Fragile X syndrome in two siblings with major congenital malformations

✍ Scribed by Giampietro, Philip F.; Haas, Bruce R.; Lipper, Evelyn; Gutman, Alyson; Zellers, Nancy J.; LaTrenta, Gregory S.; Brooks, Susan Sklower; Matalon, Reuben; Kaul, Rajinder; Ding, Xiao-Hua; Brown, W. Ted

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 17 KB
• Volume: 63
• Category: Article
• ISSN: 0148-7299
• DOI: 10.1002/(sici)1096-8628(19960517)63:2<396::aid-ajmg14>3.0.co;2-f

✦ Synopsis

We report on 2 brothers with both fragile X and VACTERL-H syndrome. The first sibling, age 5, had bilateral cleft lip and palate, ventricular septal defect, and a hypoplastic thumb. The second sibling, age 2%, had a trachesophageal fistula, esophageal atresia, and vertebral abnormality. High-resolution chromosome analysis showed a 46, XY chromosome constitution in both siblings. By PCR and Southern blot analysis, the siblings were found to have large triplet repeat expansions in the fragile X gene (FMR 1) and both had methylation mosaicism. Enzyme kinetic studies of iduronate sulfatase demonstrated a two-fold increase in activity in the first sib as compared to the second. Possible mechanisms through which the fragile X mutation can cause down-regulation of adjacent loci are discussed.