Autosomal recessive inherited disease characterized by
the triad of ACTH-resistant adrenal insufficiency, achalasia, and alacrima.
It presents in the first decade of life with severe hypoglycemic episodes,
which can result in death. A mixed pattern of upper and lower motor
neuropathy, sensory impairment, autonomic neuropathy, and mental retardation
Achalasia-Addisonianism-Alacrima Syndrome (AAA); Triple A
Syndrome; Hypoadrenalism with Achalasia.
No exact numbers are available, but the disorder is
extremely rare. No gender or racial predilection has been reported.
Autosomal recessive. Consanguinity is a
well-known risk factor. The genetic defect has been mapped to 12q13, a
region close to the type II keratin gene cluster, which may explain why
patients with Allgrove syndrome often have hyperkeratosis palmoplantaris.
Any patient who presents with a combination of alacrima
and achalasia (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 not affected,
but 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 show dysphagia because this sign is present in almost all patients.
Plasma antiadrenal antibodies are not a feature of this disorder, and their
presence should instead point the investigations to Addisonian
Alacrima is the earliest and most consistent
clinical sign of Allgrove syndrome (tearless crying) and may lead to severe
keratopathy and corneal ulcerations. However, a hypoglycemic seizure is the
most common initial presentation, and unrecognized adrenal crisis is still
the leading cause of death in this population. Hyperpigmentation of the
skin, developmental delay, seizures (not hypoglycemic), dysphagia
(achalasia), hypernasal speech (secondary to velopharyngeal incompetence),
and microcephaly are frequent findings. The face often has been described as
long and thin, with a long philtrum, narrow upper lip, and down-turned
mouth. Even in the absence of dysphagia, almost all patients show some
degree of esophageal dysmotility. Megaesophagus is a potential complication.
A history of vomiting, reflux, and dysphagia is frequent and may be
responsible for failure to thrive. Autonomic dysfunction presents with
abnormal sweating, abnormal pupillary reflexes with anisocoria, and poor
heart rate variability with postural hypotension. Other neurologic
manifestations may include polyneuropathy with sensory and motor components,
hyperreflexia, ataxia, muscle weakness parkinsonism (in adults), impaired
visual evoked potentials, and mild mental retardation. Bulbospinal
amyotrophy has been described in several patients. Because autonomic
dysfunction and amyotrophy both are common, some researchers have suggested
that autonomic dysfunction and amyotrophy both be added to the eponym,
making it a AAAAA (5A) instead of AAA (3A) syndrome. Hyperkeratosis
palmoplantaris has been found in many affected individuals. Abdominal CT may
reveal atrophy of the adrenal glands. Autopsy in one patient showed gross
atrophy of the zona fasciculata and reticularis of the adrenals, whereas the
zona glomerulosa ...