New recessive syndrome characterized by increased chromosomal breakage and several findings which overlap with Fanconi anemia.

We describe four cases with several findings of Fanconi anemia (FA), but without hypersensitivity to DNA cross-linking that is the distinguishing characteristic of FA. Two of the cases are male and female sibs of Hispanic origin, age 6 years and 11 months, respectively. Both have short stature, failure to thrive, absent thumbs, short palpebral fissures, and skin pigmentation abnormalities. The girl also has developmental "dysplasia" of her hips. Presently, both siblings are hematologically normal. Elevated baseline chromosome breakage was observed in the boy, but not in the girl. Neither sib showed elevated diepoxybutane (DEB)-induced chromosomal breakage. In a subsequent pregnancy, prenatal studies showed slightly elevated baseline and DEB induced chromosome breakage (greater than normal, but lower than the established range for FA). The fetus had intrauterine growth retardation and an absent right thumb. A review of cases referred to the International Fanconi Anemia Registry for DEB testing showed one additional case with similar findings. That patient, a girl, of Caucasian English ancestry, age 14 years, had short stature, a history of failure to thrive, skin pigmentation abnormalities, absent right thumb, hypoplastic left thumb, and hydrocephalus that resolved spontaneously. Elevated baseline chromosome breakage was observed in skin fibroblasts but not in lymphocytes. We postulate that these cases represent a previously undescribed autosomal recessive syndrome. These and other previously reported cases provide evidence for alternative genetic mechanisms that may result in developmental anomalies similar to those seen in FA.

Fragile X syndrome in two siblings with major congenital malformations.

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 1/2, 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.