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At a glance

A genetic disease characterized by the triad of adrenocorticotropic hormone (ACTH)-resistant adrenal insufficiency, achalasia, and alacrima. It presents in the first decade of life with severe and potentially fatal hypoglycemic episodes. A mixed pattern of upper and lower motor neuropathy, sensory impairment, autonomic neuropathy, and mental retardation is common.

Synonyms

Triple-A Syndrome; Alacrima-Achalasia-Addisonianism-Syndrome (AAA); Alacrima-Achalasia-Adrenal Insufficiency Neurologic Disorder; Hypoadrenalism with Achalasia; Glucocorticoid Deficiency and Achalasia; Addisonian-Achalasia Syndrome; Hypoadrenalism with Achalasia-Alacrima-Achalasia-Addisonianism; ACTH-Resistant Adrenal Insufficiency, Achalasia, Alacrima Syndrome.

History

First described in 1978 by the English pediatric endocrinologist Jeremy Allgrove and colleagues.

Incidence

Approximately 100 cases without gender or racial predilection have been described. The prevalence is estimated to be approximately 1 in 1,000,000, although due to it being most likely underdiagnosed, the real number might be higher.

Genetic inheritance

Autosomal recessive. Consanguinity is a well-known risk factor.

Most cases are caused by mutations in the AAAS-gene, which has been mapped to chromosome 12q13. The AAAS-gene encodes the nucleoporin ALADIN, which is part of the nuclear pore complex and required for the normal development of the peripheral and central nervous system, adrenal glands, and gastrointestinal tract. Most mutations cause mislocalization of the mutant ALADIN proteins in the cytoplasm instead of in the nucleus, which results in functional impairment of the mutant protein. It has been hypothesized that the close proximity of the AAAS mutations to the Type II keratin gene cluster might explain why patients with Allgrove Syndrome often suffer from hyperkeratosis palmoplantaris.

Diagnosis

Onset of symptoms (hypoglycemia, adrenal crisis, or dysphagia) is typically in the first decade of life, but can be quite variable and not simultaneous, ie, achalasia or alacrima often precede adrenal insufficiency. Any patient who presents with a combination of alacrima and achalasia (which may present as failure to thrive) should undergo complete testing of the pituitary-adrenal axis to rule out adrenal insufficiency. Baseline ACTH- and cortisol levels should be measured and an ACTH-stimulation test performed. Most often, mineralocorticoid production is unaffected; nevertheless, several cases with mineralocorticoid deficiency have been reported. Thus, serum levels of sodium, potassium, aldosterone, and renin may be helpful in establishing the diagnosis. Esophageal motility tests can be used to diagnose dysphagia since this symptom is present in almost all patients. Plasma antiadrenal antibodies are not a feature of this disorder, and their presence should instead direct the investigations to ☞Addisonian Syndrome. Often times however, the clinical picture is incomplete and the diagnosis not immediately obvious. This is particularly true when tongue atrophy, extensive neurogenic muscle damage, and upper motor neuron symptoms point to juvenile amyotrophic lateral sclerosis. A muscle biopsy may reveal extensive fatty metaplasia, an increase in endo- and perimysial connective tissue and muscle fiber size variability. Small groups of atrophic fibers, numerous degenerating ...

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