Spondyloepiphyseal dysplasia is a genetically heterogeneous hereditary disease from the group of osteochondropathies characterized by malformations of the vertebrae, epiphyses of long tubular bones and joints. Symptoms of this condition are low growth, deformities of the vertebral column (kyphosis) and chest, soreness and stiffness of large joints. Diagnosis of spondyloepiphyseal dysplasia is based on the results of X-ray examinations, general examination of the patient, study of his hereditary history and molecular genetic analysis. There is no specific treatment for this disease, physical therapy and massage are prescribed, wearing special corsets and other orthopedic means to reduce the load on the musculoskeletal system.
Spondyloepiphyseal dysplasia (Morcio-Brailsford disease) is a congenital genetically determined disease in which the processes of bone tissue growth are disrupted mainly in the vertebrae and epiphyses of long tubular bones. It should be distinguished from the syndrome of Morkio – mucopolysaccharidosis type 4. Often, the concept of “spondyloepiphyseal dysplasia” is understood as a wide group of genetic pathologies, such as Knist’s disease, spondyloepimetaphyseal dysplasia and a number of others. However, most researchers distinguish Morchio-Brailsford disease into a separate nosological unit. For the first time this disease was described in 1929 by the Uruguayan pediatrician L. Morchio and almost simultaneously with him I. Brailsford.
At the moment, the methods of modern genetics have identified several varieties of spondyloepiphyseal dysplasia, differing in the mechanism of inheritance and frequency of occurrence, which ranges from 0.2-1 case per 100 thousand population. The most common forms of this disease have an autosomal dominant nature of inheritance (according to some data – with incomplete penetrance), rarer varieties are characterized by recessive, X–linked transmission. Depending on the mechanism of inheritance of spondyloepiphyseal dysplasia, the sexual distribution of pathology also differs – usually both men and women are affected with the same frequency, but with gender-linked transmission, almost exclusively boys suffer.
Classification and causes
Like most other forms of congenital osteochondropathies, spondyloepiphyseal dysplasia develops due to a defect in the structural proteins of bone and cartilage tissues. The most common (frequency 1:100 thousand) autosomal dominant type of the disease is caused by a mutation of the COL2A1 gene located on chromosome 12. It encodes the alpha-1 chain sequence of type 2 collagen, the most common in the cartilage tissue and vitreous of the eye. In addition to spondyloepiphyseal dysplasia, defects in this gene lead to the development of Knist and Legg-Calve-Perthes diseases, type 2 achondrogenesis and a number of other genetic pathologies of the musculoskeletal system. Most disorders in COL2A1 relate to missense mutations, their result is the expression of defective collagen, unable to fully perform its functions. This form of spondyloepiphyseal dysplasia, along with skeletal lesions, is characterized by the development of visual anomalies – myopia, retinal detachment, since type 2 collagen is also present in the vitreous body.
A rarer (occurrence of about 1:200-250 thousand) type of spondyloepiphyseal dysplasia is characterized by recessive, X-linked inheritance. The cause of this form of the disease is a mutation of the SEDL gene (TRAPPC2) encoding a specific protein sedlin. According to the latest scientific data, this protein is responsible for a number of intracellular transport processes, in particular, it promotes the transfer of proteins from the endoplasmic reticulum to the Golgi complex. The pathogenesis of spondyloepiphyseal dysplasia with this genetic disorder has not been studied enough – it is assumed that a defect in the structure of sedlin leads to difficult modification of proteins, including those that are part of bone and cartilage tissues. A feature of the SEDL gene is the complete absence of its inhibition in women (which occurs in some gender-related diseases), therefore, heterozygotes are only carriers of the pathological gene and they do not show any disorders. This form of spondyloepiphyseal dysplasia is characterized by a later onset, reduced severity of symptoms and absence of damage to the organs of vision or hearing.
Static load on the musculoskeletal system plays an important role in the development of symptoms of spondyloepiphyseal dysplasia of any type. Thus, in this disease, ossification points are formed in the vertebral bodies later than usual – during this period, the body weight already has time to deform the bone structures of the vertebral column, as a result of which ossification occurs with anomalies. The situation is similar with the epiphyses of long tubular bones – that is why with spondyloepiphyseal dysplasia, the lower extremities that experience the greatest load are mainly affected. This circumstance is used in the treatment of this disease – as early as possible the use of orthopedic means reduces the load on the elements of the skeleton, allowing them to form and ossify correctly. This approach significantly reduces the severity of bone deformities in spondyloepiphyseal dysplasia.
The manifestations of spondyloepiphyseal dysplasia differ somewhat in different forms of this disease, mainly by the age of development and the degree of severity. The autosomal dominant type of pathology is characterized by the appearance of the first symptoms at the age of one and a half to two years, although radiological signs of disorders can be detected already in a newborn child. In severe cases, breathing disorders first occur due to difficulty in removing the ribs. But most often with this type of spondyloepiphyseal dysplasia, lameness develops first, which develops into a duck gait, increased fatigue when walking, pain and restriction of movement in large joints. These manifestations gradually increase over 4-5 years.
By the age of 7-9, patients with this form of spondyloepiphyseal dysplasia can already detect a lag in growth compared to healthy peers, pronounced contractures of the hip and knee joints. Curvature of the spine is detected – the severity of thoracic kyphosis and lumbar lordosis is significantly increased. In some cases, muscle weakness occurs, which can be caused by both primary damage to muscle tissue and a violation of its innervation due to compression of spinal roots and nerves. In addition, this type of spondyloepiphyseal dysplasia is characterized by frequent visual disturbances (in more than half of cases) – myopia, astigmatism, clouding or dystrophy of the lens, retinal detachment. Sometimes cardiomyopathy, enlargement of the liver and spleen are registered. Intellectual development usually does not suffer, but individual cases of mental retardation are described.
Spondyloepiphyseal dysplasia, inherited by a sex-linked mechanism, is usually not detected during the first 4-7 years of a child’s life. The first sign of the disease is a lag in growth, back pain may occur, scoliosis develops, complicated by kyphosis. The growth of adult patients with this pathology is no more than 150 centimeters, however, severe joint disorders in this form of spondyloepiphyseal dysplasia are usually not noted. Also, this type of disease is characterized by the absence of malformations of the organs of vision and internal organs, only the musculoskeletal system is affected.
The definition of spondyloepiphyseal dysplasia is based on the data of X-ray studies, the study of the patient’s hereditary history, molecular genetic analyses. The autosomal dominant form of the disease is characterized by numerous bone anomalies of the vertebrae and epiphyses of tubular bones, which is revealed on radiographs. In particular, there is an absence or delayed appearance of ossification points in the vertebral bodies, platyspondylia, especially the thoracic and lumbar vertebrae, which are subjected to wedge-shaped deformation, suffer greatly. At the same time, the arches and processes in spondyloepiphyseal dysplasia, as a rule, remain unchanged. The height of the intervertebral discs at first remains normal, later they undergo dystrophy and their thickness decreases. In rare cases, there are changes in the cervical spine, such as hypoplasia of the dentoid process.
The epiphyses of long tubular bones, especially the lower extremities, also flatten and deform. This leads to a change in the configuration of the joints – in the hip joint there is a mushroom-shaped deformation of the femoral head and the expansion of the acetabulum, which becomes deeper, thereby changing the shape of the pelvis. The knee joints are also affected with spondyloepiphyseal dysplasia – the articular surfaces of the bones flatten, the intercondylar ridge of the tibia practically disappears. Often, a lobular structure of the patella with its longitudinal cleavage is found. In the case of spondyloepiphyseal dysplasia caused by a mutation of the SEDL gene, usually only platyspondilia and a decrease in the height of the intervertebral discs are detected.
The study of the hereditary history of spondyloepiphyseal dysplasia helps to establish the type of inheritance of this disease. To finally confirm the diagnosis, they resort to the help of a geneticist. Currently, molecular genetic determination of spondyloepiphyseal dysplasia is performed using direct sequencing of disease-associated genes (COL2A1 and SEDL) in order to detect mutations. Prenatal diagnosis of the disease is also possible, an autosomal dominant form of pathology can also be detected on preventive ultrasound in 2-3 trimesters of pregnancy.
Specific treatment of spondyloepiphyseal dysplasia has not been developed to date, the main efforts of doctors are aimed at reducing the severity of skeletal deformities and symptomatic therapy of concomitant malformations. With early diagnosis of this condition (before the development of significant changes in the vertebral bodies and epiphyses of bones), the use of corsets and other orthopedic aids is prescribed to reduce the load on the musculoskeletal system. This makes it possible to avoid significant deformations of the skeletal elements before their full ossification and in some cases significantly improve the quality of life of a patient with spondyloepiphyseal dysplasia.
In the presence of existing deformities, the wearing of orthopedic products is also prescribed. In addition, surgical correction can be performed to reduce the severity of the symptoms of the disease. The autosomal dominant form of spondyloepiphyseal dysplasia requires treatment of concomitant malformations (visual disturbances, neurological pathologies) according to indications. Patients are recommended to carry out massage and exercises to strengthen muscles and improve their general condition. For back pain or joint pain, non-narcotic analgesics from the group of nonsteroidal anti-inflammatory drugs are prescribed.
Prognosis and prevention
As a rule, the prognosis of spondyloepiphyseal dysplasia is uncertain due to the fact that many factors can influence the development of this disease – the age of diagnosis, the degree of ossification disorders, the presence or absence of additional anomalies. With early diagnosis and qualified assistance of an orthopedist, it is possible to reduce the symptoms of pathology to a minimum level while maintaining the optimal quality of life of the patient. With late detection of spondyloepiphyseal dysplasia, the prognosis of this disease worsens significantly. Prevention of this condition is currently possible only within the framework of prenatal diagnostics by ultrasound or molecular genetic techniques, as well as medical and genetic counseling of parents before conception of a child.