Smith-Lemli-Opitz syndrome carrier frequency and estimates of in utero mortality rates.

OBJECTIVE: To tabulate individual allele frequencies and total carrier frequency for Smith-Lemli-Opitz syndrome (SLOS) and compare expected versus observed birth incidences. METHODS: A total of 262 399 individuals with no known indication or increased probability of SLOS carrier status, primarily US based, were screened for SLOS mutations as part of an expanded carrier screening panel. Results were retrospectively analyzed to estimate carrier frequencies in multiple ethnic groups. SLOS birth incidences obtained from existing literature were then compared with these data to estimate the effect of SLOS on fetal survival. RESULTS: Smith-Lemli-Opitz syndrome carrier frequency is highest in Ashkenazi Jews (1 in 43) and Northern Europeans (1 in 54). Comparing predicted birth incidence with that observed in published literature suggests that approximately 42% to 88% of affected conceptuses experience prenatal demise. CONCLUSION: Smith-Lemli-Opitz syndrome is relatively frequent in certain populations and, because of its impact on prenatal and postnatal morbidity and mortality, merits consideration for routine screening. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

Hirschsprung's disease in the North of England: prevalence, associated anomalies, and survival.

INTRODUCTION: Hirschsprung's disease is the commonest congenital gut motility disorder, characterized by the absence of the enteric ganglion cells along the distal gut, which causes intestinal obstruction. Few publications report its epidemiology and temporal trends. METHODS: Cases of Hirschsprung's disease delivered during 1990 to 2008 in the North of England reported to the Northern Congenital Abnormality Survey (NorCAS) formed this population-based case series. RESULTS: Of 612,916 live births, 105 cases were reported to NorCAS. After excluding one diabetic and four multiple pregnancies, the live birth prevalence was 1.63 (95% confidence interval [CI], 1.33-1.98) per 10,000 live births. There was a significant temporal increase in the prevalence of Hirschsprung's disease (p = 0.020), from 1.26 (95% CI, 0.80-1.89) in 1990 to 1994 to 2.29 (95% CI, 1.53-3.29) in 2005 to 2008. The ratio of male to female cases was 2:1. Ten (10.0%) cases occurred with Down syndrome, one with Smith-Lemli-Opitz Syndrome, and six (6.0%) with associated structural anomalies. The remaining 83 (83.0%) cases were isolated. All cases were live born, but nine (9.0%) died in the first year of life. Hirschsprung's disease was not prenatally suspected in any case. Half the cases were diagnosed within 5 days postpartum, but time of diagnosis ranged from birth to 5 years of age. CONCLUSION: This study confirmed a male predominance and an association with Down syndrome, but also found a temporal increase in Hirschsprung's disease prevalence. No cases were suspected prenatally, but half were diagnosed within 5 days of life.

Homozygosity for the W151X stop mutation in the delta7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital anomalies syndrome caused by an abnormality in cholesterol metabolism. The clinical severity may vary from very mild to lethality in utero, making diagnosis difficult at both ends of the spectrum. Patients with severe SLOS might often escape diagnosis because they die before the correct diagnosis is made. We describe an Austrian family whose first child died neonatally with multiple congenital anomalies. The second pregnancy was terminated because the fetus showed similar severe anomalies ultrasonographically. A further pregnancy ended in a spontaneous first trimester abortion. Clinical diagnosis of SLOS was not considered until the autopsy of the fetus of the terminated pregnancy. Because no material for biochemical testing was available we performed mutational analysis of the DHCR7 gene from paraffin-embedded tissue and a Guthrie card focusing on mutations known to cause a severe SLOS phenotype. This demonstrated homozygosity for the mutation W151X, which has been demonstrated to be a functional null mutation. Our data confirm the concept that homozygosity for functional null alleles of the DHCR7 locus results in intrauterine or perinatal lethality. Furthermore, our findings suggest the usefulness of molecular studies of stored material in similarly affected cases where no material for biochemical analysis is available.