Alan E. Donnenfeld

Novel HOXA13 Mutations and the Phenotypic Spectrum of Hand-Foot-Genital Syndrome

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study.

OBJECTIVE Our purpose was to examine the potential teratogenicity of calcium channel blockers. STUDY DESIGN Six teratogen information services prospectively collected and followed up 78 women with first-trimester exposure to calcium channel blockers. Pregnancy outcome was compared (by paired t text of chi2 analysis) with that of a control group matched for maternal age and smoking. RESULTS There was no increase in major malformation (2/66=3.0% [calcium channel blockers] vs 0% [nonteratogenic controls], p=0.27); a fivefold increase was ruled out (baseline 2%, alpha = 0.05, beta = 0.20). The defects reported were attributable to maternal diabetes or coingestion of teratogens. The increase in preterm delivery 28% [calcium channel blockers] vs 9% [nonteratogenic controls], p=0.003), attributed to maternal disease by stepwise regression, was the most important factor responsible for the observed decrease in birth weight (mean -334 gm vs nonteratogenic controls, p=0.08). CONCLUSION This study suggests that calcium channel blockers do not represent a major teratogenic risk.

Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis.

OBJECTIVE: To document fragile X allele frequencies in a national referral population and evaluate CGG repeat expansion in mother-offspring transmissions. METHODS: Fragile X DNA analysis by Southern blot and polymerase chain reaction was completed for 14,675 women, aged 18 years or older, and 238 mother-offspring pairs between January 1999 and June 2004. Carrier frequencies were compared between groups referred for different clinical indications. Direct comparison of the FMR1 gene CGG repeat size in mother-offspring pairs determined intermediate and premutation allele stability. RESULTS: Intermediate fragile X alleles (45–54 CGG repeats) occurred in 257 (1 in 57). The combined total number of patients with a premutation (55–200 CGG repeats) or full mutation (more than 200 CGG repeats) numbered 208 (1 in 71). One in 3.5 women with a family history of fragile X and 1 in 10 with premature ovarian failure had a FMR1 mutation. This compared with 1 in 86 for those with a family history of mental retardation and 1 in 257 for women with no known risk factors for fragile X. Among 238 mother-offspring pairings, the smallest allele to expand to a full mutation in one generation contained 60 CGG repeats. Although 6.6% (4 of 60) of intermediate repeat alleles did expand, none jumped to a clinically significant full mutation–sized allele. CONCLUSION: Based on these data and other published literature, offering invasive prenatal diagnosis for fragile X syndrome is not indicated for women with intermediate alleles. Invasive prenatal diagnosis is warranted for those women with a fragile X allele containing 55 or more CGG repeats. LEVEL OF EVIDENCE: III

Simultaneous fetal and maternal cotinine levels in pregnant women smokers

OBJECTIVE Our purpose was to determine the simultaneous concentrations of serum cotinine in both fetal and maternal blood. STUDY DESIGN Serum cotinine levels were measured in 11 maternal-fetal pairs at percutaneous umbilical blood sampling. Statistical analysis was performed by means of a one-group t test to determine whether the ratio of fetal-to-maternal cotinine was significantly different from 1. RESULTS Fetal cotinine levels ranged from 75% to 110% of maternal values (mean ratio 0.90, 95% confidence interval 0.83 to 0.97). Fetal levels were significantly lower than maternal concentrations (p = 0.02). CONCLUSIONS Cotinine, a metabolite of nicotine used to quantify exposure to tobacco smoke, readily gains access to the fetal circulation. Fetal cotinine concentrations in pregnant women smokers are, on average, 90% of maternal values throughout gestation.

Fragile X syndrome carrier screening in the prenatal genetic counseling setting.

Purpose: To document our experience with fragile X carrier screening.Methods: In this study, 29,103 women with no known or suspected family history of fragile X syndrome were offered fragile X carrier screening during their prenatal genetic counseling visit. Screening acceptance was analyzed by referral indication, carrier frequencies documented, and prenatal outcome data presented.Results: Overall, 7.9% accepted carrier screening. The premutation frequency was 1 in 382, and the intermediate allele frequency was 1 in 143.Conclusions: Fragile X screening is a desirable option for some women seeking prenatal genetic counseling and should be made available to this population.

Unexplained elevated maternal serum α-fetoprotein levels and perinatal outcome in an urban clinic population

OBJECTIVE Our purpose was to determine whether obstetric patients with unexplained elevated maternal serum alpha-fetoprotein levels from an indigent clinic population are at increased risk for adverse perinatal outcome compared with similar patients with normal values. STUDY DESIGN Perinatal outcomes from inner-city obstetric patients with unexplained elevated maternal serum alpha-fetoprotein levels (> 2.0 multiples of the median) were compared with patients from the same clinic with normal values. The frequency of adverse outcomes in the two groups was subjected to chi 2 analysis. RESULTS Adverse perinatal outcomes occurred in 33 of 57 (58%) of the subjects with unexplained elevated maternal serum alpha-fetoprotein levels compared with 163 of 719 (23%) patients with normal values (p < 0.001). Statistically significant differences were observed for abruptio placentae (p < 0.025), intrauterine growth retardation (p < 0.025), stillbirth at > 20 weeks (p < 0.001), and pregnancy-induced hypertension (p < 0.01). Differences in the frequencies of preterm premature rupture of membranes, preterm delivery, pregnancy loss < 20 weeks, and congenital malformations were not statistically significant. CONCLUSION In contrast to a previous report, we found that unexplained elevated maternal serum alpha-fetoprotein levels confer an increased risk of adverse perinatal outcome in an urban clinic population over and above the already increased risk related to socioeconomic status.

Quality assessment of routine nuchal translucency measurements: a North American laboratory perspective

Purpose: To assess nuchal translucency measurements that were performed as part of routine prenatal screening for Down syndrome.Methods: Collect ultrasound measurements of nuchal translucency and crown rump length provided by individual sonographers over a 6-month period to six North American prenatal screening laboratories, along with the laboratorys nuchal translucency interpretation in multiples of the median. For sonographers with 50 or more observations, compute three nuchal translucency quality measures (medians, standard deviations, and slopes), based on epidemiological monitoring.Results: Altogether, 23,462 nuchal translucency measurements were submitted by 850 sonographers. Among the 140 sonographers (16%) who submitted more than 50 observations, 76 (54%) were found to have all three quality measures in the target range. These 140 sonographers collectively accounted for 14,210 nuchal translucency measurements (61%). The most common single measure to be out of range was nuchal translucency multiples of the median, found for 29 of the 140 sonographers (21%).Conclusion: Laboratories should routinely monitor the quality of nuchal translucency measurements that are received for incorporation into Down syndrome screening risk calculations and interpretations. When possible, instituting sonographer-specific medians and providing individualized feedback about performance and numbers of women tested offer the potential to yield more consistent and improved performance.

Technical standards and guidelines: prenatal screening for Down syndrome that includes first-trimester biochemistry and/or ultrasound measurements.

This statement is intended to augment the current general ACMG Standards and Guidelines for Clinical Genetics Laboratories and to address guidelines specific to first-trimester screening for Down syndrome. The aim is to provide the laboratory the necessary information to ensure accurate and reliable Down syndrome screening results given a screening protocol (e.g., combined first trimester and integrated testing). Information about various test combinations and their expected performance are provided, but other issues such as availability of reagents, patient interest in early test results, access to open neural tube defect screening, and availability of chorionic villus sampling are all contextual factors in deciding which screening protocol(s) will be selected by individual health care providers. Individual laboratories are responsible for meeting the quality assurance standards described by the Clinical Laboratory Improvement Act, the College of American Pathologists, and other regulatory agencies, with respect to appropriate sample documentation, assay validation, general proficiency, and quality control measures. These guidelines address first-trimester screening that includes ultrasound measurement and interpretation of nuchal translucency thickness and protocols that combine markers from both the first and second trimesters. Laboratories can use their professional judgment to make modification or additions.

Oligohydramnios: A Review

Oligohydramnios is a relatively common complication of pregnancy. Etiologies include congenital anomalies, intrauterine growth retardation, premature rupture of the membranes, drugs, postterm gestation and postmaturity. Sequelae from prolonged oligohydramnios including pulmonary hypoplasia and fetal compression syndrome can be devastating. Perinatal morbidity and mortality are both significantly increased in pregnancies complicated by oligohydramnios. Successful management requires a thorough search for the cause of the decreased amniotic fluid volume, and close antenatal surveillance.

Therapeutic amniocentesis using a vacuum bottle aspiration system

Objective To evaluate the clinical significance of the antenatally detected discordant umbilical arteries (UAs). Methods Women with singleton gestations undergoing sonographic evaluations were examined for the presence of discordant UAs. Transverse and longitudinal diameters as well as the area of both UAs were measured. Doppler flow velocity waveforms were recorded from both arteries. Macroscopic and microscopic examination of the umbilical cord was performed after delivery and the area of each artery was measured. Mann-Whitney U test and Spearman rank correlation were used for statistical purposes. Result Data are presented as median (range). Discordance between UAs was found in 14 of 1012 women who underwent sonographic examinations. The vessel diameters and areas differed significantly between the discordant UAs (diameter 2.9 [1–4.3] versus 4.5 [3.8–6.5] mm, P Conclusion The clinical significance of discordant UAs is that newborns are generally in good condition at birth and placental anomalies are common in this group of parturients. Abnormal Doppler velocimetry of the smaller UA should be taken with caution, because it does not seem to be associated with poor perinatal outcome. (Obstet Gynecol 1998;91:86-91.