A New Variation on an Old Theme: Subtleties of the Smith-Lemli-Opitz Syndrome (RSH/SLOS)

Abstract

SLO is a well-characterized autosomal recessive disorder of cholesterol biosynthesis with a classical phenotype that is distinctive and easily recognizable. However, it was not until the recent recognition of the biochemical abnormality that existence of the mild phenotype could be confirmed. Five individuals with biochemically proven mild or “variant” SLO have been described with 7-DHC levels that are intermediate between those measured in classical SLO patients and controls. The variant phenotype also seems to be characterized by cholesterol levels within or just below the normal range, while classical patients are clearly cholesterol-deficient. We now report three additional siblings, products of a first cousin mating, who have clinical and biochemical findings consistent with variant SLO. The oldest, a 12-year-old girl, has microcephaly, mild facial dysmorphism and moderate 2-3 syndactyly of the feet. Her past history is significant for failure to thrive, mild global developmental delay and behavioral problems, including ADD. 7-DHC and cholesterol levels were 64 uM (controls <10) and 2.7 mM (controls 3.0 - 4.6), respectively. Her 7-year-old brother has microcephaly, a cleft lip, a unilateral single transverse palmar crease and mild 2-3 syndactyly of his feet. He has not been ascertained as a child with developmental delay or behavioral problems. Interestingly, his plasma 7-DHC level was just above the control range at 10 uM and his plasma cholesterol level was just within the control range at 3.0 mM. We are currently repeating these measurements on a second sample. The youngest child, 5 year old boy, has microcephaly, characteristic facial dysmorphism, a left single transverse palmar crease as well as mild 2-3 syndactyly of his feet. He has a clear history of developmental delay and behavioural problems. His plasma 7-DHC was 52 and 24 uM on two separate occasions and his plasma cholesterol was 2.9 both times. These children help to further delineate and improve recognition of the mild/variant SLO phenotype, which may account for a substantial percentage of children with minimal dysmorphism, microcephaly and developmental delay.