Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome.

OBJECTIVE: Our purpose was to determine the incidence of all types of chromosome abnormalities (i.e., trisomy 21 and other abnormalities) in women receiving prenatal chromosome analysis after a Down syndrome screen-positive result by maternal serum triple-marker testing (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol analyses). STUDY DESIGN: A total of 11,434 patients between 15.0 and 21.9 weeks' gestation received second-trimester Down syndrome risk evaluation by triple-marker testing. By use of a 1:270 midtrimester Down syndrome risk cutoff value, and after ultrasonographic confirmation of gestational age, 677 patients were screen positive for Down syndrome (corrected screen-positive rate 5.92%). Karyotypes were reviewed for 468 (69%) of these patients who received prenatal chromosome analysis. RESULTS: In addition to 12 cases of Down syndrome, 12 other fetal chromosome abnormalities were found (i.e., 5.13% had a chromosome abnormality of some type). Expressed as a proportion of all patients with a corrected Down syndrome screen-positive result, at least 3.69% had a chromosome abnormality. The overall spectrum of abnormal karyotypes (approximately 50% autosomal trisomy, 25% structural and 25% sex chromosome abnormality) appears to be comparable to that seen in patients undergoing amniocentesis because of advanced maternal age. CONCLUSIONS: As is the case for women of advanced maternal age, preamniocentesis counseling for patients with positive triple-marker testing results should reflect the relatively high probability that an abnormality other than Down syndrome may be identified.

Comparison of high resolution chromosome banding and fluorescence in situ hybridization (FISH) for the laboratory evaluation of Prader-Willi syndrome and Angelman syndrome.

The development of probes containing segments of DNA from chromosome region 15q11-q13 provides the opportunity to confirm the diagnosis of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) by fluorescence in situ hybridization (FISH). We have evaluated FISH studies and high resolution chromosome banding studies in 14 patients referred to confirm or rule out PWS and five patients referred to confirm or rule out AS. In four patients (three from the PWS category and 1 from the AS group) chromosome analysis suggested that a deletion was present but FISH failed to confirm the finding. In one AS group patient, FISH identified a deletion not detectable by high resolution banding. Review of the clinical findings in the discrepant cases suggested that the FISH results were correct and high resolution findings were erroneous. Studies with a chromosome 15 alpha satellite probe (D15Z) on both normal and abnormal individuals suggested that incorrect interpretation of chromosome banding may occasionally be attributable to alpha satellite polymorphism but other variation of 15q11-q13 chromosome bands also contributes to misinterpretation. We conclude that patients who have been reported to have a cytogenetic deletion of 15q11-q13 and who have clinical findings inconsistent with PWS and AS should be re-evaluated by molecular genetic techniques.

Jarcho-Levin syndrome: unusual survival in a classical case.

Spondylothoracic dysostosis, or Jarcho-Levin syndrome, together with spondylocostal dysostosis, constitute a heterogeneous group of rare disorders characterized by short-neck, short-trunk dwarfism and multiple vertebral anomalies at all levels of the vertebral column. The latter include hemivertebrae, fused, hypoplastic, and "butterfly" vertebrae. In most cases of Jarcho-Levin syndrome, the small size of the thorax causes respiratory death in infancy. This report of a Puerto Rican child with spondylothoracic dysostosis and unusually long survival to 11 years exemplifies the nosologic and prognostic difficulties associated with this syndrome.

Analysis of skull anthropometric measurements in patients with neurofibromatosis type-1.

RATIONALE AND OBJECTIVES: The authors studied selected anthropometric measurements of plain postero-anterior and lateral skull roentgenograms to ascertain whether these were useful in distinguishing patients with clinically probable neurofibromatosis type-1 from controls. METHODS: A retrospective review of medical records of patients for whom skull roentgenograms were available was conducted. Patients were assigned to one of three groups: definite neurofibromatosis type-1 (DNF), probable neurofibromatosis type-1 (PNF), and controls. A blinded analysis of 29 measurements, 9 qualitative assessments, and 3 area/volume calculations was performed. RESULTS: There were 58 patients (29 controls, 14 DNF, and 15 PNF). The majority (75%) of all predetermined landmarks could be ascertained in 43 of these subjects. After age and gender were held constant, analysis of covariance showed that both DNF and PNF subjects could be distinguished from controls, but not from each other when comparing the mean: sella turcica height (P < .001), sella turcica depth (P < .005), skull width (P < .001), skull length (P < .002), skull height (P < .003), and skull volume (P < .0001). CONCLUSIONS: Anthropometric analysis of skull roentgenograms coupled with results of clinical examination improves the ability to distinguish between patients with DNF and PNF from controls.

Brief clinical report: a 46,XY phenotypic female with Smith-Lemli-Opitz syndrome.

A phenotypic female infant with Smith-Lemli-Opitz (SLO) syndrome was found to have a 46,XY karyotype. Autopsy showed normal tests for age and normal Wolffian duct structures. The serum testosterone level was unusually high, suggesting that the failure of virilization of the external genitalia in the child might be due to a defect in testosterone conversion to dihydrotestosterone or a lack of end-organ receptors for the same. An additional feature not previously described in association with SLO syndrome was present, which was clinical hypoglycemia with nesidioblastosis.

Calculated risk of chromosomal abnormalities in twin gestations.

Genetic counseling concerning the risks of chromosomal abnormalities in twin gestations can be difficult; the risk of amniocentesis is weighed against that of chromosomal abnormalities in either one or both of the twins. Because most twins are dizygotic (each with a risk a priori of aneuploidy), the chance that one of the fetuses is affected is greater than would be expected for a singleton. Only three possibilities would result in either one or both twin's being affected: 1) dizygotic twins with one fetus affected, 2) dizygotic twins with both fetuses affected, and 3) monozygotic twins with both fetuses affected. Using existing tables of estimated risks of chromosomal abnormalities in singleton gestations and mathematically derived formulas, we created tables defining the age-related risks of chromosomal abnormalities in twin gestations. According to these tables, a patient at 33 years of age with a twin gestation has a risk of Down syndrome in at least one of her twins equivalent to that of a 35-year-old with a singleton. Prenatal genetic testing should be considered for women with twins at a younger age than the traditional 35.

Infant care review committees. The response to federal guidelines.

A 1986 survey of hospitals with neonatal intensive care units and/or 1500 or more births indicated (1) which hospitals had established infant care review committees and (2) what hospital and committee characteristics influenced the functioning of infant care review committees. Of the hospitals surveyed, 51.8% had established infant care review committees. This study provides baseline information on the development of infant care review committees.

Malignant osteoporosis and defective immunoregulation.

The linkage between immune cells and the osteoclast has become partially understood in the laboratory, but the full spectrum of clinical disorders of this relationship remain to be elucidated. We report a 29-month-old girl with recurrent infections and multiple fractures. Immune evaluation showed normal quantitative serum immunoglobulins but absent antibodies to the respiratory viruses and tetanus toxoid and decreased in vitro polyclonal-induced immunoglobulin production. Further analysis in vitro with separated lymphocyte populations showed normal B cell function but markedly increased suppressor T cell activity. The bone evaluation showed diffuse osteopenia on x-ray. Serum calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal for age. Urinary calcium excretion (24 h) was, however, two times normal. An iliac crest biopsy confirmed the presence of extreme osteopenia with normal mineralization and numerous small atypical osteoclasts resorbing the bone. No circulating plasma resorptive activity was demonstrated. Calcitonin therapy markedly diminished the patient's hypercalciuria. We speculate that this patient's increased bone resorption, decreased bone formation, and suppressor activity may be linked by a common pathway involving the abnormal function of immune cells. Since no similar constellation of findings has been previously reported, this case may represent a new congenital disorder: severe osteopenia associated with increased osteoclast activity in association with a defect in T cell immunoregulation.

Autosomal recessive Robinow-like syndrome with anterior chamber cleavage anomalies.

We describe 2 sisters with short stature, mesomelic brachymelia, macrocephaly, hypoplastic genitalia, and anterior chamber cleavage anomalies. Many of their manifestations have been described in individuals with Robinow syndrome; however, the anterior chamber cleavage anomalies seen in both girls, hydrocephalus seen in the younger sister, and apparent autosomal recessive inheritance do not characterize the Robinow syndrome. The syndrome present in these sisters most likely represents a previously undescribed autosomal recessive syndrome.

Screening for fetal Down's syndrome in pregnancy by measuring maternal serum alpha-fetoprotein levels.

Although the risk of Down's syndrome increases with maternal age, women under 35 bear about 80 percent of the infants born with this condition. We prospectively investigated the utility of measuring maternal serum alpha-fetoprotein during the second trimester in women under 35 in order to identify pregnancies in which the fetus was affected with Down's syndrome. Over a two-year period, 34,354 women in this age group were screened. Amniocentesis was offered when the risk of Down's syndrome, calculated as a function of maternal age and maternal serum alpha-fetoprotein concentration adjusted for maternal weight and race, was 1:270 or higher, the risk for a 35-year-old woman. This threshold was exceeded in 1451 women in whom gestational age was confirmed by ultrasound; 9 women in this group had a fetus with the syndrome. In three women whose fetuses had trisomy 18 and one whose fetus had trisomy 13, the calculated risk of Down's syndrome was 1:270 or higher. Thus, among women in whom the risk exceeded our cutoff point, 1 in 161 were found to have a pregnancy in which the fetus was affected with Down's syndrome; the figure was 1 in 112 for all autosomal trisomies. Eighteen pregnancies involving Down's syndrome, three involving trisomy 18, and two involving trisomy 13 were not associated with a calculated risk above the cutoff point. The available data indicate that in our population, using a cutoff for risk at which 5 percent of women under 35 are offered amniocentesis, we will detect one quarter to one third of pregnancies in which the fetus has Down's syndrome.

Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members.

We describe a three-generation family in which five individuals have arteriohepatic dysplasia (Alagille syndrome) with striking differences in the degree of severity. Two sisters presented with neonatal jaundice, peripheral pulmonic stenosis, and characteristic facial appearance including a broad forehead, deep-set eyes, prominent nose, and pointed chin. One died at 5 years of cirrhosis with portal hypertension and the other at 18 months of congestive heart failure. Their asymptomatic 32-year-old mother and 35-year-old maternal aunt have a similar facial appearance, pulmonic stenosis, skeletal anomalies, and bilateral posterior embryotoxon. Neither has evidence of clinical liver disease. The maternal grandfather, who refused evaluation, has a similar appearance, a history of liver disease, and a heart murmur. Extreme intrafamilial variability has not been reported previously and most affected individuals described in the past have followed a benign course. The pattern of severity in this family suggests the possibility of a maternal factor augmenting the clinical expression in affected offspring. The skeletal anomalies and posterior embryotoxon are valuable signs in detecting asymptomatic but affected individuals who are at risk for having offspring with this potentially lethal condition.

Behavioral correlates in the happy puppet syndrome: a characteristic profile?

Nine children with the "happy puppet" syndrome are presented here and 19 previously reported cases are reviewed. A characteristic psychological profile is suggested by the children's "unfocused" activities and inconsistent responsiveness to their surroundings. Behavioral characteristics are atypical for mental age and do not appear to represent unusual seizure equivalents. Recognition of such non-adaptive behavior may be of importance in selecting specific treatment and management techniques to modify the characteristics of this syndrome at an early age.

Interstitial deletion of the short arm of chromosome 7 without craniosynostosis.

Two female infants with apparently identical interstitial deletions at bands p13 to p15 of chromosome 7 are presented. They differ in phenotype. The first infant has failure to thrive, retardation in development, normal head circumference with ridged metopic suture, blepharophimosis, epicanthal folds, mild hypotelorism, small low-set ears, and a bifid right toe. The second infant has a normal weight, length, and head circumference, blepharophimosis, epicanthal folds, widely spaced nipples, enlarged clitoris, and very large hands and feet. The two patients' clinical and karyotypic findings are compared with previous reports of structural abnormalities of the short arm of chromosome 7. Of the three cases in the literature, craniosynostosis was present in the two patients with deletion of band 7p14. Our observations, thus, suggest that deletion of bands 7p13 to 7p15, in contrast to more distal deletions at band 7p2, is not associated with craniosynostosis.

Unusual mosaicism of de novo structural abnormalities and ocular anomalies in a male with 13 trisomy syndrome.

A body with the 13 trisomy syndrome was found to have a unique form of mosaicism in which each of the two cell lines had different structural rearrangements. The predominant cell line was partially trisomic for the distal portion of the long arm of chromosome 13, while the minor cell line was trisomic for all of the long arm of 13. The patient is also unusual because he had congenital glaucoma and was still alive at 10 years.

Unsuspected nutritional rickets.

Based on the presentation and clinical features of four cases of nutritional rickets, it is suggested that particular groups of children, namely vegetarians, children breast-fed for an unusually long time, and black children, are at risk to develop the nutritional deficiencies of vitamin D and calcium that lead to clinical rickets. The diagnoses in these cases were made by fortuitous radiologic examination, even though the children had been receiving regular pediatric supervision, indicating a lack of awareness of the condition. This report is intended to emphasize the reemergence of nutritional rickets and to illustrate the different modes of its clinical presentation.