Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia

Morissette, Rachel; Chen, Wuyan; Perritt, Ashley F.; Dreiling, Jennifer L.; Arai, Andrew E.; Sachdev, Vandana; Hannoush, Hwaida; Mallappa, Ashwini; Zhi, Xu; McDonnell, Nazli B.; Quezado, Martha; Merke, Deborah P.

doi:10.1210/jc.2015-2232

Cited by 58 publications

(126 citation statements)

References 38 publications

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“…A formal clinical evaluation was not performed in the first degree relatives of patients in this study, but the family history revealed that in 8 of 33 (24%) carrier individuals joint hypermobility was present (36% of the mothers, 9% of the fathers, 27% of the tested siblings), which is probably to be slightly higher than in the general population. Furthermore, patients with congenital adrenal hyperplasia and a contiguous deletion of CYP21A2 and TNXB resulting in TNX haploinsufficiency are reported to have a more severe phenotype (14,15). This was similar as the findings in the 10 haploinsufficient TNXB subjects investigated in this study on neuromuscular features: asymptomatic hypermobility (Beighton score ≥ 5) was detected in four female patients [Beighton scores not published; patients included in study by Voermans et al (7)].…”

Section: Clinical Featuressupporting

confidence: 88%

“…Cysteine at position 4058 is predicted to be engaged in a disulfide bond with Cys4028, which stabilizes the structure of the C-terminal fibrinogen domain of TNX (15). It concerns here a 120 bp deletion, c.11435_11524 + 30del, which abolishes part of exon 35 en intron 35 of TNXB.…”

Section: Molecular Analysismentioning

confidence: 96%

“…Symptoms of joint hypermobility (dislocations, functional limitations or joint pain) were not reported and relatives were not reported to have paid any medical visits for their joint hypermobility. This suggests that the endocrine milieu of Congenital Adrenal Hyperplasia (CAH) influences the severity of EDS (14,15). In a previous study, haploinsufficiency of TNX was also shown to associate with hypermobility symptoms in relatives of patients with TNX-deficiency (16).…”

Section: Clinical Featuresmentioning

confidence: 98%

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Recognizing the tenascin‐X deficient type of Ehlers–Danlos syndrome: a cross‐sectional study in 17 patients

et al. 2016

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The tenascin-X (TNX) deficient type Ehlers-Danlos syndrome (EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging.

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Section: Clinical Featuressupporting

confidence: 88%

Section: Molecular Analysismentioning

confidence: 96%

Section: Clinical Featuresmentioning

confidence: 98%

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Recognizing the tenascin‐X deficient type of Ehlers–Danlos syndrome: a cross‐sectional study in 17 patients

et al. 2016

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“…This 8.5kb CYP779f/Tena32F amplicon is able to reveal TNXA/TNXB chimeras and has been utilized to study CAH-X patients. 41,43,44 Hannah-Shmouni et al Page 7…”

Section: Molecular Analysis Of Cyp21a2 Mutationsmentioning

confidence: 99%

“…Additional chimeric genes have subsequently been identified and overall 9% of patients with CAH due to 21-OHD are estimated to have CAH-X, a connective tissue dysplasia, in addition to having CAH. 43 The deletions associated with CAH-X are TNXA/TNXB chimeras ( Figure 4) and 3 types of chimeric genes have been identified to date, designated CAH-X CH-1, CAH-X CH-2, and CAH-X CH-3. 41,43,44 CAH-X CH-1 involves the 120bp deletion in the exon 35 region of TNXB and leads to haploinsufficiency with reduced tenascin-X; CAH-X CH-2 involves the c.12174C>G (p.Cys4058Trp) variant in exon 40 of TNXB, which does not alter tenascin-X expression but rather causes a dominant-negative effect due to the loss of a critical disulfide bond in the tenascin-X fibrinogen-like domain; and CAH-X CH-3 involves a cluster of three variants and also causes a dominant-negative effect.…”

Section: Cah-x Syndromementioning

confidence: 99%

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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Recurrent pneumothorax in a case of tenascin‐X deficient Ehlers–Danlos syndrome: Broadening the phenotypic spectrum

Santoreneos

Vakulin

Ellul

et al. 2022

American J of Med Genetics Pt A

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The genomic region surrounding the Tenascin‐XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical‐like Ehlers–Danlos syndrome (clEDS) is the result of tenascin‐X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin‐XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar‐collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin‐X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis

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Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia

Abstract: CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.

Cited by 58 publications

References 38 publications

Recognizing the tenascin‐X deficient type of Ehlers–Danlos syndrome: a cross‐sectional study in 17 patients

Recognizing the tenascin‐X deficient type of Ehlers–Danlos syndrome: a cross‐sectional study in 17 patients

Genetics of Congenital Adrenal Hyperplasia

Recurrent pneumothorax in a case of tenascin‐X deficient Ehlers–Danlos syndrome: Broadening the phenotypic spectrum

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