Imperfect osteogenesis

Imperfect osteogenesis (osteogenesisimperfecta, Lobstein-Wilkin disease, Q78.0) is a hereditary disease manifested by increased bone fragility, more often caused by mutations in the genes of type I collagen, caused by impaired osteoblast functions, which leads to disruption of endosteal and periosteal ossification. The frequency of newborns is 7.2 per 10 000, the most common type IV.

Classification of imperfect osteogenesis

Describe up to 8 types of genetic defects. According to the clinical picture, there are 4 types.

Characteristics of the types of imperfect osteogenesis

A type	Inheritance	Defect localization	Clinical manifestations
IA (OMIM 166200) IB (OMIM 166240)	Autosomal dominant	The gene COL1A1 on 17q21-q22 (collagen 1, a-1 polypeptide) The gene COL1A2 at 7q22.1 (collagen I, a-2 polypeptide) The defect is not localized	Bone fragility, blue sclera, lack of hearing loss, fractures more often in preschool age with the development of progressive deformations of long tubular bones Type A - without incomplete dentinogenesis Type B - with completed dentinogenesis
II (OMIM 166210) (OMIM 610854)	Autosomal recessive	HA gene COL 1A / at 17q21-q22 (collagen I, a-1 polypeptide) gene COL1A2 at 7q22.1 (collagen I, a-2 polypeptide) IV - CASP gene on Sp22 (cartilage-associated protein)	Perinatal-lethal type: multiple fractures of the bones arising intrauterine or in labor, deformities of the femurs, breach of the bone formation of the skull by the type of "membrane", blue sclera, development of the syndrome of respiratory disorders, leading to perinatal death
III (OMIM 259420)	Autosomal recessive	The SOSH gene / on 17q21-q22 (collagen I, a-1 polypeptide)	Recurrent fractures of long tubular bones, often during labor, progressive skeletal deformity, joint hypermobility, normal sclera, unmodified hearing
IV (OMIM 166220)	Autosomal dominant	The gene COL1A1 on 17q21-q22 (collagen I, a-1 polypeptide)	Friability of bones with rare fractures that lead to deformation of bones, normal color sclera, unmodified hearing Type A - without incomplete dentinogenesis Type B - with completed dentinogenesis

According to the timing of the onset of the disease, early (Wolff, fractures appear in utero or immediately after the birth of the child) and late form (Lobstein, fractures occur after the start of walking).

What causes imperfect osteogenesis?

One of the most common monogenic diseases of connective tissue caused by mutations in genes encoding the synthesis and _x - and a ₂ -chains of type I collagen. Clinical polymorphism is caused by the nature of the mutations: insertions, fission, splicing and nonsense mutations - more than 160 are described. The most severe forms are observed in cases of replacement of glycine with another amino acid; mutations of the collagen gene a ₂ proceed more favorably than a ,. Sporadic cases are not uncommon. Reduced the differentiation of osteoblasts, the deposition of calcium and phosphorus salts is impaired, production is inadequate and bone resorption is inhibited.

Symptoms of imperfect osteogenesis

A typical sign is a tendency to fracture of tubular bones, ribs and collarbones with minimal trauma; the earlier the manifestations appear, the more severely the disease proceeds. Other abnormalities: shortening and curvature of limbs due to fractures, muscle atrophy, looseness or contracture of joints, blue sclera, yellowish-brown teeth, deformities of the spine and thorax, long-lasting uninhibition of ferns and seams of the skull, predominance due to this cerebral cranium over the facial, otosclerosis . Fractures well fuse with the formation of bone callus. Fractures of the skull bones are not characteristic. Children are often immobilized, lagging behind in somatic development.

Diagnosis of imperfect osteogenesis

Diagnostic criteria:

• increased brittleness of bones;
• blue sclera;
• yellow, "amber" teeth;
• otosclerosis.

Radiographic changes in the diaphysis of the tubular bones: diffuse osteoporosis up to the transparency of the bone, a sharp thinning of the cortical layer, a decrease in the diameter of the diaphysis with the expansion of the metaphyses, a network pattern of the spongy substance, multiple bone calluses, curvature under the influence of muscle traction. When determining the clearance of phosphates and calcium for creatinine, their renal reabsorption is reduced.

Differential diagnosis with various forms of rickets, hypophosphatase, juvenile idiopathic osteoporosis, metaphyseal chondrodysplasia.

Treatment of imperfect osteogenesis

Gentle way of life. A diet rich in protein, calcium, phosphorus and magnesium, vitamins C, E, B ,, B ₂, B ₆, supplements containing amino acids (glycine, methionine, lysine, proline, glutamine). Massage, physiotherapy (inductothermy, electrophoresis with calcium salts on tubular bones).

Apply 2 groups of drugs that affect bone remodeling: bone-forming, whose action is directed to the restoration of lost bone mass (fluorides, calcitonin) and antiresorbents, which can slow down bone loss (calcium salts, vitamin D, bisphosphonates). As a rule, Vitamin D - colcalciferol is prescribed for a long time in therapeutic doses (up to 8-10 thousand ME) or alfacalcidol (1-1.5 μg / day) and calcium-containing substances, carbonates (vitacalcine, calcium-D3-Nycomed , vitrum osteomag) or ossein-hydroxyapatite complexes (osteogenone, osteocaa). With them, you can combine the following groups of drugs.

• Calcitonin preparations (in the form of a nasal spray for 100-200 IU / day), treatment is accompanied by inhibition of bone loss, an increase in its mineral density and a decrease in fracture frequency.
• Bisphosphonates (etidronic, pamidron, alendron, zoledronic acid) have significant antiresorptive activity. Long-term administration of etidronic acid (10 mg / kg per day IV / 3-7 days per month orally at 20 mg / kg for up to 30 days). When treated with pamidronic acid (0.5-1 mg / kg), the incidence of fractures decreases, the degree of bone mineralization increases, and bone pain decreases.

With imperfect osteogenesis of type 3, early treatment (from the 2nd month of life) with neuridronate has a positive effect on the growth and frequency of fractures. The start of application at 6 months leads to a decrease in the incidence of fractures, but is not accompanied by an increase in osteocalcin and insulin-like growth factor.

During deformations, courses of conservative therapy are conducted, preparing patients for operative orthopedic methods of treatment. The prognosis is poor with early forms. A common cause of death is infectious diseases associated with immobility.

[1], [2], [3], [4], [5], [6]