Allgrove (AAA) Syndrome Workup
- Author: Robert J Ferry, Jr, MD; Chief Editor: Stephen Kemp, MD, PhD more...
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.
MRI or CT scanning of the head (if neurologic problems are observed)
Patients frequently reveal atrophic lacrimal glands on computed tomography (CT) of the orbits.
If the patient presents with a seizure, magnetic resonance 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.
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.
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.
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.
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.
Allgrove J, Clayden GS, Grant DB. Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet. 1978 Jun 17. 1(8077):1284-6. [Medline].
Kasar PA, Khadilkar VV, Tibrewala VN. Allgrove syndrome. Indian J Pediatr. 2007 Oct. 74(10):959-61. [Medline].
Kelch RP, Kaplan SL, Biglieri EG. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J Pediatr. 1972 Oct. 81(4):726-36. [Medline].
Counahan R, West R. Ocular and fingertip abnormalities in isolated glucocorticoid deficiency. J Pediatr. 1974 Oct. 85(4):580-1. [Medline].
Gazarian M, Cowell CT, Bonney M. The "4A" syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities. Eur J Pediatr. 1995 Jan. 154(1):18-23. [Medline].
Li W, Gong C, Qi Z, Wu DI, Cao B. Identification of AAAS gene mutation in Allgrove syndrome: A report of three cases. Exp Ther Med. 2015 Oct. 10 (4):1277-1282. [Medline].
Sarathi V, Shah NS. Triple-A syndrome. Adv Exp Med Biol. 2010. 685:1-8. [Medline].
Alhussaini B, Gottrand F, Goutet JM, Scaillon M, Michaud L, Spyckerelle C, et al. Clinical and manometric characteristics of Allgrove syndrome. J Pediatr Gastroenterol Nutr. 2011 Sep. 53(3):271-4. [Medline].
Moschos MM, Margetis I, Koehler K, Gatzioufas Z, Huebner A. New ophthalmic features in a family with triple A syndrome. Int Ophthalmol. 2011 Jun. 31(3):239-43. [Medline].
Vallet AE, Verschueren A, Petiot P, Vandenberghe N, Nicolino M, Roman S, et al. Neurological features in adult Triple-A (Allgrove) syndrome. J Neurol. 2012 Jan. 259(1):39-46. [Medline].
Stratakis CA, Lin JP, Pras E. Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers. Proc Assoc Am Physicians. 1997 Sep. 109(5):478-82. [Medline].
Weber A, Wienker TF, Jung M. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet. 1996 Dec. 5(12):2061-6. [Medline].
Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. 2003 May. 63(5):415-7. [Medline].
Chu ML, Berlin D, Axelrod FB. Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests. J Pediatr. 1996 Jul. 129(1):156-9. [Medline].
Alakeel A, Raynaud C, Rossi M, Reix P, Jullien D, Souillet AL. [Allgrove syndrome]. Ann Dermatol Venereol. 2015 Feb. 142 (2):121-4. [Medline].