Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance.

We report on a follow-up examination of a family with microcephaly and lymphedema. The finding of chorioretinal dysplasia with variable visual deficit in multiple relatives, which was not previously discovered, supports the concept of microcephaly, lymphedema, and chorioretinopathy as being a single autosomal dominant genetic entity with variable expression. We recommend that fundoscopic examination be performed in all patients with microcephaly with or without lymphedema.

Pathologic findings in pregnancies with unexplained increases in midtrimester maternal serum human chorionic gonadotropin levels.

Second trimester maternal serum human chorionic gonadotropin (MShCG) levels are commonly obtained as part of a screening protocol for chromosomal anomalies. Approximately 4% to 6% of patients have elevated hCG levels for gestational age, and this test has been reported to identify a group at risk for pregnancy complications. We ascertained 24 patients with unexplained elevated MShCG levels and available placental pathology among 5,790 deliveries during a 58-week period and compared them with 48 controls with normal MShCG levels delivering during the same period. Cases had a higher prevalence of preeclampsia, intrauterine growth retardation, and preterm delivery. Pathology in cases included more large-for-gestational-age placentas, fewer small-for-gestational-age placentas, lower mean fetoplacental weight ratios, more decidual plasma cell infiltrates, and more retroplacental hematomas. Other more frequent abnormalities that did not reach statistical significance included abnormal placental shape and chronic villitis. Maternal and fetal vascular abnormalities were similar in both groups. Morphometric analysis were performed on hCG-immunostained sections from placentas at 17, 21, 36, and 41 weeks' gestation. Patients with elevated MShCG showed an increased volume of hCG-positive trophoblast per unit surface area and increased intensity of hCG immunoreactivity within individual terminal villous units.

Cytogenetic and molecular genetic characterization of trisomy 20 mosaicism in fetal blood and tissues.

We report a case of mosaic trisomy 20, the most common autosomal mosaicism identified in amniocytes, ascertained in a woman referred for amniocentesis because of abnormal ultrasound at 18.1 weeks' gestation which revealed short femurs and nuchal thickening. Metaphase analysis of 98 clones revealed 47,XY, +20 in 96 cells (98 per cent). Trisomy 20 was demonstrated in 6 cells (12 per cent) in a total of 50 cells from two fetal blood cultures obtained after pregnancy termination. Fluorescence in situ hybridization (FISH) analysis of interphase nuclei utilizing a chromosome 20 alpha-satellite centromeric DNA probe revealed three signals in 57/546 nuclei (10 per cent) in fetal blood. Metaphase analysis of 167 cells from seven different fetal tissue sources revealed trisomy 20 in 32 cells (19.2 per cent). The percentage of trisomy 20 cells varied with tissue type, with the highest percentage (13/25 cells, 52 per cent) identified in the small intestine and lymph nodes and the lowest percentage (1/34 cells, 2.9 per cent) identified in a specimen of chorionic villi. Molecular genetic analyses utilizing polymerase chain reaction (PCR)-formated dinucleotide repeat polymorphisms demonstrated that the non-disjunctional event most likely occurred post-zygotically and that the origin of the extra chromosome 20 was maternal. This study is the first to demonstrate trisomy 20 cells in fetal blood, suggesting that mosaic trisomy 20 can be embryonic in origin. In cases of prenatally detected mosaic trisomy 20, examination of fetal blood should be considered, as well as study of placental membranes, skin, and urine sediment to confirm the karyotype and determine its significance.

Risk-based prenatal screening for trisomy 18 using alpha-fetoprotein, unconjugated oestriol and human chorionic gonadotropin.

Nine centres collaborated to examine the feasibility of a screening method for trisomy 18 that was based on assigning individual risk, using a combination of maternal age and measurements of alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG). Second-trimester measurements of these analytes were obtained from 94 trisomy 18 pregnancies. In the 89 pregnancies without an associated open defect, the median levels for AFP, uE3, and hCG were 0.65, 0.43 and 0.36 multiples of the unaffected population median, respectively. The strongest individual predictor of risk for trisomy 18 was uE3, followed by hCG, AFP, and maternal age, in that order. Using a method of individual risk estimation that is based on the three markers and maternal age, 60 per cent of pregnancies associated with trisomy 18 would be detected at a risk cut-off level of 1:100, with a false-positive rate of about 0.2 per cent. One in nine pregnancies identified as being at increased risk for trisomy 18 would be expected to have an affected pregnancy. This risk-based screening method is more efficient than an existing method that is based on fixed analyte cut-off levels. Even though the birth prevalence of trisomy 18 is low, prenatal screening can be justified when performed in conjunction with Down syndrome screening and when a high proportion of women offered amniocentesis have an affected fetus.

Partial X chromosome trisomy with functional disomy of Xp due to failure of X inactivation.

A 5-month-old girl with mild phenotypic abnormalities, developmental delay, and seizures was found to have the de novo karyotype 46,XX,-13,+der(13)t(X;13)(p21.2;p11.1). The partial trisomy of Xp21.2-->pter was confirmed with fluorescence in situ hybridization, using an X chromosome painting probe and several cosmid and YAC probes for Xp sequences. Replication banding showed that one of the structurally normal X chromosomes was late-replicating, but that the Xp segment of the der(13) was early-replicating in all cells examined. Since segments of the X chromosome separated from the X inactivation center in Xq13.2 cannot undergo X inactivation, the result is functional disomy of distal Xp. As the loss of short arm material from chromosome 13 is not considered to be clinically significant, the genomic imbalance of Xp expressed in this patient most likely accounts for her abnormal phenotype.

Single-operator comparison of early and mid-second-trimester amniocentesis.

We sought to determine whether early amniocentesis is a safe and acceptable method of genetic evaluation in early pregnancy. During the 54-month period from September 1986 to February 1991, 300 consecutive early second-trimester amniocenteses were performed transabdominally at 13-14 weeks' gestation and 567 consecutive mid-second-trimester transabdominal amniocenteses were performed at 16-18 weeks. Group assignment was nonrandomized, interoperator-dependent variables were eliminated, and analysis was performed in one cytogenetics laboratory. The median maternal age and indications for the procedure were similar in both groups. There were no significant differences between the early- and mid-second-trimester amniocenteses in failed sampling, ambiguous results, pregnancy loss from 4 weeks after the procedure to 28 weeks' gestation, preterm birth, or perinatal death rate. Pregnancy loss within 4 weeks of amniocentesis was more frequent in early- than in mid-second-trimester amniocenteses. We conclude that early amniocentesis is a safe and acceptable method of genetic evaluation.

A genetic association between microcephaly and lymphedema.

We discuss a family in which microcephaly and lymphedema are co-segregating as an apparently autosomal or X-linked dominant trait. A review of each malformation is presented with reference to the known genetic patterns of each. This combination of microcephaly and lymphedema may be a unique syndrome, previously undescribed because of subtleties of expression in affected individuals.

alpha-Fetoprotein: relationship between maternal serum and amniotic fluid levels.

Levels of alpha-fetoprotein were determined in 297 paired samples of maternal serum and amniotic fluid from patients with normal pregnancies at 16 to 17 completed weeks of gestation. Gestational ages were determined by menstrual history and ultrasonography, and the assays for alpha-fetoprotein were performed by a single reference laboratory. The results of the study failed to demonstrate any statistical relationship between the concentrations of alpha-fetoprotein in these two fluid compartments (r = 0.006). This finding was confirmed when the results at 16 and 17 weeks were analyzed individually. These findings indicate that amniotic fluid levels of alpha-fetoprotein cannot be predicted by those levels determined in maternal serum, and that simple diffusion is an inadequate explanation for the transfer of alpha-fetoprotein from amniotic fluid to maternal serum. The lack of correlation also emphasizes that the sensitivity and specificity of maternal serum alpha-fetoprotein screening for neural tube defects must continue to be based upon the detection rates in large population studies and the determination of "normal" values by reference laboratories.

The effects of psychosine upon growth of human skin fibroblasts from patients with globoid cell leukodystrophy.

[3H]Thymidine incorporation into cultured skin fibroblasts from patients with globoid cell leukodystrophy (GLD) and from control individuals was utilized to monitor the effects of psychosine (galactosylsphingosine) upon cell replication. The concentration of psychosine necessary to inhibit 50% (ID50) of the growth of cultured skin fibroblasts was approximately 15 microgram/ml for both normal and GLD fibroblasts deficient in the enzyme galactosylceramide beta-galactosidase. Growth inhibition curves for GLD and for control fibroblasts were comparable after 3 days and after 7 days exposure to the glycolipid, so that accumulation of psychosine was not a critical factor affecting toxicity. Galactosylceramide, the major substrate for the enzyme galactosylceramide beta-galactosidase, did not inhibit [3H]thymidine incorporation into either normal or GLD fibroblasts at the concentration tested, in contrast to the highly toxic effects of psychosine at similar concentrations. The comparable inhibitory levels of psychosine in control cells and in GLD fibroblasts which are deficient in ability to hydrolyze this glycolipid suggest that the toxicity of psychosine is nonspecific. Therefore, these results are not consistent with the concept that globoid cell leukodystrophy is primarily a psychosine lipidosis.

Studies of a synthetic substrate in canine globoid cell leukodystrophy.

Gal et al. ((1977) Clin. Chim. Acta 77, 53-59) reported the use of a new synthetic substrate, 2-hexadecanoylamino-4-nitrophenyl-beta-D-galactopyranoside for the diagnosis of human globoid cell leukodystrophy. Assay of beta-galactosidase in brain homogenates from normal, carrier, and globoid cell leukodystrophy-affected dogs utilizing this new substrate demonstrated overlapping activities. Instead of reflecting specific D-galactosyl-N-acylsphingosine galactohydrolase (EC 3.2.1.46), the 2-hexadecanoylamino-4-nitrophenyl-beta-D-galactopyranoside beta-galactosidase activity in canine brain is highly correlated with nonspecific 4-methylumbelliferyl beta-galactosidase. Optimization of the 2-hexadecanoyl-amino-4-nitrophenyl-beta-D-galactopyranoside assay system for canine brain and the use of varying concentrations of taurocholate or taurodeoxycholate in the assay mixture did not alter the lack of specificity. These results indicate a significant difference in the nature of the underlying defect in galactosylceramide beta-galactosidase in canine globoid cell leukodystrophy compared to human globoid cell leukodystrophy.