Spectrum Of Congenital Anomalies Research Articles

Disruption of chromodomain helicase DNA binding protein 2 (CHD2) causes scoliosis

Herein we characterize an apparently balanced de novo translocation, t(X;15)(p22.2;q26.1)dn, in a female patient with scoliosis, hirsutism, learning problems, and developmental delay (DGAP025). Other clinical findings include a high-arched palate, 2-3 syndactyly of the toes, and mildly elevated serum testosterone. No known or predicted genes are disrupted by the Xp22.2 breakpoint. The 15q26.1 breakpoint disrupts chromodomain helicase DNA binding protein 2 (CHD2). Another member of the chromatin-remodeling gene family, CHD7, has been associated with a defined constellation of congenital anomalies known as coloboma, heart anomaly, choanal atresia, mental retardation, genital and ear anomalies syndrome (CHARGE) and idiopathic scoliosis. Monosomy of 15q26 also has been associated with a spectrum of congenital abnormalities and growth retardation that overlaps with those of DGAP025. To provide a biological correlate, we characterized a mutant mouse model with Chd2 disruption that is associated with embryonic and perinatal lethality. Expression analysis indicated that Chd2 is expressed in the heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development. Chd2(+/m) mice showed pronounced lordokyphosis, reduced body fat, postnatal runting, and growth retardation. These data suggest that haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and possibly features similar to CHARGE syndrome.

Rubéole et grossesse

Rubella usually is a mild disease with, however, serious consequences such as foetal death and a spectrum of birth defects, known as the congenital rubella syndrome. This syndrome may occur as a result of intrauterine infection, particularly during the first 4 months of pregnancy. The syndrome may affect multiple organ systems and common anomalies include cataract, deafness, congenital heart disease and mental retardation. During pregnancy, rubella serology is used to determine the immune status of the patient but it also allows diagnosis of primary infection. This diagnosis is essentially based on the detection of rubella-specific IgM but, if IgM antibody is always detected in recent primary infection, it can also be detected in other situations. Measurement of IgG avidity may help dating rubella. When primary rubella infection occurs during the first 4 months of pregnancy, prenatal diagnosis of foetal infection can be proposed. This diagnosis is based either on the detection of IgM antibody in foetal blood or on the detection of viral genome in amniotic fluid. Post-natal diagnosis of congenital infection is reliably performed by detecting specific-IgM antibody. In fact, if immunization programmes were thoroughly applied, congenital rubella should be eradicated in France since the RA 27/3 vaccine is very efficient and safe.

Immunologic Aspects of DiGeorge Syndrome

After completing this article, readers should be able to: 1. Describe the immune defects seen in DiGeorge syndrome. 2. Review recommended immune testing and immune follow-up in patients with DiGeorge syndrome. 3. Review the indications for screening for DiGeorge syndrome. 4. Describe the variety of other congenital defects that can be associated with DiGeorge syndrome. 5. Review recommended anticipatory guidance for patients with DiGeorge syndrome. DiGeorge syndrome (DGS) is a contiguous field defect of the third and fourth pharyngeal pouches, most often due to a hemizygous microdeletion in the chromosome 22q11.2 region. Although classically defined as the triad of conotruncal cardiac anomaly, thymic hypoplasia, and hypocalcemia, the syndrome encompasses a broad spectrum of congenital defects that have varying degrees of severity. Speech delay and dysmorphic features are two of the most common and consistent findings. It shares phenotypic features with velocardiofacial syndrome, conotruncal anomaly face syndrome, Opitz-G syndrome, CHARGE syndrome, and cranio-cerebello-cardiac dysplasia syndrome. In some patients, these other syndromes are the result of the same 22q11.2 microdeletion and may represent variation in the presentation of DGS rather than separate syndromes. This review focuses on the immune defects seen in the patient population with hemizygous 22q11.2 microdeletion. The underlying defect of DGS is due to inadequate contribution of neural crest tissue to the third and fourth pharyngeal pouches that contribute to facial, cardiac, thymic, and parathyroid tissues. DGS can be caused by either genetic defects or environmental exposures in utero. Fetal exposure to ethanol, retinoids, and maternal diabetes can result in a clinical DGS phenotype. In more than 90% of patients, however, the syndrome results from hemizygosity at the chromosome 22q11.2 region (del22q11.2). In a small subset of patients, a deletion of 10p13 has been identified as the causative factor, as has monosomy 18q21.33 and trisomy 18. No genetic or environmental cause can be identified …

Notochord-gut failure of detachment and intestinal atresia.

A spectrum of congenital anomalies have been described in an adriamycin-treated model with common features to the human pattern. Multiple intestinal atresias was part of this spectrum occurring in 25% of full-term experimental rat fetuses. The aim of this study was to examine the underlying developmental mechanism that results in intestinal atresia. Virgin timed-pregnant Sprague-Dawley rats were injected with Adriamycin i.p. at a dose of 2 mg/kg on days 6-9 of gestation. Embryos were removed on different gestational days during organogenesis and serial transverse histologic sections were examined and compared with control specimens. In experimental embryos, hindgut atresia was seen in day 12 embryos. Attachment of the intestine with the notochord was obvious observation resulting in abnormal position of the intestine. In some specimens the atretic intestine was splitting the dorsal aorta or even located behind the dorsal aorta. It is concluded that in the adriamycin-animal model, notochord-intestinal failure of detachment resulted in intestinal atresia during the beginning of organogenesis period. The possible underlying mechanisms are pinching of some endodermal cells as well as interference with normal intestinal circulation resulting in ischemic necrosis.

Caudal dysgenesis in Islet-1 transgenic mice.

Maternal diabetes during pregnancy is responsible for the occurrence of diabetic embryopathy, a spectrum of birth defects that includes heart abnormalities, neural tube defects, and caudal dysgenesis syndromes. Here, we report that mice transgenic for the homeodomain transcription factor Isl-1 develop profound caudal growth defects that resemble human sacral/caudal agenesis. Isl-1 is normally expressed in the pancreas and is required for pancreas development and endocrine cell differentiation. Aberrant regulation of this pancreatic transcription factor causes increased mesodermal cell death, and the severity of defects is dependent on transgene dosage. Together with the finding that mutation of the pancreatic transcription factor HLXB9 causes sacral agenesis, our results implicate pancreatic transcription factors in the pathogenesis of birth defects associated with diabetes.

Anesthesia and airway management of pediatric patients with Smith-Lemli-Opitz syndrome.

SMITH-LEMLI-OPITZ syndrome (SLOS) is an autosomal recessive disorder with an incidence of between 1 in 26,500 pregnancies in Canada and 1 in 50,000 pregnancies in the United States. The syndrome results from an inborn error of cholesterol biosynthesis involving a deficiency of 3β-hydroxysterol Δ 7 -reductase, the enzyme that catalyzes the reduction of 7-dehydrocholesterol to cholesterol. As a result, patients with SLOS have abnormal embryonic development, high plasma concentrations of 7-dehydrocholesterol, and usually decreased plasma concentrations of cholesterol. This biochemical defect is associated with a broad spectrum of clinical manifestations with potentially profound anesthetic implications. Patients with SLOS cans have severe growth failure, congenital anomalies affecting most organ systems, early death, developmental delay, and self-injurious and ritualistic behavior. Of special concern to anesthesiologists are the typical dysmorphic facial features, including micrognathia, cleft palate, and a small and abnormally hard tongue, which can present a challenge in airway management of patients with SLOS. The broad spectrum of congenital anomalies and potential increase in lifespan with dietary cholesterol replacement therapy make it very likely that diagnostic and therapeutic interventions requirign anesthesia will be needed in patients with SLOS. However, since the discovery of the biochemical defect in SLOS, little has been reported on the anesthetic management of these patients. In this report, we describe the administration of 20 anesthetics in 14 patients with confirmed biochemical diagnosis of SLOS. Our focus was on airway management, and because of previous reports of difficult intubations in some of our patients, we chose to use fiberoptic laryngoscopy as the initial technique to achieve tracheal intubation.

Birth defects in children with newborn encephalopathy.

This study was designed to investigate birth defects found in association with newborn encephalopathy. All possible birth defects were ascertained in a population-based study of 276 term infants with moderate or severe encephalopathy and 564 unmatched term control infants. A strong association between birth defects and newborn encephalopathy was found with defects affecting 27.5% of children with encephalopathy and 4.3% of control children (odds ratio 8.55; 95% confidence interval 5.25 to 13.91;p<0.001). In 11.8% of infants with a birth defect the defect was not diagnosed until after the newborn period, illustrating one of the difficulties in attempting to exclude infants with birth defects from studies of newborn encephalopathy. The majority of defects (89%) were not specific anomalies of the CNS. In 36.8% of children with encephalopthy who had a birth defect, the defect was considered to be the probable cause of the encephalopathy. Infants with birth defects who had encephalopathy had a poorer prognosis than those without: they were twice as likely to die by the age of 2 years and three times more likely to have cerebral palsy. This study catalogues the spectrum of birth defects associated with newborn encephalopathy and illustrates the importance of their inclusion when investigating both the aetiology and outcome of this condition.

Misoprostol and congenital anomalies

Purpose- To evaluate the risk of having a baby with congenital anomalies in mothers who used misoprostol during pregnancy.Methods- Hospital-based case - control study from Hospital Chateaubriand, Fortaleza, Brasil. Cases were 37 babies weighing less than 1500 g with congenital anomalies of various types, and the comparison group included 387 infants also weighing less than 1500 g, and without congenital anomalies.Results- The multivariate odds ratio of having a baby with congenital anomalies was 2.4 (95% confidence interval 1.0 - 6.2) in mothers who reported having used misoprostol compared with those who did not.Conclusions- Misoprostol use during pregnancy might be related to a broad spectrum of congenital anomalies in infants. Copyright (c) 2000 John Wiley & Sons, Ltd.

Spectrum of Birth Defects in Children with Laterality Disorders

Spectrum of Birth Defects in Children with Laterality Disorders

Major birth defects in infants with birth weight 501 to 1500 grams † 367

Birth defects (BD) are the leading cause of infant mortality in the United States. We analyzed data from the Vermont Oxford Network from 1994 and 1995 to determine the spectrum of serious BD and their impact on mortality and hospital days in infants with a birth weight of 501to 1500 grams. This Database includes infants 501to 1500 grams born at or referred to participating hospitals within 28 days of birth. BD were reported if they belonged to a list of 40 pre-defined major BD or if they were considered lethal or life-threatening. The length of stay (LOS) was the sum of the stay at all hospitals before the first discharge home.

Prenatal irradiation: a major concern for the developing brain

Irradiation of the mammalian foetus produces a broad spectrum of congenital abnormalities, growth retardations, developmental delays, and functional deficits, depending upon the dose and the specific gestational phase of irradiation. The developing brain is particularly susceptible to production of deleterious effects, with decreased brain size, behavioural alterations, and mental retardation having been documented. Supplementing the limited human data, rodent models have been extensively used to investigate the specific processes by which relatively low doses, with correspondingly minor cellular damage to the developing neocortex, can produce dramatic postnatal consequences in brain structure and function. The effects of a variety of physical (dose, linear energy transfer, dose rate, fractionation) and biological (species, strain, gestational age, time course post-irradiation) parameters have been examined in an attempt to provide much needed information on such critical aspects as dose response, threshold doses for effect, and extrapolation to human risk estimates. Various acute cellular responses (e.g. appearance of pyknotic cells and macrophages) observed in the developing neocortex 0-24 h after in utero irradiation can be associated with postnatal effects. Moreover, it is possible to correlate thinning of specific layers of the cerebral cortex with specific behavioural aberrations, allowing prediction of brain structural changes from functional alterations, and vice versa. Thus, it is possible to speculate as to the mechanisms and targets for extremely sensitive, radiation-induced cellular damage in the developing foetal brain, that will interfere with the orderly and precisely programmed development of the mammalian brain, leading finally to postnatal expression as delays in growth and development, perturbations in behaviour, and alterations in brain structure.

The frequency and spectrum of congenital anomalies in natural family planning users in South America: no increase in a case-control study. NFP-ECLAMC Group. Natural Family Planning. Latin-American Collaborative Study of Congenital Malformations.

Users of natural family planning (NFP) practice periodic abstinence, leading many to reason that such couples should show increased anomalies in offspring as a result of fertilization involving aging gametes. In an effort to complement our NFP cohort study, we currently conducted a case-control study in the same region (South America) in which the largest number of cases have been recruited for our cohort NFP study. During 1992-94, 5324 case-control pairs of mothers were interviewed during the immediate postpartum period in 18 maternity hospitals participating in the Latin-American Collaborative Study of Congenital Malformations: ECLAMC (Spanish acronym for Latin-American Collaborative Study of Congenital Malformations). Natural family planning (NFP) usage was recorded in 6% of mothers in the ECLAMC sample studied (n = 10,648). Overall, no significant differences in frequency of NFP usage were observed between malformed cases (349/5324 = 6.6%) and normal controls (303/5324 = 5.7%) (chi 2 = 3.3; df = 1; p > 0.05). No significant differences in sex ratios were observed between children of NFP user and non-user mothers. Of special interest is the lack of association between NFP and Down syndrome, the sentinel phenotype for the hypothesis of delayed fertilization (aging gametes).

Spectrum of congenital anomalies associated with biliary atresia.

Several congenital anomalies have been reported in association with biliary atresia. We have analysed the type and frequency of anomalies observed over a 10-year period in consecutive patients operated for extrahepatic biliary atresia at our institution. Of the 107 infants who underwent a laparotomy and surgical correction of biliary atresia, 9 (8.4%) showed significant associated anomalies. Among them, 5 (55.5%) had splenic malformations, 6 (66.6%) had digestive anomalies in the form of malrotation, Meckel's diverticulum and jejunal atresia. One patient had the classical polysplenia syndrome. Our follow-up period was limited (i.e. 5 months) during which time 3 of the 9 (33.3%) patients with associated anomalies became jaundice-free. A higher incidence of malformations found in association with biliary atresia supports the congenital theory and a more thorough search for these anomalies is recommended.

Brown's syndrome associated with Smith-Magenis syndrome: Case report

Brown's syndrome is generally an isolated clinical condition. The authors observed a girl with a right Brown's syndrome and a rare condition due to an interstitial deletion of chromosome 17, known as Smith-Magenis syndrome. A wide spectrum of congenital disorders have been reported in Smith-Magenis syndrome, but never Brown's syndrome.

Congenital defects of the limbs in stillbirths: Data from a population‐based study

We analyzed limb deficiencies occurring in stillbirths with congenital anomalies registered in the Health Surveillance Registry of British Columbia between the years 1964 and 1984. Thirty stillborn infants presenting with various defects of the limbs were found during this time, giving an incidence of 39.52 in 10,000 stillbirths (1:253). This incidence is significantly higher than the incidence among liveborn individuals in the Province (5.97 in 10,000 livebirths or 1:1,842). Most cases involved the upper limbs, and most frequently the radius. Additional anomalies were present in 77% of cases, compared to 48% in liveborns. The study of stillbirths with congenital anomalies provides important information regarding the spectrum of birth defects seen in this group. This may be of relevance because of improved survival possibilities due to advances in perinatal care.

What Can Be Learned From Cordocentesis?

Cordocentesis is a well-accepted procedure that is widely practiced by experienced perinatologists. Its facile and safe access to the fetal circulation has broadened the spectrum of congenital disorders diagnosed prenatally. Some fetal disease states can now be identified and treated earlier, directly, more quickly, and more effectively than before, resulting in improved patient care. Although cordocentesis has been embraced by the perinatal community, it is, by definition, a technique of obtaining a fetal blood sample. A prerequisite for the procedure to exert its full impact on perinatal care is a highly capable clinical laboratory. The facility must be aware of the commonly requested fetal serologic, hematologic, and serum chemistry studies, as well as their normal values. Efforts must be made to perform fetal blood studies rapidly and reliably on small specimens. Laboratory personnel should be familiar with the indications and pitfalls of these tests and those that are best referred to a specialty laboratory. A general understanding of the perinatologist's needs and concerns will lead to a cooperative working relationship between clinician and laboratory. In this manner, we will truly discover what can be learned from cordocentesis.

7p deletion syndrome: an adult with mild manifestations.

Deletion of 7p results in a wide spectrum of congenital abnormalities and minor facial and hand anomalies, often including craniosynostosis. We report on the oldest recognized patient with this disorder, a 24-year-old woman with an interstitial deletion from p15.3-p21.2 or p21.3. The manifestations in this patient are milder than those of previously described patients, and include borderline mental retardation, short stature, minor facial anomalies, and several skeletal changes. The absence of craniosynostosis in this patient is noteworthy, given previous suggestions that there is a specific locus for this finding in the 7p region. Twelve cases of 7p deletion, in which the missing segment overlaps that of the current case, are reviewed. This case delineates a broader spectrum for patients with 7p deletion syndrome.

Cilioretinal Arteries in Conjunction with a Pit of the Optic Disc

Cilioretinal arteries were noted to accompany pits of the optic disc in 16 of 25 cases (64%). Fourteen of the 16 cases were found to have 2 cilioretinal arteries (86%). The cilioretinal arteries were directly related to the pit of the disc and emerged either from the bottom or the margin of the pit in a proportion of 86%. This finding reinforces the assumption that the optic disc pit belongs to the same spectrum of congenital anomalies which also includes optic disc coloboma, megalopapilla and morning glory syndrome. A fluorescein angiography study showed hyperfluorescence of the pit in 12/16 cases and in particular in all the cases in which both cilioretinal arteries emerged from the pit. Hypofluorescence was noted in 7/9 cases in which the pit was not associated with cilioretinal arteries. Our findings could support the view that hyperfluorescence of the pit, which is not a constant phenomenon, mostly depends on the presence of cilioretinal arteries emerging from the pit.

Morphogenesis and Malformations of the Skin NICHD/NIADDK Research Workshop

Developmentally caused skin malformations constitute a spectrum of birth defects, some of which can be recognized prenatally by morphologic or biochemical means. The number of prenatally diagnosable skin diseases could be greatly expanded with an increased understanding of the molecular and cellular bases of skin development and the mechanisms that result in the generation of skin defects. The National Institute of Child Health and Human Development and the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases, therefore, sponsored a workshop that recommended basic biologic studies combined with clinical investigations of normal and abnormal cutaneous development set forth in this article. Investigations resulting from these research recommendations are intended to contribute to the knowledge that should aid in the prevention of developmentally caused skin deformities.

Comparative Teratogenic Activity of Cancer Chemopreventive Retinoidal Benzoic Acid Congeners (Arotinoids)23

The benzoic acid derivatives of retinoic acid, often referred to as arotinoids, are synthetic retinoids that possess some of the properties of vitamin A. In general, these retinoids have more favorable therapeutic ratios, based on acute toxicity in adults, than all-trans-retinoic acid in cancer chemoprevention. In the present study, a single dose of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoic acid (Ro 13-7410; arotinoic acid), ethyl-(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoate (Ro 13-6298; arotinoid ethyl ester), (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]phenylmethanol (Ro 13-8320; arotinoic methanol), or (E)-1,2,3,4-tetrahydro-1,1,4, 4-tetramethyl-6-[1-(4-methylphenyl)-1-propen-2-yl]naphthalene (Ro 13-9272; methyl arotinoid) was administered to pregnant Syrian golden hamsters during the early primitive streak stage of gestation. A significant increase in the numbers of litters containing one or more malformed offspring occurred at all doses of each retinoid studied. The types of malformations induced by oral arotinoid treatment were essentially identical to those found after maternal treatment with all-trans-retinoic acid or other teratogenic retinoids during the same gestational age. The results indicate that the alcohol congener was approximately 400 times more potent on a milligram per kilogram basis than all-trans-retinoic acid as a teratogen, and it was 70 times as embryolethal as all-trans-retinoic acid. The ethyl ester congener was 132 times, and the free acid 123 times, as embryolethal as all-trans-retinoic acid. On a molar basis, the arotinoic acid was at least 375 times as teratogenic as all-trans-retinoic acid and at least 140 times as teratogenic as etretinate in hamsters. Because the dose-response curves for arotinoids were significantly parallel to that for all-trans-retinoic acid, and because the spectrum of congenital defects induced by arotinoids was identical to that induced by all-trans-retinoic acid and other teratogenic retinoids, the mechanism of embryopathic action of these conformationally restricted retinoids was concluded to be similar to that of all-trans-retinoic acid.