Biomedical subjects
Publications and source records attributed to F Greenberg.
We present a case of terminal del(22q) with Goldenhar complex including hemifacial microsomia, bilateral epibulbar dermoids, preauricular tags with sensorineural hearing loss, vertebral anomalies, and CNS and renal malformations. The case illustrates causal heterogeneity of the Goldenhar complex and a previously unreported associated chromosome deletion.
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A fetus, subsequently shown to have the deletion 17p13, was detected at 30 weeks' gestation because of multiple anomalies and polyhydramnios on ultrasonography. The fetus died and was born at 34 weeks of gestation. Pathologic examination showed intrauterine growth retardation, double outlet right ventricle (a conotruncal cardiac defect), and thymic hypoplasia suggesting partial DiGeorge anomaly. To our knowledge, DiGeorge anomaly has not been reported previously in conjunction with del(17p) nor in the Miller-Dieker syndrome. Since this deletion is the largest deletion of distal 17p observed so far, one explanation for this association may be the presence of a gene on proximal 17p for neural crest development.
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The impact of maternal serum alpha-fetoprotein (MSAFP) screening on genetic centers was investigated by a questionnaire mailed to 220 genetic centers in the United States. Eighty-four (38%) of centers responded to the questionnaire; of these (34%) were adequate for analysis. About 33% of the programs performed their own MSAFP testing. Approximately 70% of centers used 2.5 times the median (MoM) as a cutoff for MSAFP elevations and approximately 75% of centers used a sliding cutoff for low MSAFP based on both maternal age and the multiple of the median. Between 1984 and 1986, the total number of women screened by the reporting centers increased by about 4.7 fold. The percentage of women seen in their centers for prenatal counseling due to high or low MSAFP levels increased from 1.3% in 1984 to 13.1% in 1986. The percentage of prenatal diagnoses utilizing amniocentesis for high or low MSAFP increased from 3% in 1984 to 10% in 1986. During this period, 76 cases of Down syndrome were detected based on low MSAFP; this represents 1.7% of amniocenteses for low MSAFP. These data demonstrate a significant increase in the number of women seen for prenatal counseling and amniocentesis at the reporting genetic centers and is likely to represent a similar trend at all genetic centers. The impact of high MSAFP screening for neural tube defects and low MSAFP screening for Down syndrome is likely to increase over the coming years and genetic programs should prepare for the increasing utilization of services necessary to handle women with high and low MSAFP levels.
The economic consequences of using an index of maternal age and maternal serum alpha-fetoprotein (MSAFP) screening to indicate risk of Down syndrome (DS) are examined. If DS screening indicated solely by a given maternal age is economically justifiable, then amniocentesis indicated by a DS risk equivalent to that maternal age cutoff, but based on an index of maternal age (for ages below the cutoff) and low MSAFP results, is also economically justifiable. It is concluded that the extant use of MSAFP screening for DS is a move toward the cost-effective use of scarce resources that can be made available with coordinated planning. However, increased professional and public awareness may result in significant increases in aggregate demand for these services. While MSAFP screening for DS is economically justifiable, there exists some potential for bottlenecks at the aggregate level, and these should be considered in conjunction with recommendations that the technology be adopted on a widespread basis.
Forty-two subjects with classic features of Williams syndrome were evaluated to ascertain the prevalence and severity of the ophthalmologic features associated with the disorder. Twenty-six (62%) had a stellate pattern of the anterior iris stroma which was observed only in individuals with blue or hazel iris color. Twelve (29%) had strabismus, most commonly esotropia. Hypermetropic discs were noted in 18 of 33 patients (55%), a simplex vertical branching of the central retinal vessels at the disc in 23 (70%), and situs inversus vasorum in 5 (15%). No subject had accentuated vascular tortuosity, which has been reported previously as a hallmark of this syndrome. No ocular manifestation of infantile hypercalcemia was noted in any subject.
High-resolution cytogenetics analysis of peripheral blood lymphocytes was done prospectively on 27 of 28 patients with features of DiGeorge anomaly. Twenty-two patients (81%) had normal chromosome studies with no detectable deletion in chromosome 22. Five patients (18%) had demonstrable chromosome abnormalities. Three patients had monosomy 22q11, one due to a 4q;22q translocation, one due to a 20q;22q translocation, and one due to an interstitial deletion of 22q11. One patient had monosomy 10p13, and one patient had monosomy 18q21.33, although the latter had subsequent resolution of T-cell defects. These findings are consistent with the heterogeneity of DiGeorge anomaly but confirm the association with monosomy 22q11 in some cases. However, monosomy 10p13 may also lead to this phenotype. Because of these associated chromosome findings, cytogenetic analyses should be done on patients with suspected DiGeorge anomaly. This is particularly important since many of the abnormalities involving chromosome 22 are translocations that can be familial with a higher recurrence risk. Since only one subtle, interstitial deletion of chromosome 22 was observed, it is not clear whether high-resolution cytogenetic analysis is cost beneficial for all such patients.
We report on two sib fetuses with similar abnormalities detected prenatally by ultrasound. The first fetus had micrognathia, was without cleft palate, and had low-set ears, double outlet right ventricle with a ventricular septal defect, and 46,XY gonadal dysgenesis. The second sib fetus was born with cleft lip and palate, micrognathia, transposition of the great vessels, ventricular septal defect, a right-sided aorta arch, and bilateral cystic kidneys with hypospadias. We were able to identify 11 additional cases in the literature with similar findings. We think this set of defects is a recognizable syndrome that appears to be inherited either as an autosomal recessive or as an X-linked recessive and may overlap with the Smith-Lemli-Opitz syndrome.
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We describe an apparent duplication of proximal 15q, i.e., 15q11q12 or 15q12q13 in two patients. Prometaphase chromosome analysis, C-banding and distamycin A/DAPI staining were used to exclude a translocation between the abnormal 15 homolog and another chromosome. The 2 patients have many manifestations of the Prader-Willi syndrome (PWS) including at least 5 of the following: obesity, compulsive eating, mental retardation, short stature, central hypotonia, hypogonadism, small hands and feet, hypopigmentation, and feeding problems in infancy. Results of high resolution chromosome analysis of the parents of both patients were normal. A comparison between these patients and 2 subjects from previous reports demonstrates phenotypic heterogeneity among the duplication 15q PWS patients. Two patients have the hypopigmentation seen in chromosomally normal and deletion PWS patients. These cases add to the variety of chromosome 15 aberrations which are associated with PWS.
Fifteen patients with deletion of proximal 15q without typical Prader-Willi syndrome (PWS) have been reported previously [Schwartz et al, 1985]. We report on 2 additional patients without typical PWS found to have deletions of 15q11-13 on chromosome analysis done for evaluation of developmental delay. Their manifestations include broad nasal bridge with telecanthus, full nasal tip with flare of nasal alae, long upper lip, posteriorly angulated ears, highly arched palate, hypotonia, seizures and marked developmental delay. It was suggested that there may be a specific phenotype associated with this deletion which differs from PWS. Whether this deletion differs from the deletion associated with PWS awaits delineation on a molecular level.
Although Prader-Willi syndrome (PWS) patients usually first present with neonatal hypotonia and feeding difficulty, they later show hyperphagia, obesity and mental retardation. Since deletions of chromosomes 15q11-q13 are noted in most PWS patients cytogenetic analysis allows one to diagnose infants suspected of PWS with a greater certainty. We report on 5 hypotonic infants clinically suspected of PWS in the first 3 months of life, whose diagnosis was confirmed by cytogenetic studies showing monosomy of 15q11-q13. Early diagnosis of PWS can lead to prevention of obesity, but counseling of parents has been difficult. Although there are significant benefits to the early diagnosis of PWS, the cost-effectiveness and practicality of screening all hypotonic infants using high resolution cytogenetic analysis has been addressed systematically.
An infant girl with choanal atresia, athelia, minor anomalies, and mild to moderate mental retardation was born to a woman treated for hyperthyroidism throughout pregnancy with methimazole and propranolol. The patient's defects may be due to methimazole teratogenicity or could represent a previously undescribed syndrome affecting ectodermal structures.
Recently it has been shown that most cases of the Miller-Dieker syndrome (MDS) are caused by deletion 17p13.3. All familial cases have been associated with a balanced reciprocal translocation in a carrier parent and unbalanced translocations in their affected offspring. We report a new case of familial MDS in whom the mother carries a pericentric inversion of chromosome 17. She has had two children with MDS, one of whom was shown to carry a recombinant 17 consisting of dup(17q) and del(17p). The high frequency of familial MDS and its consistent association with balanced chromosomal rearrangements in one of the parents makes it important to do high-resolution chromosome analysis on all patients with MDS and possibly all patients with lissencephaly. Finding a familial balanced rearrangement makes prenatal diagnosis of this condition feasible.
In 1973, Perlman et al described a familial syndrome of bilateral renal hamartomas with or without nephroblastomatosis, macrosomia, islet cell hypertrophy, unusual facies, and early lethality. Two additional sibs were recently reported by Neri et al [1984]. We report on two sibs with polyhydramnios, fetal ascites, and abdominal muscular hypoplasia, visceromegaly, and subsequent development of Wilms tumor in one of them. Delineated features of this syndrome include visceromegaly, macrosomia, renal hamartomas, nephroblastomatosis, cryptorchidism in males, unusual facial appearance, polyhydramnios, fetal ascites, and Wilms tumor but do not include hemihypertrophy, omphalocele or umbilical abnormalities, aniridia, or other conditions known to be associated with Wilms tumor. This condition should be considered primarily in the differential diagnosis of fetal ascites without hydrops and possibly in the differential diagnosis of familial Wilms tumor, polyhydramnios, congenital hepatomegaly, or nephromegaly.
Recently, a new clinically recognizable syndrome resulting from a small interstitial deletion of 17p [del(17)(p11.2p11.2)] was described in ten unrelated patients. We have identified six additional patients with similar cytogenetic and phenotypic abnormalities. Consistent clinical manifestations include 1) brachycephaly with a broad face and nasal bridge, 2) flat midface, 3) short, broad hands, and 4) mental retardation associated with hyperactivity and often self-destructive behavior. The craniofacial and hand anomalies are reminiscent of several craniosynostosis syndromes. Most patients also had growth deficiency and several other (more variable) congenital malformations. Chromosome studies with special attention to 17 should be performed in any patient with a similar phenotype.
We reviewed 225 cases of amyoplasia, and the association of amyoplasia with gastroschisis and with monozygotic twinning was confirmed. In addition, an apparently increased association of bowel atresia and defects in the muscular layer of the trunk wall with amyoplasia was observed. The association of amyoplasia, monozygotic twinning, and these trunk wall defects strongly suggests that the pathogenesis of amyoplasia is linked to some type of vascular compromise.