Congenital fragility of bones and fragility are the causes of osteogenesis imperfecta. Metabolic - hereditary metabolic diseases Osteogenesis imperfecta Increased bone fragility

There are several different syndromes of osteogenesis imperfecta. Diseases are characterized by damage to bones, eyes, teeth, ears and of cardio-vascular system... Their classification is based on the type of inheritance and clinical manifestations.

Osteogenesis imperfecta type 1

This type is the most common. It is inherited in an autosomal dominant manner and is characterized by pronounced intrafamilial variability. The patient may be short, have frequent fractures and a pronounced decrease in working capacity, while his close relative with the same impairment can live a full life. The cause of this syndrome can be defects in both alpha 1 (0) and alpha 2 (1) procollagen. Mutations often appear in blue sclera, short stature.

Osteogenesis imperfecta type 2

Type 2 combines the classic congenital variants, in which almost all patients die in childhood or in utero). Many cases are the result of a new mutation (dominant-transmissible phenotype if the patient survives and is fertile) in alpha 1 (1) or alpha 2 (1) procollagen. The “dominant negative” model explains the severe phenotype resulting from the heterozygous mutation. Sometimes sisters and brothers of patients have the same symptoms when healthy parents... In some cases, mutations were found in the gonads at loci with a low level of expression, which is the risk of giving birth to several sick children.

Osteogenesis imperfecta type 3

Type 3 is manifested by severe skeletal deformity, kyphoscoliosis, short stature, and frequent fractures of various localization. It usually develops sporadically, which means the appearance of new mutations or an autosomal recessive mode of inheritance.

Osteogenesis imperfecta type 4

Type 4 is phenotypically and genetically similar to type 1, less common, does not present with blue sclera, and is associated with fewer fractures.

Symptoms

The medical history for fractures is usually similar. “Brittle bones” is a universal manifestation. Sometimes fractures occur in utero, especially in type 2, which makes antenatal radiographic diagnosis possible. In such cases, at birth, the limbs are short and curved, multiple fractures of the ribs give a picture of "rosary" on radiographs. Patients with type 1 or 4 usually have a history of few fractures, even though blue sclera, opalescent tooth enamel, or hearing loss indicate the presence of a mutant gene. Fragility and deformability are the result of a defect in the collagen matrix of bones. Consequently, skeletal manifestations of osteogenesis imperfecta - hereditary form osteoporosis. In elderly patients with age-related or postmenopausal changes or in young patients against the background of prolonged immobilization after fractures or orthopedic operations, fish vertebrae are often noted (depressions and ulcerations on the smooth upper and lower edges of the vertebrae due to the pressure of the tensile intervertebral disc) or flat vertebrae.

The incidence of fractures decreases during puberty in patients with types 1, 3, and 4 diseases. Sometimes after a fracture, false joints are formed. Also, quite often, patients develop hypertrophic calluswhich is difficult to distinguish from. The question of an increased risk of osteosarcoma against the background of osteogenesis imperfecta remains controversial, however, the risk is still low, but when pain appears in the absence of a fracture, especially in elderly patients, it is always necessary to exclude osteosarcoma. Relaxation of the ligamentous apparatus of the joints is most pronounced in type 1 osteogenesis imperfecta. Dislocations are the result of deformities associated with repeated fractures, ligament relaxation or tendon rupture.

Diagnostics

Differential diagnosis Osteogenesis imperfecta includes idiopathic juvenile osteoporosis, Hajdu-Chinei syndrome (osteoporosis, multiple intercalary bones of the skull, acroosteolysis), pycnodisostosis (dwarf growth, brittle bones, lack of branches of the mandible, fontanelle cleft, acroosteolysis) and hypophosphatasia. In one of the families, the tendency to osteoporosis was due to a type I collagen mutation. This highlights the fact that mutation detection does not always make it easier clinical diagnosis... Moreover, manifestations unrelated to any syndromes may result from defects in one or more components of the extracellular matrix.

Treatment

Currently, several hormonal and pharmacological approaches to the treatment of osteogenesis imperfecta have been proposed. Calcium, calcitonin, and vitamin D supplementation is ineffective prior to overt deficiency. For young patients, oral or injectable bisphosphonates are effective in reducing the incidence of fractures and improving skeletal bone growth. condition bone tissue in general, it cannot be improved, and there are no recommendations on the duration of treatment for children and the need for treatment for adults. Bone marrow transplantation to provide normal mesenchymal stem cells gives some hope. Gene therapy for autologous mesenchymal stem cells is currently being actively studied.

Treatment. Osteogenesis imperfecta is not cured. For some non-lethal forms, active physical therapy in early childhood is better than orthopedic care alone. Children with type I and sometimes type IV disease are able to move independently. Patients with types III and IV osteogenesis imperfecta are helped by high elastic stockings, crutches, as well as swimming and special training. In severe cases, a wheelchair is required, but patients can learn to care for themselves. Teens may need psychological help.

Orthopedic measures are aimed at treating fractures and correcting deformities in order to increase the patient's functionality. The fracture requires plastering or splinting; it usually heals quickly and the cast is removed to avoid immobilization osteoporosis. To correct the deformity of long bones, they resort to osteotomy and use intraosseous rods.

Calcium and fluoride supplements and calcitonin injections are ineffective. In some cases (usually with osteogenesis imperfecta of I and IV types), improvement of the histological structure of bones in children can be achieved with the help of growth hormone. Diphosphonates increase mobility and reduce symptoms in most patients. Intravenous administration of pamidronate or administration of alendronate improves the quality of life of patients and inhibits bone resorption, thereby contributing to their mineralization. These compounds reduce the risk of fractures and reduce pain, although mugan type I collagen remains in the bone matrix. They have the greatest effect, probably, on cancellous bones, increasing the density of the vertebrae and promoting the growth of patients. The therapeutic effect does not depend on the severity of the manifestations, the nature of the mutations or the age of the patient in which therapy was started. The effect of diphosphonates on the development and mechanical properties of the compact substance of long bones is being studied.

Forecast. Osteogenesis imperfecta is a chronic disease that reduces not only the functionality of patients, but also their life expectancy. Children with type II osteogenesis imperfecta, as a rule, die in the first months of life (up to a year). With osteogenesis imperfecta of type III, the peak mortality rate of patients (mainly from pulmonary pathology) occurs in early childhood, adolescence and 40-50 years. Life expectancy of patients with type I osteogenesis imperfecta and type IV osteogenesis imperfecta remains normal.

Patients with type III osteogenesis imperfecta are usually wheelchair bound. Active rehab can allow them to use public transportation and move around the house. Children with type IV disease can usually use public transportation on their own or with crutches.

RCHD (Republican Center for Healthcare Development of the Ministry of Health of the Republic of Kazakhstan)
Version: Clinical Protocols MH RK - 2016

Osteogenesis incomplete (Q78.0)

Orphan diseases

general information

Short description

--- Approved
Joint Commission for Quality medical services
Ministry of Health and Social Development of the Republic of Kazakhstan
dated September 29, 2016
Protocol No. 11

Classification

Classification

The main clinical manifestation of all types of OI is bone fragility, which manifests itself in the form of spontaneous fractures. Currently, a classification is widely used, which is based on the data of the clinical and radiological examination of the patient and allows one to distinguish four genetic types of the disease (Table 1).

Table 1.

To date, four more types of OI have been identified (V, VI, VII, VIII), which are not associated with the pathology of type I collagen and have not yet been included in the International Classification of Osteochondropathy. In this regard, another classification of osteogenesis imperfecta is presented, which has eight clinical different types of OI (Table 2).

Table 2. Classification NO

Diagnostics (outpatient clinic)

DIAGNOSTICS AT THE AMBULATORY LEVEL

Diagnostic criteria (UD - B)

Complaints:
· Increased fragility of tubular bones;
· Deformation and shortening of the limbs;
· rachiocampsis;
• gray-blue sclera of the eyes;
· Deformation of the chest and ribs;
Fragility and fragility of teeth;
· Hearing loss;
Lag in physical development;
Muscle weakness.

Anamnesis:
· The presence of the disease in one of the parents or distant relatives;
· The presence of numerous fractures;
· A clinically established diagnosis of osteogenesis imperfecta.

Physical examination:
· Increased fragility of bones.
· Reshaping and shortening of bones as a result of improper union of fractures.
Deformation (change in shape) of the chest.
· Soft bones of the skull.
Gray-blue sclera (white) of the eye due to its underdevelopment connective tissue and transilluminating the inner shell containing the pigment (colorant).
· Late teething in children (later than 1.5 years), crumbling teeth; the color of the teeth is yellow - "amber teeth".
· Weakly developed muscles (flabby, significantly reduced in volume).
· Inguinal, umbilical hernia often occurs.
· Weakness of the ligamentous apparatus of the joint.
· Hearing loss due to progressive proliferation of connective tissue between the small bones (malleus, incus, stapes) of the middle ear cavity.
· Lagging in physical development.
· Low growth.

Laboratory research: no.

(UD - B):

Diagnostic algorithm:

Picture 1. Diagnostic algorithm

Diagnostics (hospital)

DIAGNOSTICS AT STATIONARY LEVEL

Diagnostic criteria:

Diagnostic algorithm: see outpatient level.

Laboratory research:not.

Instrumental research (UD - B):
· X-ray examination - the main clinical sign of widespread osteoporosis (decrease in bone density, contributing to a decrease in strength) of the entire skeleton.
· Computed tomography - there is multiple multiplanar deformation of tubular bones, systemic osteoporosis. The cortical layer is thinned, in places where the periosteum within the diaphysis is directly adjacent to the spongy substance, a compact marginal border is absent. The medullary canal is therefore eccentrically enlarged in diameter and uneven in places. The spongy structure is sparse and has a wide looped, reticulate, and sometimes irregular chaotic pattern; some trabeculae barely protrude.

List of main diagnostic measures:
· X-ray examination;
· CT scan.

List of additional diagnostic measures:
· Densitometric study - there is a decrease in the level of bone mineral density. Low bone mineral density in relation to chronological age may be a Z score of ≤ -2.0 SD.

Differential diagnosis

1) Differential diagnosis and justification for additional research

Table 3. Differential diagnosis of OI

Treatment abroad

Undergo treatment in Korea, Israel, Germany, USA

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Treatment

Treatment (outpatient clinic)

TREATMENT AT THE AMBULATORY LEVEL

Treatment tactics:
The currently prescribed treatments include:
· Adaptation of behavior and lifestyle in order to avoid situations that may lead to a fracture;
· Orthotics;
· Posture correction;
· conservative treatment, including water procedures and physical activity;
· Special equipment, including providing movement;
· Weight control;
· oral and intravenous administration bisphosphonates.

Non-drug treatment:

Adaptation of behavior and lifestyle. Conducting gentle exercise therapy and physiotherapy.

Drug treatment

Medicines such as bisphosphonates (1, 2, 3 generations) are powerful inhibitors of bone resorption (a substance that prevents the destruction of bone tissue).

· Pamidronic acid, concentrate for preparation of solution for infusions 3 mg / ml, in vials - 30 mg / 10 ml or 90 mg / 30 ml. pharmachologic effect - inhibiting bone resorption.

Doses:
Up to 2 years - 0.5 mg / kg / day, once every 2 months.
2.1-3 g. - 0.75 mg / kg / day, once every 3 months.
\u003e 3 l. - 1 mg / kg / day, once every 4 months.
No more than 60 mg / day, average 9 mg / kg per year.

Table 4. Scheme of the use of pamidronic acid in children (Plotkinet H. et al., 2000)

Figure 2. Algorithm for prescribing pamidronic acid in patients with osteogenesis imperfecta

List of main drugs:

:
· Consultation of a geneticist - to verify the type of OI and predict the likelihood of a disease in repeated pregnancies;
· Consultation of an otorhinolaryngologist - in the presence of hearing loss;
· Dentist consultation - with imperfect dentinogenesis, dental dysplasia, caries, etc.;
· Consultation of a pediatrician - in the presence of pneumonia, anemia, decrease in body mass index and other conditions.
· Consultation of an endocrinologist - in the presence of short stature, dwarfism and other conditions.

Preventive actions :
· Medical genetic consultation;
· Conversation with parents about the high risk of having a sick child, as well as about the possibility of stillbirth in the second type of OI, as well as death from multiple fractures, etc.;
· Perinatal diagnostics;
· Medical and social rehabilitation;
· Elimination of risk factors (mechanical trauma, external and other types of impact);
· Treatment of concomitant pathology;
· Use of pneumatic tires and orthopedic products;
· Spa treatment.

Patient monitoring:
· Dispensary registration at the place of residence with a pediatric orthopedic traumatologist, surgeon, pediatrician;
· Observation and treatment by related specialists;

Treatment effectiveness indicators:
· Decrease in the number of fractures and mucous membranes;
· Correction of limb deformities;
· Improvement of motor functions;
· Improvement of the general condition.

Treatment (ambulance)

DIAGNOSTICS AND TREATMENT AT THE STAGE OF EMERGENCY EMERGENCY

Diagnostic measures:not.

Drug treatment:
Drug treatment provided at the stage of emergency emergency care (see the CP for the corresponding nosologies for fractures):
· Immobilization of the limb;
· Relief of pain syndrome.

Treatment (hospital)

STATIONARY TREATMENT

Treatment tactics:inpatient treatment for emergency hospitalization according to clinical protocols according to the corresponding nosologies for fractures.
In case of planned hospitalization for the purpose of preoperative preparation, it may include treatment at an outpatient level.

Non-drug treatment:see outpatient level.

Drug treatment: see outpatient level.

Symptomatic therapy includes narcotic and non-narcotic analgesics in the postoperative period (tramadol, paracetamol, ibuprofen, etc.), antibacterial agents for the prevention and treatment of infectious complications (antibiotics - penicillins, cephalosporins, aminoglycosides, carbapenems, etc.), antifungal agents for the prevention and treatment of mycoses (fluconazole, caspofungin, etc.).

Surgical intervention :
· Wedge-shaped osteotomy of the humerus;
· Wedge-shaped osteotomy of the tibia and fibula;
· The use of an external fixation device on other bones in diseases requiring staged correction;
Closed reduction of bone fragments of another specified bone with internal fixation
· Open reposition of bone fragments of the humerus with internal fixation;
· Open reduction of bone fragments of the humerus with internal fixation by blocking intramedullary osteosynthesis;
· Open reduction of bone fragments of the radius and ulna with internal fixation;
· Open reduction of bone fragments of the radius and ulna with internal fixation by blocking intramedullary osteosynthesis;
· Open reduction of bone fragments of the femur with internal fixation;
· Open reposition of bone fragments of the femur with internal fixation by blocking intramedullary osteosynthesis;
· Open reposition of bone fragments of the tibia and fibula with internal fixation;
· Open reduction of bone fragments of another specified bone with internal fixation;
· Open reposition of bone fragments of another specified bone with internal fixation with a blocking extramedullary implant;
· Applying an apparatus for compression-distraction osteosynthesis;
· Thoracoplasty.

Other treatments:
· Psychological training;
· Patient education.

Indications for specialist consultation:
· Consultation of a geneticist - to verify the type of OI and predict the likelihood of a disease in repeated pregnancies;
· Consultation of an otorhinolaryngologist - in the presence of hearing loss;
· Dentist consultation - with imperfect dentinogenesis, dental dysplasia, caries, etc.;
· Consultation of a pediatrician - in the presence of pneumonia, anemia, decrease in body mass index and other conditions.
· Consultation of an endocrinologist - in the presence of short stature, dwarfism and other conditions.

Indications for transfer to the intensive care unit and intensive care unit:
· traumatic shock II-III degree;
· The first day after the volumetric surgery.

Treatment effectiveness indicators:
· Decrease in the number of fractures and mucous membranes;
· Correction of limb deformities;
· Improvement of motor functions;
· Improvement of the general condition.

Further management :
· Dispensary registration at the place of residence with a pediatric orthopedic traumatologist, surgeon, pediatrician;
· Observation and treatment by related specialists.

Hospitalization

Indications for planned hospitalization:
· Presence of limb deformity.

Indications for emergency hospitalization:
· With fractures of large tubular bones, with displacement requiring their osteosynthesis.

Information

Sources and Literature

1. Minutes of meetings of the Joint Commission on the Quality of Medical Services of the MHSD of the Republic of Kazakhstan, 2016
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Osteogenesis incomplete (OI) (osteogenesis imperfecta, Lobstein-Wrolik disease; ICD-10 code: Q78.0) is a pathology that is inherited and manifests itself as increased fragility of bones. The disease is represented by four clinical types, which have a number of similar features, and males and females are equally susceptible to it. For every 20-30 thousand healthy newborns, there is one patient with OI.

OI is caused by mutations in the genes of type I collagen, which leads to disruption of endosteal and periosteal ossification, manifested in extreme fragility of bones due to a decrease in osteoblast differentiation, impaired deposition of calcium and phosphorus salts, decreased production and delayed resorption of bone matter. There are about eight types of genetic defects of this kind. The clinical variety of OI symptoms is determined by a variety of mutations - more than 160 of them have been described. The disease can have an early clinical form (Vrolik's disease: fractures occur already during intrauterine development) and a late clinical form (Lobstein's disease: fractures occur when a child begins to walk).

Symptoms of osteogenesis incomplete

Clinical forms of OI have some differences in symptomatology and course.

Early form:

• stillbirth;
• intracranial trauma during childbirth;
• fatal breathing disorders;
• respiratory tract infections;
• pallor skin;
• underdeveloped subcutaneous fat layer;
• multiple bone fractures at birth.

The prognosis of this form of OI for life is unfavorable: every 8 out of 10 newborns with this form of the disease die in the first month of life, and the rest - within two years due to infectious complications.

Late form:

• excessive fragility of bones;
• the base of the skull, spine and sternum do not break;
• blue sclera coloration;
• hearing loss;
• joint instability;
• decreased muscle tone;
• late closure of fontanelles;
• deformed and shortened limbs of the body;
• deformation of the spinal column;
• late teething;
• amber teeth;
• hyperhidrosis;
• hernia abdominal wall;
• nasal bleeding.

With this form of OI, the prognosis for life is quite favorable.

Diagnostics

Verification is quite possible already on the basis of a specific clinical picture. It is supplemented by the data of X-ray examination of bones, in which the following can be detected:

• diffuse osteoporosis;
• marked thinning of the cortical layer;
• decrease in the diameter of the bones;
• curvature of bones;
• drawing of a spongy substance in the form of a grid;
• platisponyliya;
• expansion of the cranial sutures;
• numerous calluses;

There is a decrease in renal reabsorption of phosphate and calcium. Possible prenatal diagnosis with the study of DNA in biopsies of chorionic villi. Ultrasound: if intrauterine fractures are detected, delivery is carried out by cesarean section.

Treatment of incomplete osteogenesis

It involves the most gentle lifestyle, a diet with an increased amount of protein, minerals and vitamins. To stimulate collagen synthesis, somatotropin is prescribed in / m 3 r / week. 4 units, 15 injections per course. Following this, bone mineralization is stimulated with calcitrin, oxydevit and antiresorbents are prescribed that slow down bone loss: etidronic and pamidronic acids. Vitamin D is used in therapeutic doses. Massage, physiotherapy procedures for tubular bones are prescribed. Orthopedic prevention of pathological bone fractures is carried out, surgical correction their deformations.

Essential drugs

There are contraindications. Consultation of a specialist is required.

• Growth hormone (genetically engineered growth hormone). Dosing regimen: in / m 3 r / week. 4 units, 15 injections per course. The total duration of treatment can be several years.
• Calcitrin (regulator of calcium-phosphorus metabolism). Dosage regimen: appoint i / m, s / c at 3-5 IU / kg / day daily (with a break every 7th day), for a course of 25-40 injections. The maximum dose is limited by the occurrence of nausea or vomiting.
• Etidronic acid (

Congenital fragility of bones is a genetically determined disease that affects connective tissue, and, in particular, causes disorders in the structure and function of collagen.

As the name suggests, it is associated with very poor bone structure that becomes brittle and brittle.

Osteogenesis imperfecta - causes

Collagen is an important element of the body's connective tissue. Depending on where this connective tissue is located and what functions it performs, the corresponding type of collagen is included in its composition.

Osteogenesis imperfecta Is a disease with a genetic background, and the mutation concerns one gene responsible for the correct structure of collagen - more precisely, responsible for the synthesis of the alpha-chain of collagen 1. Disorders in the structure of collagen of this type disrupt the structure and strength of bones, tendons, skin, and also the sclera ...

The disease is inherited more often in an autosomal dominant manner. This means that the presence of one defective gene obtained from one of the parents is enough for symptoms of the disease to appear.

Depending on the extent to which the mutation occurs, the severity of the symptoms associated with the disease varies. The mutation can only slightly reduce the collagen content in the connective tissue, which is reflected in the mild course of the disease. Significant disturbances involving the process of collagen synthesis can lead to very serious health conditions.

In some people, the disease is transmitted in an autosomal recessive manner, which means that damage to both genes from both parents is necessary in order to get symptoms. This can happen if each of the parents is a carrier of a genetic mutation.

Symptoms of congenital bone fragility

Even if the disease is found in several family members, its course may differ significantly. All cases, however, are characterized by varying degrees of weakening of the bone structure, increased fragility of bones, and a tendency to fracture. Damage can occur with a bruise, which in a healthy person will not cause anything, and in extremely severe cases, bone damage occurs even at rest.

Other common symptoms include:

• short stature
• bone deformities
• hypoplasia of teeth
• blue eyes
• deafness (in adulthood)
• laxity of joints
• instability of joints and ligaments
• frequent bruising

Types of congenital bone fragility

There are several types of congenital bone fragility. The mildest form - 1 type, the most common, characterized by low bone fragility, children are not too small and bone deformities are not observed. When a child begins to take the first steps, the first fractures appear, including not only the long bones, but also the small bones of the arms or legs.

Unfortunately, this tendency accompanies the child until maturity. In adulthood osteoporotic changes in bones appear much earlier than in healthy people, and hearing loss increases.

Type 2 congenital bone fragility is called lethal form... The disease manifests itself already during intrauterine life, which leads to pronounced fractures and deformities, often ends in fetal death... Having a baby with type 2 congenital bone fragility does not give him a small chance of survival for several years. Typically, these children die at an early age.

Types 3-4 - This is a moderate and severe form, when there are pronounced deformities of the bones, the disorders have a different shape and severity. They are intermediate forms between the mild form and the lethal form and can give a varied clinical picture.

Bone damage can occur even before the baby is born. In more severe cases, the child's growth is delayed, posture is deformed. Such people move in a wheelchair, because the disease makes it impossible for normal functioning.... Much earlier, such people develop deafness. Patients require constant orthopedic consultations.

Treatment of congenital bone fragility

Due to the genetic origin of the disease, there is no way to completely cure and implement an effective therapy.

Treatment is limited to minimizing the number of fractures, preventing large deformities and reducing pain. Bisphosphonate therapy is used, that is, drugs used in the treatment of osteoporosis... They control the organs of hearing, and also evaluate general state sick, to eliminate problems in other body systems.

The life expectancy of patients with congenital fragility of bones depends, first of all, on the type of disease. In type 2, the patient may not differ from the general population. In more severe forms, life expectancy is shorter than in the general population, however, this does not follow from frequent fractures, but from concomitant problems with the functioning of the respiratory or cardiovascular system, which is associated with deformation of the chest.