Allgrove Syndrome

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 is common.

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 Syndrome.

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 was normal.

Recurrent aspiration is a well-known complication in these patients with achalasia and mental retardation and may result in acute bronchopneumonia with fatal consequences. Preoperative chest radiograph should be obtained, and pulmonary function test may be indicated for selected patients (especially when recurrent aspiration occurs). Review the glucocorticoid replacement therapy and obtain a blood glucose profile. In addition, preoperative blood workup should include a complete blood count and electrolytes because mineralocorticoid deficiency has been reported in some patients. To prevent hypoglycemia, patients should be started on a dextrose-containing solution at the beginning of the preoperative fasting period. The oral glucocorticoid replacement dose should be given on the day of surgery, and additional intravenous doses may be required in the perioperative period to cover for the stress, depending on the extent of the procedure.

Patients are candidates for a rapid sequence induction because of gastroesophageal reflux, dysphagia, and recurrent vomiting. There is an increased risk of corneal abrasions because of the lack of tears, so the eyes should be well lubricated and the eyelids taped shut after induction of anesthesia. Autonomic dysfunction may result in hemodynamic instability. Cardiovascular shock secondary to adrenal crisis is possible, as is severe hypoglycemia resulting in sudden death. Consequently, frequent perioperative measurements of blood glucose are mandatory. Invasive blood pressure monitoring is helpful for early diagnosis of hemodynamic instability and simultaneously allows for frequent blood sampling.

No known specific implications with this condition.

Achalasia-Alacrima Syndrome: ACTH insensitivity syndrome is an inherited disorder but in a small minority can be an acquired abnormality induced by the formation of antibodies that block ACTH receptors. Fluid and electrolytes disorders occur. In contrast to Addison disease, the renin-angiotensin-aldosterone axis functions normally.

Addisonian Syndrome: Progressive weakness, anemia, hypoglycemia, and hyperpigmentation of the skin. Vomiting, apneic spells, cyanosis, vascular collapse, and cardiovascular shock may be consequential.

X-Linked Adrenoleukodystrophy (XLA): Disorder characterized by progressive demyelinization of the central nervous system and peripheral adrenal insufficiency.