Allgrove (AAA) Syndrome Clinical Presentation

  • Author: Bruce A Boston, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Mar 1, 2012
 

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.[7]
  • 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.[8]
  • 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.[9] 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. 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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Contributor Information and Disclosures
Author

Bruce A Boston, MD  Chief, Division of Pediatric Endocrinology, Director, Pediatric Endocrine Training Program, Doernbecher Children's Hospital; Professor, Department of Pediatrics, Division of Pediatric Endocrinology, Oregon Health and Science University School of Medicine

Bruce A Boston, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

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

Daniel L Marks, MD, PhD is a member of the following medical societies: American Academy of Pediatrics and Oregon Medical Association

Disclosure: Nothing to disclose.

Jacalyn Bishop, MD  Pediatric Endocrinologist, Private Practice

Disclosure: Nothing to disclose.

Specialty Editor Board

Phyllis W Speiser, MD  Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children's Medical Center of New York; Professor of Pediatrics, Hofstra-North Shore LIJ School of Medicine at Hofstra University

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD  Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

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