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Glucocorticoid deficiency with achalasia(AAAS)

MedGen UID:
82889
Concept ID:
C0271742
Disease or Syndrome
Synonyms: AAA syndrome; AAAS; Achalasia alacrima syndrome; Achalasia-Addisonianism-Alacrima (Triple-A) Syndrome; Achalasia-Addisonianism-Alacrima Syndrome; Achalasia-addisonianism-alacrimia syndrome; ACTH-resistant adrenal insufficiency, achalasia and alacrima; Addisonian achalasia syndrome; Alacrima-achalasia-addisonianism; Alacrima-achalasia-adrenal insufficiency neurologic disorder; Allgrove syndrome; Glucocorticoid deficiency and achalasia; Hypoadrenalism with achalasia; Triple-A syndrome
SNOMED CT: Glucocorticoid deficiency with achalasia (45414006); Achalasia-addisonian syndrome (45414006); Allgrove syndrome (45414006); Triple A syndrome (45414006); Alacrimia-achalasia-addisonianism (45414006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): AAAS (12q13.13)
 
Monarch Initiative: MONDO:0009279
OMIM®: 231550
Orphanet: ORPHA869

Definition

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood glucose (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.

Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).

People with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.

People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.

Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family. [from MedlinePlus Genetics]

Clinical features

From HPO
Palmoplantar keratosis
MedGen UID:
44017
Concept ID:
C0022596
Disease or Syndrome
Abnormal thickening of the skin localized to the palm of the hand and the sole of the foot.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Achalasia
MedGen UID:
5023
Concept ID:
C0014848
Disease or Syndrome
A disorder of esophageal motility characterized by the inability of the lower esophageal sphincter to relax during swallowing and by inadequate or lacking peristalsis in the lower half of the body of the esophagus.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Abnormal autonomic nervous system physiology
MedGen UID:
8511
Concept ID:
C0013363
Disease or Syndrome
A functional abnormality of the autonomic nervous system.
Orthostatic hypotension
MedGen UID:
43803
Concept ID:
C0020651
Disease or Syndrome
A form of hypotension characterized by a sudden fall in blood pressure that occurs when a person assumes a standing position.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Motor axonal neuropathy
MedGen UID:
413108
Concept ID:
C2749625
Disease or Syndrome
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hyperpigmentation of the skin
MedGen UID:
57992
Concept ID:
C0162834
Pathologic Function
A darkening of the skin related to an increase in melanin production and deposition.
Adrenal insufficiency
MedGen UID:
1351
Concept ID:
C0001623
Disease or Syndrome
Insufficient production of steroid hormones (primarily cortisol) by the adrenal glands.
Decreased circulating aldosterone level
MedGen UID:
208996
Concept ID:
C0857899
Finding
Abnormally reduced levels of aldosterone.
Decreased circulating cortisol level
MedGen UID:
322961
Concept ID:
C1836623
Finding
Abnormally reduced concentration of cortisol in the blood.
Adrenocorticotropin receptor defect
MedGen UID:
867190
Concept ID:
C4021548
Finding
Adrenal insufficiency secondary to a defect in the ACTH receptor.
Anisocoria
MedGen UID:
1944
Concept ID:
C0003079
Finding
Anisocoria, or unequal pupil size, may represent a benign physiologic variant or a manifestation of disease.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Alacrima
MedGen UID:
87488
Concept ID:
C0344505
Disease or Syndrome
Absence of tear secretion.
Abnormality of visual evoked potentials
MedGen UID:
105509
Concept ID:
C0522214
Finding
An anomaly of visually evoked potentials (VEP), which are electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying the visual cortex.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVGlucocorticoid deficiency with achalasia

Recent clinical studies

Diagnosis

Grant DB, Dunger DB, Smith I, Hyland K
Eur J Pediatr 1992 Feb;151(2):85-9. doi: 10.1007/BF01958948. PMID: 1537368
Pombo M, Devesa J, Taborda A, Iglesias M, García-Moreno F, Gaudiero GJ, Martinón JM, Castro-Gago M, Peña J
Clin Endocrinol (Oxf) 1985 Sep;23(3):237-43. doi: 10.1111/j.1365-2265.1985.tb00219.x. PMID: 4075537

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