Craniometaphyseal dysplasia is a hereditary condition from the group of osteochondrodysplasias characterized by anomalies in the development of the skull and metaphysical bones of the extremities. Symptoms of this disease are hypertelorism, facial malformations, often disfiguring the patient, abnormal formation of nasal passages with violation of their patency, sometimes headaches and limb curvature. Diagnosis of craniometaphyseal dysplasia is carried out based on the study of the patient’s current status, X-ray data and the results of molecular genetic studies. There is no specific treatment for this pathology, symptomatic therapy is used, in some cases surgical interventions are performed to facilitate the patient’s breathing and improve his appearance.
Craniometaphyseal dysplasia is a group of hereditary diseases that lead to malformations of the bones of the facial and cerebral parts of the skull of varying severity in combination with an anomaly of the metaphyses of long tubular bones and other disorders. Previously, this condition was attributed to the same group as Pyle’s disease (multiple metaphysical dysplasia, craniometaphyseal Pyle dysplasia), but now it is isolated into a separate nosological unit. This is due to the fact that in this disease, it is the anomalies of the structure of the skull (deformities, hyperostoses and bone sclerosis) that prevail, while the pathologies of other parts of the skeleton are poorly expressed. There are two main forms of craniometaphyseal dysplasia that differ in the mechanism of inheritance (autosomal dominant and autosomal recessive types), clinical manifestations and severity of disorders. Due to inheritance through autosomes, pathology affects both men and women with equal probability. The occurrence of craniometaphyseal dysplasia is not precisely established, the dominant type is registered many times more often than recessive.
The main cause of the more frequent but milder autosomal dominant form of craniometaphyseal dysplasia is mutations in the ANKH gene located on the 5th chromosome. The gene encodes a protein that is a membrane carrier of pyrophosphate involved in inhibiting the processes of calcification of bone tissue and its resorption. As a result of a genetic defect, the structure of the carrier protein changes, and it becomes unable to fully perform its functions, which leads to craniometaphyseal dysplasia. At the cellular level, this is manifested by an abnormal change in the activity of osteoclasts, the development of sclerosis and hyperostosis mainly of the skull bones. The configuration of the main openings of the base of the skull may also be disrupted, which causes compression of some vessels and nerves and largely determines the remaining symptoms of craniometaphyseal dysplasia (hearing disorders, headaches, lesions of the trigeminal and facial nerves). In genetics, other diseases caused by the defeat of the ANKH gene are also known, in particular, hereditary pseudopodagra or familial chondrocalcinosis.
A much rarer autosomal recessive form of craniometaphyseal dysplasia is caused by a defect in the GJA1 gene localized on the 7th chromosome. The product of its expression is a protein called connexin 43, which takes an active part in the formation of intercellular (interstitial) contacts in many tissues, which allows cells to exchange low-molecular compounds. The pathogenesis of the development of craniometaphyseal dysplasia with the missense mutation c716G >A is unknown, the main problem is to identify the causes of isolated lesions of the skull bones and bone metaphyses in the relative absence of pathologies of other organs. Given that the largest amount of connexin 43 in humans is in the heart tissue, the question of the absence of heart pathologies with this mutation is currently a mystery for most geneticists. Just as in the case of the autosomal dominant form of craniometaphyseal dysplasia, numerous secondary disorders are observed in this type of disease due to the impact of altered bones and holes on nerve structures.
Autosomal dominant type of craniometaphyseal dysplasia is characterized by a lighter course, often no symptoms of the disease are detected at the birth of a child. Only by the first year of life, hypertelorism occurs with the expansion of the bridge of the nose due to hyperostosis of the nasal bones. In the future, craniometaphyseal dysplasia leads to narrowing of the nasal passages and violation of their patency, therefore, patients often have their mouths slightly open due to impaired nasal breathing. By the age of 6-7, an increase in the metaphyses of long tubular bones may begin to be determined, which is externally manifested by an increase in the size of the knee and elbow joints. Approximately half of patients with craniometaphyseal dysplasia develop hearing disorders of varying severity up to complete deafness – most often this is due to compression of the auditory nerve in the bone canal. Due to nerve compression, other neurological disorders also occur, there may be sensitivity disorders on the face, trigeminal neuralgia and headaches.
Craniometaphyseal dysplasia of the autosomal recessive type is characterized by much more pronounced malformations of the bones of the skull and limbs, signs of pathology are often detected immediately after the birth of a child. Patients have pronounced hypertelorism, facial features are often extremely asymmetrical, deformities of the bridge of the nose and nose can acquire signs of deformity. In some cases, macrocephaly, mandibular prognathism, and other malocclusion and tooth placement disorders are observed. As the patient grows, the anomalies of the skull bones may worsen. The metaphyses of the limb bones are sharply expanded, which often causes secondary deformities (for example, X-shaped curvature of the legs). As in the previous version, with this form of craniometaphyseal dysplasia, various neurological disorders often occur caused by compression and traumatization of the cranial nerves. They can be manifested by deafness, visual disturbances, disorders of skin sensitivity on the face, paresis of facial muscles and headaches. There are separate descriptions of patients suffering from craniometaphyseal dysplasia and mental retardation at the same time, but there is no reliable data on the relationship of these two conditions to date.
Diagnosis and treatment
Diagnosis of craniometaphyseal dysplasia is based on the patient’s examination data, the study of his hereditary history, the results of X-ray studies and molecular genetic analyses. During the examination, various abnormalities of the development of the skull bones are determined, which is reflected in the patient’s facial features. At the same time, the autosomal dominant form, especially in young children, is rather weak in relation to this symptom. In both types of craniometaphyseal dysplasia, hypertelorism, expansion of the bridge of the nose due to the proliferation of nasal bones towards the cheekbones, narrowing or obstruction of the nasal passages are almost always present. As part of a physical examination and additional studies, neurological disorders may also be detected: hearing loss or absence, decreased vision, symptoms from the trigeminal and facial nerves.
Radiological methods of skeletal examination provide much more information in craniometaphyseal dysplasia. Skull x-ray with an autosomal dominant form of the disease determine the compaction of bone tissue in the occipital bone, sclerosis of the base of the skull, reduced pneumatization of the sinuses and cells of the temporal bone. In some cases, sclerosis of the interosseous sutures and expansion of the metaphyses of the tubular bones may be detected. In the autosomal recessive type of craniometaphyseal dysplasia, similar but much more pronounced disorders are found on radiographs, for example, the complete absence of the paranasal sinuses, a sharp narrowing and sometimes filling of the holes of the cranial nerves with bone tissue. In addition, there is sclerosis not only of the base, but also of the cranial vault, in some cases significant deformities of the bones of the facial region are determined. Slightly stronger than in the dominant type, the expansion and sclerosis of the metaphyses of the tubular bones are pronounced.
The study of hereditary anamnesis and genetic diagnosis are also actively used to determine craniometaphyseal dysplasia. In this case, you can first determine the type of inheritance of the disease, which allows you to adjust the molecular genetic analysis to search for mutations in a particular gene. To do this, the method of direct sequencing of the ANKH and GJA1 genes is used.
There is no specific treatment for craniometaphyseal dysplasia, symptomatic therapy is prescribed with the involvement of a variety of surgical techniques. The latter, in particular, can improve the patency of the nasal passages to facilitate breathing. It is possible to reduce the severity of neurological symptoms by expanding the openings of the corresponding cranial nerves. In addition, plastic surgeons are able to minimize the severity of aesthetic defects in craniometaphyseal dysplasia. Hearing aids are used to improve hearing.
Prognosis and prevention
In many cases, the prognosis of craniometaphyseal dysplasia of the autosomal dominant type regarding the patient’s survival is favorable – neither cranial anomalies nor secondary neurological disorders lead to serious consequences. Hearing or vision pathologies that occur in childhood can slowly progress up to 20-30 years, after which there is usually no deterioration. Autosomal recessive type of craniometaphyseal dysplasia is characterized by a more unfavorable prognosis, since bone disorders of the skull in this condition tend to worsen and can injure the nerves more and more every year. In some cases, this leads to paralysis and disorders of the autonomic nervous system. Prevention of craniometaphyseal dysplasia has not been developed, to reduce the risk of complications in the presence of such a condition, it is necessary to conduct a regular examination by a neurologist.