Allgrove (AAA) Syndrome Clinical Presentation

Updated: Dec 18, 2015
  • Author: Robert J Ferry, Jr, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
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Presentation

History

Many cases of Allgrove (AAA) syndrome present with classic symptoms of primary adrenal insufficiency, including hypoglycemic seizures and shock. Less frequently, a child may be evaluated initially for recurrent vomiting, dysphagia, and failure to thrive (achalasia) or for ocular symptoms associated with alacrima.

At presentation, review of systems may be positive for crying without tears, hyperpigmentation, developmental delay, seizures, dysphagia, hypernasal speech, and symptoms related to orthostatic hypotension.

A family history of early unexplained infant deaths and familial consanguinity provides important clues. Evaluate siblings for early signs, particularly alacrima because this defect is frequently present from birth.

Although mental retardation and hyperpigmentation in the parents or grandparents of patients have been reported, these are not common or consistent findings and are not expected with autosomal recessive inheritance.

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Physical

A distinct facial appearance associated with Allgrove syndrome consists of a long thin face with a long philtrum, narrow upper lip, and a down-turned mouth. These features are not seen in unaffected siblings. [9]

Microcephaly is associated frequently with this disorder, but whether this is a primary manifestation or simply a reflection of recurrent hypoglycemia and/or malnutrition is unclear.

Conjunctival injection and irritation may be the only obvious signs of alacrima. Slit lamp examination may reveal punctate keratopathy or corneal ulceration. [10]

Definitive diagnosis of alacrima can be made at bedside with the Schirmer test. This test evaluates the wetting of a special strip placed in the conjunctival sac for 5 minutes. Less than 10 mm of wetting is abnormal.

Cardiac examination findings may be abnormal due to a number of autonomic nervous system defects that may accompany Allgrove syndrome. Orthostatic hypotension and diminished heart rate variations during deep breathing and Valsalva maneuver are well documented. Abnormal findings on respiratory examination may be secondary to recurrent aspiration accompanying achalasia.

Skin examination of patients may reveal abnormal findings that assist in confirming diagnosis. Hyperpigmentation is common but may be observed less frequently than in other forms of primary adrenal failure. Hyperkeratosis and fine fissuring of the palms of the hands and soles of the feet represent a unique feature of this syndrome.

Neurologic features are varied and have been the subject of several case reports and reviews. [11] The most commonly described abnormal features of the neurologic examination are hyperreflexia, dysarthria, hypernasal speech with palatopharyngeal incompetence, and ataxia.

Adults may exhibit progressive neural degeneration, develop parkinsonian features, and show mental deterioration.

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Causes

Allgrove syndrome appears to have an autosomal recessive pattern of inheritance. Parental consanguinity and previously affected siblings are the primary risk factors, although many patients have no such family history.

Linkage analysis provides evidence for an Allgrove syndrome locus on band 12q13 near the type II keratin gene cluster. [12, 13] Studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN. [14, 15]

Globally, the pathology of this syndrome may be due, in part, to a progressive loss of cholinergic function throughout the body.

Patients with isolated familial glucocorticoid deficiency (type 1 FGD) have mutations in the melanocortin-2 (ACTH) receptors. Patients with Allgrove syndrome (type 2 FGD) have no mutations in the coding sequence or the promoter region of this receptor gene. In Allgrove syndrome, the functional defect may reside in the ALADIN protein, which can be involved in either cytoplasmic trafficking or in normal peroxisomal function.

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