eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Allgrove (AAA) Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Adrenal Hypoplasia
Adrenal Insufficiency
Familial Glucocorticoid Deficiency

Other Problems to Be Considered

Achalasia
Alacrima
Adrenal leukodystrophy
Autonomic neuropathy

Workup

Laboratory Studies

  • Assess adrenal function in patients with Allgrove (AAA) syndrome.
    • Patients who present with the combination of achalasia and alacrima should undergo a complete evaluation of their pituitary-adrenal axis to exclude adrenal insufficiency.
    • Incidence of glucocorticoid deficiency in patients with isolated achalasia is low, and endocrine evaluation is not warranted unless symptoms consistent with glucocorticoid deficiency are present.
    • Because no such data are available for patients with isolated alacrima, other clinical features must guide testing in this population.
    • In patients with symptoms of cortisol deficiency or combined alacrima and achalasia, draw baseline adrenocorticotropic hormone (ACTH) and cortisol values and perform an ACTH stimulation test to assess adrenal function.
  • Esophageal motility tests are pertinent in patients presenting with dysphagia, food regurgitation, or both.
  • Determine serum sodium, potassium, aldosterone, and renin levels. Although aldosterone levels are usually normal in 4A syndrome, several cases of mineralocorticoid deficiency have been reported.
  • The presence of plasma antiadrenal antibodies should direct the investigation to the possibility of Addison disease.
  • Look for normal plasma very long chain fatty acids (hexa-eicosanoate) to exclude adrenoleukodystrophy.
  • If malnutrition is present, a comprehensive metabolic panel and CBC count are warranted.
  • For patients presenting with a seizure, obtain a baseline serum glucose concentration and perform a lumbar puncture.
  • Although none of the above tests are specific for Allgrove syndrome, they may provide clues for making this diagnosis.

Imaging Studies

  • MRI or CT scanning of the head (if neurologic problems are observed)
    • Patients frequently reveal atrophic lacrimal glands on CT scans.
    • If the patient presents with a seizure, imaging of the brain is useful to exclude other causes of new-onset seizures.
    • Abdominal CT scanning may reveal cortical atrophy of the adrenal glands similar to that observed with primary adrenal insufficiency; however, this is typically not necessary to make the diagnosis.
  • Barium esophagography, esophageal manometry, and endoscopy
    • Various methods are used to demonstrate achalasia of the esophagus.
    • Perhaps the most readily available and commonly used test is barium esophagography, although esophageal manometry and endoscopy are also used.
    • Barium esophagography typically demonstrates a dilated esophagus with minimal, if any, peristaltic movement. The meal frequently passes slowly through a tight lower esophageal sphincter.

Other Tests

  • Brainstem auditory evoked response
    • Numerous investigators have demonstrated hearing deficits associated with Allgrove syndrome.
    • Brainstem auditory evoked response (BAER) testing is useful in determining which patients have hearing deficits.
    • Both normal and abnormal responses compatible with bilateral sensorineural hearing loss are found.
  • Autonomic testing
    • Investigation of the autonomic nervous system, including tilt-table and heart rate variability testing, is useful in demonstrating and following autonomic dysfunction.
    • Many patients have diminished heart rate variability and exaggerated orthostatic responses on tilt-table.
    • Formal pupillometry, when available, may demonstrate anisocoria and slowed constriction velocity.
  • Ophthalmologic evaluation for lacrimal dysfunction
    • Ophthalmologic testing is warranted in children with Allgrove syndrome.
    • A Schirmer test provides a semiquantitative measure of tearing. It consists of placing a standardized test strip in the conjunctival sac and measuring the wetting of this strip over a 5-minute interval. Less than 10 mm of wetting during this time is defined as alacrima.
    • Other ophthalmologic testing, including slit lamp examination and fluorescein staining, is helpful to identify patients with corneal pathology secondary to poor lacrimation.
  • Neurologic evaluation
    • A complete neurologic evaluation and developmental study may highlight the impaired neurologic and developmental function associated with this syndrome.
    • Palatopharyngeal incompetence, sensory impairment, ataxia, and muscle weakness are among the documented findings.

Histologic Findings

  • 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 present. The reduced or absent lacrimation that accompanies this change frequently leads to the dehydration-induced keratopathy observed with rose Bengal staining.
  • CT scanning reveals atrophic adrenal glands, but no published cases of histologic analysis have been reported. 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.

More on Allgrove (AAA) Syndrome

Overview: Allgrove (AAA) Syndrome
Differential Diagnoses & Workup: Allgrove (AAA) Syndrome
Treatment & Medication: Allgrove (AAA) Syndrome
Follow-up: Allgrove (AAA) Syndrome
References
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References

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Further Reading

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Keywords

Allgrove (AAA) syndrome, 4A syndrome, triple-A syndrome, achalasia-addisonianism-alacrima syndrome, achalasia-addisonianism-alacrima-autonomic neuropathy syndrome, addisonian-achalasia syndrome, alacrima-achalasia-addisonianism, glucocorticoid deficiency, achalasia, hypoadrenalism with achalasia, isolated glucocorticoid deficiency, adrenal insufficiency, growth failure, developmental delay, hypoglycemia, microcephaly, hypoglycemia, hyperpigmentation, hyperkeratosis

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Contributor Information and Disclosures

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

Medical Editor

Phyllis W Speiser, MD, Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine
Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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, Lawson-Wilkins 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.

CME Editor

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 Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and 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: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

 
 
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