Jarcho-Levin syndrome presenting with diaphragmatic hernia.

Jarcho-Levin syndrome (spondylothoracic or spondylocostal dysostosis) is an eponym that is used to define individuals with a short neck, short trunk, and short stature and multiple vertebral anomalies. The prognosis is directly related to respiratory complications. Reported findings associated with Jarcho-Levin syndrome include congenital heart defects, abdominal wall malformations, genitourinary malformations, upper limb anomalies, and neural tube defects. We report on a 6-day-old girl who presented with an incomplete form of Jarcho-Levin syndrome with late-presenting congenital diaphragmatic hernia and congenital heart disease.     

Segmentation anomalies of vertebrae and ribs with other abnormalities of blastogenesis: syndromes or associations?

On the basis of two recently studied human fetuses and the historical records and remnant 19th century skeletons in the Museum Vrolik in Amsterdam, we have begun an analysis of an unusual form of somite dysgenesis. This disorder includes vertebral and costal segmentation defects with or without (distal) limb malformation and deformities, anogenital anomalies, unusual colonic atresia, abdominal wall and diaphragmatic defect, Central nervous system abnormality with large head, and severe neurohypotrophic lower limb deformities. This study suggests the existence of an axial vertebral/costal dysgenesis complex with apparently or nearly normal number of cervical vertebrae. There also is some overlap with lumbosacral agenesis but different from the autosomal recessive entities Jarcho-Levin syndrome or spondylocostal dysostosis. To date, no associated heart defects have been noted.     

Spina bifida and other neural tube defects

NTDs, resulting from failure of the neural tube to close during the fourth week of embryogenesis, are the most common severely disabling birth defects in the United States, with a frequency of approximately 1 of every 2000 births. Neural tube malformations involving the spinal cord and vertebral arches are referred to as spina bifida, with severe types of spina bifida involving protrusion of the spinal cord and/or meninges through a defect in the vertebral arch. Depending on the level of the lesion, interruption of the spinal cord at the site of the spina bifida defect causes paralysis of the legs, incontinence of urine and feces, anesthesia of the skin, and abnormalities of the hips, knees, and feet. Two additional abnormalities often seen in children with spina bifida include hydrocephalus and the Arnold-Chiari type II malformation. Despite the physical and particular learning disabilities children with spina bifida must cope with, participation in individualized educational programs can allow these children to develop skills necessary for autonomy in adulthood. Advances in research to uncover the molecular basis of NTDs is enhanced by knowledge of the link between both the environmental and genetic factors involved in the etiology of NTDs. The most recent development in NTD research for disease-causing genes is the discovery of a genetic link to the most well-known environmental cause of neural tube malformation, folate deficiency in pregnant women. Nearly a decade ago, periconceptional folic acid supplementation was proven to decrease both the recurrence and occurrence of NTDs. The study of folate and its association with NTDs is an ongoing endeavor that has led to numerous studies of different genes involved in the folate metabolism pathway, including the most commonly studied thermolabile mutation (C677T) in the MTHFR gene. An additional focus for NTD research involves mouse models that exhibit both naturally occurring NTDs, as well as those created by experimental design. We hope the search for genes involved in the risk and/or development of NTDs will lead to the development of strategies for prevention and treatment. The most recent achievement in treatment of NTDs involves the repair of meningomyelocele through advancements in fetal surgery. Convincing experimental evidence exists that in utero repair preserves neurologic function, as well as resolving the hydrocephalus and Arnold-Chiari malformation that often accompany meningomyelocele defects. However, follow-up is needed to completely evaluate long-term neurologic function and overall improved quality of life. And in the words of Olutoye and Adzick, "until the benefits of fetal [meningomyelocele] repair are carefully elucidated, weighed against maternal and fetal risks, and compared to conventional postnatal therapy, this procedure should be restricted to a few centers that are committed (clinically and experimentally) to investigating these issues."     

Spondylocostal dysostosis with tetralogy of Fallot and herniation of the spleen through the diaphragm

Spondylocostal dysostosis (SCD) is a very rare syndrome characterized by vertebral malformation and rib deformity. Some of the patients with SCD have other birth defects in the central nervous system, the genitourinary tract, diaphragm or heart and so forth. There have been reported SCD with complex congenital heart disease, such as pulmonary atresia, double outlet right ventricle, and d‐transposition of great arteries. However, there have been no reported SCD patients with confirmed tetralogy of Fallot (TOF). Here, a patient with SCD having a very rare combination of rib defects on the right side and left‐sided scoliosis, tetralogy of Fallot, and diaphragmatic spleen herniation, which had not been reported before, was described.     

Congenital Cardiac Defects: A Possible Association of Aminopterin Syndrome and In Utero Methotrexate Exposure?

Folate antagonist are chemotherapeutic agents used in many neoplastic, autoimmune, and inflammatory disorders. The first suggestions that folic acid antagonists were teratogenic in humans were based on reports of failed terminations in mothers given aminopterin in the first trimester. Newborns who survived after aminopterin exposure were noted for years to have defects of the neural tube, skull, or limbs. There is now a well-defined syndrome of congenital anomalies associated with the use of aminopterin. The aminopterin syndrome consists of cranial dysostosis, hypertelorism, anomalies of the external ears, micrognathia, limb anomalies, and cleft palate. The use of aminopterin has now fallen out of favor. Methotrexate is a folate antagonist that is now used more frequently. A similar pattern of malformations has been found in fetuses exposed to methotrexate. If used during pregnancy, it can cause congenital malformations or fetal death. A consistent association between methotrexate exposure and cardiac, renal, or gastrointestinal malformations has not been reported. We report two patients who presented with classic features of aminopterin syndrome combined with significant congenital cardiac malformations after first-trimester in utero methotrexate exposure. Both of these patients survived to undergo corrective cardiac surgery.     

PHACE syndrome: new views on diagnostic criteria.

The association of large facial hemangiomas with posterior fossa malformations and vascular anomalies has been termed the PHACE syndrome. It is characterized by the association of posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and other cardiac defects, and eye abnormalities. Since most articles focus on isolated case reports, an extended retrospective literature review of all reports of large hemangiomas with associated abnormalities of the central nervous system and other malformations was performed to examine the clinical features, and other not as yet reported associated anomalies. Reports were found on 59 patients with PHACE syndrome, to which we added ten cases of our own. The Dandy-Walker syndrome is the most common CNS abnormality reported in association with PHACE syndrome and was seen in 48 (81 %) patients. Arterial malformations were found in 13 (22 %) cases; only 11 patients (19 %) had structural arterial abnormalities without associated Dandy-Walker complex. As published, about one third of patients (31 %) had further ophthalmologic abnormalities, and cardiac anomalies, including coarctation of the aorta. Subglottic hemangiomas were seen in 4 (7 %) patients and ventral developmental defects also in 3 cases. In seven of 59 patients (12 %) with PHACE syndrome, intracranial hemangiomas were present. This study demonstrates that among other CNS abnormalities, special attention should be given to intracranial hemangiomas which seems to be a peculiar phenotype of PHACE syndrome. We therefore suggest that a sixth criterion should be added to the five minimal inclusion criteria for PHACE syndrome. The inclusion criteria would then be: arterial abnormalities or/and intracranial hemangiomas. On the basis of our experience with our patients and with those previously reported, we stress the importance of using contrast-enhanced imaging to detect intracranial lesions.     

Craniosynostosis associated with neural tube defects: is there a causal association?

The majority of primary craniosynostosis cases are sporadic. Very few articles in the literature have described cases of primary craniosynostosis associated with neural tube defects (NTDs). This co-occurrence has been seen by most authors as just a coincidence. The authors report a clinical series of 4 patients of primary craniosynostosis associated with NTDs treated at their center. Among these 4 cases, 2 had lumbosacral myelomeningocele, 1 frontoethmoidal encephalocele and 1 had occipital encephalocele. Although the co-occurrence of craniosynostosis and NTD is said to be rare, there seems to exist a justified underlying explanation for the same. The NTD causes a decrease in intracranial pressure due to egress of cerebrospinal fluid in the malformed sac that results in a deficient cerebral impulse for cranial growth that might stimulate premature sutural fusion. Thus, all patients with NTDs should be thoroughly evaluated for this association and for possible surgical management.     

Subclavian Steal Syndrome in Anomalous Connection of the Left Subclavian Artery to the Pulmonary Artery in D-Transposition of the Great Arteries

Several reports have documented the occurrence of an isolated left subclavian artery in association with both tetralogy of Fallot and double-outlet right ventricle. In certain cases a congenital subclavian or pulmonary artery steal syndrome exists in which the left subclavian artery is connected to the main pulmonary artery via a ductus arteriosus. We describe a subclavian steal syndrome secondary to anomalous origin of the left subclavian artery from the pulmonary artery in d-transposition of the great arteries in a patient with Spondylocostal dysostosis (SCD). Cardiac anomalies are rare in SCD and this constellation of findings have not previously been described.     

Neural tube defects in Turkey: prevalence, distribution and risk factors

The aim of the study was to determine the prevalence rate and risk factors relevant to neural tube defects (NTDs) in Turkey. All livebirths and stillbirths recorded at the university hospitals throughout Turkey between July 1993-June 1994 were evaluated with respect to congenital anomalies. For each birth, information was recorded about the child, the mother, the pregnancy and risk factors. A total of 66 cases with a NTD were recorded in 21,907 births. Prevalence rate of NTDs was 30.1 per 10,000 births. Of these 66 cases, 29 (43.9%) were male and 37 (56.1%) female. Female/male ratio was 1.27. The ratio of spina bifida/anencephaly is 1.20 for Turkey. Maternal illiteracy, maternal advanced age and residence in northern or eastern regions of Turkey are shown to be risk factors for having a baby with a NTD. The prevalence rate of NTDs is very high for Turkey. Geographical distribution of NTDs in this country confirms a relationship between the socioeconomic status and environmental factors for the development of a NTD. The results of this study point to the importance establishing a health policy to prevent neural tube defects in Turkey.     

Spina bifida occulta and monozygotic twins

Central nervous system maldevelopment can have different presentations in twins. We report on a case of different presentations of spina bifida occulta in monozygotic twins. The first twin presented at birth with a lipomyelomeningocele; a tethered cord was diagnosed in the second twin at 2 years of age. Neural tube defects (NTDs) are a group of common congenital malformations of the brain and spine generated during neurulation. The genetic basis of this process is still not well known. Whenever an NTD is diagnosed in one of a pair of twins, the other twin should also be evaluated for NTDs.     

THE RADIAL DYSPLASIA/IMPERFORATE ANUS/VERTEBRAL ANOMALIES SYNDROME (THE VATER ASSOCIATION): DEVELOPMENTAL ASPECTS AND EYE FINDINGS

Abstract Say, B., Greenberg, D., Harris, R., DeLong, S. L. and Coldwell, J. G. (Department of Developmental Medicine & Child Neurology, Children's Medical Center, Tulsa, Oklahoma, USA). The radial dysplasia/imperforate anus/vertebral anomalies syndrome (the VATER association): developmental aspects and eye findings. Acta Paediatr Scand 66: 233, 1977.—The developmental evaluations of four children of different age groups with radial dysplasia/imperforate anus/vertebral anomalies syndrome are presented. These show that although the gross motor behavior is significantly delayed, intelligence, language, and social development are within normal range. Therefore, the patients with this syndrome merit every effort toward rehabilitation. Three of the patients discussed have ophthalmological abnormalities, in addition to their major malformations. It may be that congenital eye defects are another component of this syndrome of morphogenesis.     

Neural-tube defect in dizygotic twins

Despite the strong association between twinning and neural-tube defects (NTD), concordance of twins with NTDs is very rare. A case of concordant NTDs in dizygotic twins is reported in view of its extreme rarity. Accepted: 23 March 2001     

Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls

The aim of this study is to evaluate the folate, vitamin B12, fluoride and homocysteine levels in newborns with neural tube defect (NTD) and their parents. The study included 35 neonates with NTD and their parents, 31 neonates with congenital anomalies other than NTD formed control 1, 24 neonates with no anomalies, with the highest birth order and normal siblings formed control 2. These groups matched for socio-economic and nutritional status. Demographic, antenatal history, parental habits, folate (RBC, whole blood and serum), serum vitamin B12 and homocysteine levels were estimated using chemiluminescence technology. Chi-square test was used to assess association between factors and the outcome. One-way ANOVA was used to compare means in the three groups. To determine the risk factors for NTD, odds ratios (95% CI) was computed using bivariate and multivariate logistic regression analysis (STATA 9.0). No difference was found between NTD group and 'control 1' group. The fathers in NTD group had significantly lower folate and vitamin B12 and a higher homocysteine, in comparison to 'control 2' group (i.e. with normal babies). The babies with NTD had higher homocysteine while their mothers had significantly low folate levels in comparison to 'control 2' mothers. Low RBC folate, low serum vitamin B12 and high plasma homocysteine in both the parents had an association with NTD. Multivariate logistic regression revealed high homocysteine of father as the only independent significant risk factor [OR(95% CI):2.6(2.6, 226)] for NTD and also for other anomalies. NTD (and other congenital anomalies) may not only be due to nutritional deficiency in the mothers but also due to more intricate gene-nutrient interaction defects in the affected families, probably some abnormal folate-homocysteine metabolism. These defects seem to be affect the fathers more severely and in all likelihood, get transmitted to the babies from either or both the parents. The emergence of father's serum homocysteine levels as an independent risk factor for NTD and also other congenital anomalies calls for further studies to evaluate if this can be taken as a marker for congenital anomalies in the fetus during antenatal screening.     

Spectrum of congenital heart defects in Croatia

The aim of our study was to investigate the incidence of congenital defects in children born in Croatia during a period of 5 years, its association with extracardiac malformations, its treatment, and outcome. Medical information about the patients was obtained from 14 paediatric cardiology centres that cover the whole country. Diagnosis was made by clinical findings, electrocardiography, chest X-ray, echocardiography, catheterisation, or autopsy. Between October 1, 2002 and October 1, 2007, there were 205,051 live births in Croatia, 1,480 of which were patients diagnosed with congenital heart disease, accounting for 0.72% of the live-born children. The distribution was made up of 34.6% children with ventricular septal defect, 15.9% with atrial septal defect, 9.8% with patency of arterial duct, 4.9% with pulmonary valvar stenosis, 3.3% with tetralogy of Fallot, 3.3% with transposed great arteries, 3.3% with aortic stenosis, 3.2% with aortic coarctation, 4.3% with atrioventricular septal defect and common atrioventricular orifice, 2.3% with hypoplastic left heart syndrome, and 8.3% other with severe defects. The average age in the time of diagnoses is 70.41 days (SD, 188.13), with low average time of diagnoses of severe heart defects, 9.6 days (SD, 32.52). Among patients, 14.5% had chromosomal defects, syndromes, and/or other congenital major anomalies. During the study, 57 patients died because of cardiac anomalies or other related problems, 24 who died were operated. The rates of specific cardiac defects and association with extracardiac malformations are generally comparable with those reported in similar studies. In spite of all problems, mortality rate of 3.85% is low but could be improved.     

Serum zinc levels in newborns with neural tube defects

Neural tube defects (NTD) comprise of a group of congenital malformations that include spina bifida, anencephaly and encephalocele. Reports have implicated zinc deficiency as one of the causative factors of NTDs. We compared the serum zinc level of 23 newborns having neural tube defects with 35 healthy controls by spectrophotometery during 2003-2004. Zinc deficiency was documented in 43.5% of the cases and 8.6% of the controls (P = 0.002). Multivariate logistic regression analysis revealed a significant association between the presence of NTDs and zinc deficiency (OR = 8.2, 95% Cl: 1.9-34.7).     

Ventricular septal defect in Down syndrome. Anatomic types and associated malformations

Ventricular septal defect is a common cardiac anomaly in Down syndrome. To detect the prevalence of anatomic types and associated cardiac malformations we analyzed the echocardiographic and angiocardiographic findings of 73 children with ventricular septal defect and Down syndrome. We compared these results with those obtained in 303 patients with ventricular septal defect without Down syndrome. The prevalence of inlet ventricular septal defect was significantly higher in patients with Down syndrome, while muscular and subpulmonary ventricular septal defects were present only in patients without Down syndrome. The incidence of a cleft of the mitral valve was significantly higher in Down syndrome, while left-ventricular inflow and outflow obstructions were present only in patients without Down syndrome. Different patterns of ventricular septal defect and associated anomalies exist in patients with and without Down syndrome.     

Jarcho–Levin Syndrome Associated with a Complex Congenital Heart Anomaly

Jarcho-Levin syndrome is characterized by "crab-like" rib cage deformity and multiple vertebral anomalies that cause respiratory failure. Reports of complex congenital heart defects with this syndrome are rare. We describe a female infant with this syndrome and a complex congenital heart defect and review the literature. Congenital heart defects are occasionally complicated by Jarcho-Levin syndrome. Heart defects involving heterotaxic morphology should be included as one of the important clinical features of this syndrome.     

神经管缺陷畸形的蛋白质学研究进展

神经管缺陷(neural tube defects,NTD)是在胚胎发育过程中,神经管闭合不全所引起的一组缺陷,是环境因素和遗传因素共同作用的结果。目前已发现的与 NTD 相关的蛋白质标志物主要有血清甲胎蛋白、羊水甲胎蛋白、羊水胶质纤维酸性蛋白和 S100蛋白。该文对 NTD 相关的蛋白质标志物的研究进展进行综述。     

Noncardiac malformations in congenital heart disease: a retrospective analysis of 305 pediatric autopsies

Congenital heart disease (CHD) is one of the important groups of birth defects and contributes significantly to infant mortality. Extracardiac anomalies occur in 15-45% of cases with CHD. In this retrospective study, autopsies of cases born alive and diagnosed as CHD between 1977-2002 at Hacettepe University Ihsan Do?ramaci Children's Hospital, Pediatric Pathology Department, were investigated. In this period, a total of 3320 autopsies were performed and the incidence of CHD was 9.1%. The most commonly encountered CHD was ventricular septal defect (VSD) (15.3%). In 45.9% of cases, one or more extracardiac malformations were present. The most commonly encountered extracardiac malformation was craniofacial malformations. Less commonly seen were malformations of genitourinary, musculoskeletal, respiratory, gastrointestinal, central nervous systems and spleen anomalies. Ventricular septal defect, atrial septal defect (ASD), aortic coarctation, single ventricle, pulmonary stenosis, hypoplastic right heart syndrome, double outlet right ventricle, ASD+VSD, aortic arcus anomalies, and right and left atrial isomerism cases were often (>50%) accompanied by extracardiac malformations. No extracardiac malformations were detected accompanying pulmonary atresia with intact interventricular septum, Ebstein malformation, and mitral stenosis (MS). Spleen malformation was significantly high in cases with single ventricle (p<0.002). The anomalies of the gastrointestinal and genitourinary systems were found to be frequently associated with conotruncal heart defects (p<0.001). In the group with transposition of the great arteries, noncardiac malformations were present in only three cases (10%), differing from the rest of the material (p<0.001). In conclusion, when a heart malformation is detected in a patient, a detailed investigation should be done on extracardiac malformations or vice versa. Proper identification and treatment of CHD early in the prenatal period will save the family from the economic and emotional burden caused by having such a child with CHD.