eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Allgrove (AAA) Syndrome

Author: Bruce A Boston, MD, Chief, Division of Pediatric Endocrinology, Director, Pediatric Endocrine Training Program, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doernbecher Children's Hospital
Coauthor(s): Daniel L Marks, MD, PhD, Assistant Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health Sciences University and Doerenbecher Children's Hospital; Jacalyn Bishop, MD, Pediatric Endocrinologist, Private Practice
Contributor Information and Disclosures

Updated: Feb 20, 2009

Introduction

Background

In 1978, Allgrove and colleagues described 2 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 and Counahan and West, who reported on 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.

Several authors have investigated the genetic basis for Allgrove syndrome. Although many logical candidate genes have been investigated, including those coding for the ACTH receptor, vasoactive intestinal polypeptide (VIP), the vip-1 receptor, pituitary adenylate cyclase activating peptide, and neurotrophin-3, no mutant genes have been identified in patients with this syndrome. Linkage analysis in both European and Puerto Rican kindreds provides 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 particularly intriguing because of the hyperkeratosis of the palms and soles that is observed in several patients.

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, but no specific gene mutation has been identified.

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.

Frequency

International

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.

Mortality/Morbidity

The primary cause of mortality is unrecognized adrenal crisis. The most frequent initial presentation is a hypoglycemic seizure secondary to glucocorticoid deficiency. Most patients have previously unrecognized alacrima at the time of presentation. This leads to severe keratopathy and corneal melting (dehydration-induced ulceration). Achalasia leading to frequent vomiting or regurgitation also commonly occurs and may lead to growth failure. Most children who are diagnosed with achalasia in the general population have isolated esophageal dysfunction and do not have any other features of Allgrove syndrome.

Although the 3 main features produce the primary morbidities associated with Allgrove syndrome, a slow neurologic deterioration occurs in many patients. This most frequently includes mild mental retardation and autonomic neuropathy but may include ataxia and muscle weakness as well.

In the pediatric population, developmental delay is common. Determining if this impairment is a primary feature of the syndrome or simply a reflection of the episodic hypoglycemia that occurs in association with glucocorticoid deficiency is difficult.

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 is 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.

Clinical

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.

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.
• 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.
• 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. 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.

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. Recent studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN.
• 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 defect appears to reside in the ALADIN protein, which may be involved in either cytoplasmic trafficking or in normal peroxisomal function.

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