Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene.

Acheiropodia is an autosomal recessive developmental disorder presenting with bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. This severely handicapping condition appears to affect only the extremities, with no other systemic manifestations reported. Recently, a locus for acheiropodia was mapped on chromosome 7q36. Herein we report the narrowing of the critical region for the acheiropodia gene and the subsequent identification of a common mutation in C7orf2-the human orthologue of the mouse Lmbr1 gene-that is responsible for the disease. Analysis of five families with acheiropodia, by means of 15 polymorphic markers, narrowed the critical region to 1.3 cM, on the basis of identity by descent, and to <0.5 Mb, on the basis of physical mapping. Analysis of C7orf2, the human orthologue of the mouse Lmbr1 gene, identified a deletion in all five families, thus identifying a common acheiropodia mutation. The deletion was identified at both the genomic-DNA and mRNA level. It leads to the production of a C7orf2 transcript lacking exon 4 and introduces a premature stop codon downstream of exon 3. Given the nature of the acheiropodia phenotype, it appears likely that the Lmbr1 gene plays an important role in limb development.

Epidemiology and genetics of endemic goiter. I. Epidemiological aspects.

This study dealt with approximately 2,000 children and their parents living in a hyperendemic goiter area in Central Brazil, which is bounded by the jungle to the north and by a large plain to the south. The determination of goiter was made according to the methods and classification adopted by WHO. Conspicuous forms of goiter were found in 41% of the children examined. Multiple linear regression analysis showed an increase with age in the frequency of goiter in both sexes. Although data from the literature show that Mulattoes and Negroes have statistically higher frequencies of goiter than do Whites, our multiple linear regression analysis revealed no evidence for an effect of race on the endemism. There was no significant association with socioeconomic level. The presence of goiter in parents was shown to be statistically associated with its occurrence in the children.

Endemic goitre in whites and negroes: racial or social effect?

A sample of 2688 individuals, about half of them showing endemic goitre, has been studied in a hyper-endemic area of the state of Mato Grosso, Brazil. The codified data were processed in computers. Analyses through contrasts among multinominal proportions showed Negroes and Mulattoes with higher frequencies of goitre than Whites, thus agreeing with results from the literature. A number of multiple regression models, including 21 independent variables, showed no evidence of any intrinsic racial effect on the occurrence of goitre. The authors conclude that the higher prevalence of goitre among Malattoes and Negroes probably reflects the influence of their poorer socio-economic conditions. Although genetic factors are generally assumed to play some role in the development of goitre, it is to environmental causes that the most important role is ascribed.

Sex and age prevalence of endemic goitre: an epidemiological study.

A hyperendemic goitre are ain the State of Mato Grosso, Brazil, has been epidemiologically surveyed, following a methodology adopted by the World Health Organization. 3,757 individuals (1,762 males and 1,995 females) have been examined. The distribution of goitre according to sex and age has been analysed through simultaneous confidence intervals for contrasts among multinomial proportions, as well as multivariate models, using computer programs. Low frequencies of goitre have been found in both males and females younger than 5, while in the older groups the frequencies were very high. Females showed higher frequencies of goitre than males in puberty and adulthood. Multivariate analyses, where 21 independent variables entered in a number of multiple regression models, confirmed the influence of age and sex on the manifestation of endemic goitre.

Historical note: the extraordinary handless and footless families of Brazil - 50 years of acheiropodia.

The history of acheiropodia is divided into 4 phases: discovery, exploration, modern studies, and contemporary knowledge. The discovery phase (1929-1930) is represented by the publication of the 1st family. For about 30 years, it remained the only family referred to in a number of textbooks of medicine, biology, and others. In the exploration phase (1956-1966), the first family was reanalyzed, other families were ascertained and analysed, and some radiologic aspects of the anomaly were published. The modern phase (1968-1972) is characterized by a large series of studies on the clinical aspects of acheiropodia, including laboratory and radiological examinations, psychological tests, status of vision, electrocardiograms, etc. In the contemporary phase (since 1974), genetic aspects prevailed, and studies were published on segregation analysis, selection pressure, genetic load, mutation rate, etc. Each one of these 4 phases is analyzed in detail.

Genetics of acheiropodia ("the handless and footless families of Brazil"): XI. Pathologic aspects.

We report another case of acheiropodia, a rare autosomal recessive trait of distal limb deficiency, to date seen only in Brazil in persons of Portuguese ancestry. The patient's parent were first cousins; she had two younger affected sisters. She presented with signs of vascular insufficiency of the lower stumps, which after amputation were found to lack large vessels below the knee.

Genetics of acheiropodia ("The handless and footless families of Brazil"): X. Roentgenologic study.

The main radiologic findings from four unrelated cases and two sibs with acheiropodia are presented and discussed. On the basis of such analysis, a clinical and radiologic description of the anomaly is given. The presence of one or more fingers and of a small bone (Bohomoletz bone) in the upper stumps is discussed. These unusual findings in bone structure were assumed to be due to a variability in the expression of the acheiropodia gene. Radiologic studies of some of the acheiropods' normal parents failed to reveal even mild manifestations of the gene in the heterozygous state. No recognizable pattern was found in the dermal ridges on the end of the acheiropods' upper or lower stumps.

Genetics of acheiropodia ("The handless and footless families of Brazil"): IV. Sex ratio, consanguinity and birth order.

The sex ratio among acheiropods is shown to be not significantly different from the sex ratio among their normal sibs, as well as among other segments of the family (parental sibships, cousin sibships and other sibships). The frequency of consanguineous marriages among the parents of acheiropods (82%) is one of the highest thus far reported among parents of individuals affected with rare autosomal recessive anomalies or diseases. No evidence was found of any overall positive or negative birth order effect on the incidence of acheiropodia. These results further strengthen the hypothesis of a simple genetic mechanism for acheiropodia, namely autosomal recessive inheritance, without any detectable complication as regards sex ratio, consanguinity and birth order. Although the family size from heterozygous parents (producing at least one acheiropod) was twice as large as family sizes in other segments of the families (8 against 4), we have at present no evidence to support either heterozygous advantage or reproductive compensation.

Genetics of acheiropodia (the handless and footless families of Brazil). VII. Population dynamics.

Since carriers of the acheiropodia gene cannot be distinguished from noncarriers, parents and normal sibs of affected individuals have been used to estimate the fitness of heterozygotes. No significant difference in biologic fitness (viability and fertility) between normal sibs and the general population could be detected. A comparison between acheiropods and their normal sibs showed the following: (1) a nonsignificant difference in stillbirth rate; (2) a higher mortality rate of acheiropods in the first 5 years of life; (3) a relative viability not larger than .7; (4) a relative fertility no greater than .14, due to "cosmetic effects"; and (5) a fitness of .10 or lower. The total number of acheiropodia genes in Brazil has been calculated as 25,000 in the 1970s. The data are compatible with an extremely low mutation rate and a very stable locus. It is suggested that all Brazilian acheiropods can be traced to a single mutation. A conservative estimate of the number of acheiropods to appear in the future in Brazil is 14,000 with an extinction time of no less than 2,300 generations or almost 70,000 years. A variety of other parameters have been calculated.

Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis.

A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases were detected. The ascertainment of the probands was through multiple incomplete selection (pi = .55 +/- .07). The data are consistent with the hypothesis of an extremely rare autosomal recessive gene as the etiological factor in acheiropodia. Prevalence is estimated as 29 +/- 4, which is the same as the number of high risk cases; gene frequency equals .0009 +/- .0005, and the incidence at birth is 4 times 10(-6) by the indirect method or 7 times 10(-6) by the direct method. The frequency of heterozygotes at birth is assumed to be 0.18% (450 times the frequency of affected). Population size is approximately 10 million, and the number of founders on a unique-mutation hypothesis is estimated as about 500. All these estimates are first approximations and must be accepted with caution.

[Human genetics studies in areas of high natural radiation. VII. Genetic load]. / Estudos de genética humana em áreas de alta radiacão natural. VII. Carga genetica

Two methods to estimate the inbreeding load (Morton, Crow and Muller17 1956; Freire-Maia and Freire-Maia6 1965) are reviewed. Both are employed in the analysis of our data. Besides the total population, a sample constituted of individuals with no alien ancestral is also analysed. No clean effect of natural radioactivity, as measured by genetic load models, has been found (this is especially valid for abortions, pre-natal mortality, anomalies, and abnormalities in general). The results on stillbirths and post-natal and total mortalities are discussed, and it is concluded that most probably the differences found are due to uncontrolled concomitant variables (if not to chance alone). Further analysis are under way.