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Objective: To examine genetic and environmental factors in the origin of isolated congenital limb deficiencies., Design: Case-control study with questionnaire at a family interview of cases of isolated congenital limb deficiencies (six types), negative controls (matched for age, sex, and place of residence), and positive controls (cases of sentinel anomalies)., Setting: The database of the Hungarian Congenital Abnormality Registry, 1975-84, complemented by three other sources of ascertainment (1,575,904 births)., Subjects: 537 case-control pairs; 392 positive controls., Main Outcome Measures: Smoking during pregnancy, congenital limb deficiencies., Results: The adjusted rate of smoking during pregnancy was significantly higher in the mothers of cases of terminal transverse defect (relative odds 1.48; 95% confidence interval 0.98 to 2.23; P = 0.017). This finding supports the hypothesis of vascular disruption as a cause of congenital limb deficiency., Conclusions: Maternal smoking during pregnancy raises the relative odds for terminal transverse limb deficiencies.

A population-based and validated data set of 195 cases with isolated terminal transverse-type congenital limb deficiency was evaluated in Hungary, 1975-1984. Terminal transverse types of congenital limb deficiency are not usually associated with non-limb defects, and typically only one limb is affected. Upper limb is more frequently affected than lower (9:1) in monomelic cases. The left side and females are affected more often in upper limbs while lower limb defects are evenly distributed between right and left sides and both sexes. Familial occurrence was not found.

Radial and tibial deficiencies are frequently (70%) associated with non-limb abnormalities. Isolated radial and tibial deficiencies may have a different etiology: in this study radial deficiencies were more frequent, there were milder subtypes and one-limb involvement was found in 70% of cases, tibial deficiencies were rare, mild subtypes did not occur and in general more limbs were involved. Among multimelic cases, one case had hypoplasia of the tibia with polydactyly and two cases had tibial aplasia with split hand +/- foot of autosomal dominant inheritance. Of 40 cases, four were familial. Findings of a case-control study on this population-based and validated 10-year cohort showed a lower mean birth weight and a higher rate of low birth weight in cases with isolated radial and tibial deficiency.

A population based and validated 10 year cohort of 94 cases with split hand/foot born in Hungary, 1975-1984 was evaluated. This type of congenital limb deficiency was relatively frequently (43%) associated with non-limb defects. Fifty-four cases with isolated split hand/foot are evaluated in this paper. A single limb was affected in 78% of cases. The upper limbs were 21 times more frequently affected in unimelic cases with a right sided predominance and male excess. Case-control analysis indicated intrauterine growth retardation and lower socioeconomic status of parents of cases. Family study showed six familial cases with autosomal dominant inheritance among 152 first and 452 second degree relatives. All familial cases were males.

A population-based and validated data set of 206 cases with apparent amniogenic limb deficiency was ascertained in Hungary between 1975 and 1984. Such limb defects frequently (36%) associated with nonlimb abnormalities. In 134 cases with isolated defects typically more limbs are affected, upper and lower limbs, right and left sides, and both sexes are equally affected. Case-control analysis of such isolated cases indicates a lower socioeconomic status of parents, a higher parity, more frequent unwanted pregnancies, preterm birth, and a higher rate of threatened abortion. Familial occurrence was not found in 415 first-degree relatives.

A population-based and validated data set of 114 cases with isolated ulnar-fibular deficiency was evaluated in Hungary, 1975-1984. Ulnar-fibular type had the third most common birth prevalence (0.07 per 1000) among isolated congenital limb deficiency types. This type is relatively rarely associated with nonlimb defects, a single limb is affected in two-thirds of cases, nearly all other cases had femur-fibula-ulna (FFU) dysostosis. Upper and lower limbs, right and left sides, are equally affected, however, there is an obvious male excess (71%). Case-control analysis indicated a lower birth weight due to intrauterine growth retardation, higher birth order, lower socioeconomic status of parents, and a more frequent reported subfertility. The family study identified one familial cluster (one siboccurrence) among 331 first-degree relatives.

A population-based and validated data set of 14 cases with isolated proximal intercalary type of congenital limb deficiency born in Hungary between 1975-84 was evaluated. Two cases had phocomelia of upper limbs, while 12 cases were affected with classical intercalary defects mainly in femurs. Of 14 cases, 13 had unimelic manifestation and both sexes were equally affected. The intrauterine growth retardation, the excess of second birth order, a higher rate of acute maternal disorder of the respiratory system and the lack of familial cluster are noteworthy. The vascular disruption hypothesis seems to be the most plausible explanation for the origin of isolated proximal intercalary defects.

998 cases affected with limb reduction deficiency were evaluated in Hungary, 1975-1984. Through the check-up of other sources of ascertainments, the Hungarian Congenital Abnormality Registry was found to be 98.4% complete. The proportion of misdiagnoses was 12.6%. In the period encompassed by the study, the birth prevalence of revised cases affected with congenital limb reduction deficiency was 0.55 per 1000 total births. Isolated and multiple cases were separated. The birth prevalence of revised isolated cases was 0.35 per 1000. Six types were separated based on their phenotypic manifestations. As the number of affected limbs, ratio of isolated and multiple cases and sex ratio showed obvious differences, etiological factors should be evaluated separately in these different types of congenital limb deficiencies.

Congenital limb reduction abnormalities have been reported in Hungary since 1970. A clinical and genetic study was made of 274 cases reported from 1975 to 1977, corresponding to a total number of 561915 births. A classification according to type of defect, involvement of one or more limbs and other associated defects is attempted. Data on incidence, sex ratio, laterality and mortality are presented.

A family study of 274 index patients with limb reduction malformations born in Hungary from 1975 to 1977 is reported. The majority of 789 first-degree relatives were personally examined. Information was collected on 1094 uncles and aunts and on 1095 cousins, and those affected by limb malformations were examined. Among 789 first-degree relatives six were affected by a similar malformation (radial, ulnar and central ray defects) and 1 by a malformation of a different type; no secondary cases of the same type were found among the relatives of patients with terminal transverse and amniogenic malformations, and with limb malformations which were part of syndromes or unclassifiable associations with other malformations. While a few rare types of limb defects are due to dominant genes, the aetiology of most cases is obscure. There is no evidence of sex-linked inheritance, of multifactorial causation or of environmental factors shared by relatives. These results are similar to those of an earlier study by Birch-Jensen.