Ehlers–Danlos Syndrome: Molecular and Clinical Characterization of TNXA/TNXB Chimeras in Congenital Adrenal Hyperplasia
Open accessAbstract
Context: The syndrome CAH-X is due to a contiguous gene deletion of CYP21A2 and TNXB resulting in TNXA/TNXB chimeras. Objective: To analyze TNXB gene status and to clinically evaluate the Ehlers–Danlos syndrome phenotype in a large cohort of Argentine congenital adrenal hyperplasia (CAH) patients to assess the prevalence of this condition in our population. Methods: TNXB gene analysis was performed in 66 nonrelated CAH patients that were carriers of the CYP21A2 gene deletion. A molecular strategy based on multiplex ligation–dependent probe amplification and Sanger sequencing analysis was developed allowing for the detection of different, previously described TNXA/TNXB chimeras, named CH1, CH2, and CH3. The main outcome measures were TNXB status of CAH patients that were carriers of the CYP21A2 deletion in the homozygous or heterozygous state. Results: TNXA/TNXB CH1 was found in 41%, CH2 in 29%, and CH3 in 1% of nonrelated alleles carrying the CYP21A2 deletion. Thus, overall 71% of alleles were found to carry a contiguous gene deletion. Sixty-seven percent of patients analyzed had a monoallelic form and 6% a biallelic form. All patients with the biallelic form had severe skin hyperextensibility and generalized joint hypermobility. Conclusion: Based on the high frequency of TNXB alterations found in CYP21A2 deletion carrier alleles, we recommend evaluating TNXB status in these patients, and assessing connective tissue dysplasia, including cardiologic alterations in positive cases. The number of patients undergoing cardiological evaluation should be expanded to determine the incidence of structural and functional abnormalities in this cohort.
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Several studies have reported an incidence of IVS2-13A/C > G combined with the chimeric TNXA/TNXB (CAH-X CH-1) genotype in patients with 21-OH deficiency and with no EDS manifestations.
“Several other studies that followed have reported an incidence of IVS2-13A/C > G combined with the chimeric TNXA/TNXB (CAH-X CH-1) genotype in patients with 21-OH deficiency and with no EDS manifestations [32, 44].”
From Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene (2023) · cites this paper as [44]
The Molecular Analysis table lists patients with an “In2” variant and CH1, but does not establish that these patients lacked EDS manifestations. The Clinical Findings section says all evaluated probands had features of the hEDS phenotype, and the Discussion says EDS features were found in every patient available for clinical evaluation. Patients who were not evaluated cannot be counted as having no manifestations. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredOnly 10% of CAH-X patients also have EDS manifestations.
“Since the first CAH-X syndrome report by Merke et al. [14], it has been established that only 10% of CAH-X patients also have EDS manifestations [15, 44].”
From Salt-wasting congenital adrenal hyperplasia phenotype as a result of the TNXA/TNXB chimera 1 (CAH-X CH-1) and the pathogenic IVS2-13A/C > G in CYP21A2 gene (2023) · cites this paper as [44]
The Discussion (page not provided) says that every CAH-X patient who could be clinically evaluated had features of EDS, contrary to the claim that only 10% do. The authors acknowledge that some patients were unavailable for evaluation, so their finding does not establish a rate for all CAH-X patients; the paper does not report the claimed 10% rate. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredCAH-X is a hypermobility-type Ehlers-Danlos syndrome connective tissue dysplasia affecting approximately 15% of patients with 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) due to contiguous deletion of CYP21A2 and TNXB genes.
“CAH-X is a hypermobility-type Ehlers–Danlos syndrome connective tissue dysplasia affecting approximately 15% of patients with 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) due to contiguous deletion of CYP21A2 and TNXB genes.”
From Pseudogene TNXA Variants May Interfere with the Genetic Testing of CAH-X (2023) · cites this paper as [12]
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- Authors
- Marino, R., Garrido, N. P., Ramirez, P., Notaristéfano, G., Moresco, A., Touzon, M. S., Vaiani, E., Finkielstain, G., Obregón, M. G., Balbi, V., Soria, I., & Belgorosky, A.
- Affiliations
- Garrahan Hospital (AR)
- Molecular Biology Laboratory, Endocrinology Service, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Hospital de Niños Superiora Sor María Ludovica (AR)
- Endocrinology Service, Hospital de la Madre y el Niño, La Rioja, Argentina
- Corresponding author
- Belgorosky, Alicia
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-01-22
- Volume
- 106
- Issue
- 7
- Pages
- e2789-e2802
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3122712636
- Cited by
- 23
- References
- 27
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 3
- FWCI
- 2.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Ehlers-Danlos syndrome, congenital adrenal hyperplasia, TNXB, contiguous gene deletion, skin hyperextensibility, joint hypermobility, connective tissue dysplasia, prevalence, Argentine patients
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Adult, Argentina, Child, Child, Preschool, Chimera, Ehlers-Danlos Syndrome, Female, Humans, Infant, Infant, Newborn, Male, Phenotype, Steroid 21-Hydroxylase, Prevalence, Tenascin, Young Adult
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