1. Tenascin-X Haploinsufficiency Associated with Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia
- Author
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Ana T. Acevedo, Vandana Sachdev, Sujata M Shanbhag, Deborah P. Merke, Nazli B. McDonnell, Andrew E. Arai, Zhi Xu, Wuyan Chen, Carol Van Ryzin, Miki Nishitani, Rachel Morissette, and Hwaida Hannoush
- Subjects
Adult ,Joint Instability ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Pathology ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Joint Dislocations ,Tenascin ,Pain ,Context (language use) ,Haploinsufficiency ,Biochemistry ,Tenascin X ,Endocrinology ,Internal medicine ,medicine ,Humans ,Congenital adrenal hyperplasia ,Clinical significance ,Child ,Southern blot ,Aged ,biology ,JCEM Online: Advances in Genetics ,Adrenal Hyperplasia, Congenital ,business.industry ,Biochemistry (medical) ,nutritional and metabolic diseases ,Infant ,Middle Aged ,medicine.disease ,Ehlers–Danlos syndrome ,Child, Preschool ,Mutation ,biology.protein ,Ehlers-Danlos Syndrome ,Female ,Steroid 21-Hydroxylase ,business - Abstract
The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described.The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients.A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed.The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls.TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P.001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings.Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.
- Published
- 2013