Congenital adrenal hyperplasia with a CYP21A2 deletion overlapping the tenascin-X gene: an atypical presentation
-
Catarina Rodrigues Ivo
,
Ana Laura Fitas
Abstract
Objectives
Congenital Adrenal Hyperplasia (CAH) is a group of genetic diseases characterized by impaired cortisol biosynthesis. 95% of CAH cases result from mutation in the CYP21A2 gene encoding 21-hydroxilase. TNX-B gene partially overlaps CYP21A2 and encodes a matrix protein called Tenascin-X (TNX). Complete tenascin deficiency causes Enlers-Danlos syndrome (EDS). A mono allelic variant called CAH-X CH-1 was recently described, resulting from a CYP21A2 complete deletion that extends into the TNXB. This haploinsufficiency of TNX may be associated with a mild hypermobility form of EDS, as well as other connective tissue comorbidities such as hernia, cardiac defects and chronic arthralgia.
Case presentation
We report four patients heterozygous for a CAH-X CH-1 allele that do not present clinical manifestations of the EDS.
Conclusions
All CAH patients, carriers of these TNXA/TNXB chimeras, should be evaluated for clinical manifestations related to connective tissue hypermobility, cardiac abnormalities and other EDS features, allowing for better clinical surveillance management.
-
Research funding: None declared.
-
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Competing interests: Authors state no conflict of interest.
-
Informed consent: Informed consent was obtained from all individuals included in this study.
-
Ethical approval: The authors declare that the procedures were followed according to the regulations established by the local Clinical Research and Ethics Committee and to the Helsinki Declaration.
References
1. Chen, W, Kim, MS, Shanbhag, S, Arai, A, VanRyzin, C, McDonnell, NB, et al.. The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: quadricuspid aortic valve and other midline defects. Am J Med Genet Part A 2009;149A:2803–8.10.1002/ajmg.a.33092Search in Google Scholar PubMed PubMed Central
2. Miller, WL, Merke, DP. Tenascin-X, congenital adrenal hyperplasia, and the CAH-X syndrome. Horm Res Paediatr 2018;89:352–61. https://doi.org/10.1159/000481911.Search in Google Scholar PubMed PubMed Central
3. Lao, Q, Mallappa, A, Rueda Faucz, F, Joyal, E, Veeraraghavan, P, Chen, W, et al.. A TNXB splice donor site variant as a cause of hypermobility type Ehlers–Danlos syndrome in patients with congenital adrenal hyperplasia. Mol Genet Genomic Med 2021;9:1–9. https://doi.org/10.1002/mgg3.1556.Search in Google Scholar PubMed PubMed Central
4. 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;98:1–17. https://doi.org/10.1210/jc.2012-3148.Search in Google Scholar PubMed PubMed Central
5. Forghani, I. Updates in clinical and genetics aspects of hypermobile ehlers danlos syndrome. Balkan Med J 2019;26:12–6. https://doi.org/10.4274/balkanmedj.2018.1113.Search in Google Scholar PubMed PubMed Central
6. Deodhar, AA, Woolf, AD. Ehlers Danlos syndrome and osteoporosis. Ann Rheum Dis 1994;53:841–2.10.1136/ard.53.12.841-cSearch in Google Scholar PubMed PubMed Central
7. 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;105:2288–99. https://doi.org/10.1210/clinem/dgaa199.Search in Google Scholar PubMed
8. Bizzarri, C, Improda, N, Maggioli, C, Capalbo, D, Roma, S, Porzio, O, et al.. Hydrocortisone therapy and growth trajectory in children with classical congenital adrenal hyperplasia. Endocr Pract 2017;23:546–56. https://doi.org/10.4158/ep171751.or.Search in Google Scholar PubMed
9. Finkielstain, GP, Chen, W, Mehta, SP, Fujimura, FK, Hanna, RM, Van Ryzin, C, et al.. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2011;96:E161–72. https://doi.org/10.1210/jc.2010-0319.Search in Google Scholar PubMed PubMed Central
10. 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;37:893–7.10.1002/humu.23028Search in Google Scholar PubMed PubMed Central
11. 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:E1143–52.10.1210/jc.2015-2232Search in Google Scholar PubMed PubMed Central
12. 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;345:1167–75.10.1056/NEJMoa002939Search in Google Scholar PubMed
© 2022 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Disorders of sex development – biologic, genetic, cultural, societal, and psychologic diversity of the human nature
- Review
- Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement
- Original Articles
- Penile diameter during puberty in boys: a retrospective analysis of longitudinally obtained data
- Evaluation of bladder dysfunction in children and adolescents with type 1 diabetes mellitus by uroflowmetry
- All aspects of galactosemia: a single center experience
- The evolution of pituitary cysts in growth hormone-treated children
- Phototherapy-induced hypocalcemia and hypoparathyroidism in icteric term newborns
- Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience
- Does cystatin C have an immunomodulatory role in Hashimoto’s thyroiditis?
- Molecular genetic etiology by whole exome sequence analysis in cases with familial type 1 diabetes mellitus without HLA haplotype predisposition or incomplete predisposition
- Features of BSCL2 related congenital generalized lipodystrophy in China: long-term follow-up of three patients and literature review
- Case Reports
- Congenital adrenal hyperplasia with a CYP21A2 deletion overlapping the tenascin-X gene: an atypical presentation
- The smallest dislocated microduplication of Xq27.1 harboring SOX3 gene associated with XX male phenotype
- Rare PHEX intron variant causes complete and severe phenotype in a family with hypophosphatemic rickets: a case report
- Human chorionic gonadotrophin secreting adrenocortical neoplasm presenting with peripheral precocious puberty in an infant
- Atypical familial diabetes associated with a novel NEUROD1 nonsense variant
Articles in the same Issue
- Frontmatter
- Editorial
- Disorders of sex development – biologic, genetic, cultural, societal, and psychologic diversity of the human nature
- Review
- Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement
- Original Articles
- Penile diameter during puberty in boys: a retrospective analysis of longitudinally obtained data
- Evaluation of bladder dysfunction in children and adolescents with type 1 diabetes mellitus by uroflowmetry
- All aspects of galactosemia: a single center experience
- The evolution of pituitary cysts in growth hormone-treated children
- Phototherapy-induced hypocalcemia and hypoparathyroidism in icteric term newborns
- Clinical and laboratory evaluation of children with congenital hyperinsulinism: a single center experience
- Does cystatin C have an immunomodulatory role in Hashimoto’s thyroiditis?
- Molecular genetic etiology by whole exome sequence analysis in cases with familial type 1 diabetes mellitus without HLA haplotype predisposition or incomplete predisposition
- Features of BSCL2 related congenital generalized lipodystrophy in China: long-term follow-up of three patients and literature review
- Case Reports
- Congenital adrenal hyperplasia with a CYP21A2 deletion overlapping the tenascin-X gene: an atypical presentation
- The smallest dislocated microduplication of Xq27.1 harboring SOX3 gene associated with XX male phenotype
- Rare PHEX intron variant causes complete and severe phenotype in a family with hypophosphatemic rickets: a case report
- Human chorionic gonadotrophin secreting adrenocortical neoplasm presenting with peripheral precocious puberty in an infant
- Atypical familial diabetes associated with a novel NEUROD1 nonsense variant
