Leri-Weil dyschondrosteosis is a hereditary disease characterized by the development of numerous skeletal anomalies, which together lead to dwarfism and other disorders. Symptoms of this condition are low growth, mesomelia (shortening of the middle parts of the limbs), deformities of the bones of the forearms, lower leg and wrist, scoliosis. Diagnosis is made on the basis of the patient’s examination data, the study of his hereditary anamnesis, X-ray studies of the skeleton and molecular genetic analyses. There is no specific treatment for the disease, symptomatic therapy is used, including surgical correction of deformed and shortened bones.
Leri-Weil dyschondrosteosis or enchondral polytopic dysostosis is a genetic pathology caused by a violation of the formation of enchondral bones. Causes dwarfism and numerous skeletal anomalies. This condition was first described in 1929 by French neurologist A. Leri and pediatrician J. Weil, the results of the research in 1959 were confirmed by their colleagues and compatriots M. Lamy and K. Binenfeld. For a long time it was believed that this pathology is autosomal dominant, but the genes responsible for its development could not be found. At the present stage of the development of genetics, the cause of this disease was found in the sex chromosomes. At the same time, Leri-Weil dyschondrosteosis is not a sex-linked disease, since the genes whose defects lead to its development are located on the so-called pseudoautosomal sites of the sex chromosomes, and the inheritance of these sites does not depend on the sex of the patient. For this reason, the disease affects individuals of both sexes, but phenotypically it is more severe in women. Leri-Weil dyschondrosteosis is a fairly rare condition, its exact occurrence has not been clarified.
Leri-Weil dyschondrosteosis is a genetic disease with a pseudoautosomal dominant inheritance mechanism. The genes whose mutations lead to this condition are located on the sex chromosomes (both X and Y), but are transmitted to offspring as normal autosomal sites. These genes are SHOX and SHOXY, located on the short arms of the X and Y chromosomes (more precisely, on the pseudoautosomal site 1 or PAR1). The product of the expression of these genes are proteins of the same name, which are highly active transcription factors – the largest number of them in a healthy person is detected in bone tissue. Leri-Weil dyschondrosteosis develops due to a violation of the structure or expression of the SHOX and SHOXY proteins, which entails a distortion of the processes of cell division and differentiation in the enchondral bones (vertebrae, long tubular bones of the extremities).
For the development of Leri-Weil dyschondrosteosis, a mutation of the SHOX or SHOXY genes must necessarily be in a heterozygous state – homozygotes with such genetic defects have a much more severe disease (Langer’s mesomelic dysplasia). In some cases, in the presence of characteristic phenotypic manifestations of this pathology, mutations in the SHOX and SHOXY genes may not be detected. Most often, the genetic defect is localized in highly conservative non-coding regions that are located before and after these genes. These sites control the processes of transcription and expression of SHOX, that is, they act as its enhancers. When they are damaged, the expression processes of the above genes are disrupted, which also leads to the development of Leri-Weil dyschondrosteosis. Duplications of sequences of these genes have similar manifestations. Sometimes the presence of mutations in the SHOX gene does not lead to the development of such serious skeletal abnormalities, but to a condition known as idiopathic low growth.
In most cases, Leri-Weil dyschondrosteosis can be diagnosed already at the birth of a child, however, cases of pronounced symptoms of the disease have also been described in older children (up to adolescence). In a newborn, a characteristic sign of pathology is the shortening of the upper and lower extremities relative to the overall proportions of the body. In the future, varus deformities of the radius and tibia in the frontal plane and the ulna in the sagittal are added to this manifestation. The structure of bones and their joints in the wrist area is disrupted, which also leads to deformities (Madelung’s disease) and makes it difficult to move the hand. The growth rate of patients with Leri-Weil dyschondrosteosis is slowed down, ultimately the body length of adults with this condition does not exceed 130 centimeters.
Quite often, with Leri-Weil dyschondrosteosis, various spinal curvatures are registered in patients, mainly scoliosis. At the same time, there are no anomalies of the bones of the skull, ribs and pelvis. Malformations of internal organs for this disease are also uncharacteristic, the intellect of patients is completely preserved. The functions of the reproductive system do not suffer either, almost all patients are able to have children – only in severe cases in women, bearing a child may be difficult due to secondary disorders (severe scoliosis or other skeletal abnormalities). Thus, Leri-Weil dyschondrosteosis is manifested only by abnormalities of the spine and long tubular bones of the extremities, without affecting other systems and other parts of the skeleton.
Diagnosis and treatment
Diagnosis of Leri-Weil dyschondrosteosis is based on the study of the patient’s status, bones x-ray of the limbs and spine, genetic analysis. When examined, attention is drawn to shortened limbs – arms in the forearms and legs at the expense of the shins. Often with the naked eye you can see the deformation of these elements of the skeleton. An important manifestation of Leri-Weil dyschondrosteosis is obstructed supination and extension of the hand due to the deformation of the wrist according to the Madelung type. The stunting of patients and the insufficiency of their general physical development are always noted.
Radiography reveals shortening and deformities of the ulna, radius and tibia, in some cases, fibular aplasia is detected, leading to pronounced deformation of the foot. The interosseous space of the forearm is greatly expanded, the bones of the wrist are deformed, their first row forms a bend that visually pushes apart the distal ends of the ulna and radius bones. Radiographs with Leri-Weil dyschondrosteosis can also reveal scoliosis of the vertebral column of varying severity. A geneticist can make a genetic diagnosis of this disease – sequencing the sequence of the SHOX and SHOXY genes to identify point mutations, analyzing their number to exclude duplication, studying the structure of enhancers. Differential diagnosis of Leri-Weil dyschondrosteosis should be performed with other types of skeletal dysplasia.
There is no specific treatment for Leri-Weil dyschondrosteosis, symptomatic therapy consists in reducing the load on bones and joints, surgical correction of pronounced deformities and anomalies. It is possible to use the so-called corrective osteotomy. With a strong violation of the structure of the feet (which is observed with fibular aplasia), due to dyschondrosteosis, arthrosis is resorted to. Sometimes, at the request of the patient, surgical methods are used to lengthen the limbs by applying distraction devices after a longitudinal osteotomy. In severe forms of scoliosis, the help of an orthopedic surgeon and a vertebrologist may be required.
Prognosis and prevention
Despite the fact that Leri-Weil dyschondrosteosis often leads to disability of the patient, and significantly shortened limbs greatly reduce the quality of his life, the prognosis of the disease regarding survival is favorable. This is due to the fact that the disorder affects only the bone elements of the limbs and partly the spine, without affecting the internal organs, intellectual development and metabolism. In severe scoliosis, secondary disorders of the respiratory and cardiovascular systems may develop, therefore, this complication of Leri-Weil dyschondrosteosis requires timely treatment. Prevention of this condition is carried out only by the method of prenatal genetic diagnosis, which is especially important in the presence of such a disease in relatives.