Phenotypic spectrum of fetal Smith–Lemli–Opitz syndrome

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation syndrome caused by dehydrocholesterol reductase deficiency. The diagnosis is confirmed by high 7- and secondarily 8-dehydrocholesterol levels in plasma and tissues and/or by detection of biallelic mutations in the DHCR7 gene. The phenotypic spectrum of SLOS is broad, ranging from a mild phenotype combining subtle physical anomalies with behavioral and learning problems, to a perinatally lethal multiple malformations syndrome. The fetal phenotype of SLOS has been poorly described in the literature. We report a series of 10 fetuses with molecularly proven SLOS. Even in young fetuses, the facial dysmorphism appears characteristic. Genital abnormalities are rare in 46,XX subjects. Gonadal differentiation appears histologically normal and in agreement with the chromosomal sex, contrary to what has been previously stated. We observed some previously unreported anomalies: ulnar hypoplasia, vertebral segmentation anomalies, congenital pulmonary adenomatoid malformation, fused lungs, gastroschisis, holomyelia and hypothalamic hamartoma. This latter malformation proves that SLOS phenotypically overlaps with Pallister-Hall syndrome which remains clinically a major differential diagnosis of SLOS.

New insights into genotype–phenotype correlation for GLI3 mutations

“…This observation underlines the phenotypic overlap of PHS and SLO that was suggested previously, 22 both disorders associating IUGR, PD and possible renal agenesis but IA, insertional PD and HH are exceptional in SLO. 33 …”

Radiographic features of the skeleton in disorders of post-squalene cholesterol biosynthesis

“…Pallister-Hall syndrome is an autosomal-dominant syndrome of multiple congenital abnormalities clinically characterised by the presence of hypothalamic hamartoma, central polydactyly and visceral malformations. Hypothalamic hamartoma has been observed occasionally in a foetus affected by Smith-Lemli-Opitz syndrome, suggesting a phenotypic similarity with the Pallister-Hall syndrome [55]. The observed interdigital abnormalities in children affected by Smith-Lemli-Opitz syndrome (Figs.…”

“…However, to the best of our knowledge, this sign has been reported in only one child with a biochemically confirmed diagnosis [53,58]; this child showed an "extra manubrial ossification site" and also carried a de novo balanced translocation 46,XX,t(7;20)(q32.1;q13.2). In the recently reported series of foetuses affected by Smith-LemliOpitz syndrome [55], stippling was not observed. In summary, epiphyseal stippling does not seem to be part of the Smith-Lemli-Opitz phenotype and the presence of chondrodysplasia punctata most likely indicates an alternative diagnosis [59].…”

“…7). Foetuses affected by Smith-Lemli-Opitz syndrome frequently show a brachymesophalangy of the second finger [55]; postnatally, a few affected children show short index fingers, occasionally associated with a pseudoepiphysis of the 2nd metacarpal (Fig. 8).…”

“…Brachymesophalangy of the second finger was frequently observed in a recently reported series of 10 foetuses affected by Smith-Lemli-Opitz syndrome [55]. A deep distal palmar crease between the second and third fingers, giving a splithand-like appearance was also observed but, to the best of our Figures (a) and (d-g) are reproduced from [14], with permission from Radcliffe Publishers knowledge, true ectrodactyly has been reported in only one child affected by Smith-Lemli-Opitz syndrome that was biochemically confirmed [56].…”