Allgrove (AAA) Syndrome

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

Background

In 1978, Allgrove and colleagues described two unrelated pairs of siblings with isolated glucocorticoid deficiency and achalasia of the esophagus cardia. [1] The latter condition involved delayed passage of food into the stomach and consequent dilation of the thoracic esophagus. Three of these individuals also had defective tear production, leading the authors to speculate that the combination of achalasia, adrenal deficiency, and alacrima represented an inherited familial disorder. [2] The authors also referred to the prior publications of Kelch et al as well as Counahan and West, who reported patients with hereditary adrenal unresponsiveness to adrenocorticotropic hormone (ACTH). [3, 4] Allgrove pointed out that these patients developed achalasia and suggested that all of the patients shared a common syndrome.

Similarly, patients originally reported as having isolated achalasia were subsequently given a diagnosis of adrenal insufficiency, highlighting the variable presentation of this syndrome. Indeed, the adrenal dysfunction in a subset of patients was not limited to glucocorticoid deficiency but was also shown to include mineralocorticoid deficiency.

In the years following, numerous authors published similar reports that have helped to define the primary and associated features of this syndrome. Several authors published descriptions of a more global autonomic disturbance associated with the original Allgrove triad, leading one author to suggest the name 4A syndrome (adrenal insufficiency, achalasia of the cardia, alacrima, autonomic abnormalities). [5] Specific autonomic disturbances described in this syndrome include abnormal pupillary reflexes, poor heart rate variability, and orthostatic hypotension. Other phenotypic features occasionally associated with this syndrome are described below.

The protean presentation of this disorder is related to dysfunction of nuclear pore complexes (NPC), despite apparently normal structure of these large multiprotein assemblies. Allgrove syndrome can arise from mutations of the ADRACALIN (or AAAS) gene encoding the ALADIN protein of the NPC. [6, 7] Surprisingly, among many logical candidate genes that have not been associated with the disorder are those coding for the ACTH receptor, vasoactive intestinal polypeptide (VIP), the vip-1 receptor, pituitary adenylate cyclase activating peptide, and neurotrophin-3. Linkage analyses in both European and Puerto Rican kindreds provide evidence for linkage to band 12q13 near the type II keratin gene cluster. The linkage to a region of the genome containing a keratin gene cluster is intriguing because of hyperkeratosis of the palms and soles has been observed in several patients.

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Pathophysiology

No unifying pathologic features common to the 3 primary sites affected in this syndrome (esophagus, lacrimal glands, adrenal glands) are known. Linkage analysis provides evidence for an Allgrove syndrome locus on band 12q13 near the type II keratin gene cluster. [8]

Globally, the pathology of this syndrome may be due to a progressive loss of cholinergic function throughout the body. Alternatively, this disorder may represent a dysfunction of melanocortin receptor signaling, as melanocortin receptors are known to regulate adrenal function and skin exocrine gland function.

A lacrimal gland biopsy from a child with Allgrove syndrome was examined with an electron microscope. Evidence of neuronal degeneration associated with depletion of secretory granules in the acinar cells was observed. The reduced or absent lacrimation that accompanies this change frequently leads to dehydration-induced keratopathy that can be observed with rose bengal staining.

CT scanning reveals atrophic adrenal glands, but no reports of histologic analysis are available. As with all states of ACTH unresponsiveness, one may expect to see atrophy of the zona fasciculata; however, other changes more specific to this syndrome may have yet to be described.

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Epidemiology

Frequency

Incidence is unknown, and only scattered family and case reports are noted in the literature. Review of multiple kindreds and analysis of a large, highly inbred kindred provide evidence that this is a rare syndrome with an autosomal recessive inheritance. The probable recurrence risk for future pregnancies from parents with a child affected with Allgrove syndrome is 25%. The actual incidence is difficult to determine because of the variable presentation, including unexplained childhood death due to adrenal crisis and mild disease that is not apparent until adulthood.

Race

Allgrove syndrome is considered an autosomal recessive disorder with variable presentation. No evidence suggests that race affects the frequency. Allgrove syndrome has been reported in male and female blacks, whites, Hispanics, Native Americans, Indians, and Arabs around the world.

Sex

Allgrove syndrome is considered an autosomal recessive disorder with a variable presentation. No evidence suggests that gender affects the frequency.

Age

Age at onset of symptoms varies. The glucocorticoid deficiency is not apparent at birth but develops during the first 2 decades of life. Progression from normal adrenal function to adrenal insufficiency has been documented in numerous individuals. Biochemical analysis in siblings of index cases documented several cases in which normal adrenal function is followed years later by adrenal crisis or glucocorticoid deficiency in these same individuals. Alacrima is typically present from early infancy, whereas symptoms of achalasia may appear in individuals as young as 6 months or as late as early adulthood.

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