The Phenotypic Spectrum of Contiguous Deletion of CYP21A2 and Tenascin XB: Quadricuspid Aortic Valve and Other Midline Defects

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 12/2009; 149A(12):2803-8. DOI: 10.1002/ajmg.a.33092
Source: PubMed


Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder and is the most common cause of ambiguous genitalia in the newborn. The genes encoding 21-hydroxylase, CYP21A2, and tenascin-X (TNX), TNXB, are located within the HLA complex, in a region of high gene density termed the RCCX module. The module has multiple pseudogenes as well as tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause CAH, and TNX deficiency has been identified as a cause of hypermobility type Ehlers-Danlos syndrome (EDS). Here we report on a three-generation family with a heterozygous deletion encompassing CYP21A2 and TNXB that initially came to medical attention due to the diagnosis of CAH in the proposita. Southern blotting and PCR-based analysis of the RCCX module revealed a CYP21A2 deletion extending into TNXB in one allele and a CYP21A2 point mutation in the other allele. Family history is notable for joint hypermobility. Additional radiological and clinical investigations showed a quadricuspid aortic valve, single kidney, bicornuate uterus and a bifid uvula in the proposita, and mitral valve prolapse in her mother. These findings further delineate the phenotype of the CAH-TNX contiguous gene deletion syndrome and point to an intersection of connective tissue dysplasias with a common gene-mediated endocrine disorder.

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Available from: Sujata M Shanbhag, Dec 19, 2013
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    • "An association of EDS and CAH has been described in only a few patients, which is compatible with a contiguous gene deletion syndrome . In those cases, the patients had a deletion in the region with a TNXB / XA fusion gene [Burch et al., 1997; Schalkwijk et al., 2001; Chen et al., 2009]. MSH5 is another gene whose deletion could explain other clinical features , specifically hypergonadotrophic hypogonadism. "
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    • "In particular, large gene deletions result in chimera genes at the centromeric tail of the RCCX module, which account for approximately 30 % of CYP21A2 mutations (Finkielstain et al. 2011; Stikkelbroeck et al. 2003). These chimera genes are mostly present in a form of CYP21A1P/CYP21A2 (Chen et al. 2012), but also TNXA/ TNXB in subset of patients in which the functional CYP21A2 gene is completely deleted and the deletion extends into the TNXB gene (Burch et al. 1997; Chen et al. 2009). As expected, we found that having a chimera gene at the RCCX locus was associated with a decrease in total C4 copy number, but this was not associated with autoimmune disease. "
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