Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder. Heterozygous point mutations in three genes (NIPBL, SMC3 and SMC1A), encoding components of the sister chromatid cohesion apparatus, are responsible for approximately 50-60% of CdLS cases. Recent studies have revealed a high degree of genomic rearrangements (for example, deletions and duplications) in the human genome, which result in gene copy number variations (CNVs). CNVs have been associated with a wide range of both Mendelian and complex traits including disease phenotypes such as Charcot-Marie-Tooth type 1A, Pelizaeus-Merzbacher, Parkinson, Alzheimer, autism and schizophrenia. Increased versus decreased copy number of the same gene can potentially cause either similar or different clinical features. METHODS AND RESULTS: This study identified duplications on chromosomes 5 or X using genome wide array comparative genomic hybridisation (aCGH). The duplicated regions contain either the NIPBL or the SMC1A genes. Junction sequences analyses revealed the involvement of three genomic rearrangement mechanisms. The patients share some common features including mental retardation, developmental delay, sleep abnormalities, and craniofacial and limb defects. The systems affected are the same as in CdLS, but clinical manifestations are distinct from CdLS; particularly the absence of the CdLS facial gestalt. CONCLUSIONS: The results confirm the notion that duplication CNV of genes can be a common mechanism for human genetic diseases. Defining the clinical consequences for a specific gene dosage alteration represents a new "reverse genomics" trend in medical genetics that is reciprocal to the traditional approach of delineation of the common clinical phenotype preceding the discovery of the genetic aetiology.

Weaver syndrome with neuroblastoma and cardiovascular anomalies.

We report on an infant with Weaver syndrome, neoplasia and cardiovascular anomalies. Stage 4S neuroblastoma underwent spontaneous resolution. Three neoplasms have been reported in Weaver syndrome: another stage 4S neuroblastoma [Muhonen and Menezes, 1990: J Pediatr 116:596-599], an ovarian endodermal sinus tumor [Derry et al., 1999: J Med Genet 36:725-728], and a sacrococcygeal teratoma [Kelly et al., 2000: Am J Med Genet 95:492-495]. No case was associated with cardiovascular anomalies. Our patient had VSD and PDA, and although several other patients with Weaver syndrome have had cardiovascular anomalies, they were shown not to have neoplasia.

Fetal age: methods of estimation and effects of pathology.

Accurate identification of fetal age is important in a wide variety of circumstances. Seventeen anthropometric and radiographic measurements were taken on fetuses between 15 and 42 weeks of gestational age, both with and without pathologic conditions. A full evaluation including radiographic, karyotypic, gross anatomic, and histologic examination of the fetus and placenta identified 72 individuals as nondysmorphic with no signs of chronic uterovascular insufficiency. These specimens served as the control group. Based on least-squares regressions of this group, age-estimation equations were calculated for all variables. Six models were adequately described by linear equations; the remaining 11 required a quadratic term. Based on standard error of the estimate (S(y:x)), skeletal measures proved the most accurate age estimators. Pathologic conditions were shown to have an influence on age estimation indicated by high levels of inaccuracy and, in some instances, significant bias.

Histiocytoid cardiomyopathy: three new cases and a review of the literature.

Histiocytoid cardiomyopathy (HC), a rare arrhythmogenic disorder, presents as difficult-to-control arrhythmias or sudden death in infants and children, particularly girls. Three cases are described with autopsy findings. In two cases, yellow-tan nodules were grossly visible in the myocardium; in the third case, no gross lesions were identified. Microscopic examination in all three cases revealed multiple, scattered clusters of histiocytoid myocytes which on ultrastructural examination were filled with abnormal mitochondria, scattered lipid droplets, and scanty myofibrils. These pathologic findings are similar to those previously described. The pathogenesis of this entity remains controversial. It was recently proposed that this disorder is X-linked dominant with the associated gene located in the region of Xp22.

Pattern and process of growth of the abnormal human fetus.

Identifying patterns of fetal growth alteration benefits both the clinician and the researcher. Twenty-four measurements in three variable sets (anthropometric measures, organ weights, and long-bone measures from radiographs) were taken on fetuses both with and without pathological conditions that are suspected to result in growth alteration. In addition, radiographs of each case were examined for the presence or absence of ossification centers. Based on least-squares regressions of the normal group, we calculated standardized residuals for the affected group to identify patterns of growth alteration. A large sample of fetuses between 15 and 42 weeks of gestational age with a variety of pathological conditions is described and evaluated for growth alterations. Symmetric and asymmetric growth alteration was detected in a small part of the sample and was predominantly isolated to fetuses in the late third trimester. Although patterns of growth alteration have been suggested as a means for noninvasive diagnoses of syndromes (such as trisomy 21), no consistent patterns are discernible in the current group. The sample provides a unique opportunity to evaluate fetal growth in terms of the interaction between genetic and environmental influences.

Coincident DiGeorge anomaly and renal agenesis and its relation to maternal diabetes.

We describe 2 cases of DiGeorge anomaly with bilateral renal agenesis-one, who also had hemivertebrae, in an infant of an insulin-dependent diabetic mother (IDDM). In a review we identified 2 other instances of this combination, both in IDDMs. The currently accepted notion that DiGeorge anomaly and renal agenesis are developmental field defects, coupled with their coincidence in IDDM, suggests that this combination is an association.

Standardized residuals as a means for detection of growth alteration in the pathologic human fetus.

This paper introduces and discusses the use of standardized residuals as a technique for comparing the growth of normal and pathologic human fetuses. Anthropometric measures, radiographic measures, and organ weights were regressed on known gestational age of second- and third-trimester fetuses. Standardized residuals were calculated for a group of potentially growth-impaired fetuses. Use of residuals aids in identification of patterns of growth alteration in specific pathologies. Most important, studying the response of developing organ systems to a variety of insults may elucidate mechanisms of growth regulation in the fetus. We emphasize the special quality of the multivariate measures of the core sample of fetuses from the Akron Children's Hospital collection.

Adverse outcome in pregnancy following amniotic fluid isolation of Ureaplasma urealyticum.

Infections in pregnancy with Ureaplasma urealyticum have been associated with a wide range of adverse outcomes, such as early abortion, stillbirth, prematurity, and neonatal morbidity and mortality. Causality has been difficult to demonstrate secondary to the high prevalence of asymptomatic lower genital tract (LGT) colonization and culture data from inaccessible or potentially contaminated sites. Between 1985 and 1989, 2461 second-trimester genetic amniocenteses were evaluated at the cytogenetics section of the Children's Hospital Medical Center of Akron. All were cultured for the genital mycoplasmas: Mycoplasma hominis and Ureaplasma urealyticum. A total of nine patients were positive, all for Ureaplasma urealyticum, with one patient excluded because of subsequent therapeutic abortion. In addition, complete follow-up data, such as indication for amniocentesis, serum alpha-fetoprotein levels, gestational age at parturition, and outcome of pregnancy, were available on 86 Ureaplasma-negative (U-) patients during an approximate 2-year span within the time-frame of the study. This was in part due to physician response to a questionnaire sent after amniocentesis. Of the eight positive cultures, 100 per cent were associated with an adverse outcome, defined as fetal loss or premature delivery. This was significant compared with the U- group (p less than 0.001) with a more than eight times greater risk of adverse outcome. Six (75 per cent) resulted in spontaneous miscarriage within 4 weeks of amniocentesis and at less than 21 weeks' gestation. Two (25 per cent) delivered prematurely, with one (12.5 per cent) neonatal death at 24+ weeks. Histological examination of all eight placentae and the seven fetuses revealed a 100 per cent incidence of chorioamnionitis and pneumonia, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Placental emboli from a fetus papyraceous.

A syndrome in monozygotic twins that consists of a macerated twin fetus (fetus papyraceous) and a live-born twin with various anatomical defects has been described. The etiology is thought to be placental transfer of emboli or thromboplastic material through vascular shunts. Thromboplastic material precipitates disseminated intravascular coagulation (DIC) in the fetus, with a resultant hypercoagulable state due to relative fetal antithrombin III deficiency. Two cases of this syndrome will be discussed. The case of a live-born twin with intestinal atresia, who developed in utero with a fetus papyraceous, is reported. Emboli were demonstrated in vascular shunts of the diamniotic-monochorionic placenta. The hypothesis of intestinal atresia as a result of a vascular accident is reviewed. Another case involving a live-born twin with congenital skin defects, who developed in utero with a fetus papyraceous, is also reported. The skin defects were a congenital disruption from fetal DIC with resultant hypercoagulable state. Several other manifestations of the placental emboli syndrome will be discussed and the vascular etiology of the disruptions explained.

Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings.

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Agenesis of the cloacal membrane. A probable teratogenic anomaly.

Five infants with a rare and distinct malformation complex were encountered in a single community within a 7 1/2-month period. Only seven previous reports of this condition were found in the 54-year period between 1926 and 1980. The principal findings in the previously published cases were absence of external genitalia, urinary, genital, and anal orifices, and persistence of the cloaca. This report documents the occurrence of the syndrome in a temporal and regional cluster. Detailed morphologic evaluation of each infant provides the basis for a theory of embryogenesis of the complex, and preliminary data suggest a teratogenic cause. Embryonic exposure to doxylamine succinate within the first 50 days of the pregnancy was certain in three and was probable in two of the five pregnancies.

Screening for the Tay-Sachs carrier: a compromise program.

A modified program designed to screen for the Tay-Sachs carrier is presented in which testing is limited to one or both partners, as needed, in an Ashkenazi Jewish (Jews of central and eastern Europe ancestry) mating when there is a definite commitment toward having a child, or in the early stages of the pregnancy. Testing of unmarried individuals is discouraged. The approach maximizes individualization of both the medical and laboratory aspects of the program and promotes a positive and beneficial relationship between physician and clinical chemist. There is little involvement of the lay population or clergy, and no special sources of funding are required. Whereas most mass screening programs for the Tay-Sachs carrier have attempted to educate large numbers of the lay public to bring pressure upon the medical community, we have reversed this approach and taken the much easier course of educating small numbers of physicians to better care for their patients. The program has been used successfully in a moderate-size city in which communication lines between laboratory and physician are easily established.

Apparent normal leukocyte acid maltase activity in glycogen storage disease type II (Pompe's disease).

We present a case of glycogen storage disease type II (Pompe's disease) with the classical clinical presentation and characteristic electrocardiographic changes of this disorder. An acid maltase (EC 3.2.1.20) determination in the peripheral leukocytes revealed normal activity; however, acid maltase activity was completely absent in a pre-mortem skeletal muscle biopsy. Post-mortem studies showed acid maltase activity to be absent in all tissues examined, including cultured skin fibroblasts. Massive glycogen deposition corresponded to the localization of the enzymic deficiency, except in the brain, where glycogen content was within the normal range. The acid maltase activity in mixed peripheral leukocytes was due to an isoenzyme of acid maltase in the granulocyte series. Antenatal diagnosis was accurate in a subsequent pregnancy, but discordance between enzyme activity in different cell lines in an individual with a genetic disease is a conceivable source of error in both prenatal and postnatal diagnoses.

Internal vascular access for hemodialysis in children weighing less than fifteen kilograms.

An arteroarterial femoral graft using expanded polytetrafluoroethylene is described which has been successfully for vascular access in young children having small peripheral vessels. This graft allows high flow and favorable patency for dialysis without the complications of arteriovenous shunting or the risks associated with an external hemodialysis device. This graft has been used successfully for outpatient dialysis in children weighing as little as 9 kg and may be a useful adjunct in long-term dialysis of patients for whom more conventional means of vascular access are not acceptable.

Discussion and management of late failures in reconstructive procedures involving the abdominal aorta.

Review of fifty-eight late failures of 326 procedures performed for revascularization of the abdominal aorta over the past six years showed a low overall operative mortality of 9 per cent. Secondary vascular procedures directed at the aorta itself or at its graft substitute proved more effective in relieving symptoms and restoring flow than did secondary procedures directed at more distal problems in the lower extremities. The aortofemoral graft in conjunction with profundaplasty proved to be the most effective means of restoring flow to the lower extermity after graft occlusion in a previous aortoiliac or aortofemoral graft.