Connective tissue dysplasia is a group of clinically polymorphic pathological conditions caused by hereditary or congenital defects in collagen synthesis and accompanied by impaired functioning of internal organs and the musculoskeletal system. Dysplasia is most often manifested by changes in body proportions, bone deformities, joint hypermobility, habitual dislocations, hyperelastic skin, valvular heart defects, vascular fragility, muscle weakness. Diagnosis is based on phenotypic signs, biochemical parameters, and biopsy data. Treatment includes physical therapy, massage, diet, and drug therapy.
Connective tissue dysplasia is a concept that combines various diseases caused by hereditary generalized collagenopathy and manifested by a decrease in the strength of connective tissue of all body systems. The population frequency is 7-8%, however, it is assumed that its individual signs and small undifferentiated forms may occur in 60-70% of the population. Disease comes to the attention of clinicians working in various medical fields – pediatrics, traumatology and orthopedics, rheumatology, cardiology, ophthalmology, gastroenterology, immunology, pulmonology, urology, etc.
The development of this disease is based on a defect in the synthesis or structure of collagen, protein-carbohydrate complexes, structural proteins, as well as the necessary enzymes and cofactors. The direct cause of the considered connective tissue pathology is various kinds of effects on the fetus, leading to a genetically determined change in the fibrillogenesis of the extracellular matrix. Such mutagenic factors include:
- unfavorable environmental conditions,
- poor nutrition and bad habits of the mother,
- burdened pregnancy, etc.
Some researchers point to the pathogenetic role of hypomagnesemia in the development of pathology, based on the detection of magnesium deficiency in the spectral study of hair, blood, oral fluid. Collagen synthesis in the body is encoded by more than 40 genes, for which over 1300 types of mutations have been described. This causes a variety of clinical manifestations of this disease and complicates their diagnosis.
Connective tissue dysplasia is divided into differentiated and undifferentiated. Differentiated dysplasias include diseases with a certain, established type of inheritance, a clear clinical picture, known genetic defects and biochemical disorders. The most typical representatives of this group of hereditary connective tissue diseases are Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, mucopolysaccharidosis, systemic elastosis, dysplastic scoliosis, Beals syndrome (congenital contractural arachnodactyly), etc. The group of undifferentiated disease consists of various pathologies whose phenotypic signs do not correspond to any of the differentiated diseases.
According to the degree of severity, the following types of this disease are distinguished: small (in the presence of 3 or more phenotypic signs), isolated (with localization in one organ) and actually hereditary connective tissue diseases. Depending on the prevailing dysplastic stigmas , 10 phenotypic variants of disease are distinguished:
- Marfanopodo6 appearance (includes 4 or more phenotypic signs of skeletal dysplasia).
- Marfanopodo6 phenotype (incomplete set of signs of Marfan syndrome).
- MASS-phenotype (includes aortic, mitral valve, skeletal and skin lesions).
- Primary mitral valve prolapse (characterized by EchoCG signs of mitral prolapse, changes in the skin, skeleton, joints).
- Classic Ehlers-like phenotype (incomplete set of signs of Ehlers-Danlos syndrome).
- Hypermobile ehlers–like phenotype (characterized by hypermobility of joints and concomitant complications – subluxations, dislocations, sprains, flat feet; arthralgia, involvement of bones and skeleton).
- Joint hypermobility is benign (includes an increased volume of movements in the joints without the interest of the skeletal system and arthralgia).
- Undifferentiated connective tissue dysplasia (includes 6 or more dysplastic stigmas, which, however, are not enough to diagnose differentiated syndromes).
- Increased dysplastic stigmatization with predominant bone-joint and skeletal signs.
- Increased dysplastic stigmatization with predominant visceral signs (small anomalies of the heart or other internal organs).
Since the description of differentiated forms of connective tissue dysplasia is given in detail in the corresponding independent reviews, in the future we will talk about its undifferentiated variants. In the case when the localization of connective tissue dysplasia is limited to one organ or system, it is isolated. If connective tissue dysplasia manifests phenotypically and captures at least one of the internal organs, this condition is considered as a syndrome of connective tissue dysplasia.
External signs of connective tissue dysplasia are represented by constitutional features, anomalies in the development of skeletal bones, skin, etc. Patients with connective tissue dysplasia have an asthenic constitution: tall stature, narrow shoulders, body weight deficiency. Disorders of the development of the axial skeleton can be represented by scoliosis, kyphosis, funnel-shaped or keeled deformities of the chest, juvenile osteochondrosis.
Craniocephalic stigmas of connective tissue dysplasia often include dolichocephaly, malocclusion, dental anomalies, Gothic palate, non-fusion of the upper lip and palate. Pathology of the osteoarticular system is characterized by O-shaped or X-shaped deformity of the limbs, syndactyly, arachnodactyly, hypermobility of the joints, flat feet, a tendency to habitual dislocations and subluxations, bone fractures.
On the part of the skin, there is increased extensibility (hyperelasticity) or, on the contrary, fragility and dryness of the skin. Often, striae, pigmented spots or foci of depigmentation, vascular defects (telangiectasia, hemangiomas) occur on it for no apparent reason. Weakness of the muscular system in connective tissue dysplasia causes a tendency to omission and prolapse of internal organs, hernias, muscular torticollis. Among other external signs of connective tissue dysplasia, microanomalias such as hypo- or hypertelorism, lop-earedness, asymmetry of the ears, low hairline on the forehead and neck, etc. may occur.
Changes on the part of internal organs
Visceral lesions occur with the involvement of the central nervous system and the autonomic nervous system, various internal organs. Neurological disorders associated with connective tissue dysplasia are characterized by vegetative-vascular dystonia, asthenia, enuresis, chronic migraine, speech disorders, high anxiety and emotional instability. The syndrome of connective tissue dysplasia of the heart may include mitral valve prolapse, an open oval window, hypoplasia of the aorta and pulmonary trunk, elongation and excessive mobility of the chords, aneurysms of the coronary arteries or atrial septum.
The consequence of the weakness of the walls of venous vessels is the development of varicose veins of the lower extremities and pelvis, hemorrhoids, varicocele. Patients with connective tissue dysplasia are prone to arterial hypotension, arrhythmias, atrioventricular and intraventricular blockages, cardialgia, sudden death.
Cardiac manifestations are often accompanied by bronchopulmonary syndrome, characterized by the presence of cystic hypoplasia of the lungs, bronchiectasis, bullous emphysema, repeated spontaneous pneumothorax. The defeat of the gastrointestinal tract in the form of omission of internal organs, diverticula of the esophagus, gastroesophageal reflux, hernia of the esophageal orifice of the diaphragm is characteristic. Typical manifestations of the pathology of the organ of vision in connective tissue dysplasia are myopia, astigmatism, hyperopia, nystagmus, strabismus, subluxation and dislocation of the lens.
On the part of the urinary system, nephroptosis, urinary incontinence, renal abnormalities (hypoplasia, doubling, horseshoe kidney), etc. may be noted. Reproductive disorders associated with connective tissue dysplasia in women may be represented by uterine and vaginal prolapse, metro- and menorrhagia, spontaneous abortions, postpartum bleeding; cryptorchidism is possible in men. Persons with signs of connective tissue dysplasia are prone to frequent acute respiratory infections, allergic reactions, hemorrhagic syndrome.
Diseases from the group of connective tissue dysplasia are not always diagnosed correctly and in a timely manner. Often patients with various signs of dysplasia are observed by doctors of different specialties: traumatologists, neurologists, cardiologists, pulmonologists, nephrologists, gastroenterologists, ophthalmologists, etc. The recognition of undifferentiated forms of connective tissue dysplasia is complicated by the lack of unified diagnostic algorithms.
The greatest diagnostic significance is the identification of a set of phenotypic and visceral signs. In order to detect the latter, ultrasound (EchoCG, ultrasound of the kidneys, ultrasound of the abdominal cavity), endoscopic (FGDS), electrophysiological (ECG, EEG), radiological (radiography of the lungs, joints, spine, etc.) methods are widely used. The identification of characteristic multiple organ disorders, mainly from the musculoskeletal, nervous and cardiovascular systems, with a high degree of probability indicates the presence of connective tissue dysplasia.
Additionally, the biochemical parameters of the blood, the hemostasis system, the immune status are examined, a skin biopsy is performed. As a method of screening diagnostics of connective tissue dysplasia, it is proposed to conduct a study of the papillary pattern of the skin of the anterior abdominal wall: the detection of an unformed type of papillary pattern serves as a marker of dysplastic disorders. Families where there are cases of connective tissue dysplasia are recommended to undergo medical and genetic counseling.
There is no specific treatment for connective tissue dysplasia. Patients are recommended to adhere to a rational daily routine and nutrition, recreational physical activity. In order to activate compensatory and adaptive capabilities, courses of physical therapy, massage, balneotherapy, physiotherapy, acupuncture, osteopathy are prescribed.
In the complex of therapeutic measures, along with syndromic drug therapy, metabolic drugs (L-carnitine, coenzyme Q10), calcium and magnesium preparations, chondroprotectors, vitamin and mineral complexes, antioxidant and immunomodulatory agents, phytotherapy, psychotherapy are used.
The prognosis of connective tissue dysplasia largely depends on the severity of dysplastic disorders. In patients with isolated forms, the quality of life may not be impaired. Patients with polysystemic lesion have an increased risk of early and severe disability, premature death, the causes of which may be ventricular fibrillation, PE, rupture of an aortic aneurysm, hemorrhagic stroke, severe internal bleeding, etc.