Achalasia-Addisonianism-Alacrima syndrome; AAAS

What is Achalasia-Addisonianism-Alacrima syndrome; AAAS?

Achalasia-Addisonianism-Alacrima syndrome; AAAS is a rare disease. It is also known as 3A syndrome 4A syndrome Achalasia - adrenocortical insufficiency Achalasia - alacrima - ACTH insensitivity Achalasia-adrenocortical insufficiency Achalasia-alacrima-ACTH insensitivity Acth-resistant Adrenal Insufficiency, Achalasia And Alacrima Addisonian-achalasia Syndrome Adrenal insufficiency - alacrima - achalasia Adrenal insufficiency-alacrima-achalasia Alacrima-achalasia-addisonianism Alacrima-achalasia-adrenal Insufficiency Neurologic Disorder Allgrove Syndrome Glucocorticoid Deficiency And Achalasia Hypoadrenalism With Achalasia Triple A syndrome Triple-a Syndrome.

Achalasia has been noted to occur with adrenocortical insufficiency and absent tears (Allgrove et al., 1978) and, separately, in association with microcephaly, mental retardation, optic atrophy and ataxia (Tyce and Brough, 1962). Ehrich et al., (1987) described a sib-pair who both had adrenal insufficiency, mental retardation, a lack of tears, optic atrophy and microcephaly, suggesting that a single gene might encompass all of the abnormalities mentioned above. The Allgrove et al., (1978) patients were followed up by Grant et al., (1992) and it was found that they developed a peripheral sensory, motor and autonomic neuropathy, extrapyramidal features and mental deterioration. CSF homovanillic acid and 5-hydroxyindole acetic acid levels were low, suggesting a defect of dopamine and serotonin metabolism. Red cell folate levels were markedly reduced. El-Rayyes et al., (1991) reported a case with achalasia, neurological abnormalities and alacrima, but normal adrenal function. Tsilou et al., (2001) review the ocular findings of the condition, stressing the need for early diagnosis.
Grant et al., (1993) reported follow-up of 20 patients and stressed the neurological abnormalities including hyperreflexia, muscle weakness, dysarthria and ataxia, as well as the autonomic neuropathy and mental deterioration mentioned above. Gazarian et al., (1995) also reported autonomic and peripheral neuropathies in patients with this condition. They suggested that it should be renamed the "4A syndrome". Chu et al., (1996) reported two cases and also stressed the autonomic dysfunction. Dumic et al., (2000) report five cases of the condition and point out that xerostomia with candidiasis is a feature of the condition.
The patient reported by Dundar et al., (1996) with absent lacrimal glands, hypertelorism and achalasia whose parents were first cousins, may fall into this group. He certainly did not have G syndrome as suggested in the title of the paper. Rusu et al., (1996) reported a 17-year-old male with features of the condition. The father was thought to have some features suggesting autosomal dominant inheritance. In this patient, the thumbs were both short and broad. Bentes et al., (2001) reported a 35-year-old man with the condition. He presented at 25 years of age of achalasia, but presented again at 35 years with spastic tetraparesis, distal limb atrophy, dysarthria and dysphagia. A progressive axonal neuropathy also occurred in the 14-year-old girl reported by Koehler et al., (2008). Dysautonomic symptoms developed a year later and adrenal insufficiency was diagnosed. The authors note the similarity to amyotrophic lateral sclerosis. Reshmi-Skarja et al., (2003) reported abnormalities in the heterochromatic region of chromosome nine, including chromatid breaks, chromosome breaks and whole chromosome arm loss in both homozygotes and heterozygotes.
Kimber et al., (2003) reported a brother and sister in their fifth decade and a further unrelated sixty-year-old male with typical clinical features of Allgrove's syndrome, who exhibited signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases developed adrenal insufficiency but all had progressive neurological disability. Luigetti et al., (2010), reported a similar patient. Polyneuropathy was the presenting feature in the sibs reported by Dumic et al., (2011).
MOLECULAR GENETICS
Weber et al., (1996) mapped the gene to 12q13 in eight families. Tullio-Pelet et al., (2000) reported a mutation in the gene AAAS encoding a protein ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder) which belongs to the WD-repeat family of regulatory proteins. Further mutations were reported by Handschug et al., (2001). Prpic et al., (2003) reported a patient with isolated achalasia where the diagnosis of triple A syndrome could only be made on the basis of the molecular analysis. Lovrecic et al., (2006) reported a case who was a compound heterozygote for two known mutations. An Israeli Arab kindred had alacrima, achalasia and mental retardation (Marom et al., 2011). No mutations were found.
Kurnaz et. al., (2017) described six patients from consanguineous families with homozygous mutations in the AAAS gene. All had neurological abnormalities including hyperreflexia, muscle wasting, dysarthria, nasal speech, speech delay, ataxia, polyneuropathy, epilepsy, and optic atrophy.


NB - see "Glycosylation disorder - autonomic dysfunction - intellectual disability" - for a similar syndrome with mutations in GMPPA.

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* This information is courtesy of the L M D.

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What gene changes cause Achalasia-Addisonianism-Alacrima syndrome; AAAS?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.


In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 231550 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
AAAS - 12q13.13
GMPPA - 2q35
TRAPPC11 - 4q35.1

What are the main symptoms of Achalasia-Addisonianism-Alacrima syndrome; AAAS?

The typical symptoms of the syndrome are:
Autosomal recessive inheritance, Orthostatic hypotension, Optic atrophy, Palmoplantar hyperkeratosis, Hypocortisolemia, Decreased circulating aldosterone level, Global developmental delay, Hyperpigmentation of the skin, Hyperreflexia, Short stature, Muscle weakness, Intellectual disability, Progressive, Childhood onset, Microcephaly, Motor axonal neuropathy, Dysautonomia, Dysarthria, Babinski sign, Ataxia, Alacrima, Adrenocorticotropin receptor defect, Anisocoria, Achalasia, Abnormality of visual evoked potentials

How does someone get tested for Achalasia-Addisonianism-Alacrima syndrome; AAAS?

The initial testing for Achalasia-Addisonianism-Alacrima syndrome; AAAS can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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