Biomedical subjects
Publications and source records attributed to P Beighton.
We have completed a survey of the causes of deafness in 3,064 children with defective hearing who attend special schools in Southern Africa. Specific genetic or multifactorial syndromes were diagnosed in 7 per cent, familial undifferentiated deafness was recognized in 11 per cent, while in 25 per cent the deafness was acquired.
Thirty-one sets of conjoined twins were born in Southern Africa during the period February 1974 to May 1982 with a striking increase in incidence in 1974 and 1975. There was no ethnic or social predilection, but clustering of cases occurred in a remote area of Zimbabwe. No aetiological agent was discovered, and there was no seasonal variation in the time of conception. Female conjoined twins accounted for 62% of cases, and twenty sets were of the thoracopagus type. Four pairs were separated, three of which were of the xiphopagus subtype and have survived.
Three siblings of Indian stock had profound bilateral conductive deafness with variable malformations of the external ears, stapedial abnormalities and facial paralysis. Their mother was similarly affected and inheritance of this private syndrome is evidently autosomal dominant. Some improvement of auditory function was obtained by surgical intervention in the middle ear.
A large Indian kindred in which the fragile X chromosome is segregating has been investigated in Cape Town. Eight male hemizygotes and four female heterozygotes were mentally retarded. There is suggestive evidence that one deceased male of reportedly normal intelligence may have been a hemizygote. The existence of the fragile X syndrome in a number of different ethnic groups supports the contention that the gene controlling the phenotype and the fragile site are the same, or at least overlap.
Eight members of a large kindred of mixed ancestry from a remote rural area of South Africa were investigated for deafness. In each, severe permanent perceptive hearing loss had developed during antituberculous therapy with streptomycin sulphate in conventional doses. Although unproven by the data available in this study, the familial aggregation and pattern of distribution of sensitivity to streptomycin suggested autosomal dominant inheritance.
The clinical features of nine new patients with dysplasia epiphysialis hemimelica are reported, with a long-term follow-up on a further seven patients who were described in the earliest case reports of this disease. Each of these 16 patients had only one leg involved, but 12 had multiple epiphyses affected. The distal femur, distal tibia and talus were the commonest sites and most patients presented with painless swelling or deformity. Wasting of the muscles of the affected leg was a common finding, and was occasionally disproportionate to the degree of disuse. One patient had the unique combination of involvement of the lateral and medial halves of different epiphyses in the same limb and another had unusual metaphysial changes. Diagnosis was often delayed despite typical radiographic appearances. There was no evidence for a genetic component in the aetiology nor was any common environmental factor identified. Treatment by local excision was generally effective for lesions in the vicinity of the knee, but some patients with involvement of the talus required arthrodesis around the ankle. The long-term prognosis appears to be good and so far only two of these patients have developed premature osteoarthritis.
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In the past decade dramatic developments have taken place in antenatal diagnosis. Various techniques are now fully established as routine procedures and these are applicable to several categories of genetic diseases. Transabdominal amniocentesis is currently the most important method for the prenatal diagnosis of chromosomal conditions, neural tube defects and biochemical disorders. Ultrasonography is playing an increasingly important role in the detection of malformations, while fetoscopy is now employed for fetal blood sampling, biopsy and visualization. Recombinant DNA techniques hold great promise for the intra-uterine diagnosis of common and important disorders in which the fundamental defect is unknown.
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Six patients with fibrodysplasia ossificans progressiva, a condition not previously reported in Blacks in this country, have been reviewed. All had serious physical disability and medical or surgical therapy did not influence the course of the disease. By extrapolation from prevalence data established in Britain, it can be estimated that there are at least 10 additional affected individuals in southern Africa.
In a nationwide survey of South Africa we ascertained and investigated 157 persons with Huntington's chorea and collected data on a further 328 deceased individuals who had probably been affected. Of the 157 respondents, 17 had a juvenile onset and in 13 of these the father had been the affected parent. Further analysis of these data shows that the father had transmitted the gene to 5 of the 6 children with onset in the first decade. The heterozygote frequency in the combined white population and the group of mixed ancestry is 6.7 X 10(-5) and the minimum number of heterozygotes is 458 in South Africa (1 in 13,000). The disorder is extremely rare in African Negroes; only 3 affected individuals were identified out of a population of 19 million.
The name atelosteogenesis is proposed for a lethal chondrodysplasia characterized by deficient ossification of various bones, notably the humerus, femur, thoracic spine, and hand bones. Clinically, the patients have micromelic dwarfism with incurvated legs, club feet, often dislocation of the elbows, and, rarely, a cleft palate. The most characteristic radiographic signs are incomplete ossification of the vertebral bodies with coronal clefts of the lumbar and hypoplasia of the upper thoracic vertebral bodies, a distal hypoplasia and club shape of the humerus and the femur, and the lack of ossification of single phalanges and metacarpals in most patients. Histologically, there are clusters of chondrocytes surrounded by fibrous capsules and, more frequently, degeneration zones containing degenerated chondrocytes and copious amounts of metachromatic material in the epiphyses and the basal zone of the growth plate.
When are Wormian bones significant is not an easy question to answer, but its relevance is important in relation to bone dysplasias such as osteogenesis imperfecta. Recognition will differ with age of patient, radiographic objectivity, and personal subjectivity. In order to attempt an answer, the skull radiographs of 81 cases of osteogenesis imperfecta of varying ages were examined for the presence of Wormian bones. These were compared against the incidence of Wormian bones in 500 skull radiographs of normal children. Significant Wormian bones as against normal developmental variants were considered to be those more than 10 in number, measuring greater than 6 mm by 4 mm, and arranged in a general mosaic pattern. They were found in all the cases of osteogenesis imperfecta but not in the normal skulls. The occurrence of significant Wormian bones in other bone dysplasias from our material and that of the literature was recorded. Other incidental findings in the skulls of the cases of osteogenesis imperfecta were also appraised.
The clinical and radiographic features of 47 cases of neonatally manifest osteogenesis imperfecta were analyzed. A scoring system was devised to code the degree of skeletal changes. A score of 2.7 and more carried a prospective mortality of 88%. Scores of 2.6 and less were associated with a survival rate of 90%. The prognosis was particularly favourable in a subgroup of patients characterized by marked bowing of the lower extremities, mild involvement of the rest of the skeleton and white sclerae. Neonates with these features tended to have a good long-term prognosis, with few additional fractures and partial or total spontaneous resolution of the limb deformity. The study confirmed the genetic and prognostic heterogeneity of the disorder, which comprises several autosomal dominant and recessive entities.
The radiographic manifestations of nine South African patients with fibrodysplasia ossificans progressiva (FOP) have been analysed in detail. In three of these individuals, a 10--15 year follow-up was available. The condition usually presents before the age of 5 years; in one infant, abnormal calcification was demonstrated at 9 months. The disorder is remorselessly progressive but the hands, diaphragm and viscera are spared. Ossification in ligaments at the site of their attachment to long bones produces a 'pseudo-exostosis' appearance. Tethering of the shafts of long bones and growth at the proximal metaphyses can result in dislocation of shoulder and hip joints. In the hip joint the sloping configuration of the acetabular roof is produced by normal growth at the proximal metaphyseal end of the tethered femur. Calcification in periarticular tissues, together with bony and fibrous ankylosis, contributed to joint fixation. A similar process of growth inhibition leads to disparity in size between the bodies of the cervical vertebrae and their posterior appendages. It is concluded that apart from the developmental abnormality in the great toes, the skeletal changes in FOP are the consequence of soft tissue ossification and that the condition is not a primary bone dysplasia.
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Electrophoresis of the beta-glucosidase isozymes from various normal human sources revealed that cultured fibroblasts expressed only the acid beta-glucosidase isozyme. Therefore, selected physical and kinetic properties of the residual acid beta-glucosidase activities in fibroblasts from Gaucher Type 1 homozygotes of various ethnic backgrounds were compared. The findings of different specific activities, thermostabilities, apparent Km values, and electrophoretic migrations of the residual activities from the ethnic variants provided the first biochemical evidence of genetic heterogeneity in Type 1 Gaucher disease.