Keywords: Molecular Basis of Mendelian Disorders, KW037 - DYSMORPHOLOGY, KW040 - ENDOCRINE SYSTEM, KW008 - BONE/JOINT ABNORMALITIES, KW099 - NATURAL HISTORY, KW110 - PHENOTYPE

Deletions of Tenascin-X are associated with joint hypermobility and features of Ehlers-Danlos syndromes in a cohort of Congenital Adrenal Hyperplasia (CAH) patients. N.B. McDonnell¹, W. Chen¹, B.F. Griswold¹, A.C.M. Smith³, M. Berk², C. VanRyzin², D. Merke² 1) LCI, NIA/NIH, Baltimore, MD; 2) NICHD/NIH, Bethesda, MD; 3) NHGRI/NIH, Bethesda, MD.
   Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is thought to be the most common autosomal recessive disorder, leading to cortisol deficiency, with or without aldosterone deficiency (salt wasting), and androgen excess (virilization). The gene encoding 21-hydroxylase, CYP21A2, is mapped to the short arm of chromosome 6 within the HLA complex, in a region of high gene density with multiple pseudogenes. This region, termed the RCCX module, has tandem repeat sequences that promote misalignment during meiosis leading to gene rearrangements, deletions and gene conversion events. Flanking CYP21A2 is the gene encoding tenascin-X (TNX), an extracellular matrix protein that is highly expressed in connective tissue. Homozygous TNX deficiency has been proposed as a cause of autosomal recessive form of Ehlers-Danlos syndrome (EDS) characterized by hypermobile joints, stretchy skin and easy bruising and hypermobility type EDS has been linked to heterozygosity for TNX mutations. A high incidence of joint hypermobility was noted in a large cohort of CAH patients with genetically confirmed CAH due to 21-hydroxylase deficiency seen at the National Institute of Child Health and Development. Molecular investigations of the RCXX module were initiated to analyze the presence of TNX deletions and gene conversion events, utilizing Southern blotting and PCR approaches. Out of 96 probands with CAH and 83 family members, 12 subjects were found to be heterozygous for a non functional TNX gene conversion product resulting from a 30 kb deletion. All of these persons also had deletions of the CYP21A2 gene. Results suggest that 6-7% of persons affected with CAH may also have TNX deletions leading to joint abnormalities. CYP21A2 deletions were detected in 30% of the chromosomes in the cohort, and amongst those subjects, 11% also had a TNX deletion. Further studies are underway to better define the clinical, molecular and biochemical aspects of this novel CAH-TNX (CAH-X) Contiguous Gene Deletion Syndrome.