a case of a 2-year old child with alacrima, achalasia, and neurological anomalies. The male child had, however, normal adrenocortical function, which was proved by clinical and laboratory studies. The presence of parental consanguinity suggested an autosomal recessive mode of inheritance.

[See also: Kuwait > Ismail et al., 2006].

Palestine

Ismail et al. (2006) reported two Palestinian sibs living in Kuwait suffering from Allgrove syndrome. They were born to consanguineous first-cousin parents with three healthy children. The subjects represented a boy and a girl aged 12 and 19 years old, respectively. Both patients developed adrenal insufficiency that led to neuroautonomic dysfunction which represented as a main feature of Allgrove Syndrome. Diagnosis was further confirmed by examining the family gene mutation through sequencing the AAAS gene, which revealed a novel homozygous mutation within intron 5 (IVS5 + 1G-A) in both patients and a heterozygous mutation in both parents and their three children. Ismail et al. (2006) concluded that these two subjects demonstrated the heterogenous nature and the intrafamilial phenotypic variability of the disorder.

Saudi Arabia

Lanes et al. (1980) reported the case of an 8.8-year-old Saudi Arabian girl with alacrima, achalasia and adrenal insufficiency, which included partial mineralocorticoid deficiency as well as glucocorticoid deficiency. Lanes et al. (1980) suggested that a degenerative process of progressive nature may be responsible for the three features of this syndrome of alacrima-achalasia-addisonianism, and suggested that the 'triple-A syndrome' may be a useful designation.

Modebe (2000) described two siblings born to first cousin Saudi parents with Achalasia-Alacrima-ACTH Insensitivity syndrome.  The first patient was a 6-year-old boy who was admitted to the hospital many times for febrile illness sometimes associated with upper and lower respiratory tract infections, mucopurulent conjunctivitis, bronchospasm, or vomiting and diarrhea.  When he was 4- and 5-years old, he had episodes of hypoglycemic coma.  At the age of 5-years, he had diffuse hyperpigmentation.  Laboratory tests showed high concentration of ACTH and very low concentration of serum cortisol.  Barium meals showed a smooth tapering of the lower end of the esophagus, delay in the clearance of barium from the esophagus, and features consistent with achalasia.  He was on 2.5 mg prednisolone daily and had substantial clinical improvement.  His 4-year-old sister presented with darkening of the lips, knuckles of the hand, and elbows.  She had mild, diffuse hyperpigmentation of the skin, and more severe hyperpigmentation in the lips, gums, buccal mucosa, creases of the palms, and elbows.  Barium meals showed a smooth tapering of the lower esophagus, and delay of esophageal emptying.  She was also in a good health on 1.25 mg prednisolone daily.

Yasawy (2009) described two brothers in Saudi Arabia with Allgrove Syndrome. The index case presented at 18-years of age with deterioration of general health, cachexia and weight loss. He was born to healthy unrelated parents. At the age of 3-4 years, he had started having progressive nasal speech, anorexia, and lack of weight gain, at which point he was diagnosed with achalasia. He continued to deteriorate for the next 3-years, and then was lost to follow-up. At this presentation, he was cachetic and wasted, with a pronounced nasal speech. He had areas of hyper-pigmentation, most obvious over the buccal mucosa and gums. He was hypotensive, had limited joint motions because of muscle contractures, spastic tertraparesis with mild ataxia, and increased deep tendon reflexes. Schirmer's test revealed alacrima, and CT brain and orbit tomography showed reduced lacrimal gland tissue. He was put on full supportive therapy, and he responded well to graded pneumatic dilatation. Within a year, he was able to eat well, walk without support, and gain significant weight (25 Kg). His 10-year-old brother presented with frequent regurgitation, weight loss and failure to thrive. At 4-years of age, he had been diagnosed with achalasia and subjected to open cardiomyotomy. At this presentation, he was diagnosed with an early and slow progressing form of Allgrove Syndrome. At the time of writing, he was on regular follow up without any pharmacological support.

Tunisia

[See: Algeria > Hadj-Rabia et al., 2000; Tullio-Pelet et al., 2000].

United Arab Emirates

Torab et al. (2012) described a family with two siblings (a male and a female) who suffered from Allgrove syndrome. Both presented with repeated attacks of vomiting, alacrima, and lack of weight gain. Barium swallow in both cases showed features of achalasia. The older boy showed biochemical features of adrenal insufficiency as well. Both were treated by Robotic-assisted Heler's myotomy and improved remarkably.

© CAGS 2021. All rights reserved.