Hypochondroplasia is a hereditary disease belonging to the group of chondrodysplasia, the cause of which is a violation of the formation of cartilage and some types of bones, which leads to dwarfism. Symptoms of this pathology are shortened limbs and fingers, enlarged relative sizes of hands and feet, slight restriction of movements in the elbow joint and lumbar lordosis. Diagnosis is made on the basis of examination of the patient, X-ray data, molecular genetic analysis. There is no treatment for hypochondroplasia, however, serious complications that significantly worsen the patient’s quality of life (except dwarfism) are also not observed.
General information
Hypochondroplasia is a genetic pathology that is in many ways similar to related chondrodysplasia – for example, achondroplasia and thanatoform dysplasia. This condition was first described in 1913 by Ravenna, who revealed the hereditary nature of this form of dwarfism and its differences from achondroplasia. The occurrence of hypochondroplasia is currently unknown for sure – some geneticists indicate the numbers 1:100,000, but not all researchers agree with this.
The main difficulty in calculating the occurrence of this disease is due to the fact that in more than 80% of cases it occurs spontaneously due to de novo mutations. The remaining proportion of cases of hypochondroplasia (less than 20%) is transmitted by an autosomal dominant mechanism. However, it is precisely established that this pathology is much less common than achondroplasia (1:20,000), although it has a lighter course. The disease is equally likely to affect both men and women.
Causes
The great similarity of the manifestations of hypochondroplasia with achondroplasia is due to the fact that the cause of these diseases are mutations of the same gene – FGFR3, located on the 4th chromosome. It encodes the sequence of fibroblast growth factor-3, which is a transmembrane tyrosine kinase receptor. Normally, it somewhat inhibits the growth of fibroblasts and chondrocytes in the growth plates of endochondral bones, thereby controlling the proper development of bone tissue. With FGFR3 gene mutations, the resulting fibroblast growth factor-3 has a defect and cannot fully perform its functions – depending on the nature of the genetic defect, this can lead to thanatoform dysplasia, achondroplasia or hypochondroplasia.
Several dozen mutations of the FGFR3 gene have been identified, the result of which is the development of dwarfism by the type of hypochondroplasia. The most common is a defect that occurs due to the replacement of a nitrogenous base (adenine or guanine) at position 1620 of the thirteenth exon of the gene. As a result, in the protein obtained from such a gene at position 540, asparagine is replaced by lysine, which significantly changes the tyrosine kinase sensitivity of the receptor.
In addition, many other substitutions of nitrogenous bases in the gene and, as a consequence, amino acids in the resulting protein have been described, which lead to the development of symptoms of hypochondroplasia. However, there are indications that in some patients with a clinical picture of this disease, no FGFR3 defects were detected during genetic examination. This may indicate that other genes may be involved in the development of hypochondroplasia.
All mutations of the above gene are inherited by an autosomal dominant mechanism, however, in the vast majority of cases they are spontaneous and are not detected in the parents or relatives of the patient. It was noted that in many patients with hypochondroplasia, the age of the fathers exceeds the average, which may indicate the germinative nature of the appearance of FGFR3 gene mutations.
Symptoms
As a rule, in the first years of a child’s life, hypochondroplasia does not manifest itself in any way – at birth there are no deviations from the norm, weight gain and psychophysical development occur normally. The first signs of stunting are registered at the age of 3-4 years, a slight disproportion of the body becomes noticeable (short arms and legs, enlarged feet and hands). In many cases, the surrounding people do not even immediately identify any unusual proportions in patients – they just look like short, stocky people. The shape of the skull and facial features in hypochondroplasia are often without features, sometimes a small brachycephaly can be detected.
Patients sometimes have minor flexion contractures of the elbow joints and very rarely of the hip joints. Valgus curvature of the femurs in hypochondroplasia is not observed, similar deformities of the lower leg are possible. In about half of cases, patients develop lordosis of the lumbar spine. Since all these manifestations are similar to the symptoms of achondroplasia, only much less pronounced, for a long time it was believed that this is the same pathology, only some researchers attributed it to an independent nosological unit. Only modern research in the field of genetics has unequivocally proved the validity of such hypochondroplasia isolation.
Diagnostics
Detection of hypochondroplasia is performed on the basis of a set of medical measures: consultations of a pediatrician and an orthopedist, X-ray studies, molecular genetic analysis. When examining patients older than 3-4 years, changes characteristic of pathology are found – shortened limbs, increased relative size of feet and hands, mobility disorders in the elbow and sometimes in the hip joint, lumbar lordosis. If hypochondroplasia is hereditary, then such manifestations are always present in one of the parents, since this disease is autosomal dominant. With healthy parents, an indirect sign indicating this pathology may be the age of the father at the time of conception more than 40-45 years.
Much more information about hypochondroplasia is provided by X-ray examinations of bones, joints and spine. Examination of the latter reveals narrowing of the spinal canal in the caudal direction, concave contours of the posterior surface of the lumbar vertebrae. Also, radiologically, there is shortening and compaction of the femoral and humerus bones, slight elongation of the tibia, epiphyses of square-shaped bones in the knee joints, flattening of the acetabulum. Approximately two-thirds of cases of hypochondroplasia are also diagnosed with shortening of the ulna.
The genetic diagnosis of hypochondroplasia involves direct sequencing of the sequence of the FGFR3 gene or its individual exons to detect mutations. Most often, the 13th exon of the gene is examined, since it is there that defects are located in most cases of the disease. Prenatal diagnosis is possible by amniocentesis or chorionic villus biopsy.
Differential diagnosis should be carried out with achondroplasia and other conditions that are accompanied by shortening of the limbs. These pathologies are distinguished from each other using radiological and genetic research methods.
Treatment
There is no specific treatment for hypochondroplasia, dwarfism remains in a person for life. However, a number of other manifestations, such as joint contracture and lordosis of the lumbar spine, are moderately pronounced. Therefore, the prognosis of hypochondroplasia regarding life and its quality is favorable in most cases. Only in some cases, adult patients may require surgical intervention due to compression of the lumbar spinal cord or its roots (sciatica), which occur due to lordosis and disorders of the structure of the vertebrae.
Prevention
Prevention of the disease is reduced to prenatal genetic diagnosis, especially for married couples where one of the parents suffers from hypochondroplasia. Given the autosomal dominant nature of inheritance of this pathology, the probability of having a sick child with a healthy second parent is 50%.