CLINICAL SPECTRUM OF PATIENTS WITH RSH/SMITH-LEMLI-OPITZ SYNDROME. •474

Abstract

The biochemical finding of increased 7-dehydrocholesterol (7-DHC) provides a reliable marker for diagnostic confirmation of the clinical diagnosis of the RSH/Smith-Lemli-Opitz (SLO) syndrome. We report on 80 patients with biochemically confirmed SLO to delineate the clinical spectrum of this disorder and to provide information about population genetics. The 7-DHC levels varied from 1.7 mcg/ml to 470 mcg/ml (normal ± SD = 0.10± 0.05 mcg/ml). Although 7-DHC levels were not correlated with clinical severity, cholesterol levels were inversely correlated, indicating that low cholesterol rather than high 7-DHC is the primary teratogenic factor in SLO. A continuum of biochemical and clinical severity was observed, with no discrete separation between those patients with the “type I” and“type II” phenotypes, suggesting that the type I and II phenotypes do not represent separate disorders. The most common clinical finding was 2-3 toe syndactyly (99%), followed by cleft palate (52%), postaxial polydactyly(43%), and cardiac defects (38%). One patient had alobar holoprosencephaly; and 2 others had midline cleft lip, a feature commonly seen in those with the holoprosencephaly sequence. Two patients died of cholestatic liver disease. Cases were generally restricted to those of Northern European and Hispanic ancestry, and none was identified in those of African or Asian background. In 3 of 68 index families studied there were additional cases identified in extended family members. These included 2 first cousins, 2 maternal aunts, and 1 paternal uncle. No instances of known consanguinity were identified, although parents of one child were both of Native American Cherokee ancestry. This high rate of affected relatives and low rate of consanguinity indicate that the heterozygote frequency for SLO may be high, as has been suggested previously.