Journal Mobile Options
Table of Contents
Vol. 70, No. 6, 2008
Issue release date: December 2008
Horm Res 2008;70:364–372

Late-Onset Triple A Syndrome: A Risk of Overlooked or Delayed Diagnosis and Management

Salmaggi A. · Zirilli L. · Pantaleoni C. · De Joanna G. · Del Sorbo F. · Koehler K. · Krumbholz M. · Huebner A. · Rochira V.
aIstituto Nazionale Neurologico Carlo Besta, IRCCS, Milan; bChair of Endocrinology, Department of Medicine, Endocrinology and Metabolism, and Geriatrics, University of Modena and Reggio Emilia, Ospedale S. Agostino-Estense di Baggiovara, Modena, Italy; cChildren’s Hospital, Technical University Dresden, Dresden, Germany

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background/Aims: A 33-year-old man was referred for the first time to the Division of Neurology because of the presence and progression of neurological symptoms. Dysphagia, weakness, reduced tear production, and nasal speech were present. In order to point the attention of late-onset triple A syndrome we describe this case and review the literature. Methods: Hormonal and biochemical evaluation, Schirmer test, tilt test and genetic testing for AAAS gene mutations. Results: Late-onset triple A syndrome caused by a novel homozygous missense mutation in the AAAS gene (A167V in exon 6) was diagnosed at least 17 years after symptom onset. Conclusions: The association between typical signs and symptoms of triple A syndrome should suggest the diagnosis even if they manifest in adulthood. The diagnosis should be confirmed by Schirmer test, endocrine testing (both basal and dynamic), genetic analysis, and detailed gastroenterological and neurological evaluations. Awareness of the possible late onset of the disease and of diagnosis in adulthood is still poor among clinicians, the acquaintance with the disease is more common among pediatricians. The importance of an adequate multidisciplinary clinical approach, dynamic testing for early diagnosis of adrenal insufficiency and periodical reassessment of adrenal function are emphasized.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Allgrove J, Clayden GS, Grant DB, Macaulay JC: Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1978;1:1284–1286.
  2. Online Mendelian Inheritance in Man. OMIM (TM). Bethesda, Center for Medical Genetics, Johns Hopkins University, and National Center for Biotechnology Information, National Library of Medicine, 1999. URL:
  3. Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A: Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet 2001;10:283–290.
  4. Houlden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW, Reilly MM: Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain2002;125:2681–2690.
  5. Prpic I, Huebner A, Persic M, Handschug K, Pavletic M: Triple A syndrome: genotype-phenotype assessment. Clin Genet 2003;63:415–417.
  6. Clark AJ, Weber A: Adrenocorticotropin insensitivity syndromes. Endocr Rev 1998;19:828–843.
  7. Geffner ME, Lippe BM, Kaplan SA, Berquist WE, Bateman JB, Paterno VI, Seegan R: Selective ACTH insensitivity, achalasia, and alacrima: a multisystem disorder presenting in childhood. Pediatr Res 1983;17:532–536.
  8. Grant DB, Dunger DB, Smith I, Hyland K: Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia. Eur J Pediatr 1992;151:85–89.
  9. Moore PS, Couch RM, Perry YS, Shuckett EP, Winter JS: Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima. Clin Endocrinol 1991;34:107–114.
  10. Bentes C, Santos-Bento M, de Sá J, de Lurdes Sales Luís M, de Carvalho M: Allgrove syndrome in adulthood. Muscle Nerve 2001;24:292–296.
  11. Kimber J, McLean BN, Prevett M, Hammans SR: Allgrove or 4 ‘A’ syndrome: an autosomal recessive syndrome causing multisystem neurological disease. J Neurol Neurosurg Psychiatr 2003;74:654–657.
  12. Pedreira CC, Zacharin MR: Allgrove syndrome: when a recognizable paediatric disorder occurs in adulthood. Med J Aust 2004;180:74–75.
  13. Cronshaw JM, Matunis MJ: The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci USA 2003;100:5823–5827.
  14. Salehi M, Houlden H, Sheikh A, Poretsky L: The diagnosis of adrenal insufficiency in a patient with Allgrove syndrome and a novel mutation in the ALADIN gene. Metabolism 2005;54:200–205.
  15. Nieman KL: Dynamic evaluation of adrenal hypofunction. J Endocrinol Invest 2003;26:74–82.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50