European Journal of Pediatrics

, Volume 169, Issue 11, pp 1323–1328 | Cite as

Triple A syndrome: 32 years experience of a single centre (1977–2008)

  • Tatjana Milenkovic
  • Dragan Zdravkovic
  • Natasa Savic
  • Sladjana Todorovic
  • Katarina Mitrovic
  • Katrin Koehler
  • Angela Huebner
Original Paper

Abstract

Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977–2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype–phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.

Keywords

Achalasia Adrenal insufficiency Alacrima Triple A syndrome AAAS gene mutation 

References

  1. 1.
    Allgrove J, Clayden GS, Grant DB, Macaulay JC (1978) Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production. Lancet 1:1284–1286CrossRefPubMedGoogle Scholar
  2. 2.
    Barat P, Goizet C, Tullio-Pelet A, Puel O, Labessan C, Barthelemy A (2004) Phenotypic heterogeneity in AAAS gene mutation. Acta Paediatr 93:1257–1259CrossRefPubMedGoogle Scholar
  3. 3.
    Brooks BP, Kleta R, Caruso RC, Stuart C, Ludlow J, Stratakis CA (2004) Triple-A syndrome with prominent ophtalmic features and a novel mutation in the AAAS gene: a case report. BMC Ophtalmol 4:7CrossRefGoogle Scholar
  4. 4.
    Brooks BP, Kleta R, Stuart C, Tuchman M, Jeong A, Stergiopoulos SG, Bei T, Bjornson B, Russell L, Chanoine JP, Tsagarakis S, Kalsner L, Stratakis C (2005) Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005. Clin Genet 68:215–221CrossRefPubMedGoogle Scholar
  5. 5.
    Clark AJ, Weber A (1998) Adrenocorticotropin insensitivity syndromes. Endocr Rev 19:828–843CrossRefPubMedGoogle Scholar
  6. 6.
    Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ (2002) Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol 158:915–927CrossRefPubMedGoogle Scholar
  7. 7.
    Gazarian M, Cowell CT, Bonney M, Grigor WG (1995) The 4A syndrome: adrenocortical insufficiency associated with achalasia, alacrima, autonomic and other neurological abnormalities. Eur J Pediatr 154:18–23CrossRefPubMedGoogle Scholar
  8. 8.
    Gilio F, Di Rezze S, Conte A, Frasca V, Iacovelli E, Marini Bettolo C, Gabriele M, Giacomelli E, Pizzuti A, Pirro C, Fattapposta F, Habib FI, Prencipe M, Inghilleri M (2007) Case report of adult-onset Allgrove syndrome. Neurol Sci 28:331–335CrossRefPubMedGoogle Scholar
  9. 9.
    Goizet C, Catargi B, Tison F, Tullio-Pelet A, Hadj-Rabia S, Pujol F, Lagueny A, Lyonnet S, Lacombe D (2002) Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. Neurology 58:962–965PubMedGoogle Scholar
  10. 10.
    Grant DB, Dunger DB, Smith I, Hyland K (1992) Familial glucocorticoid deficiency with achalasia of the cardia associated with mixed neuropathy, long-tract degeneration and mild dementia. Eur J Pediatr 151:85–89CrossRefPubMedGoogle Scholar
  11. 11.
    Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A (2001) Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet 10:283–290CrossRefPubMedGoogle Scholar
  12. 12.
    Houlden H, Smith S, De Carvalho M, Blake J, Mathias C, Wood NW, Reilly MM (2002) Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain 125:2681–2690CrossRefPubMedGoogle Scholar
  13. 13.
    Huebner A, Elias LLK, Clark AJL (1999) ACTH resistance syndromes. J Pediatr Endocrinol Metab 12:277–293PubMedGoogle Scholar
  14. 14.
    Krumbholz M, Koehler K, Huebner A (2006) Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome—shedding light on an unexpected splice mutation. Biochem Cell Biol 84:243–249CrossRefPubMedGoogle Scholar
  15. 15.
    Kurca E, Grofik M, Kucera P, Varsik P (2005) Familial occurrence of adrenocortical insufficiency in two brothers with Allgrove syndrome. A case report of 4A (Allgrove) syndrome with epilepsy and a new AAAS gene mutation. Neuro Endocrinol Lett 26:499–502PubMedGoogle Scholar
  16. 16.
    Laureti S, Arvat E, Candeloro P, Di Vito L, Ghigo E, Santeusanio F, Falorni A (2000) Low dose (1 microg) ACTH test in the evaluation of adrenal dysfunction in pre-clinical Addison’s disease. Clin Endocrinol (Oxf) 53:107–115CrossRefGoogle Scholar
  17. 17.
    Milenković T, Koehler K, Krumbholz M, Zivanović S, Zdravković D, Huebner A (2008) Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation. Eur J Pediatr 167:1049–1055CrossRefPubMedGoogle Scholar
  18. 18.
    Phillip M, Hershkovitz E, Schulman H (1996) Adrenal insufficiency after achalasia in the triple A syndrome. Clin Pediatr (Philadelphia) 35:99–100CrossRefGoogle Scholar
  19. 19.
    Prpic I, Huebner A, Persic M, Handschug K, Pavletic M (2003) Triple A syndrome: genotype–phenotype assessment. Clin Genet 63:415–417CrossRefPubMedGoogle Scholar
  20. 20.
    Rabut G, Doye V, Ellenberg J (2004) Mapping the dynamic organization of the nuclear pore complex inside single living cells. Nat Cell Biol 6:1114–1121CrossRefPubMedGoogle Scholar
  21. 21.
    Salehi M, Houlden H, Sheikh A, Poretsky L (2005) The diagnosis of adrenal insufficiency in a patient with Allgrove syndrome and a novel mutation in the ALADIN gene. Metabolism 54:200–205CrossRefPubMedGoogle Scholar
  22. 22.
    Toromanovic A, Tahirovic H, Milenkovic T, Koehler K, Kind B, Zdravkovic D, Hasanhodzic M, Huebner A (2009) Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome. Eur J Pediatr 168:317–320CrossRefPubMedGoogle Scholar
  23. 23.
    Weber A, Wienker TF, Jung M, Easton D, Dean HJ, Heinrichs C, Reis A, Clark AJ (1996) Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 5:2061–2066CrossRefPubMedGoogle Scholar
  24. 24.
    Weintrob N, Sprecher E, Josefsberg Z, Weininger C, Aurbach-Klipper Y, Lazard D, Karp M, Pertzelan A (1998) Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 83:88–92CrossRefPubMedGoogle Scholar
  25. 25.
    Zdravković D, Banićević M, Subotić Z, Janković B (1990) Primarna insuficijencija kore nadbubrežnih žlezda u detinjstvu—etiologija, terapija i prognoza. Jugosl Pediatr 33:5–12 (Serbian)Google Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Tatjana Milenkovic
    • 1
  • Dragan Zdravkovic
    • 1
  • Natasa Savic
    • 1
  • Sladjana Todorovic
    • 1
  • Katarina Mitrovic
    • 1
  • Katrin Koehler
    • 2
  • Angela Huebner
    • 2
  1. 1.Mother and Child Healthcare Institute of Serbia “Dr Vukan Cupic”BelgradeSerbia
  2. 2.Children’s HospitalTechnical University DresdenDresdenGermany

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