Skip to main content
SpringerLink
Log in

CAH-X Syndrome: Genetic and Clinical Profile

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

The term CAH-X was coined to describe a subset of patients with 21-hydroxylase deficiency displaying a phenotype compatible with the hypermobility type of Ehlers Danlos syndrome. The genetic defect is due to the monoallelic presence of a CYP21A2 deletion extending into the gene encoding tenascin X (TNXB), a connective tissue extracellular matrix protein. The result is a chimeric TNXA/TNXB gene causing tenascin-X haploinsufficiency. The prevalence of CAH-X was estimated to be around 14–15% in large cohorts of patients with 21-hydroxylase deficiency. However, population studies are still scarce and the clinical picture of the syndrome has yet to be fully defined. In this review, we discuss the current knowledge regarding the genetic and clinical profile of the CAH-X syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, et al. Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene. Genome Biol Evol. 2013;5:98–112.

    Article  Google Scholar 

  2. Horton R, Wilming L, Rand V, Lovering RC, Bruford EA, Khodiyar VK, et al. Gene map of the extended human MHC. Nat Rev Genet. 2004;5:889–99.

    Article  CAS  Google Scholar 

  3. Carrozza C, Foca L, De Paolis E, Concolino P. Genes and pseudogenes: complexity of the RCCX locus and disease. Front Endocrinol (Lausanne). 2021;30(12): 709758.

    Article  Google Scholar 

  4. Doleschall M, Luczay A, Koncz K, Hadzsiev K, Erhardt É, Szilágyi Á, et al. A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics. Eur J Hum Genet. 2017;25:702–10.

    Article  CAS  Google Scholar 

  5. Bánlaki Z, Doleschall M, Rajczy K, Fust G, Szilágyi A. Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes. Genes Immun. 2012;13:530–5.

    Article  Google Scholar 

  6. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, et al. Congenital adrenal hyperplasia: current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43:91–159.

    Article  Google Scholar 

  7. Concolino P, Costella A. Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: a comprehensive focus on 233 pathogenic variants of CYP21A2 gene. Mol Diagn Ther. 2018;22:261–80.

    Article  CAS  Google Scholar 

  8. Higashi Y, Tanae A, Inoue H, Fujii-Kuriyama Y. Evidence for frequent gene conversion in the steroid 21-hydroxylase P-450(C21) gene: implications for steroid 21-hydroxylase deficiency. Am J Hum Genet. 1988;42:17–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tusié-Luna MT, White PC. Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms. Proc Natl Acad Sci USA. 1995;92:10796–800.

    Article  Google Scholar 

  10. Falhammar H, Wedell A, Nordenström A. Biochemical and genetic diagnosis of 21-hydroxylase deficiency. Endocrine. 2015;50:306–14.

    Article  CAS  Google Scholar 

  11. Falhammar H, Thorén M. Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine. 2012;41:355–73.

    Article  CAS  Google Scholar 

  12. Nordenström A, Falhammar H. Management of endocrine disease: diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency. Eur J Endocrinol. 2019;180:R127–45.

    Article  Google Scholar 

  13. Speiser PW. Nonclassic adrenal hyperplasia. Rev Endocr Metab Disord. 2009;10:77–82.

    Article  Google Scholar 

  14. Witchel SF, Azziz R. Nonclassic congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010;2010: 625105.

    Article  Google Scholar 

  15. Gomes LG, Bachega TASS, Mendonca BB. Classic congenital adrenal hyperplasia and its impact on reproduction. Fertil Steril. 2019;111:7–12.

    Article  Google Scholar 

  16. Valcourt U, Alcaraz LB, Exposito JY, Lethias C, Bartholin L. Tenascin-X: beyond the architectural function. Cell Adhes Migr. 2015;9:154–65.

    Article  CAS  Google Scholar 

  17. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.

    Article  Google Scholar 

  18. Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M, et al. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers–Danlos syndrome. Am J Hum Genet. 2003;73:214–7.

    Article  CAS  Google Scholar 

  19. Gensemer C, Burks R, Kautz S, Judge DP, Lavallee M, Norris RA. Hypermobile Ehlers–Danlos syndromes: complex phenotypes, challenging diagnoses, and poorly understood causes. Dev Dyn. 2021;250:318–44.

    Article  CAS  Google Scholar 

  20. Burch GH, Gong Y, Liu W, Dettman RW, Curry CJ, Smith L, et al. Tenascin-X deficiency is associated with Ehlers–Danlos syndrome. Nat Genet. 1997;17:104–8.

    Article  CAS  Google Scholar 

  21. Miller WL. Tenascin-X-discovery and early research. Front Immunol. 2021;11: 612497.

    Article  Google Scholar 

  22. Merke DP, Chen W, Morissette R, Xu Z, Van Ryzin C, Sachdev V, et al. Tenascin-X haploinsufficiency associated with Ehlers–Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2013;98:E379–87.

    Article  CAS  Google Scholar 

  23. Miller WL, Merke DP. Tenascin-X, congenital adrenal hyperplasia, and the CAH-X syndrome. Horm Res Paediatr. 2018;89:352–61.

    Article  CAS  Google Scholar 

  24. Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. EMQN best practice guidelines for molecular genetic testing and reporting of 21-hydroxylase deficiency. Eur J Hum Genet. 2020;28:1341–67.

    Article  CAS  Google Scholar 

  25. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 2020;383:1248–61.

    Article  CAS  Google Scholar 

  26. Concolino P, Mello E, Minucci A, Giardina E, Zuppi C, Toscano V, et al. A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form. BMC Med Genet. 2009;10:72.

    Article  Google Scholar 

  27. Chen W, Xu Z, Sullivan A, Finkielstain GP, Van Ryzin C, Merke DP, et al. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem. 2012;58:421–30.

    Article  CAS  Google Scholar 

  28. Morissette R, Chen W, Perritt AF, Dreiling JL, Arai AE, Sachdev V, et al. Broadening the spectrum of Ehlers Danlos syndrome in patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2015;100:E1143–52.

    Article  Google Scholar 

  29. Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, et al. A recessive form of the Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345:1167–75.

    Article  CAS  Google Scholar 

  30. Chen W, Perritt AF, Morissette R, Dreiling JL, Bohn MF, Mallappa A, et al. Ehlers–Danlos syndrome caused by biallelic TNXB variants in patients with congenital adrenal hyperplasia. Hum Mutat. 2016;37:893–7.

    Article  CAS  Google Scholar 

  31. Lao Q, Brookner B, Merke DP. High-throughput screening for CYP21A1P-TNXA/TNXB chimeric genes responsible for Ehlers–Danlos syndrome in patients with congenital adrenal hyperplasia. J Mol Diagn. 2019;21:924–31.

    Article  CAS  Google Scholar 

  32. Gao Y, Lu L, Yu B, Mao J, Wang X, Nie M, et al. The prevalence of the chimeric TNXA/TNXB gene and clinical symptoms of Ehlers–Danlos syndrome with 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2020;105:dgaa199.

    Article  Google Scholar 

  33. Marino R, Garrido NP, Ramirez P, Notaristéfano G, Moresco A, Touzon MS, et al. Ehlers–Danlos syndrome: molecular and clinical characterization of TNXA/TNXB chimeras in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2021;106:e2789–802.

    Article  Google Scholar 

  34. Lee HH, Lee YJ, Lin CY. PCR-based detection of the CYP21 deletion and TNXA/TNXB hybrid in the RCCX module. Genomics. 2004;83:944–50.

    Article  CAS  Google Scholar 

  35. Lao Q, Merke DP. Molecular genetic testing of congenital adrenal hyperplasia due to 21-hydroxylase deficiency should include CAH-X chimeras. Eur J Hum Genet. 2021;29:1047–8.

    Article  Google Scholar 

  36. Baumgartner-Parzer S, Witsch-Baumgartner M, Hoeppner W. Reply to Lao Q and Merke DP. Eur J Hum Genet. 2021;29:1045–6.

    Article  Google Scholar 

  37. Falhammar H, Claahsen-van der Grinten H, Reisch N, Slowikowska-Hilczer J, Nordenström A, Roehle R, Bouvattier C, dsd-LIFE Group, et al. Health status in 1040 adults with disorders of sex development (DSD): a European multicenter study. Endocr Connect. 2018;7:466–78.

    Article  CAS  Google Scholar 

  38. Falhammar H, Frisén L, Hirschberg AL, Nordenskjöld A, Almqvist C, Nordenström A. Increased risk of autoimmune disorders in 21-hydroxylase deficiency: a Swedish population-based national cohort study. J Endocr Soc. 2019;3:1039–52.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Scienze di Laboratorio e Infettivologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy

    Paola Concolino

  2. Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden

    Henrik Falhammar

  3. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Henrik Falhammar

Authors
  1. Paola Concolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henrik Falhammar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Concolino.

Ethics declarations

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors (PC and HF) declare that they have no conflicts of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Data availability

Not applicable.

Code availability

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 13 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Concolino, P., Falhammar, H. CAH-X Syndrome: Genetic and Clinical Profile. Mol Diagn Ther 26, 293–300 (2022). https://doi.org/10.1007/s40291-022-00588-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-022-00588-0

Search

Navigation