Multiple epiphyseal dysplasia is a large group of genetically heterogeneous skeletal dysplasias, which are united by a violation of the formation of the enchondral spongiose bone in the area of the metaphyses and epiphyses of bones, as well as (in some cases) vertebral bodies. The symptoms of this condition vary depending on the type of disease, most often there is a curvature of the legs, abnormalities of the joints of the extremities, a decrease in growth. Diagnosis is carried out on the basis of X-ray studies, the study of the patient’s hereditary history, molecular genetic analyses. There is no specific therapy, palliative and symptomatic treatment is possible, including orthopedic measures and surgical correction.
Multiple epiphyseal dysplasia is one of the most common forms of congenital skeletal lesions, having a genetic nature with a diverse nature of inheritance and clinical manifestations. Many variants of this pathology have been known for a long time, but it was described as a separate nosological unit in 1935 by the German doctor T. Fairbank, who was able to correctly determine the cause of the disease – a violation of the development of bone epiphyses.
The occurrence of a condition with an autosomal dominant inheritance pattern is about 1:10,000, the frequency of a rare autosomal recessive type of the disease is unknown. Disease of most types is equally likely to affect both men and women, however, some varieties are characterized by a slightly more frequent occurrence in males (the distribution is approximately 3:1).
Pathology is characterized by pronounced genetic heterogeneity, so there are several different variants of this disease in modern orthopedics. In addition, there are certain phenotypic differences in the course of pathology and its prognosis.
According to geneticists, more than half of all clinical cases of multiple epiphyseal dysplasia are based on molecular genetic disorders unknown to date, so research on this disease continues. Most forms are characterized by an autosomal dominant nature of inheritance, however, penetrance and expressiveness vary very widely, which affects the clinical course of pathology.
There are a number of other types, for some key genes have been identified. But they are much less common – there are forms of these diseases described in only a few families. In addition to the etiology itself, various forms may differ in clinical course – different age of onset of the disease, the presence or absence of other disorders (hearing loss, deafness, myopia, skin abnormalities).
In total, more than 10 different forms of this pathology are currently known, the most common are types 1, 2, 3 and 4:
- Type 1 (Fairbank’s disease) is an autosomal dominant disease and the most common type of this malformation of the skeleton. It is caused by mutations in the COMP gene, which is located on the 19th chromosome and encodes an oligomeric protein of the cartilage matrix – one of the proteins responsible for the metabolism and development of bone and cartilage tissue. In addition to epiphyseal dysplasia type 1, mutations in this gene can lead to another well-known disease of the musculoskeletal system – pseudoachondroplasia. One of the reasons for the widespread spread of this pathology is the autosomal dominant nature of inheritance.
- Type 2 is caused by a mutation of the COL9A2 gene, which encodes the alpha-2 chain of type 9 collagen, the most widely represented in bone and cartilage tissue. As a rule, missense mutations are noted in this gene, leading to a change in the structure of the encoded protein, which causes pathological changes.
- Type 3 is largely similar in its etiology to the previous variant of the disease, as it is caused by a mutation of the COL9A3 gene located on the 20th chromosome. It encodes another type 9 collagen chain, so disorders in its structure lead to the development of skeletal pathologies and complicate the formation of enchondral bones.
- Type 4 is caused by mutations of the SLC26A2 gene located on the 5th chromosome. It is an autosomal recessive disease. The transmembrane protein of chondroblasts and osteoblasts is considered to be the product of expression of this gene, which is responsible for the transport of sulfate ions, which are extremely necessary for the formation of proteoglycans of cartilage and bone tissue. The structural features of SLC26A2 lead to a relatively high frequency of defects in it, therefore mutations of this gene are the cause of many hereditary diseases of the musculoskeletal system. In addition to multiple epiphyseal dysplasia, SLC26A2 defects are the cause of some types of achondrogenesis, atelosteogenesis, and diastopic dysplasia.
The nature of skeletal disorders in different forms is very similar and boils down to abnormalities in the development of joints, especially those that experience the greatest loads – hip, knee, ankle. The role of physical exertion in the development of skeletal abnormalities in epiphyseal dysplasia is quite large, so various orthopedic methods of treatment can significantly improve the condition of patients.
Due to the pronounced heterogeneity, the onset of symptoms of this disease can begin at different ages, depending on the type of pathology. Some forms lead to skeletal abnormalities registered already at the birth of the patient, a significant part of the varieties is characterized by the development of defects at the age of 2-3 years, some rare types are diagnosed in adolescence or even adulthood. The reason why this disease usually begins to manifest itself in younger childhood is due to increased loads on bones and joints after the start of walking and an increase in the weight of the child.
Many forms are characterized by the development of X- or O-shaped leg curvatures caused by deformation of the femoral and tibial epiphyses. In some cases, stunting is noted, caused by both a reduction in the length of the limbs (due to shortening of long tubular bones) and a decrease in the trunk due to spinal deformity.
Almost all types to a greater or lesser extent lead to hypoplasia of the vertebral bodies and the delayed formation of ossification points in them. This can cause a decrease in the length of the spinal column and its various curvatures (scoliosis, lordosis) – especially in the absence of orthopedic correction methods. A common symptom of many types of epiphyseal dysplasia is also increased mobility of a number of joints.
In addition to skeletal disorders, certain forms are accompanied by lesions of internal organs, eyes, auditory and endocrine systems. For example, the Walcott-Ralshson type is manifested by the early development of insulin-dependent diabetes mellitus and myopia, some other forms are combined with deafness. Varieties are described, which are also characterized by osteoporosis and skin atrophy.
Intellectual development in most types of the disease does not suffer, but in some forms there may be mental retardation of varying degrees of severity. Most often, multiple epiphyseal dysplasia does not affect the life expectancy of patients, but concomitant disorders characteristic of some forms can lead to severe complications.
The leading role in determining any type is played by X-ray examinations, general examination of patients and molecular genetic analyses. In some cases, the study of hereditary anamnesis is additionally used – its results may vary depending on the autosomal recessive or dominant nature of the inheritance of pathology.
- Radiography. On radiographs, depending on the form and the age of patients, a slowdown in the processes of ossification of the epiphyses, their deformation, shortening of long tubular bones can be determined. In older patients, expansion and deformation of the knee and ankle joints are often detected. Many forms also lead to deformations of the vertebral bodies, their bone age often lags behind the actual one.
- Molecular genetic diagnostics. It is possible with respect to only some of the most common forms of epiphyseal dysplasia with a reliably known etiology. As a rule, most laboratories and clinics provide such an opportunity for types of pathology caused by mutations of the COMP, COL9A2, COL9A3 and SLC26A2 genes. Most often, the method of direct automatic sequencing of the above genes is used in order to detect mutations.
To diagnose forms of multiple epiphyseal dysplasia that are combined with other malformations (for example, deafness, ocular and endocrine disorders), other research methods may be required – examination by a specialist of the appropriate profile, blood and urine tests.
There is no specific treatment at the moment, various methods of supportive and symptomatic therapy are used. It is especially important to prescribe orthopedic correction in a timely manner – wearing bandages and corsets to reduce the load on the spine and leg joints. This avoids severe deformities and, thereby, improves the quality of life of patients. Some already developed curvatures and defects can be corrected by surgical intervention. Symptomatic treatment is also indicated for disorders accompanying some forms of multiple epiphyseal dysplasia – diabetes mellitus, myopia, osteoporosis.
Prognosis and prevention
As a rule, the prognosis of most forms of multiple epiphyseal dysplasia in relation to the survival of patients is favorable – limb deformities and stunting do not threaten life and do not shorten its duration. Only some severe forms of curvature of the spine can lead to disorders of the internal organs, which aggravates the course of the disease. With the timely detection of epiphyseal dysplasia and the beginning of orthopedic treatment, disability of patients is relatively rare, many retain mobility and ability to work (albeit somewhat limited). The presence of concomitant disorders worsens the prognosis, especially from the endocrine system (diabetes mellitus).
Prevention is possible only within the framework of medical and genetic counseling of parents before conception of a child (with burdened heredity) and prenatal diagnosis by molecular genetic techniques.