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Hormones

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Triple A syndrome: two siblings with a novel mutation in the AAAS gene

  • Athanasia Bouliari
  • Xuexin Lu
  • Rebecca W. Persky
  • Constantine A. Stratakis
Case Report

Abstract

Objective

Triple A syndrome is a rare autosomal recessive disorder caused by mutations in the AAAS gene on chromosome 12q13. Its main clinical features are alacrima, achalasia, and adrenal insufficiency, with most patients also having neurological symptoms and autonomic dysfunction. The neurologic manifestations are less well-understood, especially in children. Here, we examine two siblings who were found to have a novel mutation in the AAAS gene and who were found to have subtle, but important, neurologic findings.

Design

This is a case report of two siblings.

Results

We discuss two siblings exhibiting different signs of the disorder including neurologic dysfunction found at varying ages. Genetic analysis revealed that both patients have the same compound heterozygous mutations in the AAAS gene consisting of one novel mutation (c.500 C>A, A167E) and one previously described mutation (c.1331+1G> A/IVS14+1 G>A). A diagnosis of triple A syndrome was reached based on their clinical and genetic findings.

Conclusions

The unique characteristic of these two cases is the novel mutation in the AAAS gene, which is likely pathogenic. In addition, they showcase the genotype-phenotype variability of the disease, as well as the importance of early identification of the neurologic abnormalities, which can result in early intervention and possibly improved outcomes.

Keywords

Triple A syndrome AAAS Allgrove syndrome Novel variant 

Notes

Author contributions

All authors have accepted the responsibility for the entire content of this submitted manuscript and approved the submission.

Funding

This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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(8077):1284–1286CrossRefGoogle Scholar
  2. 2.
    Brooks BP, Kleta R, Stuart C et al (2005) Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005. Clin Genet 68(3):215–221CrossRefGoogle Scholar
  3. 3.
    Lovrecic L, Pelet A, Peterlin B (2006) Heterogeneity of the triple A syndrome and assessment of a case. Genet Couns 17(2):191–195PubMedGoogle Scholar
  4. 4.
    Barat P, Goizet C, Tullio-Pelet A, Puel O, Labessan C, Barthelemy A (2004) Phenotypic heterogeneity in AAAS gene mutation. Acta Paediatr 93(9):1257–1259CrossRefGoogle Scholar
  5. 5.
    Patt H, Koehler K, Lodha S et al (2017) Phenotype-genotype spectrum of AAA syndrome from Western India and systematic review of literature. Endocr Connect 6(8):901–913CrossRefGoogle Scholar
  6. 6.
    Tibussek D, Ghosh S, Huebner A, Schaper J, Mayatepek E, Koehler K (2018) “Crying without tears” as an early diagnostic sign-post of triple A (Allgrove) syndrome: two case reports. BMC Pediatr 18(1):6CrossRefGoogle Scholar
  7. 7.
    Brown B, Agdere L, Muntean C, David K (2016) Alacrima as a harbinger of adrenal insufficiency in a child with Allgrove (AAA) syndrome. Am J Case Rep 17:703–706CrossRefGoogle Scholar
  8. 8.
    Aragona P, Rania L, Roszkowska AM et al (2014) 4A syndrome: ocular surface investigation in an Italian young patient. BMC Ophthalmol 14:155CrossRefGoogle Scholar
  9. 9.
    Thomas J, Subramanyam S, Vijayaraghavan S, Bhaskar E (2015) Late onset adrenal insufficiency and achalasia in Allgrove syndrome. BMJ Case Rep 2015Google Scholar
  10. 10.
    Sanyal D, Bhattacharjee S (2013) A case of late-onset Allgrove syndrome presenting with predominant autonomic dysfunction. Ann Indian Acad Neurol 16(2):266–268CrossRefGoogle Scholar
  11. 11.
    Houlden H, Smith S, De Carvalho M et al (2002) Clinical and genetic characterization of families with triple A (Allgrove) syndrome. Brain 125(Pt 12):2681–2690CrossRefGoogle Scholar
  12. 12.
    Dumic M, Barisic N, Kusec V et al (2012) Long-term clinical follow-up and molecular genetic findings in eight patients with triple A syndrome. Eur J Pediatr 171(10):1453–1459CrossRefGoogle Scholar
  13. 13.
    Dumic M, Putarek NR, Kusec V, Barisic N, Koehler K, Huebner A (2016) Low bone mineral density for age/osteoporosis in triple A syndrome-an overlooked symptom of unexplained etiology. Osteoporos Int 27(2):521–526CrossRefGoogle Scholar
  14. 14.
    Dumic M, Mravak-Stipetic M, Kaic Z et al (2000) Xerostomia in patients with triple A syndrome--a newly recognised finding. Eur J Pediatr 159(12):885–888CrossRefGoogle Scholar
  15. 15.
    Kallabi F, Ben Rebeh I, Felhi R et al (2016) Molecular analysis of Libyan families with Allgrove syndrome: geographic expansion of the ancestral mutation c.1331+1G>A in North Africa. Horm Res Paediatr 85(1):18–21CrossRefGoogle Scholar
  16. 16.
    Tullio-Pelet A, Salomon R, Hadj-Rabia S et al (2000) Mutant WD-repeat protein in triple-A syndrome. Nat Genet 26(3):332–335CrossRefGoogle Scholar
  17. 17.
    Weber A, Wienker TF, Jung M et al (1996) Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet 5(12):2061–2066CrossRefGoogle Scholar
  18. 18.
    Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ (2002) Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol 158(5):915–927CrossRefGoogle Scholar
  19. 19.
    Cronshaw JM, Matunis MJ (2003) The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome. Proc Natl Acad Sci U S A 100(10):5823–5827CrossRefGoogle Scholar
  20. 20.
    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(3):283–290CrossRefGoogle Scholar
  21. 21.
    Nakamura K, Yoshida K, Yoshinaga T et al (2010) Adult or late-onset triple A syndrome: case report and literature review. J Neurol Sci 297(1–2):85–88CrossRefGoogle Scholar
  22. 22.
    Kurnaz E, Duminuco P, Aycan Z et al (2018) Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr 177(3):363–369CrossRefGoogle Scholar
  23. 23.
    Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133(1):1–9CrossRefGoogle Scholar
  24. 24.
    Grant DB, Barnes ND, Dumic M et al (1993) Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome. Arch Dis Child 68(6):779–782CrossRefGoogle Scholar
  25. 25.
    Koehler K, Brockmann K, Krumbholz M et al (2008) Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe. Eur J Hum Genet 16(12):1499–1506CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Athanasia Bouliari
    • 1
  • Xuexin Lu
    • 1
  • Rebecca W. Persky
    • 1
  • Constantine A. Stratakis
    • 1
  1. 1.Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaUSA

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