Prenatal diagnosis of Bardet-Biedl syndrome by targeted second-trimester sonography.

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by mental retardation, obesity, retinal degeneration, polydactyly and syndactyly, diabetes mellitus, hypogenitalism, renal dysplasia and short stature. Definitive molecular diagnosis for BBS is not currently available and counseling of affected families is based on the 25% recurrence risk consistent with autosomal recessive inheritance. Our case presents the first successful use of second trimester targeted sonographic anatomy scanning to prospectively identify a fetus affected with BBS, and indicates that ultrasound can be of critical importance in providing precise as well as timely prenatal diagnosis for families at risk for this serious disorder.

Incontinentia pigmenti in a newborn male infant with DNA confirmation.

We report on a woman with incontinentia pigmenti (IP), who had two successive term pregnancies. The first pregnancy ended in the birth of a male infant, who is alive and well at 2 years. A second liveborn male had early postnatal distress and died after 1 day of life, after a fulminating clinical course. Polymorphic microsatellite markers, closely linked to the IP gene on the X chromosome, showed that each son inherited a different X chromosome from his mother. Although in most instances IP appears to be prenatally lethal for the male, the phenotype is not completely known. We propose that the neonatal phenotype may be characterized by lethal disturbances in the hematopoietic and immunologic systems.

Procedure-related fetal losses in transplacental versus nontransplacental genetic amniocentesis.

OBJECTIVE: We hypothesize that loss rates after amniocentesis do not differ in transplacental and nontransplacental taps performed by experienced operators. STUDY DESIGN: Subjects were 1000 women undergoing second-trimester amniocentesis: 745 were referred for maternal age; 132 for positive maternal serum alpha-fetoprotein screens, 41 indicating a risk for fetal neural tube defect, 91 indicating a risk for fetal chromosome abnormality; and 123 were referred for other reasons. All procedures were videotaped. The placenta was anterior in 518 cases; in 306 of these the needle went through the placenta. All pregnancies were prospectively evaluated through delivery. RESULTS: There were 13 losses among the 1000 procedures (1.3%). The transplacental losses occurred from 4 to 71 days after procedure, median 26.5 days; the nontransplacental losses from 12 days after procedure to term, median 25 days. The loss rate was essentially similar in the two categories: six transplacental (1.96%) and seven nontransplacental (1%) (relative risk 1.52 [95% confidence limits 0.84 to 2.75], p = 0.23). If the three patients with elevated maternal serum alpha-fetoprotein values were excluded from data analysis, the loss rates in the two groups were virtually identical (relative risk 0.98 [95% confidence limits 0.38 to 2.54], p = 1.0000). CONCLUSION: Transplacental amniocentesis does not appear to increase the fetal loss rate in the hands of experienced surgeons. Moreover, in view of the time span between amniocentesis and loss in both groups, a procedural cause seems questionable.

Further delineation of the McKusick-Kaufman hydrometrocolpos-polydactyly syndrome.

Six cases of the McKusick-Kaufman syndrome (MKS), including two cases that were diagnosed prenatally, were studied. Review of the 54 previously described cases indicates that postaxial polydactyly and hydrometrocolpos in female patients are the hallmark features of this entity. Other manifestations, such as malformations of gastrointestinal, cardiovascular, and ophthalmic structures, occur less consistently. Affected children require careful medical follow-up. Recurrence of hydrometrocolpos following surgical repair may lead to serious sequelae, such as chronic renal failure. We believe that MKS is a distinct panethnic genetic entity, inherited in an autosomal recessive fashion, and that the diagnosis should be made only in female patients with hydrometrocolpos and polydactyly or in male patients with polydactyly who have an affected female relative.

Partial duplication 16q: report of two affected siblings resulting from a maternal translocation and literature review.

Two siblings with a partial duplication 16q, born to a woman with a balanced translocation (6;16), are described. The first infant died at 8 weeks of age; the second died at 4 months. Fifteen other cases of duplications involving 16q have been reported, all of them derived from a balanced parental translocation. The most frequent physical findings have included dysmorphic facies characterized by high forehead, prominent nose, antimongoloid slant, malformed ears, and micrognathia, as well as flexion contractures of the joints, deformity of the feet, and genital hypoplasia in the male. Anorectal, intestinal and cardiac malformations were less frequent findings. Most of the affected infants died at ages ranging from 8 days to 6 months. The few with longer survival (up to 6 years) had a shorter, more distal segment duplication of chromosome 16. Although intrauterine growth retardation and microcephaly were not always present at birth, most of the infants had postnatal growth failure. The phenotypic and clinical findings of the two infants in this report are compared with those of previously reported cases, from which there appears to be correlation of the length of the 16q duplication with clinical phenotype and survivals.

Ring chromosome 6: report of a patient and literature review.

A patient with ring chromosome 6 had most of the manifestations previously reported in this syndrome and also had albinoid fundi and unilateral aniridia, findings not previously described. In most peripheral leukocyte metaphases analyzed, one chromosome 6 was replaced by a monocentric ring chromosome with deletion of the 6p and 6q. Fifteen other patients with a ring chromosome 6 have been reported. The most frequent findings were mental retardation, prenatal and postnatal failure, epicanthal folds, flat nasal bridge, short neck, apparently low-set and/or malformed ears, microphthalmia, and micrognathia. Studies of coagulation Factors XII and XIII and of the P blood group for possible assignment on distal 6p and 6q did not provide evidence for localization of the genes for these factors on the pter----p24 part of chromosome 6.

Elevation of serum beta-hexosaminidase and alpha-D-mannosidase in type 2 Gaucher disease: a clinical and biochemical study.

We report a case of a black infant who died at 9 months of age with clinical and pathological findings consistent with the acute neuronopathic form of Gaucher disease (Type 2). Analysis of peripheral blood platelets obtained from this child demonstrated very low levels of beta-glucosidase activity. beta-hexosaminidase (HEX) activity in the serum, however, was 30 times greater than the level in control sera and 15 times greater than the level observed in individuals affected with the chronic form of Gaucher disease (Type 1). Similarly, alpha-D-mannosidase (MANN) activity in the proband's serum was significantly elevated when compared with controls, and chronic Gaucher disease patients. We postulate that the cause of the elevation of these lysosomal enzymes is similar to the cause of elevation in Type 1 individuals but that patients with Type 2 Gaucher disease have a more serious cellular defect.

An association between low maternal serum alpha-fetoprotein and fetal chromosomal abnormalities.

An index case of "undetectable" maternal serum alpha-fetoprotein at 16 weeks in the first pregnancy of a 28-year-old woman was associated with birth of an infant with trisomy 18. This fortuitous finding stimulated a retrospective study of prenatally diagnosed chromosomal abnormalities. From among a series of 3,862 genetic amniocenteses, 32 cases of fetal autosomal trisomy were diagnosed for which corresponding maternal serum and amniotic fluid alpha-fetoprotein data could be retrieved. From a second laboratory, nine additional cases were added. The maternal serum alpha-fetoprotein levels expressed as multiples of the median were significantly lower in distribution for these 41 women than those from a group of normal matched control subjects (p less than 0.001). Since maternal age is shown to be a less than adequate predictor of autosomal trisomic birth, we proposed that a low level of maternal serum alpha-fetoprotein obtained through routine screening may prove to be valuable in improving the prenatal detection of these serious anomalies.

Changes of serum hexosaminidase for the presumptive diagnosis of type I Gaucher disease in Tay-Sachs carrier screening.

Although reduced acid beta-glucosidase activity appears to be the primary enzyme defect in type I Gaucher disease, patients with this disorder also have marked elevation of serum acid phosphatase and beta-hexosaminidase activities but with a normal level of lactic dehydrogenase activity. Moreover, there is a characteristic alteration in the hexosaminidase isozyme distribution with a striking increase in hexosaminidase B. Since these changes appear to be consistent and unlike those associated with other disorders or the hormonally induced alterations associated with pregnancy, routine serum testing for the Tay-Sachs carrier state may offer a useful approach for the presumptive diagnosis and screening for Gaucher disease. Unlike the changes in affected homozygotes, there are no characteristic alterations of acid phosphatase or hexosaminidase in heterozygotes for Gaucher disease.

The prenatal diagnosis of adrenoleukodystrophy. Demonstration of increased hexacosanoic acid levels in cultured amniocytes and fetal adrenal gland.

Amniocentesis was performed in two women heterozygous for adrenoleukodystrophy (ALD). One fetus was male, and the hexacosanoic acid (C26) level in the cultured amniotic cells was 0.808 microgram per mg of protein, compared to 0.104 +/- 0.069 (S.D.) in controls. Pregnancy was interrupted at 22 wk gestation. The fetal adrenal cortex showed the ultrastructural inclusions characteristic of ALD and C26 accounted for 35% of the fatty acids in the cholesterol esters extracted from this tissue, more than one thousand times control. The second amniocentesis was performed in a woman who was also heterozygous for an electrophoretic variant of glucose 6- phosphate dehydrogenase (G6PD), and a member of a kindred showing genetic linkage of loci for ALD and G6PD. The fetus was female and the C26 level in cultured amniotic cells was 0.577. Pregnancy was interrupted at 11 wk for reasons unrelated to ALD. Study of C26 level and G6PD type in cultured fetal tissues confirmed heterozygosity for ALD.

Heterozygote detection of type I Gaucher disease using blood platelets.

This report describes a reliable and reproducible method for the identification of carriers of Type I Gaucher disease using blood platelets as the source of beta-glucosidase and 4-methylumbelliferyl-beta-D-glucoside as substrate. Platelet lysates have at least two identifiable beta-glucosidase activities with the synthetic substrate. One is maximally active at pH 5.0 in the absence of sodium taurocholate and the other at pH 5.6 in the presence of taurocholate. In platelets of Gaucher homozygotes and heterozygotes, the beta-glucosidase activity at pH 5.6 with the bile salt is reduced whereas the activity at pH 5.0 is the same in non-carriers, carriers and affected patients. In addition to differences in specific activity, the ratio of beta-hexosaminidase to beta-glucosidase activities is a useful parameter in the evaluation of the carrier state. Since carriers have normal activity of hexosaminidase and a reduced activity of beta-glucosidase, their mean activity ratio is about 70% higher than in non-carriers. Therefore we propose that the specific activity of beta-glucosidase at pH 5.6 in the presence of sodium taurocholate with the ratio of beta-hexosaminidase to beta-glucosidase serve as useful and reliable indices in the evaluation of the carrier state for Gaucher disease.

Dermatoglyphic and cytogenetic studies in parents of children with trisomy 21.

Dermatoglyphic studies were carried out of 131 mothers and 95 fathers of children with Down syndrome and 200 controls (100 males and 100 females) using the Hopkins single score method. Twelve percent of the mothers and 2% of the fathers showed dermatoglyphic abnormalities including a distal axial triradius (t"), hypothenar ulnar loops, radial loops on digits IV and V and abnormal palmar creases, resulting in a positive Hopkins score or a score in the "overlapping range" (greater than -3). The origin of the extra chromosome could be determined in 23 of a total group of 40 families. In 22 of the former, the mother was the donor of the extra chromosome; in one it was the father, In these 23 families, a Hopkins score in the overlapping range was found in three mothers who were all under the age of 35 years at the birth of the affected child. Since cytogenetic studies cannot easily differentiate between meiotic nondisjunction and mosaicism as a basis for 21 trisomy in the progeny, it is possible that mothers with positive overlapping Hopkins scores represent undetected mosaics for a trisomic cell line. The dual approach utilizing dermatoglyphic and cytogenetic studies may aid in identifying persons with an enhanced risk for having children with Down syndrome.

Ring chromosome 14: a distinct clinical entity.

An infant girl with ring chromosome 14 is presented. The findings in this patient and in six previously reported cases of a ring 14 suggest that a characteristic clinical syndrome is associated with this chromosome aberration. The major features of the ring chromosome 14 syndrome include mental retardation, a disorder of skin pigmentation, seizures, and dysmorphic features, including flat occiput, epicanthal folds, downward slanting eyes, flat nasal bridge, upturned nostrils, short neck, and large low set ears.