Kniest dysplasia is one of the forms of dwarfism caused by genetic disorders that lead to the formation of defective forms of one of the varieties of the main protein of connective tissues – collagen. The symptoms of this condition can be determined already at birth – in patients, a relative shortening of the limbs and impaired mobility of the joints are detected, sometimes a cleft of the hard palate is recorded. In the future, the picture of the disease is supplemented by other manifestations of dwarfism. Diagnosis of Kniest dysplasia is made on the basis of patient status data, X-ray examination of the skeleton and genetic and molecular analyses. There is no specific treatment for the disease, symptomatic and supportive therapy is carried out.
Kniest dysplasia (type 2 metatropic dysplasia) is a rather rare genetic disease characterized by a violation of the formation of individual elements of the skeleton with the development of dwarfism and other pathologies. For the first time this condition was described and defined as a hereditary pathology in 1952 by V. Kniest, since then this type of skeletal dysplasia bears his name. Due to the low prevalence of Kniest dysplasia in the population, it is not yet possible to reliably determine the occurrence of this condition. The problem is further complicated by the fact that there are many very similar syndromes caused by defects in the same gene (Col2A1). Until recently, it was believed that the only mechanism of inheritance of Kniest dysplasia is autosomal dominant, but in recent years there have been indications of the existence of autosomal recessive forms of pathology. Perhaps this is due to incomplete penetrance of the defective form of the Col2A1 gene. The sexual distribution of dysplasia of the Kniest does not have any features, the disease affects boys and girls equally often.
The main cause of Kniest dysplasia is mutations in the Col2A1 gene located on the 12th chromosome. The gene encodes the sequence of one of the most common connective tissue proteins – type 2 collagen of the alpha-1 subclass, which is widely represented in the bone and cartilage structures of the body. In addition to Kniest dysplasia, defects in the structure of Col2A1 can be the cause of such well-known conditions in genetics as type 2 achondrogenesis, Legg-Calve-Perthes disease, congenital spondyloepiphyseal dysplasia and a number of other skeletal abnormalities. The reasons why certain syndromes occur are reduced to the degree of disruption of the collagen structure expressed by the defective gene – the more damaged it is, the more pronounced the manifestations of dysplasia will be.
In the vast majority of cases, Col2A1 gene mutations leading to the development of Kniest dysplasia are inherited by an autosomal dominant mechanism. The reports of some geneticists about the discovery of recessive forms of this pathology were doubtfully perceived by the scientific community – experts made assumptions about the possible incomplete penetrance of the defective gene, which can be mistaken for its recessiveness. However, later there was more serious evidence of the existence of autosomal recessive forms of Kniest dysplasia.
Pathological changes in the body of patients suffering from this disease are not limited to skeletal abnormalities – a defective collagen structure can cause impaired joint mobility, muscle weakness and vision disorders. Also, in some patients with Kniest dysplasia, the presence of sensorineural deafness is noted, but the mechanism of development of this anomaly in this disease is unknown.
A number of manifestations of Kniest disease can be registered already at the birth of a child, the remaining symptoms are detected in the first years of life. Among the earliest signs of the disease, a combination of a round, flat face, large and bulging eyes in a newborn can be distinguished. In some cases, these violations are combined with a cleft of the hard palate. The trunk of patients with dysplasia of the Kniest is shortened, the relative dimensions of the limbs are reduced, thickening is observed in the joints. The child has muscle weakness, sometimes myopia and deafness are detected. The patient significantly lags behind his peers in physical development. In the future, with dysplasia of the Kniest, curvature of the vertebral column develops, kyphosis appears at the level of the thoracic department, and pronounced lordosis appears at the level of the lumbar. In some cases, these processes can cause breathing difficulties and heart failure, which can lead to death.
Due to the above-described skeletal anomalies in patients with Kniest dysplasia, a wide and flat chest is formed, often with a depression in the center. Contractures of the hip, knee and elbow joints and relative elongation of the fingers are detected quite early. Sometimes alopecia occurs. Children begin to talk much later than healthy peers, but most often this is due to violations of the structure and innervation of the elements of the palate and articulatory apparatus – intelligence in patients with this disease is almost always preserved. The lack of speech development may also indicate deafness of the patient, also due to a hereditary disease. Half of patients with dysplasia of the Kniest have various visual disorders: myopia, retinal detachment, dislocation of the lens and a number of others. The height of an adult with this pathology is about 110-115 centimeters.
Diagnosis of dysplasia of the Kniest is carried out on the basis of the data of the physical examination of the patient, the study of his hereditary history, X-ray and molecular genetic studies. When examining a newborn, a characteristic appearance is revealed (a flat round face, a saddle-shaped nose, bug-eyed), a shortened trunk and limbs, thickening in the joints. As the patient grows, these manifestations of spinal dysplasia are joined by curvature of the spinal column (thoracic kyphosis and lumbar lordosis), joint contractures, clubfoot and other skeletal anomalies. Limbs with this variant of bone dysplasia may have different sizes. Delayed speech development may be associated with both defects of the articulatory apparatus and sensorineural deafness of the patient.
The greatest amount of information important for the diagnosis of dysplasia is provided by X-ray research methods. The images of the vertebral column determine the flattening of individual vertebrae (platyspondylia). The long tubular bones of the limbs are shortened, their metaphyses are often expanded, and the epiphyses are flattened. A characteristic symptom of Kniest dysplasia is the expansion of the ends of short tubular bones (for example, the phalanges of the fingers). Almost always there are signs of a violation of metaepiphyseal ossification – the nuclei of ossification (for example, in the metaphyses of the femurs) appear much later than usual or do not develop at all.
An ophthalmological examination of a patient with Kniest dysplasia may reveal nearsightedness (myopia), which over time is sometimes complicated by retinal detachment and blindness. Among such patients, the number of cases of umbilical and inguinal hernias is increased. The molecular genetic diagnosis of Kniest dysplasia consists in direct automatic sequencing of the Col2A1 gene sequence in order to detect mutations. To exclude quite rare autosomal recessive forms of the disease, a similar analysis is performed in the parents and relatives of the patient to determine the carrier of the pathological gene. Differential diagnosis is carried out with type 4 mucopolysaccharidosis and hereditary syndromes caused by defects in the Col2A1 gene.
Treatment and prevention
There is no specific therapy for Kniest dysplasia. Symptomatic treatment may include surgical correction of the cleft of the hard palate, performed in the first months of the child’s life. In addition, with Kniest dysplasia, surgical interventions may be required to increase joint mobility in severe contractures. Myopia in this disease is quite difficult to treat, but regular observation by an ophthalmologist is necessary for the timely detection and elimination of retinal detachment. Supportive therapy includes taking vitamin and mineral complexes, a diet with a high protein content, and reducing the load on the joints. Due to the predominantly dominant nature of the disease, preventive measures have not been developed.
Kniest dysplasia is a rather severe variant of hereditary skeletal abnormality and dwarfism and often leads to disability of the patient at an early age. In the severe course of the disease, curvature of the spinal column and deformity of the chest can provoke respiratory or cardiovascular insufficiency. In general, the prognosis of Kniest dysplasia is unfavorable. Despite the fact that many patients live to adulthood, their life span is significantly reduced compared to healthy people. The fatal outcome most often occurs due to secondary disorders in the work of internal organs caused by severe skeletal abnormalities and malformations.