title: Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients.
  
  
  METHODS
  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.
  
  
  METHODS
  The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.
authors.affiliation: National Institutes of Health Clinical Center, Building 10, CRC, Room 1-2740, 10 Center Drive, MSC 1932, Bethesda, Maryland 20892-1932, USA. dmerke@nih.gov
authors.forename: Deborah P
authors.initials: DP
authors.lastname: Merke
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Morissette
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xu
authors.forename: Carol
authors.initials: C
authors.lastname: Van Ryzin
authors.forename: Vandana
authors.initials: V
authors.lastname: Sachdev
authors.forename: Hwaida
authors.initials: H
authors.lastname: Hannoush
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Shanbhag
authors.forename: Ana T
authors.initials: AT
authors.lastname: Acevedo
authors.forename: Miki
authors.initials: M
authors.lastname: Nishitani
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arai
authors.forename: Nazli B
authors.initials: NB
authors.lastname: McDonnell
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000503:physiopathology; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D004204:Joint Dislocations / Q000235:genetics / Q000503:physiopathology; D007593:Joint Instability / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010146:Pain / Q000235:genetics / Q000503:physiopathology; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D019063:Tenascin / Q000235:genetics*
chemical_list: D019063:Tenascin; C081865:tenascin X; D013255:Steroid 21-Hydroxylase