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302 DUPLICATION 22Q11.2: CLINICALLY HETEROGENEOUS NEW SYNDROME OR GENETIC POLYMORPHISM?
  1. J. A. Bernstein1,
  2. K. C. Chen1,
  3. H. M. Saal2,
  4. F. S. Alkuraya3,
  5. C. A. Stevens4,
  6. A. M. Cherry1,
  7. H. E. Hoyme1
  1. 1Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA
  2. 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH
  3. 3Division of Genetics and Metabolism, Children's Hospital Boston, Boston, MA
  4. 4T.C. Thompson Children's Hospital, Chattanooga, TN.

Abstract

Duplication of 22q11.2, the velocardiofacial syndrome (VCFS) region, has been described as the mechanism underlying a new condition associated with a spectrum of physical and developmental features. We are aware of 50 cases in the literature. Duplication at 22q11.2 is expected to occur at equal frequency as its deletion; however, the duplication syndrome has been diagnosed much less frequently than VCFS. This apparent underdetection may result from the clinical variability of the syndrome. In reported cases common features have included dysmorphic facies, cleft palate, congenital heart disease, poor postnatal growth, seizures, and mild to severe cognitive impairment. Significant interfamilial and intrafamilial variation has been described. In an effort to refine our understanding of duplication 22q11.2, we present six newly ascertained cases from four families, including two mother-daughter pairs. Our cases demonstrate many clinical features that have been associated with the syndrome. However, they also include several manifestations not previously described: hemihyperplasia, multiple hemangiomas, congenital hypothyroidism, infantile cholelithiasis, and radial aplasia. Notably, two of our cases are parents of affected children who carry duplication 22q11.2 without apparent clinical sequelae. Our observations expand the range of anomalies associated with duplication 22q11.2. The presence of unaffected parents in our families suggests a complicated mechanism inheritance for this syndrome. Alternatively, duplication 22q11.2 may represent a polymorphism that has incidentally been detected in patients with unrelated conditions. We expect that duplication 22q11.2 will be found with increasing frequency as the range of associated clinical manifestations is more widely recognized. Careful study of families carrying this duplication will be necessary to distinguish a new syndrome from a possible polymorphism.

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