Diaphragmatic defects,limb deficiencies,and ossification defects of the skull: A distinctive malformation syndrome

We report on prenatal and postnatal findings in 4 consecutive fetuses with a pattern of severe congenital anomalies who were born to a healthy nonconsanguineous couple. The spectrum of malformations includes diaphragmatic defects, hypoplastic lungs, omphalocele, limb deficiencies, syndactyly of toes, and ossification defects of the skull. This specific spectrum of anomalies is not fully compatible with that of any established syndrome. No prenatal exposure to any possible teratogen was found. Family history is suggestive for autosomal recessive inheritance, even though germ-line mosaicism in one of the parents cannot completely be excluded. © 1996 Wiley-Liss, Inc.     

Anencephaly and limb deficiencies

Limb deficiencies (LDs) are rarely reported in anencephalic infants. A review of 662 patients in the literature on non-neural defects in an-encephaly only showed five patients with LDs. We report on eight patients with various LDs from the records of 141 necropsies of the anencephalic infants found among 495,830 births. Compared with another group of anencephalic infants reported in the literature, the patients in this group of anencephalic infants with LDs were predominantly male, their mean gestational age was younger by approximately 5 weeks, their mean birth-weight was approximately 1,400 g less, and they presented with a higher incidence of polyhydramnios during gestational development. The association of this pair of anomalies, which was 100 times more frequent than expected, seems not due to chance. Since all eight patients had other multiple congenital anomalies (MCA), in addition to anencephaly and LDs, the postmortem study should be mandatory in anencephalic infants with LDs. The most common associated anomalies were cardiovascular and renal defects. Oral clefts, diaphragmatic hernia, esophageal atresia, and imperforate anus were also observed in these infants. The recognition of LDs in anen-cephalic infants indicates severe and extensive disturbance of the early embryogenesis (blastogenesis), which affects the midline of the embryo. © 1992 Wiley-Liss, Inc.     

Anencephaly and limb deficiencies.

Limb deficiencies (LDs) are rarely reported in anencephalic infants. A review of 662 patients in the literature on non-neural defects in anencephaly only showed five patients with LDs. We report on eight patients with various LDs from the records of 141 necropsies of the anencephalic infants found among 495,830 births. Compared with another group of anencephalic infants reported in the literature, the patients in this group of anencephalic infants with LDs were predominantly male, their mean gestational age was younger by approximately 5 weeks, their mean birth-weight was approximately 1,400 g less, and they presented with a higher incidence of polyhydramnios during gestational development. The association of this pair of anomalies, which was 100 times more frequent than expected, seems not due to chance. Since all eight patients had other multiple congenital anomalies (MCA), in addition to anencephaly and LDs, the postmortem study should be mandatory in anencephalic infants with LDs. The most common associated anomalies were cardiovascular and renal defects. Oral clefts, diaphragmatic hernia, esophageal atresia, and imperforate anus were also observed in these infants. The recognition of LDs in anencephalic infants indicates severe and extensive disturbance of the early embryogenesis (blastogenesis), which affects the midline of the embryo.     

Maternal periconceptional use of multivitamins and reduced risk for conotruncal heart defects and limb deficiencies among offspring

We investigated whether a woman's periconceptional use of a multivitamin containing folic acid was associated with a reduced risk for delivering offspring with a conotruncal heart defect or a limb deficiency. Data were derived from a population-based case-control study of fetuses and liveborn infants with conotruncal or limb defects among a 1987–88 cohort of births in California. Telephone interviews were conducted with mothers of 207 (87.0% of eligible) conotruncal cases, 178 (82.0%) limb defect cases, and of 481 (76.2%) randomly selected liveborn nonmalformed control infants. Reduced risks were observed for maternal use of multivitamins containing folic acid from one month before until two months after conception. Odds ratios and 95% confidence intervals for any compared to no multivitamin use were 0.70 (0.46–1.1) for conotruncal defects and 0.64 (0.41–1.0) for limb defects. Controlling for maternal race/ethnicity, age, education, gravidity, alcohol use, and cigarette use resulted in a further reduction to the odds ratio for conotruncal defects, 0.53 (0.34–0.85), but not for limb defects. Among non-vitamin using women, consumption of cereal containing folic acid was also associated with reduced risks for both defects. Women who take multivitamins have 30–35% lower risk of delivering offspring with either conotruncal or limb defects. This association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin components, or some unknown behaviors that highly correlate with regular use of a multivitamin. However, should the association prove causal, it offers an important opportunity for preventing thousands of serious birth defects. © 1995 Wiley-Liss, Inc.     

Anatomic and etiological classification of congenital limb deficiencies

Limb deficiencies, the congenital absence or hypoplasia of a long bone and/or digits, vary greatly in their anatomy and etiology. Previous attempts to classify the range of possible phenotypes have not included all types of deficiencies. We present a new classification system, which includes all potential phenotypes. Infants with limb deficiencies were identified in the hospital-based Active Malformations Surveillance Program at Brigham and Women's Hospital in Boston, MA from the years 1972 to 1974 and 1979 to 2000. Affected infants were classified based on the anatomy and apparent cause of their deficiencies. The prevalence rate of all types of limb deficiency was 0.79/1,000. Upper limb deficiencies were significantly more common than lower limb deficiencies. There was no significant difference in frequencies between deficiencies on the left and right sides of the body. Longitudinal defects were more common than terminal transverse defects; intercalary defects were uncommon. Longitudinal defects were most likely to occur on the preaxial side of the limb. Almost half of affected infants had affected digits, with normal long bones. The most common apparent cause of limb deficiencies was vascular disruption defects (0.22/1,000), such as amniotic band-related limb deficiency. This new classification system includes deficiency of each long bone, as well as absence of any finger or toe. This system will make it possible to establish the prevalence of each specific phenotype. The large number of distinct apparent causes illustrates the marked etiologic heterogeneity of limb deficiencies.     

Teratogen-induced limb defects

Limb abnormalities are one of the most common and visible phenotypic effects of several human teratogens. The specific effects are different for most teratogens and include effects on limb morphogenesis (thalidomide, warfarin, phenytoin, valproic acid) and the effect of vascular disruption on a limb that had formed normally (misoprostol, chorionic villus sampling, and phenytoin). Either duplication (preaxial polydactyly of hands and feet) or deficiency (absence of thumb) is a common effect of thalidomide; no other human teratogen identified to date has this effect on the developing limb. Procedures during pregnancy, including chorionic villus sampling and dilation and curettage, produce defects of vascular disruption. For common exposures, such as alcohol and cocaine, it has been difficult to confirm objectively the exposure during embryogenesis and to ascribe specific limb defects that are produced. The molecular basis for the limb defects produced by the recognized human teratogens remains unknown.     

Associated malformations in patients with limb reduction deficiencies

Infants with limb reduction deficiencies (LRD) often have other associated congenital malformations. The purpose of this investigation was to assess the prevalence and the types of associated malformations in a defined population. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for malformations was continued until 1 year of age. The associated malformations in infants with LRD were collected in all livebirths, stillbirths and terminations of pregnancy during 25 years in 347,810 consecutive births in the area covered by our population based registry of congenital malformations. Of the 271 LRD infants born during this period, representing a prevalence of 7.8 per 10,000, 57.9% had associated malformations. There were 17(6.3%) patients with chromosomal abnormalities including 10 trisomies 18, and 62 (22.9%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VA(C)TER(L) association. However numerous recognized dysmorphic conditions were registered including Poland, ectrodactyly-ectodermal dysplasia-clefting, oral-facial-digital, Klippel–Trenaunay–Weber, oculo-auriculo-vertebral defect spectrum, CHARGE, Townes-Brocks, Moebius, Du Pan, Smith-Lemli-Opitz, hypoglossia-hypodactyly, amniotic band, De Lange, Rubinstein-Taybi, Fanconi, radius aplasia- thrombocytopenia, Roberts, Holt-Oram, and fetal diethylstilbestrol. Seventy eight (28.8%) of the patients were multiply, non-syndromic, non chromosomal malformed infants (MCA). Malformations in the cardiac system, in the genital system, and in the central nervous system were the most common other malformations, 11.4%, 9.4%, and 7.7% of the associated malformations, respectively, followed by malformations in the renal system (4.8%), and in the digestive system (4.6%). Prenatal diagnosis was performed in 48.4% of dysmorphic syndromes with LRD. The overall prevalence of associated malformations, which was more than one in two infants, emphasizes the need for a thorough investigation of infants with LRD.A routine screening for other malformations especially cardiovascular system, urogenital system, central nervous system, and digestive system may be considered in infants and in fetuses with LRD.     

Upper limb deficiencies and associated malformations: A population-based study

As part of an ongoing analysis of limb deficiencies occurring among 1,213,913 consecutive livebirths in British Columbia during the years 1952–1984, all cases with deficiencies of the upper limbs were analysed with a view to identifying associated patterns of anomalies. This analysis resulted in seven subgroups. For each subgroup, incidence figures for cases with and without additional anomalies were calculated separately. The proportion of cases with additional anomalies varied markedly by subgroup. For example, 89% of cases with longitudinal defects of the radius had additional malformations, while only 28% of cases with transverse defects of the radius had other organ anomalies (χ² = 40.55; P < 0.001, one degree of freedom). A preponderance of males was found among the cases with associated defects, particularly in the group with longitudinal defects of the radius (28 males, 14 females; χ² = 14.10; P < 0.001). Clustering of specific patterns of associated malformations is described within subgroups. © 1992 Wiley-Liss, Inc.     

Vitamin deficiencies and neural-tube defects: human and animal studies

The evidence for an association between vitamin deficiency in early pregnancy and the prevalence of neural-tube defects in humans is reviewed, with particular emphasis on the methodological problems encountered in conducting such studies. It is apparent that there is strong evidence for an association between maternal vitamin status and the outcome of pregnancy, but this is not universally accepted, due to ethical and practical constraints on the design of the studies. There are also problems in obtaining precise information from experiments on animals in vivo. By culturing rat embryos in dialysed serum in which the micromolecular component is defined, it has been possible to demonstrate that significant numbers of neural-tube defects can be produced by the deficiency of a single vitamin (inositol), and that multiple vitamin deficiency produces a further significant increase in the frequency of such defects.     

Upper limb deficiencies and associated malformations: a population-based study.

As part of an ongoing analysis of limb deficiencies occurring among 1,213,913 consecutive livebirths in British Columbia during the years 1952-1984, all cases with deficiencies of the upper limbs were analysed with a view to identifying associated patterns of anomalies. This analysis resulted in seven subgroups. For each subgroup, incidence figures for cases with and without additional anomalies were calculated separately. The proportion of cases with additional anomalies varied markedly by subgroup. For example, 89% of cases with longitudinal defects of the radius had additional malformations, while only 28% of cases with transverse defects of the radius had other organ anomalies (chi 2 = 40.55; P < 0.001, one degree of freedom). A preponderance of males was found among the cases with associated defects, particularly in the group with longitudinal defects of the radius (28 males, 14 females; chi 2 = 14.10; P < 0.001). Clustering of specific patterns of associated malformations is described within subgroups.     

Psychosocial adaptation of children and adolescents with limb deficiencies: A review

Children and adolescents with congenital or acquired limb loss must contend with a number of medical and psychosocial Stressors that might be expected to increase their risk of maladjustment. Yet several studies suggest remarkably good psychosocial adjustment in this population. This paper reviews the available data on the psychosocial status of the pediatric patient with a limb deficiency. Possible explanations related to disability characteristics, such as degree of disease visibility, are offered for the reported positive outcomes. Psychosocial factors that may influence the adaptation process are also reviewed. Finally, methodological limitations of prior studies are delineated and suggestions for future research are offered. Clearly, prospective longitudinal studies with appropriate control groups are necessary for an understanding of the adaptive process in specific pediatrie groups with limb deficiencies.     

Teratogen‐induced limb defects

Limb abnormalities are one of the most common and visible phenotypic effects of several human teratogens. The specific effects are different for most teratogens and include effects on limb morphogenesis (thalidomide, warfarin, phenytoin, valproic acid) and the effect of vascular disruption on a limb that had formed normally (misoprostol, chorionic villus sampling, and phenytoin). Either duplication (preaxial polydactyly of hands and feet) or deficiency (absence of thumb) is a common effect of thalidomide; no other human teratogen identified to date has this effect on the developing limb. Procedures during pregnancy, including chorionic villus sampling and dilation and curettage, produce defects of vascular disruption. For common exposures, such as alcohol and cocaine, it has been difficult to confirm objectively the exposure during embryogenesis and to ascribe specific limb defects that are produced. The molecular basis for the limb defects produced by the recognized human teratogens remains unknown. © 2002 Wiley‐Liss, Inc.     

Mental retardation, spasticity, and transverse limb defects

We report on a mentally retarded boy with spastic paraplegia and a transverse defect of the left foot who was born to consanguineous parents. This association of ectrodactyly, mental retardation, and spastic paraplegia was first reported by Jancar [1967].     

Bactericidal screening test for late complement component deficiencies or defects.

Congenital complement deficiency has been described in disseminated Neisseria infections. Its occurrences in humans with other kinds of infections have not been described. In the past, CH50 determinations have been used to detect these deficiencies, but this procedure is time consuming and cumbersome. A method of determining the presence of late component deficiencies or defects is described which is easy and inexpensive to perform. An agar pour plate with a serum-sensitive Escherichia coli strain is made, and 2.5-mm wells are put in the agar. Unknown fresh sera are used to fill the wells. An absence of a zone of bacterial growth inhibition around the well after incubation at 37 degrees C overnight indicates a late component defect or deficiency in the test serum. By applying this assay to 35 selected patients, four deficient patients were identified. One had a congenital C5 deficiency and three had C6 deficidencies. It is suggested that the assay be used as a screening test to study the relationship between congenital complement deficiencies and various kinds of infections, especially those caused by organisms which are partially serum sensitive.