Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia.

Type X collagen is a homotrimer of alpha 1 (X) chains encoded by the COL10A1 gene. It is synthesised specifically and transiently by hypertrophic chondrocytes at sites of endochondral ossification. Point mutations and deletions in the region of the COL10A1 gene encoding the alpha 1 (X) carboxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS).

Genetic mapping of a locus for multiple epiphyseal dysplasia (EDM2) to a region of chromosome 1 containing a type IX collagen gene.

Multiple epiphyseal dysplasia (MED) is a dominantly inherited chondrodysplasia characterized by mild short stature and early-onset osteoarthrosis. Some forms of MED clinically resemble another chondrodysplasia phenotype, the mild form of pseudoachondroplasia (PSACH). On the basis of their clinical similarities as well as similar ultrastructural and biochemical features in cartilage from some patients, it has been proposed that MED and PSACH belong to a single bone-dysplasia family.

Structural and segregation analysis of the type II collagen gene (COL2A1) in some heritable chondrodysplasias.

Seventy-seven persons with a variety of heritable chondrodysplasias were screened for gross rearrangements of the structural gene encoding the major cartilage collagen, collagen II. None was found. Segregation of the locus (COL2A1) was studied in 19 pedigrees using three restriction site dimorphisms (shown by PvuII, HindIII, and BamHI) and a length polymorphism as linkage markers.

Pseudoachondroplasia: clinical diagnosis at different ages and comparison of autosomal dominant and recessive types. A review of 32 patients (26 kindreds).

This survey reviews the diagnosis (predominantly radiological) of 32 cases of pseudoachondroplasia from 26 kindreds and illustrates the natural history and varying appearance of the disordered bone growth from infancy to adult life. In addition, an attempt has been made to detect phenotypic differences between autosomal dominant and recessive types (excluding isolated cases), analysing 10 kindreds of dominant inheritance (three in the current survey, seven from published reports) and six of recessive inheritance (three in the current survey, three from published reports). There appears to be no clinical or radiographical feature which clearly distinguishes them, but, using height as a criterion of severity, among those with autosomal recessive inheritance there was a disproportionate number of the most severely affected cases and there also appears to be very little intrafamilial variation.

Research for genetic and environmental factors in orthopedic diseases.

This is a review article of the past 40 years of research in Britain on the etiology of developmental disorders of the skeleton, covering both rare unifactorial diseases (chondroosteodystrophies) and common localized disorders (e.g., clubfoot and congenital dislocation of the hip) of multifactorial inheritance.

The tricho-rhino-phalangeal syndrome. A report of 14 cases in 7 kindreds.

Tricho-rhino-phalangeal syndrome is probably not so much uncommon as unrecognised. Its significance to orthopaedic surgeons, apart from the functionally unimportant minor finger deformities, lies in its mimicking both Perthes' disease and diaphyseal aclasis. The 14 cases analysed in this paper illustrate the wide range of clinical variation.

The prevalence of skeletal dysplasias. An estimate of their minimum frequency and the number of patients requiring orthopaedic care.

An attempt has been made to estimate the number of living people with skeletal dysplasias (osteochondrodysplasias) in Scotland, England and Wales, ascertained through five orthopaedic centres in different parts of Britain. Index patients and their affected relatives were sought and reassessed. Over the 30-year period between 1950 and 1979 inclusive a minimum prevalence was calculated (excluding stillbirths, perinatal deaths, and patients with chromosome anomalies, metabolic bone disease and short stature per se).

The infrequency of malignant disease in diaphyseal aclasis and neurofibromatosis.

The association of diaphyseal aclasis and neurofibromatosis with malignant neoplasms has been variously reported as between 5 and 28% of all cases, but malignant disease invariably presents at hospital and the true frequency from an unselected group is unknown. The current survey reviews not only hospital patients but also their affected relatives, with particular reference to malignant disease and the cause of death in all family members. A survey of 36 index patients and 80 known affected relatives with diaphyseal aclasis and 37 index patients and 33 known affected relatives with neurofibromatosis has been carried out.

Bilateral failure of the capital femoral epiphysis: bilateral Perthes disease, multiple epiphyseal dysplasia, pseudoachondroplasia, and spondyloepiphyseal dysplasia congenita and tarda.

A radiographic survey of 25 patients with bilateral Perthes disease is compared with four inherited skeletal dysplasias also affecting the hip joints (45 patients with multiple epiphyseal dysplasia, 22 with spondyloepiphyseal dysplasia tarda, 18 with pseudoachondroplasia, and 17 with spondyloepiphyseal dysplasia congenita). The distinguishing features in relation to the pelvis and hip joint in the growing child are ascertained, in view of the importance of differentiating as early as possible the transient disorder of Perthes disease from the more serious progressive disorders.

Five-fingered hand associated with partial or complete tibial absence and pre-axial polydactyly. A kindred of 15 affected individuals in five generations.

A kindred of 15 affected individuals in five generations is described with autosomal dominant inheritance of bilateral five-fingered hand. Some of them had additional pre-axial polydactyly of the fingers or toes and some had partial or complete absence of the tibia. The range of expression of the gene is variable and genetic advice to these families must take account of the whole spectrum of defects.

Aetiology and interrelationship of some common skeletal deformities. (Talipes equinovarus and calcaneovalgus, metatarsus varus, congenital dislocation of the hip, and infantile idiopathic scoliosis).

The Edinburgh Register of the Newborn 1964-1968 and the Edinburgh Scoliosis Clinic 1964-1971 have been used to establish the population frequency in the city of the idiopathic forms of talipes equinovarus and calcaneovalgus, metatarsus varus, congenital dislocation of the hip, and infantile scoliosis. A survey of 165 patients now aged 7 to 11 years showed an aetiological relationship, but with differing environmental factors. These factors were established by comparison with the Edinburgh Register control group of 692 normal infants born over the same period, giving a unique opportunity to obtain more accurate antenatal data than has previously been possible.

Two first cousins with spondyloepiphyseal dysplasia tarda (X linked recessive form), one also with poikiloderma atrophicans vasculare progressing to lymphocytic lymphoma.

Two male cousins with spondyloepiphyseal dysplasia tarda (X linked recessive form) are described. One presented with a poorly differentiated lymphocytic lymphoma of the skin in areas of poikiloderma atrophicans vasculare which had been present for 10 years.

Clinical variation in dyschondrosteosis. A report on 13 individuals in 8 families.

Thirteen patients with dyschondrosteosis from eight families are reviewed and their clinical and radiographic variation noted. Inheritance is likely to be autosomal dominant but with only 50 per cent penetrance. Stature was moderately reduced, due to shortening of the bones of the leg.

Two clinical variants of spondylo-epiphysial dysplasia congenita.

Seventeen patients with congenital spondylo-epiphysial dysplasia from six centres in Britain have been investigated and two variants delineated. There is wide clinical and radiological variability in each group with overlap between them, but 12 of the patients had very short stature and grossly disorganised hips with severe coxa vara, and the five remaining patients were less seriously affected with height only a little below the third percentile and only mild coxa vara. Both groups can be diagnosed at birth but the two cannot be differentiated on clinical and radiological grounds until after the age of three to four years when the developing severe coxa vara and difference in stature become apparent.

Are congenital vertebral anomalies and spina bifida cystica aetiologically related?

Radiological records of 104 patients with multiple vertebral anomalies without apparent spina bifida and 112 infants with spina bifida cystica were surveyed and the incidences of hemivertebrae and of rib, vertebral body, and vertebral arch fusions were recorded. The distributions of these four anomalies along the vertebral axis were found not to be statistically different between the two age groups. This is additional evidence to support the hypothesis that multiple vertebral anomalies and anencephaly-spina bifida cystica are aetiologically related.

Congenital vertebral anomalies and the possible aetiological relationship with spina bifida.

The frequency and distribution of hemivertebrae, fused vertebral bodies, fused vertebral arches and fused ribs were recorded in 376 children and young adults with either spina bifida cystica or occulta, or solitary vertebral body anomalies, or multiple vertebral body anomalies. An attempt was made to find evidence to support the hypotheses that multiple vertebral anomalies and anencephaly-spina bifida are aetiologically related, and that solitary vertebral body anomalies are sporadic and developmentally distinct. Statistical analysis of the distribution of the vertebral and rib defects partly supported these hypotheses.

Retinitis pigmentosa, metaphyseal chondrodysplasia, and brachydactyly: an affected brother and sister.

A brother and sister, children of normal parents are described. They had retinitis pigmentosa, causing near-blindness as a result of very narrow fields of vision, associated with metaphyseal chondrodysplasia and marked shortening of the metacarpals and terminal phalanges. Autosomal recessive inheritance is suggested with a common biochemical cause for all these defects.

The 1960s epidemic of arthrogryposis multiplex congenita: a survey from the United Kingdom, Australia and the United States of America.

Arthrogryposis multiplex congenita is believed to be a specific clinical entity which is aetiologically unrelated to the "arthrogryposis-like" deformities of known neurological diseases such as myelomeningocele and myelodysplasia. The observation that the condition appeared to be three times as common in Melbourne, Australia, as in four centres in the United Kingdom (Wynne-Davies and Lloyd-Roberts 1976), prompted this survey of 132 patients: 73 from the United Kingdom, 34 from Australia and 25 from Wilmington, Delaware, USA. The survey aimed to established the same criteria for diagnosis in the three countries and to search for prenatal and genetic aetiological factors.

Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis.

Forty-eight patients with achondroplasia and 24 with hypochondroplasia have been reviewed in order to clarify the differences between the two disorders and establish the height, body proportions and other clinical and radiological variations within each group. Some of the "classical" findings in achondroplasia are not always present, and hypochondroplasia at its most severe is indistinguishable from achondroplasia at its least severe. The frequency of spinal stenosis and neurological complications was established in an unselected group of 27 achondroplastic and 12 hypochondroplastic patients aged 10 years and over.