Absence of limbs and gross body wall defects: an epidemiological study of related rare malformation conditions.

The study is based on almost 10 million births and reports on 215 infants with two unusual malformations: amelia and gross body wall defect. Amelia without body wall defect was present in 116 cases, 67 had body wall defects without amelia, and 32 had both. The total rate was 2.2 per 100,000 births. The infants were divided into five mutually exclusive groups. There were 40 infants (0.4 per 100,000) with agenesis of the body stalk, 18 with amelia and other types of gross body wall defects (0.2 per 100,000), 56 with amelia and malformations other than gross body wall defects (0.6 per 100,000), 41 with amelia (with or without other limb reduction defects) but no nonlimb malformations (0.4 per 100,000), and 60 infants with gross body wall defects of a type other than agenesis of body stalk and without amelia (0.6 per 100,000). A weak trend of decreasing prevalence of these malformations was found during the observation period. Infants with agenesis of the body stalk and infants with amelia combined with other types of gross body wall defects occurred at an increased rate in infants of young women. This maternal age effect is also found with gastroschisis, but not with omphalocele, and may indicate etiological or pathogenetic similarities between gastroschisis and the two former groups of defect. In infants with amelia, additional limb reduction defects could be of any type: transverse, longitudinal, or intercalary. Therefore, amelia may be the end result of different types of disturbances of limb morphogenesis. There was an increased rate of twinning. The relationship with amniotic band syndrome is discussed.     

Hind limb malformations in free-living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies

BACKGROUND: Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. METHODS: During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens) were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). RESULTS: Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota. CONCLUSIONS: Clustering of malformation type suggests that developmental events may produce a variety of phenotypes depending on the timing, sequence, and severity of the environmental insult. Hind limb malformations in free-living frogs transcend current mechanistic explanations of tetrapod limb development.     

FFU complex: an analysis of 491 cases

A study of 491 patients with femur-fibula-ulna (FFU) complex is presented. The term FFU complex has been proposed for cases in which the femur, fibula and/or ulna show defects, which tend to be associated. These cases are usually sporadic. Some rare anomalies of the arms which are present are particularly frequent in FFU complex. These are amelia, peromelia of humerus, humeroradial synostosis and defect of ulna. In our study, 491 patients were investigated for involvement of limb malformations. Our results, showing nearly equal proportions of the most common malformations in four analysed groups (with one, two, three and four limbs affected) supports the hypothesis that even if one arm or one leg only is affected, the cases may still be classifiable as FFU complex. There is a striking asymmetry in presence and in degree. All malformations are more often unilateral than bilateral. Upper limbs are affected more often than lower limbs. The right side and the male sex are preferentially affected. The limb malformations present in the FFU complex are different from those seen in most other types of limb defects, so there is virtually no overlap between FFU and other limb malformations. Some arguments in favour of early somatic mutation as a cause are discussed.     

Major limb malformations following intrauterine exposure to ethanol: two additional cases and literature review

Two children are reported in whom major limb malformations were identified and whose mothers had consumed large quantities of alcohol in the first trimester of pregnancy. In one there was complete amelia of the upper limbs, while the other had preaxial polydactyly of both hands. These cases, taken together with previously reported instances of major limb anomalies following intrauterine ethanol exposure, as well as animal investigations that have demonstrated virtually identical limb malformations following ethanol administration, suggest that maternal ethanol abuse may be casually related to these limb malformations. We suggest that interruption of blood supply to the developing limb may be caused by ethanol exposure and may result in all of the various limb malformations described.     

Limb reduction defects in over one million consecutive livebirths

Limb reduction defects occurring among 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 inclusive were reviewed. A total of 659 cases of limb reduction defects were identified, 393 of them involving the long bones and 190 of them more than one limb. The time period 1966-1984, during which ascertainment was consistent, was evaluated, and an incidence of 5.97 per 10,000 livebirths (1 in 1,692 live births) was found. The data were evaluated for trends over time, sex ratio, and regional and ethnic distribution. Associated anomalies of other organ systems in these cases were analyzed, and overall about one-half of the cases have additional defects. The majority of these additional defects affect the musculoskeletal system and include such entities as clubfoot, hip dislocation, and congenital contractures. Defects are also frequent in other organ systems, such as the cardiovascular, gastrointestinal, and genitourinary systems. By far the most common limb defects are terminal longitudinal defects then terminal transverse defects. Of all cases of limb defects, 75% are upper limb and 25% lower limb. We found no evidence that one side is affected more frequently. About 6.5% of cases had another family member registered with a skeletal defect; 12.9% of cases died within the first year of life, the majority (85%) of those dying having additional defects. Etiological considerations are discussed for some subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of incidence trends for esophageal atresia and tracheoesophageal fistula, and infectious disease

There has been a suggestion that esophageal atresia with tracheoesophageal fistula (EA/TEF) may be related to the occurrence of infectious disease in the population during the time of early gestation. There is therefore a need for further data on trends in incidence related to infectious diseases. Data on the occurrence of EA/TEF with and without additional congenital malformations may also be relevant. The British Columbia Health Surveillance Registry is population-based with excellent case ascertainment of birth defects, and data are available on the incidence of infectious diseases for B.C., allowing comparison of trends to be made. One hundred forty-nine cases of EA/TEF occurred among 534,834 consecutive livebirths during the period 1966-1980 for an incidence rate of 1/3,590. No significant (p less than 0.05) annual, seasonal or monthly incidence trends were observed. In addition, the occurrence of EA/TEF could not be correlated with the prior incidence of infectious hepatitis, rubella, salmonella, or rubeola. Fifty-five percent of individuals with EA/TEF had congenital malformations in other systems, most frequently cardiovascular, gastrointestinal, and genitourinary. Most individuals with additional congenital malformations had multiple system involvement.     

On the symmetry of limb deficiencies among children with multiple congenital anomalies

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.     

Independent effects of maternal age and birth order on the incidence of selected congenital malformations

Incidence rates, specific for maternal age and birth order, were calculated for 16 categories of congenital malformations reported on birth certificates from a population of more than 8 million registered, white, single livebirths. With maternal age held constant, none of the malformations showed increasing incidence as birth order increased. Hypospadias, esophageal defects, omphalocele, and Down syndrome showed evidence of decreasing incidence as birth order increased. Some of the other malformation categories showed an excess of 1st births in most age groups, while no relation to birth order was observed in the incidence of other malformations. By contrast, most of the malformations analyzed exhibited increasing incidence as maternal age increased. Especially high rates of several malformations were observed among 1st births to women over age 40.     

Severe congenital limb deficiencies,vertebral hypersegmentation,absent thymus and mirror polydactyly: A defect expression of a developmental control gene?

We describe two unrelated patients with a complex malformation pattern that may be a candidate for a developmental gene disorder. These two patients had severe, symmetrical upper and lower limb deficiencies, vertebral hypersegmentation, and duodenal atresia. Patient 1 also had mirror-image polydactyly of his feet; patient 2 was athymic. The concurrence in two unrelated patients of additional vertebrae with severe anomalies in limb development, including a symmetrical deficiency of the four limbs and either mirror-image duplication of some toes (only in patient 1) or absence of the thymus (only in patient 2), represents an early alteration in body-plan organization. Since limb development, thymus development and segmentation are possibly under the control of homeobox genes in the human embryo, it seems reasonable that the malformations observed in these two patients resulted from a defect of a gene controlling developmental pattern formation, possibly a homeobox gene or a paired-box gene. Severe limb deficiencies have been reported in other well-known genetic entities, such as Roberts syndrome, Baller-Gerold syndrome, X-linked amelia, and DK-phocomelia syndrome. However, since the specific pattern of anomalies observed in these patients makes the diagnosis of some of the abovementioned disorders unlikely, we conclude that our patients have a previously undescribed disorder.     

Patterns of combined limb malformations.

Seven different limb malformations types were defined in 544 affected newborns, apparently free from other anomalies, obtained from a series of 297,299 livebirths. These seven malformation types were: polydactyly, limb reduction, brachydactyly, symphalangy, syndactyly and split hand/foot. One anomaly type was present in 472 newborns (1.58/1,000) and two or three in 72 (0.24/1,000). The observed combinations of two or three limb malformation types cannot be explained as chance association. Therefore, a common etiopathogenic mechanism has to be considered when two or more limb malformation types are combined in a given individual. The most frequent observed combinations were: reduction-brachydactyly, reduction-syndactyly, brachydactyly-syndactyly, polydactyly-syndactyly, and reduction-brachydactyly-syndactyly. Based on affected limb distribution, sex ratio, and familial recurrence rates, it is suggest that a reduction anomaly is the primary component in all tested combinations while syndactyly tends to be a secondary one when combined with any other limb anomaly type.     

Evidence of a Neural Inductive Phase in Limb Development

To demonstrate a causal relationship between neuronal damage and peripheral mesodermal anomalies, an operation was performed through oblique incisions in the dorsum of 247 chick embryos at stages 12–15 of development. In the region of the 24–30th presumptive somites, a three to four somite length of the right half of the neural tube was cut with fine glass sytlettes and removed with a 40μm glass pipette. Immediately after the operation and at intervals during continued incubation (37±, 75% R.H.), embryos were processed for histology. Fifty one embryos survived until day 14 when they were examined for malformations. Excision frequently resulted in a variety of reduction deformities: some embryos appeared normal; 31 displayed unilateral hemimelia or amelia. Examination of serially sectioned embryos fixed immediately and at varying intervals after the operation, demonstrated that this range of malformations was consistent with variation in the amount of neural tissue excised. Disruption of the mesoderm and regeneration of nervous tissue was minimal. It is concluded that the nervous system per se or some factor produced by the nervous system is essential for the development of the limb.     

Hirschsprung disease in a large birth cohort

The incidence of Hirschsprung disease was studied in a series of almost 700,000 consecutive livebirths in British Columbia from 1964-1982, by means of the records of a health surveillance registry that uses multiple sources of ascertainment. The estimated liveborn incidence rate for Hirschsprung disease was 1 in 4,417 livebirths (156 cases out of 689,118 livebirths). Data pertaining to sex ratio, additional anomalies, recurrence, and mortality were also analyzed over the caseload period 1952 to 1983. A total of 29.8% of cases had some additional anomaly--the majority being nonregional anomalies in other systems or more distantly in the gastrointestinal tract. Cardiovascular and gastrointestinal anomalies not a direct consequence of Hirschsprung disease were the most frequent additional anomalies found, occurring in 10 and 12 of 178 cases, respectively. Sensorineural anomalies were also frequent, occurring in 12 of 178 cases. Clinical implications arising from the study regarding the neonatal assessment of infants with these anomalies are discussed.     

Drug-Induced (Thalidomide) Malformations

Phocomelia (flipper-like limbs) has long been recognized as a rare malformation. Numerous cases of phocomelia and other congenital malformations have recently been reported in the United Kingdom, Australia, Europe and Canada in which the common factor appears to have been the administration of the hypnotic compound thalidomide during early pregnancy. Two additional cases of infants born with phocomelia, amelia and alimentary abnormalities are presented. In both of these cases the administration of thalidomide was initiated early during pregnancy (five to eight weeks after the last normal menstrual period) and maintained for several weeks. Thalidomide (alpha-phthalimido glutarimide) is related chemically to other glutarimides currently in clinical use. The possibility that these compounds and/or their metabolites may induce teratogenic effects warrants consideration. Emphasis is added to the view that caution should be exercised when prescribing new drugs.     

Threatened abortion, hormone therapy and malformed embryos

Causal relations between maternal genital bleeding, supportive hormone therapy and external malformations of the embryos were investigated with special reference to the critical period of organogenesis. This was done using morphological and obstetrical data obtained by Nishimura and his associates from 667 undamaged embryos derived from induced abortions whose mothers had genital bleeding in early pregnancy. In addition, data from 90 embryos with polydactyly and 38 with limb reductions in the Nishimura collection were used for case history studies. Evidence was presented to demonstrate that, for major malformations such as CNS anomalies, cleft lip, polydactyly and limb reductions, maternal genital bleeding was not a cause but a consequence of the conception of an abnormal embryo. No indication was revealed that exogenous female hormones currently used in Japan for preventing miscarraiges could produce major malformations recognizable at the embryonic stage, including limb reductions, nor salvage the severely malformed embryos. This does not however mean to exclude the possible relationship of progestogens/estrogens intake during early pregnancy with an increased incidence at birth of certain internal and/or external malformations. It was suggested that most, if not all, of the minor anomalies observed at certain embryonic stages are kinds of normal variants without any functional impairment of embryonic development.     

Facial clefts in Saudi Arabia: an epidemiologic analysis in 179 patients

One hundred and seventy-nine consecutive cases of facial clefts that were treated at the King Khalid University Hospital, in Riyadh, Saudi Arabia, were analyzed for an epidemiologic study. Isolated cleft lip was present in 38 percent, cleft of lip and palate in 37.4 percent, and cleft of the posterior palate in only 22.4 percent. There was a male preponderance in all types. In cases of cleft lip with or without cleft palate, the more commonly affected side was the left, followed by bilateral cases. Associated malformations were present in 13.4 percent. A positive family history was found in 26.8 percent of cases. A significant number of patients (7.8 percent) were first seen at more than 10 years of age. The incidence of facial clefts at this hospital was 0.3 per 1000 live births, computed over a period of 6 years. This incidence is significantly lower than that reported from European and Far Eastern countries.     

产前超声诊断及漏诊胎儿肢体畸形分析

目的：探讨胎儿肢体畸形超声特征及诊断价值。方法：采用连续顺序追踪法对66342 例妊娠12-40 周孕妇行胎儿四肢畸形筛查。将产前超声诊断结果与引产或产后结果进行对比分析。结果：发生肢体畸形271 例,发生率为0.41 %（271/66342）,包括四肢短小5 例,桡骨发育不全1 例,缺肢畸形5 例,足内翻17 例,手掌畸形3 例,指趾畸形222 例及骨骼多发畸形18 例。其中产前诊断胎儿肢体畸形49 例;漏诊222 例,包括：足内翻3 例、指趾畸形218 例、多发骨骼畸形1 例。胎儿肢体畸形的出现率和产前检出率分别为：四肢短小1.84 %（5/271）、100 %（5/5）;桡骨发育不全0.36 %（1/271）、100 %（1/1）;缺肢畸形1.84 %（5/271）、100 %（5/5）;足内翻6.27 %（17/271）、82.35 %（14/17）;手掌畸形1.10 %（3/271）、100 %（3/3）;指趾畸形81.91 %（222/217）、1. 8%（4/222）;多发骨骼畸形6.64 %（18/271）、94.44 %（17/18）。结论：超声对胎儿手掌、脚掌部位以上畸形的检出率较高。指趾畸形出现率最高,但检出率最低。     

Incidence of anencephaly and other major malformations when oestriol excretion is very low.

A study of 533 women with very low urinary oestriol excretion during the third trimester of pregnancy showed an incidence of major fetal malformations among their infants of 7-1% and a perinatal mortality rate of 14-6%. Thirteen of the malformations were cases of anencephaly, and 26 of the 78 perinatal deaths were due to or associated with major fetal malformations. The incidence of these complications was higher when maternal oestriol excretion was lower. Routine screening by urinary oestriol assay, with fetal radiography when values below 20-8 mumol/24 hours (6 mg/24 h) are detected is the most reliable method of detecting anencephaly before birth.     

产前超声诊断及漏诊胎儿肢体畸形分析

目的:探讨胎儿肢体畸形超声特征及诊断价值。方法:采用连续顺序追踪法对66342例妊娠12-40周孕妇行胎儿四肢畸形筛查。将产前超声诊断结果与引产或产后结果进行对比分析。结果:发生肢体畸形271例,发生率为0.41%(271/66342),包括四肢短小5例,桡骨发育不全1例,缺肢畸形5例,足内翻17例,手掌畸形3例,指趾畸形222例及骨骼多发畸形18例。其中产前诊断胎儿肢体畸形49例;漏诊222例,包括:足内翻3例、指趾畸形218例、多发骨骼畸形1例。胎儿肢体畸形的出现率和产前检出率分别为:四肢短小1.84%(5/271)、100%(5/5);桡骨发育不全0.36%(1/271)、100%(1/1);缺肢畸形1.84%(5/271)、100%(5/5);足内翻6.27%(17/271)、82.35%(14/17);手掌畸形1.10%(3/271)、100%(3/3);指趾畸形81.91%(222/217)、1.8%(4/222);多发骨骼畸形6.64%(18/271)、94.44%(17/18)。结论:超声对胎儿手掌、脚掌部位以上畸形的检出率较高。指趾畸形出现率最高,但检出率最低。     

Further clinical delineation in trisomy 1q32 syndrome.

A male newborn with multiple congenital abnormalities was studied. Clinically, he showed prominent forehead, facial dysmorphism, ear malformations, congenital heart defect and limb anomalies. The cytogenetic studies demonstrated a karyotype 46,XY, der(18) t(1;18)(q32;p11.3)pat with partial trisomy 1q32-qter and a monosomy 18p. The patient displayed clinical features of trisomy 1q but not of monosomy 18p. There are around 80 reports of trisomy 1q32. The purpose of this paper is to describe the first case of a translocation involving 1q and 18p chromosome breakpoints. Additional findings detected in the propositus permit us a further delineation of the trisomy 1q syndrome.