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Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted., (© 2013 Wiley Periodicals, Inc.)

Neu-Laxova syndrome is a rare autosomal recessive disorder characterized by severe intra-uterine growth restriction, extreme microcephaly, marked edema with skin restriction, ichthyosis, craniofacial anomalies, limb deformities, and a spectrum of central nervous system malformations. Less than 70 cases have been described since the first report in 1971. To this day the etiology and genetic basis remains unknown. Consanguinity has been reported. Some authors have postulated the syndrome to be a form of neuro-ectodermal dysplasia, while others suggest that it is a malformation syndrome secondary to severe skin restriction. Although the outcome of this syndrome is lethal, a single case of longer survival (6 months) has been reported. The majority of cases are stillborn or die shortly after birth. Thus, it is clear that Neu-Laxova exhibits a spectrum of disease, with varying degrees of phenotypic expression. We are presenting three new cases of Neu-Laxova syndrome; two were stillbirths and one lived for eleven weeks. Our microscopic and post-mortem findings in these three cases display the vast spectrum of this rare syndrome.

Objective: To determine the feasibility of using calculated nucleated red blood cell (RBC) counts from histologic placental slides to predict newborn nucleated RBC counts., Methods: This retrospective study compared absolute nucleated RBC counts from 24 newborns, diagnosed with fetal distress in labor, with counts calculated from their histologic placental slides. A simple linear regression model was tested with newborn nucleated RBC counts as the dependent variable and calculated placental nucleated RBC counts as the independent variable., Results: The mean +/- standard deviation newborn nucleated RBC count was 4.81 x 10(9) +/- 5.46 x 10(9)/L compared with 1.37 x 10(9) +/- 1.78 x 10(9)/L calculated from placental sections. These data were normalized by logarithmic transformation. A significant linear regression was obtained, r(2) = 0.74, P <.001. The prediction equation obtained was natural logarithm (newborn nucleated RBC count) is equal to 1.002 x natural logarithm (placental nucleated RBC count) + 1.173., Conclusion: It is feasible to calculate nucleated RBC counts from histologic slides of the placenta that are predictive of newborn nucleated RBC counts. Further work on more homogeneous groups of subjects is necessary to increase the precision of the method. The placenta could serve as a surrogate source for newborn whole blood nucleated RBC counts around the time of birth.

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., (Copyright 2001 Wiley-Liss. Inc.)

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., (Copyright 2000 Wiley-Liss, Inc.)

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.

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.

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.

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.

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)

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.

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.

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.

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.

A new case of the cerebro-hepato-renal syndrome is being reported. The neuropathologic changes consisted of developmental abnormalities of cerebral and cerebellar cortex and of the inferior olives. In addition, there were metabolic changes in the central nervous system, indicated by an accumulation of lipid within histiocytes of free in gray and white matter, deficiency in myelination and gliosis of the white matter, and marked proliferation of protoplasmic astrocytes in the gray matter. A unique feature of this case was the presence of numerous clusters of lipid-filled macrophages and occasional cholesterol crystals in the molecular layer of the cerebellum. The histochemical reactions and ultrastructural appearances of the lipid deposits are suggestive of accumulation of several different types of lipids.

A postoperative left ventricular pseudoaneurysm is reported in a seven-year-old after closure of an atrial septal defect and repair of partial anomalous venous drainage. A discussion of the etiology and clinical presentation of post operative aneurysms are presented. Cardiac aneurysms of both the true and false variety have been commonly reported following myocardial infarction, blunt and penetrating trauma and infectious processes such as tuberculosis and syphilis. As the frequency of open heart correction of congenital and acquired lesions increases, the incidence of post-operative pseudoaneurysm of heart can also be expected to increase. The diagnosis of this entity in the postoperative period is often difficult and may lead to delay in detection and correction. The clinical presentation and subsequent course of false anurysm differs from the more common true aneurysm to an extent which should be recognized by both cardiologists and cardiac surgeons. A case of left ventricular pseudoaneurysm after open heart repair of an atrial septal defect is reported and a clinical profile which may be helpful in the earlier recognition of this entity is presented.

Six new cases of the III-IV pharyngeal pouch syndrome were encountered at autopsy among 897 consecutive pediatric autoposies. All occurred in patients with conotruncal cardiac anomalies. The anatomic characteristics of the heart defect suggest a possible mechanism for the pathogenesis of this developmental anomaly. It is postulated that premature involution of the thyroidea ima artery, which is the principal embryonic blood source to the 3rd and 4th pharyngeal pouches and the ultimobranchial body, may be the critical event in the embryogenesis of the syndrome. Hemodynamic alterations in the course of anomalous morphogenesis of conotruncal anomalies may favor premature involution of certain vessels including the left 4th aortic arch and the thyroidea ima. Deficiencies of thymus, parathyroid glands and ultimobranchial tissue ("C" cells) may be the consequence of vascular deprivation during embryogenesis. These cases are discussed with regard to the proposed mechanism of pathogenesis and the influence of varying quantities of thymus upon peripheral lymphoid tissue. Both embryologic and clinical data support the possibility of a deficiency of ultimobranchial tissue. The range of minor and inconstant anomalies seen in patients with this syndrome is presented.

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.