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Nonimmune hydrops fetalis (NIHF) is a rare disorder with a high perinatal mortality of at least 50%. One cause of NIHF is generalized lymphatic dysplasia (GLD), a rare form of primary lymphedema of the extremities and systemic involvement including chylothoraces and pericardial effusions. An autosomal recessive form of GLD has been described, caused by variants in the PIEZO1 gene. It has been reported clinically to cause NIHF and childhood onset of facial and limb lymphedema, most of which were diagnosed postnatally. We present a case of a woman with recurrent pregnancies affected by NIHF because of novel compound heterozygous variants in the PIEZO1 gene diagnosed prenatally using exome sequencing (ES). Two variants in PIEZO1 (c.3206G>A and c.6208A>C) were identified that were inherited from the father and mother, and are predicted to cause a nonsense and missense change, respectively, in the PIEZO1 subunits. Ultrasound demonstrated severe bilateral pleural effusions, whole body edema and polyhydramnios. Histopathology revealed an increased number of lymphatic channels, many of which showed failure of luminal canalization. Sanger sequencing confirmed the same variants in a prior fetal demise. We provide phenotypic correlation with ultrasound and autopsy finding, review PIEZO1 variants as a cause of GLD and discuss the uses of prenatal ES to date., (© 2018 Wiley Periodicals, Inc.)

In this exciting era of "next-gen cytogenetics," integrating genomic sequencing into the prenatal diagnostic setting is possible within an actionable time frame and can provide precise delineation of balanced chromosomal rearrangements at the nucleotide level. Given the increased risk of congenital abnormalities in newborns with de novo balanced chromosomal rearrangements, comprehensive interpretation of breakpoints could substantially improve prediction of phenotypic outcomes and support perinatal medical care. Herein, we present and evaluate sequencing results of balanced chromosomal rearrangements in ten prenatal subjects with respect to the location of regulatory chromatin domains (topologically associated domains [TADs]). The genomic material from all subjects was interpreted to be "normal" by microarray analyses, and their rearrangements would not have been detected by cell-free DNA (cfDNA) screening. The findings of our systematic approach correlate with phenotypes of both pregnancies with untoward outcomes (5/10) and with healthy newborns (3/10). Two pregnancies, one with a chromosomal aberration predicted to be of unknown clinical significance and another one predicted to be likely benign, were terminated prior to phenotype-genotype correlation (2/10). We demonstrate that the clinical interpretation of structural rearrangements should not be limited to interruption, deletion, or duplication of specific genes and should also incorporate regulatory domains of the human genome with critical ramifications for the control of gene expression. As detailed in this study, our molecular approach to both detecting and interpreting the breakpoints of structural rearrangements yields unparalleled information in comparison to other commonly used first-tier diagnostic methods, such as non-invasive cfDNA screening and microarray analysis, to provide improved genetic counseling for phenotypic outcome in the prenatal setting., (Copyright © 2016 American Society of Human Genetics. All rights reserved.)

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport.

We report two sisters with congenital olivopontocerebellar atrophy, including immunohistochemical studies of autopsy brain tissue. Both cases showed microcephaly with disproportionately marked hypoplasia of the posterior fossa structures including pons, inferior olivary nuclei, and cerebellum. Microscopically, the pons was atrophic with near total loss of pontine nuclei and transverse pontocerebellar tracts (inferior and middle cerebellar peduncles). The medulla showed absent inferior olivary and arcuate nuclei. The cerebellum showed hypoplasia with rudimentary dentate nuclei, profound loss of Purkinje cells and external granule cell layer, a sparse internal granule cell layer of the entire dorsal vermis and the dorsal portions of the lateral folia, as well as markedly reduced underlying axon fibers in the white matter with marked astrogliosis. These features were highlighted by immunohistochemical study using antibodies against Purkinje cell epitopes, synaptophysin, neurofilament, glial fibrillary acidic protein, and tuberin. The cerebral hemispheres were unremarkable. Our cases are characterized by a pattern of diffuse posterior cerebellar involvement that has rarely been described in previous reports. An autosomal recessive pattern of inheritance is suggested. The abnormalities may result from antenatal degeneration or atrophy of neurons in the involved sites rather than hypoplasia or developmental arrest starting in the second and third month of late embryonic life.

Objective: The aim of the study was to determine if an association exists between intracardiac echogenic foci in the second-trimester fetus and trisomy 21., Subjects and Methods: Over a 2-year period, targeted fetal sonography was performed for various indications in 1593 second-trimester high-risk pregnant women. Presence or absence of echogenic foci was recorded for each fetus. Amniocentesis for karyotype analysis was performed in 901 subjects immediately after sonography. The findings of these 901 subjects formed the basis of this report., Results: Intracardiac echogenic foci were present in the left ventricle of 24 (3%) of the 901 fetuses. Three (13%) of these 24 fetuses had trisomy 21; no chromosomal abnormalities were found in the other 21 fetuses. Karyotype analysis revealed trisomy 21 in 14 (2%) of the remaining 877 fetuses who did not exhibit intracardiac echogenic foci. The sensitivity, specificity, positive predictive values, and negative predictive values for intracardiac echogenic foci in predicting trisomy 21 were 18%, 98%, 13%, and 98%, respectively. The association of intracardiac echogenic foci and trisomy 21 was significant (p < .009) by the two-tailed Fisher's exact test., Conclusion: In a high-risk obstetric population, the association between fetal intracardiac echogenic foci and trisomy 21 was statistically significant. Therefore, women carrying fetuses with intracardiac echogenic foci should be informed of the statistical association with trisomy 21.

In the 2 years between 1993 and 1995, we assayed alpha-fetoprotein (AFP) in 48,412 amniotic fluids (AFs). One thousand and eighty-six (2.2 per cent) measured > or = 2.0 MOM and these were subdivided into three groups; mildly (2.0-4.9 MOM), moderately (5.0-9.9 MOM), and very elevated (> or = 10.0 MOM). Abnormalities occurred in 25 per cent of the mildly elevated compared with 88 per cent of the moderately and 98 per cent of the very elevated cases. Forty-five per cent of the neural tube defects (NTDs) had AF-AFPs in the 5.0-9.9 and 36 per cent in the > or = 10.0 MOM range. After a positive acetylcholinesterase (AChE) test, both the moderately and the very elevated groups had abnormalities in > or = 95 per cent of cases, compared with 85 per cent in the mildly elevated group. After a negative AChE test, abnormalities occurred in 79, 52 and 18 per cent in the very elevated, moderately, and mildly elevated groups, respectively. Excluding chromosome abnormalities, an abnormal twin, and bloody samples, the risk of a fetal abnormality after a normal ultrasound was less than 1 per cent if the AChE was positive in both the moderately and the very elevated groups. If the AChE was negative, the risk was 18 per cent for the moderately and 55 per cent for the very elevated groups, of which congenital nephrosis accounted for 75 per cent; AFP levels usually increased in a later AF sample. Repeat amniocentesis may be offered to women with AF-AFPs > or = 5.0 MOM if no abnormality is seen with high-resolution ultrasound.

As the most common lethal autosomal recessive disorder in North America, cystic fibrosis (CF) is an obvious candidate for general population carrier screening. Although the identification of the causative gene has made detection of asymptomatic carriers possible, the extreme heterogeneity of its mutations has limited the sensitivity of the available DNA screening tests and has called into question their utility when they are applied to patients with no family history of the disease. The purpose of this study was to determine the technical feasibility, patient acceptance and understanding, and psychosocial impact of large-scale CF carrier screening in an ethnically diverse pregnant population. A total of 4,739 pregnant women attending prenatal clinics located in both an academic medical center and a large HMO were invited in person to participate. Of this group, 3,543 received CF instruction and assessments of knowledge and mood, and 3,192 underwent DNA testing for the six most common CF mutations, by means of a noninvasive PCR-based reverse-dot-blot method. Overall participation rates (ranging from 53% at the HMO to 77% at the academic center) and consent rates for DNA testing after CF instruction (>98%) exceeded those of most other American studies. The PCR-based screening method worked efficiently on large numbers of samples, and 55 carriers and one at-risk couple were identified. Understanding of residual risk, anxiety levels, and overall satisfaction with the program were acceptable across all ethnic groups. Our strategy of approaching a motivated pregnant population in person with a rapid and noninvasive testing method may provide a practical model for developing a larger CF screening program targeting appropriate high-risk groups at the national level, and may also serve as a paradigm for population-based screening of other genetically heterogeneous disorders in the future.

In this study we examined the relations among psychosocial factors associated with pregnant women's attitudes toward genetic carrier testing for cystic fibrosis (CF). A sample of 511 pregnant women attending various health clinics for general prenatal care were educated about CF. Women's health beliefs, coping styles, and attitudes toward CF carrier screening were assessed. Results from structural equation modeling analyses indicated that women who perceived themselves as more likely to be carriers of the CF gene and who perceived greater benefits of screening were positively inclined toward genetic screening. Perceived barriers to screening were negatively associated with women's attitudes toward CF genetic testing. In addition, the findings suggest that some types of avoidant coping styles may indirectly influence one's decision to undergo genetic screening through perceptions of risk, benefits, and barriers. Given the advent of genetic screening options for many diseases, in this study we address some issue in women's attitudes toward prenatal screening that are relevant to a variety of genetic screening programs.

Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0.3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10.3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15.3 per cent) were mosaic for a marker chromosome. Ninety-five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype-phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian-Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40.4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.

We have collected and analyzed clinical information from 11 patients with chromosome 4p deletions or rearrangements characterized by various molecular techniques. Comparing the extent of these patients' deletions with their respective clinical presentations led to the proposal of a preliminary phenotypic map of chromosome 4p. This map consists of regions which, when deleted, are associated with specific clinical manifestations. Nonspecific changes such as mental and growth retardation are not localized, and probably result from the deletion of more than one gene or region. The region associated with most of the facial traits considered typical in Wolf-Hirschhorn syndrome (WHS) patients coincides with the currently proposed WHS critical region (WHSCR), but some anomalies commonly seen in WHS appear to map outside of the WHSCR. The observation of clinodactyly in 2 patients with nonoverlapping deletions allows assignment of these defects to at least 2 separate regions in 4p16. These initial observations and attempts at genotype/phenotype correlation lay the groundwork for identifying the genetic basis of these malformations, a common objective of gene mapping efforts and chromosome deletion studies.

Forty-two open neural tube defects (NTDs) were identified in our series of 7440 amniocenteses tested between 11 and 15 weeks of gestation. Using a cut-off of > or = 2.0 MOM, the detection rate for open NTDs was 95 per cent; 100 per cent each for anencephaly and spina bifida; and 78 per cent for encephalocele. Two encephaloceles had AFP levels less than 2.0 MOM and negative AChEs. Thirty-four (81 per cent) of these NTDs were tested between 13 and 15 weeks and 8 (19 per cent) before 13 weeks. There were 0.6 per cent false positives by AFP (excluding serious abnormalities and fetal death) and 0.1 per cent after AChE. The likelihood of an open NTD after an elevated AFP (> or = 2.0 MOM) was 24 and 77 per cent for any serious abnormality. These results, when combined with an earlier study, indicate that amniotic fluid AFP appears to be as sensitive a test for open NTDs between 13 and 15 weeks as between 16 and 20 weeks. Additional experience is necessary to determine this before 13 weeks.

Population-based screening for cystic fibrosis carrier mutations presents a number of challenges for genetic counselors, owing primarily to the inability of current DNA testing technology to identify all possible mutations and the difficulty involved in conveying the concept of residual risk to those patients who test negative. To address these issues, we are conducting a pilot study, as part of a consortium established by the National Center for Human Genome Research, to explore the efficacy, acceptance, and psychosocial impact of various approaches to carrier screening in an ethnically diverse Southern California population. This article reports the patient instructional and screening strategies we developed in the initial phase of the project in order to optimize our chances of answering these questions and delivering this service on a large scale.

We studied 693 consecutive early amniocenteses (prior to 15 weeks) and found a spontaneous abortion rate to 28 weeks' gestation of 1.5 per cent. A control group of women having standard amniocentesis (15-20 weeks) experienced a 0.6 per cent fetal loss in the same period. There were no other apparent differences between the two groups. Early amniocentesis results are generally available 4-6 weeks before standard amniocentesis and 1-3 weeks after chorionic villus sampling (CVS). Alpha-fetoprotein (AFP) can be accurately assayed in 11- to 15-week amniotic fluid samples but additional studies are necessary to determine the accuracy of neural tube defect (NTD) detection. Including the present study, over 5800 early amniocenteses have been reported and the results suggest that this is a relatively safe prenatal diagnostic test and an alternative to CVS and later amniocentesis.

The finding of a 'faint-positive' acetylcholinesterase band in amniotic fluid samples of women at 15 weeks' gestation or above is associated with an increased risk of fetal abnormalities, most commonly gastroschisis. This finding warrants a targeted sonographic evaluation, in order to rule out significant fetal malformations.

Objective: The purpose of this prospective study was to assess the value of maternal serum screening between 11 and 15 weeks of gestation to detect fetal Down syndrome., Study Design: Blood samples were collected on 993 women between 11 and 15 weeks' gestation before amniocentesis. Ninety percent were > or = 35 years old. Samples were coded and assayed for alpha-fetoprotein, unconjugated estriol, and human chorionic gonadotropin. Medians were established at each week between 11 and 15 from 836 normal, singleton pregnancies., Results: We used a computer-generated cut-off risk for Down syndrome of one in 365 at term; nine of 11 (82%) Down syndrome pregnancies were identified. There were 23% false-positive results in women > or = 35 years old and 6% in those < 35 years., Conclusion: These results suggest that maternal serum screening between 11 and 15 weeks may provide an acceptable alternative to screening between 16 and 20 weeks.

We assayed maternal serum samples from 134 black and 268 white women from 16 to 18 weeks of gestation for intact human chorionic gonadotropin (hCG), and unconjugated oestriol (uE3). Serum from women with high (> or = 2.5 MOMs) or low (risk for Down syndrome > or = 1/365) maternal serum alpha-fetoprotein (MSAFP) levels were excluded. After correcting for maternal weight, we found that median hCG levels were 16 per cent higher in black women but uE3 levels were not significantly different. These results confirm three other studies for hCG and one study for uE3. Corrections are recommended for both maternal serum hCG and AFP before calculating the risk for Down syndrome in black women.

We studied a mother and daughter with an extremely rare constellation of signs and symptoms. One or both had absent lacrimal puncta, nasolacrimal duct obstruction, chronic dacryocystitis, dry eyes, and epiphora. Systemic findings included salivary gland hyposecretion, dental hypoplasia and dysplasia, cup-shaped ears with hearing loss, and digital anomalies. These findings are consistent with those of the lacrimo-auriculo-dento-digital syndrome, a genetic disorder. Our study supports the autosomal dominant inheritance of this syndrome, delineates the ophthalmic manifestations, and provides evidence that renal anomalies are part of the disorder.

A case of fatal generalized dystrophic epidermolysis bullosa is described in a prematurely born female whose mother had strikingly elevated mid-trimester serum and amniotic fluid alpha-fetoprotein concentrations, a positive amniotic fluid acetylcholinesterase band, and negative serial ultrasound studies. This case lends further support to an association between autosomal recessive generalized dystrophic epidermolysis bullosa and increased levels of alpha-fetoprotein, positive amniotic fluid acetylcholinesterase, and normal ultrasound findings.

Prior to the development of the DNA-based technology reliable prenatal diagnosis of G6PD deficiency was not possible. We show that, using PCR amplification and restriction endonuclease digestion, prenatal diagnosis is possible. We have now been able to determine that the male fetus of a mother heterozygous for G6PD Mediterranean had inherited the maternal X chromosome with the normal G6PD gene.

To enhance visualization of anatomic structures of the human embryo, the authors used a commercially available catheter-based ultrasound (US) transducer (12.5 MHz) introduced through the cervix and into the endometrial cavity of seven women about to undergo voluntary termination of first-trimester pregnancy. The authors term this technique endoluminal catheter-assisted transcervical (ELCAT) sonography. In none of the patients did the US catheter rupture the fluid-filled chorionic/amniotic cavity. The duration of pregnancy ranged from 5.2 to 10.0 menstrual weeks. The most prominent anatomic structures visualized were the heart and neural tube. As an investigational technique, ELCAT US can be used to image anatomic structures of the developing human embryo.

Among 58,187 women tested, 1002 had a maternal serum alpha-fetoprotein measuring greater than or equal to 2.5 multiples of the median after correction for race, weight, and insulin-dependent diabetes. They were stratified into three groups: group 1, 2.5 to 2.9; group 2, 3.0 to 5.0; group 3, greater than or equal to 5.0 multiples of the median. The initial risk of a serious abnormality detected by ultrasonography or amniocentesis was 17% (5%, 12% and 65% in groups 1, 2, and 3, respectively). After correction for twins and dates, this risk became 23% (7%, 18%, and 71% in groups, 1, 2, and 3, respectively). Among the women with high maternal serum alpha-fetoprotein levels, 556 (77%) had normal ultrasonographic and amniocentesis studies, and the risk of adverse pregnancy outcome ws 27% (19%, 29%, and 70% in groups 1, 2, and 3, respectively). There was a statistically significant increase in late fetal and perinatal death, prematurity and growth retardation, oligohydramnios, abruptio placentae, preeclampsia, and congenital abnormalities. The overall risk for abnormality or adverse outcome was 24% in group 1, 41% in group 2, and 91% in group 3.

Maternal sera (MS) taken from 1396 women prior to chorionic villus sampling at 9-12 menstrual weeks were assayed for unconjugated oestriol (uE3) and alpha-fetoprotein (AFP). Median levels increased by 41 and 26 per cent per week respectively in normal pregnancies. There were 32 pregnancies with a chromosome abnormality. The median MS uE3 and AFP were 0.73 and 0.75 multiples of the median (MoM) respectively in the ten cases of Down's syndrome (DS) but not decreased in the other abnormalities. These results suggest that both uE3 and AFP may be useful in identifying DS in the first trimester. Additional prospective studies are needed to confirm these findings.

Two and two-tenths percent of 85,000 consecutive amniotic fluid (AF) samples had alpha-fetoprotein (AFP) levels greater than or equal to 2.0 MoM. Half measured 2.0-2.4 MoM, and 93% had a normal outcome. Sixty-seven percent of those with higher levels had abnormalities. A positive acetylcholinesterase (AChE) increased the risk from 67% for levels between 2.0 and 2.4 MoM to 99% at greater than or equal to 5.0 MoMs. After a normal ultrasound and chromosome studies, the risk for a fetal abnormality was 1% for AF AFP measuring 2.0-2.4 MoM and 3% for higher levels.

Forty patients underwent fetal reduction at approximately 12 weeks' gestation for multiple pregnancy. Twenty-two had maternal serum alpha-fetoprotein (MSAFP) determinations and all but one was elevated, with a mean value of 9.41 multiples of the median (MOM). A total of 53 amniotic fluid specimens were evaluated for AFP; 25% were elevated above 2.0 MOM and one sample was positive for acetylcholinesterase. None of these elevations were associated with a neural tube defect, although two neural tube defects were detected by other means. Routine MSAFP is not recommended for patients with multifetal pregnancy reduction.

In the majority of pregnancies involving a Down's syndrome (DS) fetus, the level of alpha-fetoprotein (AFP) measured in maternal serum and amniotic fluid is reduced to about 70 per cent of the level attained in normal pregnancies. Causes of this decrease may include the production of an altered AFP molecule with modified turnover or transport properties, or a reduction in the level of AFP synthesis. We examined hepatic AFP mRNA transcripts and compared AFP polypeptide isoforms in liver tissue samples obtained from a group of DS and normal abortuses. No differences was detected in the structure of the AFP mRNA transcript or in the charge or mass of AFP polypeptides in the two sample groups. However, the hepatic AFP level, expressed as microgram AFP/mg protein, was significantly lower in a group of 28 DS cases relative to a group of 47 normal controls (p = 0.04). This difference in hepatic AFP concentration did not appear to be the result of a general reduction in the level of total protein or total RNA production. The greatest difference between the AFP levels of the DS and normal groups was observed in the earliest samples examined (i.e., at 17-19 weeks of age) where the median AFP levels differed by about 20 per cent.

Linkage analysis of 146 informative families for MN and Ss resulted in an estimate of the recombination frequency greater than previously reported. Our total is 7 recombinant children out of 467 individuals, including 1 confirmed recombinant (retested and HLA-compatible) and 6 not verified. The 95% confidence interval of our estimate of recombination is 0.0033-0.0167. Our results are compared with two earlier studies.

We confirmed the relation between maternal weight and serum alpha-fetoprotein concentration and have shown a further relation--to ethnic origin. Of these two, maternal weight is the more closely related. Oriental, white, and Hispanic women showed no significant differences in serum AFP concentrations when corrections for maternal weight were applied. Black women showed consistently higher values, by an average of 10% at each week of gestation. These corrections only affected values falling just above or below the 95th centile cutoff. We conclude that corrections for maternal weight and race should be applied when values for alpha-fetoprotein in maternal serum are being interpreted.

Proteins in first voided urine from premature and term neonates were analyzed by two-dimensional gel electrophoresis. At 22-28 weeks of gestation, urine contained many identifiable serum proteins and the presence of an array of minor polypeptides with masses below 40 kilodaltons (kd) made the patterns quite complex. In contrast, the abundance of serum proteins in term urine was markedly decreased and the polypeptide patterns approached the relative simplicity seen in adult urine. Urine contained three major nonserum polypeptide groups at 30.5, 33-49, and 97 kd. The 97-kd species was identified as the Tamm-Horsfall glycoprotein, which is known to be derived from the renal tubule.

The Gesell Developmental Evaluation was administered to 150 children between 8 and 37 months of age whose mothers had second-trimester amniocentesis. The results of the evaluation were analyzed with respect to 1) maternal age at the time of the amniocentesis; 2) volume of fluid aspirated; 3) presence of bloody amniotic fluid; 4) repeat amniotic taps; and 5) medical problems during the first year of life. There was no statistical relationship found between an abnormal developmental score and any of the above 5 items. The results from the same developmental test administered to the control group of 64 young children were not significantly different from the index group.

Karyotypes of blood and skin fibroblasts at ages 3 and 8.5 years had shown non-mosaic trisomy 18 in a male now of age 19. Because of his prolonged survival and an atypical phenotype, skin fibroblast cultures from a new biopsy were established at age 18, and only normal 46,XY cells were observed, while peripheral blood lymphocytes still demonstrated 47,XY, + 18. This patient and six others with trisomy 18 mosaicism illustrate the advisability of looking for such a pattern in individuals whose phenotype in early life is not fully consistent with the trisomy 18 syndrome. Additional clues to the presence of trisomy 18 mosaicism are male sex, survival beyond 2 years and lack of fingertip arches.

Genetic linkage studies are reported on two families with cleft lip +/- cleft palate. For the first family (LP01) the etiology of the clefting is unknown, and the linkage analyses were done assuming both autosomal dominant and autosomal recessive inheritance. Close linkage is rejected with the Duffy blood group under the dominant model and with four loci (Duffy, Kidd, and ABO blood groups and haptoglobin) under the recessive model. The second family (LP02) is a Mexican-American family segregating the van der Woude syndrome with lip pits. The linkage analyses for this autosomal dominant trait excluded close linkage with seven genetic markers, including three on chromosome one. The maximum lod scores were 0.6 with BF (chromosome 6) and 0.4 with the P blood group, which is not yet mapped.

One hundred thirty-four obstetrical diagnostic sonographic examinations were performed on patients of 12--26 gestational weeks. The following abdominal diameter measurements were obtained: (1) anteroposterior transverse diameter; (2) right-to-left transverse diameter; (3) average of (1) and (2); and (4) greatest longitudinal diameter. These measurements were plotted against the respective biparietal diameters, and normal statistical distribution curves were developed. These curves have proven helpful in cases with a questionable disproportionate relation between the fetal head and body size in early pregnancy. The data have facilitated identification of fetal abnormalities sufficiently early in the pregnancies to permit advising therapeutic abortion. Five cases outside the normal range are discussed and compared to normal. In several cases, the sonographic results played a major role in the decision-making process of the patient involved.

Two cases of constriction of the umbilical cord resulting in fetal demise following midtrimester amniocentesis are presented. In both cases, real-time ultrasonography prior to amniocentesis revealed a viable fetus. Fetal demise was identified immediately following the procedure in the first case and one month later in the other. A localized constriction at the fetal end of the umbilical cord in both, with torsion of the constricted segment in the second case, was observed. Wharton's jelly was noted to be deficient in this segment of the cord in the first case. The mechanism of fetal demise is discussed. It is suggested that this abnormality should be considered when fetal demise follows midtrimester amniocentesis.

Thyroid hormone and thyrotropin concentrations in amniotic fluid were studied by radioimmunoassays during pregnancy. The mean thyroxine concentration was 398 ng per 100 ml at 15 to 19 and 440 ng per 100 ml at 36 to 42 weeks. Although 3,3',5-tri-iodothyronine was undetectable (less than 25 ng per 100 ml), 3,3',5'-tri-iodothyronine levels were very high (range, 132 to 605 ng per 100 ml) at 15 to 30 weeks, but decreased substantially (range, 54 to 130 ng per 100 ml) thereafter. Thyrotropin was undetectable. The mean thyroxine and 3,3',5-tri-iodothyronine levels in amniotic fluid were much lower and the mean 3,3'5'-tri-iodothyronine much higher than the corresponding values in maternal serum at both 15 to 19 and 36 to 42 weeks of pregnancy. Measuring thyroid hormones in amniotic fluid, especially 3,3',5'-tri-iodothyronine, may aid in the diagnosis of fetal thyroid dysfunction and in identification of pregnancies of less than 30 weeks' gestation.

A family is described with congenital hydrocephalus occurring in two pregnancies following the birth of a child with a neural tube defect (NTD). Prenatal diagnosis of hydrocephalus at mid-gestation was achieved by ultrasonography. The increased frequency of hydrocephalus among sibs of probands with a NTD and vice versa suggests that, following the birth of a child with either malformations, subsequent pregnancies should be monitored at mid-gestation by amniotic fluid AFP and serial ultrasound examination.

Chromosome replication pattern was reevaluated in an unbalanced X/13 translocation carrier, 46,X,der (X),t(X;13)(q27;q12), using the BudR-acridine orange technique. The translocated chromosome, Xpter leads to q27::13q12 leads to 13qter, was late replicating in all analyzed cells. The autosomal segment showed a replication pattern comparable to the two normal, and presumably genetically active, chromosome 13's, with the exception of band 13q22, which was consistently late replicating. Measurements of red-cell levels of esterase D (ESD) (a marker assigned to 13q14) showed a 50% increase in ESD activity, compared to that in normal controls and parents of the patient. This suggests noninactivation of the ESD locus on the der(X) chromosome, a finding consistent with the late-replication data.

Neural tube defects represent some of the most common and serious of the congenital malformations. Although elevation of alpha-fetoprotein in amniotic fluid is not diagnostic, it does indicate an abnormality of the fetus in a very high proportion of cases. A normal level, however, does not exclude the possibility of a closed neural tube defect. It is therefore recommended that all amniocenteses performed between 15 and 20 weeks of gestation include measurement of alpha-fetoprotein. Maternal serum alpha-fetoprotein assay is a screening test and pilot studies will be necessary to determine its value as a routine prenatal blood test.

A two-year-old girl has the following features of the cri du chat syndrome: microcephaly, hypertelorism, downward slanting of the palpebral fissures, psychomotor retardation and a cat-like cry. She is only of five patients having the cat cry syndrome with 45 chromosomes. Her karyotype is 45,XX, -5, -14, +t(5; 14)(5qter leads to 5p11: : 14q11 leads to 14qter) with the translocation inherited from her mother and maternal grandmother, each of whom is the carrier of a balanced translocation 46,XX,t(5;14)(p11q11). Normal plasma activity for hexosaminidase B suggests the locus for this enzyme is not located in the delected segment of 5 p.

Two sibs, one girl and one boy, were observed in infancy with a severe lethal skeletal dysplasia syndrome that radiologically and histologically resembled Kniest dysplasia but clearly differed in clinical course and inheritance. Kniest dysplasia is a nonlethal syndrome, whereas both of these infants died in the neonatal period. Kniest dysplasia appears to be inherited as an autosomal dominant trait; the likely transmission in this family was autosomal recessive. Roentgenograms revealed dumbbell-shaped long bones superficially similar to Kniest dysplasia, but with markedly shortened diaphyses and metaphyseal irregularities. Chondro-osseous morphology demonstrated a superficially similar foamy "Swiss cheese" appearance to the cartilage matrix, as seen in Kniest dysplasia, but there were distinctly different changes in the growth plate and resting cartilage. Ultrastructurally, the chondrocytic endoplasmic reticulum was found to have an appearance different from that observed in either normal or Kniest cartilage. These cases likely represent a distinct chondrodysplasia.

A 4-day-old Caucasian male presented with midline defects of the skull and face and extensive skeletal malformations. Chromosome analysis of peripheral blood lymphocytes showed tetrasomy 9p (47,XY, + i(9p) with no evidence of mosaicism. Confirmation of the cytogenetic interpretation was obtained from the assay of the enzyme galactose-1-P uridyl transferase, the locus for which is on 9p, which showed twice the normal activity.