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Allgrove (AAA) Syndrome Clinical Presentation

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

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.[9]

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.[10]

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.[11] 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.[12, 13] Studies implicate mutations in the AAAS gene, which codes for a WD-repeat protein termed ALADIN.[14, 15]

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 functional defect may reside in the ALADIN protein, which can be involved in either cytoplasmic trafficking or in normal peroxisomal function.

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Contributor Information and Disclosures
Author

Robert J Ferry, Jr, MD Professor, Division of Pediatric Endocrinology, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry, Jr, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Received research funds for: Eli Lilly & Co.

Specialty Editor Board

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 Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

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, Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgements

Jacalyn Bishop, MD Pediatric Endocrinologist, Private Practice

Disclosure: Nothing to disclose.

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.

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.

References
  1. 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].

  2. Kasar PA, Khadilkar VV, Tibrewala VN. Allgrove syndrome. Indian J Pediatr. 2007 Oct. 74(10):959-61. [Medline].

  3. Kelch RP, Kaplan SL, Biglieri EG. Hereditary adrenocortical unresponsiveness to adrenocorticotropic hormone. J Pediatr. 1972 Oct. 81(4):726-36. [Medline].

  4. Counahan R, West R. Ocular and fingertip abnormalities in isolated glucocorticoid deficiency. J Pediatr. 1974 Oct. 85(4):580-1. [Medline].

  5. 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].

  6. Cronshaw JM, Matunis MJ. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A. 2003 May 13. 100(10):5823-7. [Medline]. [Full Text].

  7. 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].

  8. Sarathi V, Shah NS. Triple-A syndrome. Adv Exp Med Biol. 2010. 685:1-8. [Medline].

  9. 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].

  10. 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].

  11. 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].

  12. 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].

  13. 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].

  14. Handschug K, Sperling S, Kim Yoon S. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Human Molecular Genetics. 2001. 10:283-290. [Medline]. [Full Text].

  15. Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. 2003 May. 63(5):415-7. [Medline].

  16. Chu ML, Berlin D, Axelrod FB. Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests. J Pediatr. 1996 Jul. 129(1):156-9. [Medline].

  17. Alakeel A, Raynaud C, Rossi M, Reix P, Jullien D, Souillet AL. [Allgrove syndrome]. Ann Dermatol Venereol. 2015 Feb. 142 (2):121-4. [Medline].

 
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