Pycnodysostosis is a hereditary disease belonging to the group of lysosomal accumulation diseases, accompanied by compaction of bone tissue, increased fragility of bones and cranioclavicular dysostosis. Symptoms of this condition are low growth of patients, characteristic facial changes (enlarged nose, hypoplasia of the lower jaw, protruding occipital and frontal tubercles), frequent pathological fractures. Diagnosis of pycnodysostosis is made on the basis of radiological data, the study of hereditary history, histological examination of bone tissue and molecular genetic analyses. There is no specific treatment for this disease, symptomatic measures imply the correction of fractures, the elimination of other malformations.
Pycnodysostosis is a genetic disease characterized by a violation of the processes of physiological regeneration, resorption and remodeling of bone tissue, which leads to osteosclerosis and an increase in bone fragility. For the first time this condition was described by famous French researchers – pediatrician Pierre Maroto and his teacher, geneticist Maurice Lamy in 1962. It was they who were able to distinguish pycnodysostosis as a separate nosological unit as osteodysplasia, which has a family character.
For a long time it was believed that this disease belongs to the type 6 mucopolysaccharidosis variety, but later it was determined that it is a form of lysosomal accumulation disease and is not related to the metabolism of mucopolysaccharides. Pycnodysostosis is considered a pathology with an autosomal recessive nature of inheritance, affects both men and women with the same probability, and its occurrence is approximately 1.5-1.7:1,000,000. Racial or national characteristics of the distribution of the disease have not been revealed, however, in regions of the planet where closely related marriages are allowed, this condition is statistically more common.
The cause of the development of pycnodysostosis is mutations of the CTSK gene, which is located on the 1st chromosome and is especially intensively expressed in osteoclasts – cells responsible for the dissolution of bone tissue. It encodes the amino acid sequence of the protein cathepsin K, which is a specific enzyme-protease, the substrate of which are collagen molecules (mainly type 1 collagen). Thus, cathepsin K plays an important role in the process of bone resorption, destroying its organic matrix, consisting mainly of collagen fibers. Missense mutations in the coding regions of the CTSK gene lead to a change in the conformation of the active center of this enzyme, as a result of which it becomes unable to perform its functions, which leads to pycnodisostosis.
Osteoclasts are involved in bone resorption, which is an integral part of the process of physiological regeneration, growth and development of bones. With pycnodysostosis, these cells retain the ability to dissolve the inorganic component of bones (calcium salts), however, the organic matrix consisting of collagen is not destroyed due to the inferiority of the enzyme cathepsin K. The result of this is the prevalence of bone formation processes and abnormal bone mineralization. This phenomenon leads to an increase in bone density (osteosclerosis) and, at the same time, to an increase in its fragility, as a result of which pycnodisostosis develops.
Molecular genetic and biochemical studies confirm the above-described mechanism of pathogenesis of pycnodysostosis. In particular, histological examination of the bone tissue of patients determines the increased size of resorption lacunae around osteoclasts, and significant inclusions filled with collagen and other components of the organic bone matrix are detected in their cytoplasm. These inclusions are lysosomes whose enzymes (mainly cathepsin K) are unable to cleave the above compounds. This fact allowed us to attribute pycnodisostosis to lysosomal accumulation diseases. An important difference between this disease and other forms of genetically determined osteosclerosis is the absence of bone deformation (especially epiphyses and diaphysis) and narrowing of the bone marrow canal. This circumstance makes the course of pycnodysostosis easier and improves the prognosis of pathology.
It is possible to suspect the presence of pycnodysostosis already in early childhood by the characteristic features of the child’s face and other malformations. In patients, there is a disproportion in the structure of the skull (the predominance of the brain over the facial), an enlarged nose, in some cases, hypoplasia of the lower jaw, a protruding forehead is determined. Fontanelles and cranial sutures with pycnodysostosis overgrow much later than usual, children also show late teething, significant deformities of the dentition are possible. In the future, dental problems with this disease persist – in addition to the curvature of the teeth, such patients often have caries, which in some cases takes a severe course.
Due to clavicle dysplasia, narrow shoulders are found in patients with pycnodysostosis. Mobility in the shoulders is significantly increased – often they can close in front of the sternum. This leads to frequent dislocations of the shoulder joint, including the usual nature. As a child suffering from pycnodysostosis grows, the most important symptom of this pathology comes to the fore – the fragility of the bones of the skeleton. Fractures very often occur even with minor physical effort, but the speed of bone tissue recovery does not suffer – healing occurs in the usual time. Changes in the shape of long tubular bones or the width of the medullary canal, as with other osteodysplasias, are not observed in the case of pycnodysostosis.
Adults with this disease have low growth (no more than one and a half meters), micrognathia is determined in them, in the absence of dental intervention, anomalies of the dentition and pronounced caries persist, which over time can lead to tooth loss. Also, with pycnodysostosis, shortening of the distal phalanges of the fingers, flattening of the nails and transverse striation of the nail plates are noted. The skin on the back of the brushes becomes dry, wrinkles are easily formed on it. Pycnodisostosis does not affect a person’s mobility and does not reduce his life expectancy – the only potential danger is the risk of fractures and their severe complications (fat embolism, fractures of the base or arch of the skull).
To determine pycnodysostosis, a general examination of the patient, the study of anamnesis (including hereditary), X-ray studies and molecular genetic analyses are used. When examined by a pediatrician or a geneticist, characteristic facial features, violations of teething and formation of teeth, late overgrowth of fontanelles attract attention. In the future, these manifestations of pycnodysostosis may be accompanied by a slight lag in physical development, low height and narrow shoulders. However, it is impossible to reliably determine this disease only on the basis of the patient’s current status. In the anamnesis of patients with pycnodysostosis, there are always numerous episodes of fractures, the heredity of such persons is usually burdened – blood relatives often also had cases of similar symptoms.
Much more diagnostic information in pycnodysostosis is provided by X-ray methods of investigation. For example, when radiography of the skull in patients, late overgrowth of sutures is often detected, vorm bones are almost always formed in them, and underdevelopment or absence of paranasal sinuses in adult patients is also observed. Diffuse osteosclerosis is detected on radiographs of all parts of the skeleton, the study of the hands confirms acroosteolysis of the nail phalanges. Bone deformities in pycnodysostosis are uncharacteristic, but they can develop as a result of fractures and subsequent incorrect reposition of fragments. Approximately one third of patients have hypoplasia of the clavicles with severe underdevelopment of the acromial processes.
Examination at the dentist with pycnodysostosis determines anomalies in the development of the dentition and a pronounced delay in the change of milk teeth, which can persist up to 20-25 years. Also, such patients are found to have caries, often taking a severe course. Partial adentia is possible. Most of the above manifestations of pycnodysostosis are partly characteristic of other osteodysplasias, it is possible to differentiate them only with the help of modern genetics methods. As a rule, direct automatic sequencing of the CTSK gene is performed in order to detect mutations. A similar method can be used to determine the carrier of the gene (in heterozygotes) and prenatal diagnosis of this disease.
There is no specific treatment for pycnodysostosis at the moment, mainly symptomatic and supportive measures are used. The main threat in this disease is fractures that can develop even with minor physical impact. It is necessary to limit the child in outdoor games and other activities with increased injury. Correction of fractures in pycnodysostosis does not have any special features, traditional techniques of traumatology and orthopedics are used for this. Elimination of problems with teeth (curvature of the row, caries) is performed at the dentist. A number of experts recommend that such children and adults use special physical therapy regimens that will strengthen the muscles, which reduces the risk of fractures.
Prognosis and prevention
The prognosis of pycnodysostosis, according to most experts, is relatively favorable – in itself, this disease does not pose a risk to life and does not reduce its duration, does not lead to disability and does not affect fertility. However, due to the fragility of the bones, there is an increased risk of severe fractures and life-threatening complications. In addition, the treatment of some injuries with pycnodysostosis may be the cause of prolonged disability of the patient. Prevention of this condition is reduced to the genetic diagnosis of the carrier of the pathological form of the CTSK gene (with heredity burdened by this disease). Prenatal diagnosis of pycnodysostosis is justified only in cases where both parents are carriers of a defective form of the gene.