Fryns syndrome: two further cases without lateral diaphragmatic defects

We report on two unrelated infants with Fryns syndrome but without lateral diaphragmatic defects. In case 1, a female stillborn, pertinent findings included a coarse facies, cleft palate, short neck with a broad pterygium, heart defect, lung hypoplasia, omphalocele, urogenital malformations, anal atresia, and distal digital hypoplasia. Case 2 showed a coarse facies with cleft lip and palate, para-oesophageal hernia with herniation of the stomach into the thoracic cavity, malrotation of the intestine, hydronephrosis, and anal atresia. At age 14 months she was developmentally severely retarded. These observations represent the 11th and 12th reports of probable Fryns syndrome without lateral diaphragmatic defect.     

Thrombolytic treatment of acute myocardial infarct. 3]

In a population of close to 2.5 million infants born from 1983 to 1993 registered in the California Birth Defects Monitoring Program, we compared the prevalence of structural birth defects among 2,894 infants with Down syndrome (DS) with that of infants without DS. Among 61 defects uniformly ascertained in affected and unaffected infants, 45 were significantly more common in DS, with atrioventricular canal (risk ratio = 1,009), duodenal atresia (risk ratio = 265), and annular pancreas (risk ratio = 430) being the most common. Most defects of blastogenesis and most midline defects were either nonsignificantly associated or not observed in infants with DS. Theories on the pathogenesis of defects in trisomies must account for the lack of and for the presence of specific defects.     

Risk factors in congenital anal atresias

Congenital anal atresias were studied in a small geographical area in 225,752 consecutive births. For each of the 108 new cases studied during the period 1979 to 1995, more than 50 factors were compared in probands and in controls. The prevalence rate of congenital anal atresias was 4.8 per 10,000 births. Sex ratio was 0.96. Prenatal diagnosis was performed in 14 cases and 11 cases were induced abortions. The more common types of associated malformations in the 45 non syndromic affected cases with at least one major anomaly other than anal atresia were renal agenesia, genital anomalies and ventricular septal defect. At births infants with anal atresia and other malformations were smaller, weighted less and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with anal atresia were more often complicated by threatened abortion, oligoamnios and polyhydramnios. Mothers of children with congenital anal atresia took more often drugs during pregnancy than mothers of controls. Fathers of children with anal atresia were more often exposed to occupational hazards than fathers of controls. There was a significant association between anal atresia and consanguinity of parents (p < 0.05). The recurrence risk for first degree relatives of probands was 3.7%. First degree relatives of probands had more than twice the prevalence of non-anal atresia malformations than controls.     

Descriptive epidemiology of alimentary tract atresia

A study has been made on certain epidemiological characteristics of infants with alimentary tract atresia: esophageal atresia, small and large gut atresia, and anal atresia. Data were collected from three malformation registries and represent a material of more than 4.5 million births. A total of 3,550 infants with alimentary atresia were identified corresponding to a total rate of about 8 per 10,000 births. In 167 infants (4.7%) more than one of the major atresia types were present simultaneously. Racial differences were found (based on data from California) for esophageal atresia where whites had a higher rate than other races. For gastrointestinal atresia, a high rate in blacks was found, while no differences between races were seen for anal atresia. Also, differences in registered rates between the three programs were found, at least partly explainable by different ascertainment. The different forms of atresia were compared from the point of view of sex ratio, twinning rate, maternal age and parity distribution, presence of chromosome anomalies, and types of associated malformations. The pathogenesis and etiology of the various types of atresia are discussed based on these observations. The conclusion is that although undoubtedly other pathogenetic mechanisms may exist for gastrointestinal atresia, a substantial proportion of all infants with alimentary atresia had their malformations as a result of early disturbances of intestinal morphogenesis. Within each subgroup, apparently different etiologies may exist, resulting in differences in epidemiological characteristics.     

Vater or Vacterl syndrome (author's transl)

Analysis of malformations in 65 newborns with limb anomalies, 39 with esophageal atresia with tracheoesophageal fistula, and 41 with anal atresia confirmed the nonrandom tendency for the defects of the VATER or VACTERL syndrome to associate together. 11 new patients with 4 or more of these anomalies were compared with 41 previously reported cases. There was good agreement with reference to the frequency of the major malformations noted in the VACTERL association. While anal atresia was not so common in our patients, cardiac anomalies and radial limb dysplasia occurred somewhat more frequently. In accordance with previous findings we also emphasize a single umbilical artery as one of the malformations in the spectrum of the VACTERL association (V = vertebral defects and vascular anomalies). Because of the high incidence of rib anomalies in our patients and in earlier cases with complete medical records it is suggested that the scope of the VACTERL association should be enlarged by this malformation. Thus the R in VACTERL would stand not only for renal defects but als for rib anomalies. Furthermore, the spectrum of anomalies could be extended by auricular defects (A = anal atresia and auricular defects). When one of these VACTERL components is found attention should be drawn to the possibility of the presence of the other associated anomalies. The developmentally correlated malformations seen in the VACTERL syndrome are generally sporadically observed. At the present time the etiology is unknown but heterogeneity is suggested. Although a causal relationship between maternal intake of progesteron/estrogen during the vulnerable period of embryogenesis and the VACTERL syndrome has been suggested, none of the mothers of our patients were exposed to these hormones during early pregnancy. Cytogenetic investigation in one patient and his mother showed a so-called marker chromosome 9 (C9qh+ variant) which is difficult to interpret at the present time.     

Modification of IgH PCR clonal analysis by the addition of sucrose and cresol red directly to PCR reaction mixes

We present the findings of a "new" sublethal MCA syndrome in three siblings, one female and two boys, the only children of healthy, non-consanguineous parents. In addition to prenatal growth retardation and early demise, they presented the same pattern of multiple malformations: relative microcephaly with bird-headed face, microphthalmos/coloboma iris/cloudy corneae, genital anomalies with hypospadias and cryptorchidism in the two males. Associated anomalies included: cardiac defects (2/3), unilateral cleft lip/cleft palate (1/3), anal stenosis (2/3) and unilateral renal agenesis (1/3).     

Cleft palate in domestic animals: epidemiologic features

Among 331 animals with cleft palate in a veterinary clinic-hospital population, cats, mixed breed dogs and German Shepherd Dogs had low risk for cleft palate; high rates were seen in English Bulldogs, some small purebred dogs and Charolais cattle, where cleft palate occurred as part of a syndrome of multiple malformations. Many of the epidemiologic characteristics resemble features of cleft palate in humans and suggest animal breeds suitable for exploration as animal models for use by experimental teratologists, developmental biologists, and clinicians.     

A distinct Mendelian autosomal recessive syndrome involving the association of anotia, palate agenesis, bifid tongue, and polydactyly in the dog

A presumed genetic syndrome is described in a family of St. Bernards. Four identically affected littermates presented the association of palate agenesis, anotia, incomplete bifid tongue, preaxial hind paw polydactyly, and an extra thoracic vertebra and rib. Pedigree analysis is compatible with an autosomal recessive gene.     

Transforming growth factor-beta isoforms expressions in pulmonary adenocarcinomas as prognostic markers: an immunohistological study of one hundred and twenty patients

Congenital eye malformations were studied in a small geographical area in 212,479 consecutive births. For each of the 145 new cases studied during the period 1979 to 1994, more than 50 factors were compared in probands and in controls. The prevalence rate of congenital eye malformations was 6.8 per 10,000 for microphthalmia 1.7, anophthalmia 0.23, cataract 2.7 and coloboma 1.4 respectively. Sex ratio was 0.82. Prenatal diagnosis was performed in 18 cases and 7 cases were induced abortions. The more common types of associated malformations in the 81 affected cases (53.8%) with at least one anomaly other than an eye malformation were clubfeet, microcephaly, hydrocephaly, cleft lip/palate and facial dysmorphia. At birth infants with eye malformations and other malformations were smaller, weighted less and their head circumference was lower than in controls. Placental weight was also lower than in controls. Pregnancies with eye malformations were more often complicated by threatened abortion, oligoamnios and polyhydramnios. Mothers of children with congenital eye malformations took more often drugs during pregnancy than mothers of controls. Fathers of children with congenital eye malformations were more often exposed to occupational hazards than fathers of controls. There was a significant association between eye malformations and consanguinity of parents. The recurrence risk for first degree relatives of probands was 8.9%. First degree relatives of probands had more than three times the prevalence of non-eye malformations than controls. These results are of relevance to genetic counseling.     

Progressive myelopathy caused by human T-cell lymphotropic virus type I (HTLV-I) in 3 patients in The Netherlands]

Liability to neural tube defects is increased by maternal dietary deficiency, and children with neural tube defects show a possibly related seasonal variation in date of birth. Since maternal dietary insufficiency may also increase liability to cleft lip, with or without cleft palate (CLP), we wondered if children with CLP would also show a seasonal variation in birth date. The multifactorial-threshold model predicts that any such effect would be more apparent in males than females, since CLP is more frequent in males. Month of birth was obtained from records of 598 children with CLP seen at The Montreal Children's Hospital between 1950 and 1996. Children with syndromes or associated malformations were excluded. There was a significant tendency for children with CLP to be born more often in the summer than in winter. The difference was greater in males than in females. The seasonal fluctuation in month of birth of children with CLP is consistent with the presence of an environmental factor increasing liability, with a maximal effect in November-December. This might be related, at least in part, to a seasonal fluctuation in maternal nutrition. The data support the prediction that analyzing the data for the sexes separately would amplify the effects of variation in liability for a multifactorial threshold trait that has a different frequency in males and females. This approach could be useful in the study of other gene-environment interactions.     

The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition

Seven patients from four families are reported who had an inherited condition of which the main features were ankyloblepharon, ectodermal defects and cleft lip and palate. The ectodermal defects were partial or complete hair loss, absent or dystrophic nails, pointed widely spaced teeth and partial anhidrosis. Associated anomalies included lacrimal duct atresia, supernumerary nipples, syndactyly and auricular deformities. The inheritance of this abnormality was consistent with that of an autosomal dominant trait. The relationship between this and similar syndromes is discussed.     

Comparative teratogenicity of selected glucocorticoids applied ocularly in mice

Three glucocorticoids (dexamethasone, hydrocortisone, and prednisolone), were ocularly applied to pregnant CD-1 mice on days 10-13 of gestation. The drug concentrations were various multiples of the common therapeutic dose levels and were applied to both eyes in 1 microliter drops five times a day. Eighteen-day fetuses were examined for malformations. A significant increase in the incidence of cleft palate was observed in fetuses treated with each of these glucocorticoids. There appeared to be a dose related effect on cleft palate width among fetuses from both dexamethasone and prednisolone treated dams. The incidence of sex organ anomalies, although lower than the incidence of cleft palate, also showed a positive dose relationship. Analysis of variance was used to compare the teratogenic effects of these glucocorticoids ocularly applied in equipotent anti-inflammatory concentrations. Our results indicate that dexamethasone produces a higher incidence of cleft palate, than either of the other two drugs when given in equipotent concentrations. It appears that the teratogenic potency of these ocularly applied glucocorticoids cannot be predicted on the basis of anti-inflammatory potency.     

Primary gastrointestinal lymphoma--disease spectrum and management: a 15-year review from north India

The anthropometric measurements of face were taken in 21 infants of 6-9 months (15 boys, 6 girls) with bilateral cleft lip, alveolus and palate, prior to surgery. The control group consisted of 30 normal infants, without facial defects. In each child 9 measurements were performed. The comparative analysis revealed an underdevelopment of maxilla and mandible and an increase in nasal width in children with bilateral cleft lip and palate.     

Stringent delineation of Pallister-Hall syndrome in two long surviving patients: importance of radiological anomalies of the hands

We report two unrelated, long surviving patients (2 and 17 years) with syndromal hypothalamic hamartoblastoma. Both showed mild facial dysmorphism (downward slanted palpebral fissures, ptosis, microretrognathia), cleft epiglottis, and developmental delay. The younger child had stenosis of the pulmonary arteries, complex urogenital malformations, and anal atresia. In the oldest patient, the hamartoma caused precocious puberty of the central type, combined with complete hGH deficiency. Both patients showed bony anomalies of the extremities: variable proximal synostosis between central (2nd to 4th) metacarpals or intercalary polydactyly with generalised brachydactyly, severe brachytelephalangism, syndactyly, and nail hypoplasia. Together with the absence of anomalies of cholesterol metabolism, a combination of oral frenula, laryngeal malformations, digestive abnormalities, intercalary polysyndactyly, generalised brachytelephalangism, and nail hypoplasia should allow the delineation of Pallister-Hall syndrome, even when a CNS tumour is absent. The radiological abnormalities are helpful in differentiating Pallister-Hall syndrome from the other syndromes in which hypothalamic hamartoblastoma is observed. This is of major importance for genetic counselling, since Pallister-Hall syndrome may be a dominantly inherited disorder, thus contrasting with most of the other disorders with the CAVE phenotype, which are recessively inherited.     

Orofacial clefts in Hungary. Epidemiological and genetic data, primary prevention

The occurrences (birth prevalences) of different types of isolated and multiple orofacial clefts are known in Hungary. The empiric risk figures in the first-degree relatives of probands with cleft lip +/- cleft palate, cleft palate, Robin sequence and multiple congenital abnormalities including orofacial clefts as component defects were also determined. Finally the recent controversial data concerning the primary prevention of isolated orofacial clefts by periconceptional folic acid-containing multivitamins are summarized.     

Diphenylhydantoin affects glycosaminoglycans and collagen production by human fibroblasts from cleft palate patients

During embryonic development, the proper production of extracellular matrix molecules mediates morphogenetic processes involved in palatogenesis. In the present study, we investigated whether any differences exist in glycosaminoglycan (GAG) and collagen synthesis between palate fibroblasts from infants, with or without cleft palate, in two age ranges. Subsequently, the effects of diphenylhydantoin (PHT), a teratogen known to induce cleft palate in human and mammalian newborns, on extracellular matrix (ECM) production were studied. We found that cleft palate fibroblasts (CPFs) synthesize greater amounts of GAG and collagen than normal fibroblasts (NFs). CPFs produced less cellular hyaluronic acid (HA) and more sulphated GAG. HA was the principal GAG species in the medium, and its percentage was lower in one- to three-year-old CPFs. Cleft palate fibroblasts produced more extracellular chondroitin 4- and 6-sulphate (CS) and dermatan sulphate (DS). Associated with a higher production of sulphated GAG, we observed a higher synthesis of type III and type I collagen with a normal ratio of alpha2(I) to alpha1(I) chains. PHT treatment of NFs reduced collagen and GAG synthesis, with a marked effect on sulphated GAG. The drug changed collagen synthesis, whereas it did not affect GAG production in CPFs whose phenotype may already be impaired. These findings indicate that, in CPFs, modifications in the pattern of ECM components, which are most likely responsible for the anomalous development, persist in infants. In addition, NFs and CPFs with a different phenotype respond differently to PHT treatment.     

Correlation between Down's syndrome and malformations of pediatric surgical interest

PURPOSE: This is a collaborative study carried out by Pediatric Surgeons of the "G.D'Annunzio" University and the Regional Association of Down Children of Abruzzo (Italy). METHODS: Data were collected of malformations combined with Down Syndrome (DS) during a 10-year period in a population of defined age to look for a possible improvement of the patients' life conditions. Reportedly, 50% of these patients may reach an age of about 60 years. RESULTS: One hundred twenty-seven DS subjects from this region were evaluated, 54% of whom had associated malformations (13% cardiac, 41% extracardiac, and 13% both). Seventeen patients of 53 underwent surgery for extracardiac malformations, with gastrointestinal malformations prevailing. The largest number of DS babies were born from mothers under 30 years of age; this is attributed to the largest birth rate and the least prevention at this age. Mothers older than 38 years gave birth to DS babies with the lowest rate of associated malformations. CONCLUSION: The role of the pediatric surgeon in multidisciplinary assistance for DS patients is stressed.     

Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia

Down syndrome (DS) children with acute myeloid leukemia (AML) have significantly higher event-free survival (EFS) rates compared with non-DS children when treated with protocols containing 1-beta-D-arabinofuranosylcytosine (ara-C). Sensitivity and metabolism of ara-C was examined in myeloblasts from DS and non-DS patients with AML, DS infants with the transient myeloproliferative disorder, and Epstein-Barr Virus (EBV) transformed lymphoblastoid cell lines with and without trisomy 21. DS myeloblasts were approximately 10-fold more sensitive to ara-C (measured by the 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric sensitivity assay), compared with non-DS myeloblasts, following exposure to ara-C for 72 hours. Mean levels of l-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) were significantly higher in DS myeloblasts compared with non-DS myeloblasts after incubation with 5 micromol/L ara-C (621.4 v 228.4 pmol/mg protein). DS cell lines also generated higher levels of ara-CTP compared with cell lines with diploid chromosome numbers (66.5 v 13.6 pmol/mg protein and 137.6 v 41.7 pmol/mg protein at 1 and 5 micromol/L ara-C, respectively). Elevated ara-CTP levels in the DS cells were accompanied by slightly lower levels of endogenous deoxycytidine triphosphate (dCTP) pools, slightly greater extent of ara-C incorporation into DNA, and increased relative numbers of double strand DNA strand breaks. There were no significant differences in the cell cycle distributions of DS and non-DS cells. These in vitro studies support our hypothesis that enhanced metabolism of ara-C in DS cells may be a contributing factor to the superior survival rate of DS children with AML and is possibly based on a gene dosage effect of genes localized to chromosome 21 including cystathionine-beta-synthase. Further study of the mechanisms (ie, alterations in dCTP pools and DNA methylation) involved may lead to improvements in the treatment of all AML patients.     

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies

OBJECTIVE: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate. DESIGN: Meta-analysis. SETTING: Studies from 1966 to present. SUBJECTS: Studies were located with Medline, Embase, Reprotox, and from references of textbooks, reviews, and included articles. Included studies were original, concurrently controlled studies in any language. INTERVENTIONS: Data extraction and quality assessment were done independently and in duplicate. MAIN OUTCOME MEASURES: Maternal exposure to benzodiazepines in at least the first trimester; incidence of major malformations or oral cleft alone, measured as odds ratios and 95% confidence intervals with a random effects model. RESULTS: Of over 1400 studies reviewed, 74 were retrieved and 23 included. In the analysis of cohort studies fetal exposure to benzodiazepine was not associated with major malformations (odds ratio 0.90; 95% confidence interval 0.61 to 1. 35) or oral cleft (1.19; 0.34 to 4.15). Analysis of case-control studies showed an association between exposure to benzodiazepines and development of major malformations (3.01; 1.32 to 6.84) or oral cleft alone (1.79; 1.13 to 2.82). CONCLUSIONS: Pooled data from cohort studies showed no association between fetal exposure to benzodiazepines and the risk of major malformations or oral cleft. On the basis of pooled data from case-control studies, however, there was a significant increased risk for major malformations or oral cleft alone. Until more research is reported, level 2 ultrasonography should be used to rule out visible forms of cleft lip.     

Athlete''s heart in elite disabled athletes

Nineteen children with congenital upper alimentary tract malformation were studied prospectively at the Department of Paediatrics, University College Hospital (UCH), Ibadan, over a period of 12 months. There were 20 cases, grouped into six types comprising congenital hypertrophic pyloric stenosis, seven; cleft lip and/or cleft palate, five; oesophagal atresia with or without tracheo-oesophageal fistula, four; jejunal atresia two and a case each of achalasia and annular pancreas. One patient had oesophageal atresia and congenital hypertrophic pyloric stenosis. The mortality rate was 31.51% (six out of nineteen). Low mortality was recorded in cases of cleft lip and/or palate, while mortalities of over 70% were recorded among cases of jejunal atresia, and oesophageal atresia with or without tracheo-oesophageal fistul. The common causes of death were milk feed aspiration (28.6%-two cases), purulent peritonitis (14.3%-one case), and probable septicaemia (14.3%-one case). The cause of death in two cases could not be determined.