Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1.

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

Risk of congenital anomalies detected during antenatal serum screening in women with pregestational diabetes.

BACKGROUND: Most studies comparing women with and without pregestational diabetes mellitus have not systematically screened for fetal anomalies in early pregnancy, potentially leading to selection bias. AIM: To evaluate the risk for certain congenital anomalies in women participating in an antenatal maternal screening program. DESIGN: Retrospective cohort study. METHODS: We studied all women who underwent antenatal maternal serum screening in Ontario from 1994 to 2000. Fetal anomalies were documented antenatally by ultrasonography or at autopsy, and postnatally diagnosed birth defects were recorded after 20 weeks gestational age for all live- and stillborn affected infants. We compared the risk of open neural tube defects and urinary tract defects among women with and without pregestational diabetes. RESULTS: Of 413,219 women screened during pregnancy, 2069 (0.5%) had diabetes. Compared to non-diabetic women, the adjusted odds ratios (95%CI) for neural tube and urinary tract defects among women with diabetes were 2.5 (0.9-6.8) and 2.6 (1.4-4.9), respectively. DISCUSSION: Among women who undergo second trimester maternal serum screening, pregestational diabetes is associated with an increased risk of having a fetus with an open neural tube defect or urinary tract disorder.

Maternal serum screening in Ontario using the triple marker test.

OBJECTIVES: To summarise the experience and evaluate the performance of the Ontario maternal serum screening (MSS) programme. SETTING: The Ontario MSS programme between October 1993 and September 2000. METHODS: This study used information collected in the Ontario MSS database, which contains data on each screened pregnancy. In the Ontario MSS programme, women are screened between 15 and 20 weeks of gestation. The risk cut-off for Down's syndrome was >or= 1 in 385 at term and women with a serum alpha-fetoprotein >or= 2.2 multiples of the unaffected population median were defined as screen-positive for open neural tube defects. RESULTS: Between 1 October 1993 and 30 September 2000, 428410 women residing in Ontario were screened for open neural tube defects, and 423895 women were screened for Down's syndrome and trisomy 18. Approximately 48% of all pregnant women in the province had MSS. The uptake rate of amniocentesis following a positive Down's syndrome screening was 67%. Of 717 cases of Down's syndrome ascertained in the screened population, 531 were detected by MSS, giving a term detection rate (DR) of 70.6%, with a false-positive rate (FPR) of 7.2%. For neural tube defects, the DR was 72.7%, with a FPR of 2.0%. The screen also detected 50% of cases of trisomy 18 at term, with a FPR of 0.2%. Coincidentally, 113 cases of chromosome aneuploidies other than Down's syndrome and trisomy 18 were detected. DISCUSSION: In the Ontario MSS programme, MSS performed as expected in the detection of Down's syndrome, open neural tube defects and trisomy 18. MSS is an effective and practical method for large-scale second trimester screening for Down's syndrome, open neural tube defects and trisomy 18, and the MSS database is an extremely useful tool in monitoring the performance of this screen.

Preconception clinical genetics.

In Canada today, the average family size is declining and the expectation of most couples regarding health for their children is rising. These trends are placing more "value" on each pregnancy. Couples who are concerned about future pregnancies are now more often seeking advice relating to their family history and the risks of having children born with significant disorders before they undertake a conception. The family physician can play a key role in providing preconception counselling.

Prenatal diagnosis of tetrasomy 21.

Amniocentesis and prenatal diagnosis were done for late maternal age and an abnormality consistent with Tetrasomy 21 (47,XX, + t(21;21] was found in every cell examined of the initial amniotic fluid. Clinical examination revealed a fetus with many of the signs of Down Syndrome and pathological examination revealed gross abnormalities of the internal structures. Follow-up tissues showed mosaic Tetrasomy 21.

Tay-Sachs disease: ultrastructural studies on cultured fibroblasts.

The knowledge that the biochemical lesion associated with Tay-Sachs disease is demonstrable in many tissues, and in particular in cultured fibroblasts, suggested that ultrastructural lesions might also accompany hexosaminidase A deficiency in cultured fibroblasts. Electron microscopic studies on six human skin fibroblast lines and four amniotic fluid fibroblast lines, biochemically confirmed to be deficient in hexosaminidase A, showed characteristic cytoplasmic inclusions not observed in any normal lines studied. Up to 60 of these abnormal cytoplasmic inclusions were observed in full cell cross sections in all affected lines examined.

Utilization of electron microscopy in the prenatal diagnosis of genetic disease.

The use of electron microscopy as a further method of diagnosis of disease in cultured skin fibroblasts and cultured amniotic fluid fibroblasts is presented. It was demonstrated that Tay-Sachs disease, Fabry's disease, and metachromatic leukodystrophy had distinctive abnormalities in both cultured skin fibroblasts and cultured amniotic fluid fibroblasts. It was shown that control of culturing conditions made it possible to distinguish normal cell lines from certain cell lines carrying known genetic diseases.

Duchenne's muscular dystrophy: studies in cultured fibroblasts.

Fibroblast cell-lines derived from four patients with clinically confirmed Duchenne's muscular dystrophy were examined by Duchenne's muscular dystrophy were examined by transmission electron microscopy. Cell-lines from patients with Duchenne's muscular dystrophy could be distinguished from normal cell-lines by the presence of characteristic inclusion bodies.

John Humphrey Noyes and the stirpicultural experiment.

PIP: The Perfectionist religious Oneida Community was founded by John Humphrey Noyes at Putney, Vermont, in 1841. Due to unpopularity of some of its beliefs, the Community was forced to migrate to Oneida, New York, in 1848. The community practiced male continence, complex marriage, community child care, and stirpicultural childbreeding. These 4 aspects of community behavior were aimed at self-perfection within the community and production of healthier and more moral offspring. Male continence was necessary as a method of birth control in a community which practiced sexual communism and as a means of freeing women from family responsibilities. It was evidently successful because there were only 43 births in the community during the period from 1846 to 1869. All adult members participated as a large married family, sharing economic, social, cultural, and sexual benefits of such an arrangement. Communal child care allowed all the other members of the community to contribute to its economic cooperative efforts. A stirpicultural committee controlled the matings within the community with a view to the production of perfect children. The experiment suffered a remarkably low mortality among the children born. Follow-up shows them to have been remarkably healthy. Such success can probably be attributed to a combination of the community care and stirpicultural breeding programs within the Oneida Community.^ieng