A girl with pervasive developmental disorder and complex chromosome rearrangement involving 8p and 10p.

We report a 4-year-old girl with a de novo, apparently balanced complex chromosome rearrangement. She initially presented for assessment of velopharyngeal insufficiency due to hypernasal speech. She has distinctive facial features (long face, broad nasal bridge, and protuberant ears with simplified helices), bifid uvula, strabismus, and joint laxity. She is developmentally delayed, with language and cognitive skills approximately 2 SD below the mean expected for her age, and meets ADI, ADOS, and DSM-IV criteria for pervasive developmental disorder. She has poor eye contact, atypical communication and social interaction, repetitive behaviours and significant difficulties with processing sensory input. Her karyotype is characterized by the presence of two derivative chromosomes; 46,XX, der(8)(10pter- >10pl2.32::8p12- >8qter), der(l0)(8pter- >8p21.3::10p12.32- >10p11.23::8p21.3- > 8p12::10p11.23- >l0qter). The der(8) is a result of translocation of the segment 10p12.32-pter onto 8p12. The der(l0) has two 8p segments collectively from 8p12-pter in that the segment 8p21.3-pter is translocated onto 10p12.32 and the segment 8p12-p21.3 is inserted at 10p11.23. FISH analysis showed no microdeletion of the major locus at 22q11.2 nor for the minor locus at 10p13p14. This case suggests that aberrations at 8p12, 8p21.3, 10p11.23 and/or 10p12.32 may result in pervasive developmental disorder, associated with mild cognitive delay and specific facial anomalies.

DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7-dehydrocholesterol reductase gene (DHCR7). We report on three cousins with SLOS, all of whom were found to be compound heterozygotes for the common splice site mutation IVS8-1G-->C and the missense mutation T289I. DNA analysis of one set of parents demonstrated that the father carried the missense mutation and the mother carried the IVS8-1G-->C mutation. By extension, the two unrelated mothers were both heterozygous for IVS8-1G-->C. This finding supports the notion of a high carrier frequency of the IVS8-1G-->C null mutation in Northern European Caucasians.

Wolf-Hirschorn syndrome resulting from partial monosomy 4p/trisomy 9p.

An infant girl was referred for a genetic consultation because of facial appearance suggestive of Wolf-Hirschorn syndrome (WHS), growth retardation and generalized hypotonia. She had an unbalanced karyotype 46,XX,der(4)t(4;9)(p15.2;p22)mat resulting in the deletion of the critical region for WHS and duplication of the critical region for the 9p duplication syndrome. The mother and the grandmother of proposita were the carriers of an apparently balanced translocation 46,XX,t(4;9)(p15.2;p22). The infant's phenotype was characteristic of WHS syndrome rather than that of duplication 9p phenotype. This is probably the first description of WHS phenotype resulting from a familial 4;9 translocation.

Difficult prenatal diagnosis in mild Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations of the 7-dehydrocholesterol (7DHC) reductase gene (DHCR7). We present our experience with prenatal diagnosis of an affected fetus with a very mild form of SLOS. The mother underwent prenatal diagnosis by chorionic villus (CV) sampling at 11 2/7 weeks because of having two prior affected sons with SLOS. The 7DHC/total-sterol ratio in the fetus was higher than in normal control fetuses but lower than the ratio observed in CV of three other fetuses in whom SLOS was diagnosed prenatally. The pregnancy was terminated at 13 2/7 weeks. The level of 7DHC in amniotic fluid (AF) obtained at the time of pregnancy termination was unequivocally elevated, confirming the diagnosis of SLOS. This report illustrates the difficulties with the interpretation of biochemical prenatal diagnosis based on the determination of 7DHC/total-sterol ratio in CV sample in a case of mild SLOS, whereas biochemical testing of amniotic fluid clearly manifests the biochemical defects of SLOS as early as 13 weeks of gestation.

Smith-Lemli-Opitz syndrome: a treatable inherited error of metabolism causing mental retardation.

Smith-Lemli-Opitz syndrome, a syndrome of multiple malformations and mental retardation that for years was relegated to the atlases of genetic esoterica, was recently found to be a relatively common inborn error of metabolism. The underlying defect is absent or deficient activity of 7-dehydrocholesterol- delta 7-reductase, the enzyme catalysing the final step of cholesterol synthesis. The discovery of the biochemical defect causing Smith-Lemli-Opitz syndrome has resulted in the development of a diagnostic test and a potentially beneficial treatment (dietary cholesterol supplementation). Infants and young children with the syndrome have shown marked improvement in growth, behaviour and general health after receiving cholesterol therapy; older children and adults have shown some improvement in development and intellectual functioning. Despite the excitement these developments have elicited among geneticists and biochemists, this syndrome remains relatively unknown to many primary care physicians. Increased awareness of Smith-Lemli-Opitz syndrome is needed to identify affected patients so that they and their families can benefit from appropriate treatment and genetic counselling.