Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies.

OBJECTIVE: To ascertain how many fetuses with prenatally diagnosed cleft lip with or without cleft palate have associated congenital structural and/or chromosomal abnormalities and whether there is an association with the anatomical type of cleft lip or palate. METHODS: This was a retrospective review of infants referred to the North-West England Regional Cleft Lip and Palate (CLAP) team between January 2000 and January 2006. Referrals made to the Regional Fetal Management Unit (FMU) in the same time period were investigated to identify the corresponding antenatal ultrasound findings and data on termination of pregnancy and intrauterine fetal death. RESULTS: Over the 6-year period investigated, 570 infants were referred to the FMU and/or CLAP team. Among these, there were 24 terminations of pregnancy, two intrauterine fetal deaths and one early neonatal death identified. Data on 69 of the 543 patients that survived were incomplete. Of 188 cases with unilateral and 34 cases with bilateral cleft lip +/- palate there were no karyotypical abnormalities without other structural abnormalities. The incidence of associated structural abnormalities varied with the anatomical type of cleft: that of unilateral cleft lip +/- palate was 9.8% (19/194), that of bilateral cleft lip and palate was 25% (11/44) and that of midline cleft lip and palate was 100% (11/11). None of 252 cases with isolated cleft palate was identified antenatally; of these, 5.6% (n = 14) had either karyotypical or associated structural abnormalities and 21.0% (n = 53) had a genetic syndrome as an underlying diagnosis. CONCLUSIONS: It is essential to tailor the antenatal counseling of patients to the specific scan diagnosis, considering both the anatomical type of cleft and the presence or absence of associated abnormalities. It is inappropriate to offer invasive testing to all patients. The use of three-dimensional ultrasound as an adjunct should be considered in these patients to improve the accuracy of prenatal diagnosis.

Investigation of the epidemiology and prenatal diagnosis of holoprosencephaly in the North of England.

OBJECTIVE: This study was undertaken to provide epidemiologic data on the prevalence of holoprosencephaly and to assess the sensitivity of routine ultrasonographic screening in a low-risk population. STUDY DESIGN: A population-based register of congenital abnormalities was used to identify reported cases of holoprosencephaly between 1985 and 1998. Sources included fetal losses, termination for fetal anomaly, stillbirths, and live births. Prenatal diagnoses and pregnancy outcomes were determined. RESULTS: Sixty-eight cases of holoprosencephaly were found among 531,686 births. The total prevalence (including pregnancy terminations) was 1.2 cases/10,000 registered births, and the birth prevalence (affected live births and stillbirths at >24 weeks' gestation) was 0.49 cases/10,000 births. Prenatal diagnosis was achieved in 71% of cases, rising to 86% during the second half of the study period; the mean gestational age at diagnosis was 19.8 weeks' gestation. Chromosomal abnormalities (75% of which were trisomy 13) were present in 38% of cases in which a karyotype was established. All those with aneuploidy (80% diagnosed prenatally) had other nonfacial anomalies; additional anomalies were also common in the euploid group (61% diagnosed prenatally), with 90% having facial abnormalities and 70% having other abnormalities. CONCLUSION: The prevalence of holoprosencephaly in second-trimester pregnancies was about 1 in 8000. Prenatal detection reached 86% with a routine anomaly scanning program. The etiology could usually be determined, which has important implications for recurrence risks.

Human post-implantation embryo collection: medical and surgical techniques.

Knowledge of the genetic control of early human development is limited with most information being extrapolated from studies in animal models. There is compelling evidence that undertaking gene expression studies in human embryos can be expected to dramatically enhance our understanding of embryonic formation and malformation. Such studies require the systematic and coordinated collection, storage and study of human embryos. We have successfully collected intact embryos from cases undergoing termination of pregnancy (TOP). Embryonic material was collected from 62% of attempts using a technique of surgical aspiration carried out under ultrasound guidance. Collection rates were lower after medical termination of pregnancy (41%) although the proportion of undisrupted embryos was identical with the two methods (26%). Surgical aspiration provided intact embryos between Carnegie stages (CS) 16-22 while earlier developmental stages were collected from medical terminations. Our collection of over 60 intact specimens, spanning Carnegie stages 10 to 22 (about 21 to 53 days of development) covers a huge window of critical developmental events and hence represents an exciting and valuable research resource.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.

Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.