Symptoms of undifferentiated connective tissue dysplasia

Phenotypic features of connective tissue dysplasia:

• constitutional features (asthenic body type, weight deficit);
• CTD syndrome itself (anomalies in the development of the facial skull and skeleton, limbs, including kyphoscoliosis, chest deformity, joint hypermobility, skin hyperelasticity, flat feet);
• minor developmental anomalies that in themselves have no clinical significance, but act as stigmas.

A close relationship has been established between the number of external phenotypes, the degree of expression of external dysplastic disorders and changes in the connective tissue framework of internal organs - internal phenotypic features of the syndrome.

One of the important signs of undifferentiated connective tissue dysplasia is asthenic constitution, which is typically combined with bone deformities and joint hypermobility. Skin thinning, hyperelasticity, and vulnerability, as well as foci of depigmentation and subatrophy are noted. Systolic murmur is often detected during examination of the cardiovascular system. Half of the patients are diagnosed with heart rhythm disturbances, most often right bundle branch block and extrasystoles. ECG reveals valve prolapses, aneurysms of the interatrial septum and sinuses of Valsalva, aortic root dilation, and so-called minor cardiac anomalies: additional chords in the left ventricular cavity, papillary muscle dystonia. Heart damage usually proceeds relatively favorably.

There is a certain relationship between the number, degree of expression of phenes of undifferentiated connective tissue dysplasia and the number of minor cardiac anomalies. Generalized form of undifferentiated connective tissue dysplasia should be called cases in which it is possible to identify signs of clinically significant involvement in the defect of 3 or more organs and systems.

A frequent combination of inferiority of connective tissue structures of the heart with deviations in the functioning of the autonomic nervous system is noted. Frequent symptoms are psychovegetative disorders: increased anxiety, emotional instability. In children with undifferentiated connective tissue dysplasia with rhythm and conduction disorders, the autonomic dysfunction syndrome occurs mainly according to the vagotonic type, in the form of syncopal and asthenic conditions, cardialgia, tension headaches and is often accompanied by psychopathological disorders. According to cardiointervalography, almost all children with CTD of the heart have manifestations of vegetative dysregulation, which indicates a decrease in the ability to adapt. As the CTD syndrome increases, changes in personality and characterological features are observed, reflecting an increased tendency to mental maladaptation.

Tracheobronchial dyskinesia is recorded in a number of cases due to a violation of the elasticity of the trachea and bronchi; the obstructive syndrome is severe and long-lasting.

The gastrointestinal tract, as one of the richest in collagen, is involved in the pathological process in CTD, which is manifested by intestinal microdiverticulosis, impaired excretion of digestive juices and peristalsis. Almost all patients with hereditary connective tissue diseases have superficial inflammatory changes in the gastric mucosa, pathological refluxes in combination with Helicobacter colonization, and impaired gastric motility.

From the urinary system, nephroptosis, increased mobility of the kidneys, pyelectasis, kidney doubling, orthostatic proteinuria, increased excretion of oxyproline and glycosaminoglycans are of diagnostic significance.

The clinical picture includes hemorrhagic syndrome due to platelet disorders and decreased synthesis of von Willebrand factor. Frequent nosebleeds, petechial-spotted skin rashes, bleeding gums, and prolonged bleeding from cuts. The development of hemorrhagic syndrome is associated not only with the inferiority of the vascular connective tissue, but also with the failure of the contractile apparatus of platelets and is associated with autonomic disorders. These changes are often combined with the development of leukopenia and thrombocytopenia, with impaired platelet hemostasis, and coagulation deficiency. Violations of immunological competence due to dystrophic changes in thymolymphoid tissue are common. A large number of foci of chronic infection are characteristic. With DST, a tendency for patients to develop autoimmune processes was found.

Neurological pathology is detected in the majority of sick children (vertebrobasilar insufficiency against the background of instability or dysplasia of the cervical spine, juvenile osteochondrosis, spina bifida, intracranial hypertension, migraines, thermoregulation disorders). In children of puberty, the symptoms are transformed, the main target organs are the spine and the organ of vision.

The process of unification of medical terminology has led to the approval of the international term "hypermobility syndrome". Although this term does not exhaust the entire variety of combinations of non-inflammatory connective tissue lesions, today it must be recognized as successful. The advantages of the term are the identification of generalized joint hypermobility as the most characteristic and easily identifiable clinical sign of this group of diseases, and the absence of the word "joint" in the definition directs the doctor to extra-articular (systemic) manifestations of the syndrome. An important reason for the adoption of this name by the international medical community was the development of diagnostic criteria for hypermobility syndrome and the existence of a simple scoring system (Beighton scale) allowing to assess the presence of generalized hypermobility. Standard examination of arthrological patients (radiography of the affected joint, blood test for acute phase indices) does not reveal signs of pathology. The key to diagnosis is the detection of joint hypermobility while excluding other rheumatic diseases (the latter is a prerequisite). It is important to remember that a person with hypermobility can develop any other joint disease.

Recognition of generalized joint hypermobility (Beighton P.)

	Ability	On the right	Left
1	Extension of the little finger >90'	1	1
2	Bringing the thumb sideways and back until it touches the forearm	1	1
3	Elbow hyperextension >10"	1	1
4	Knee hyperextension >10"	1	1
5	Press your hands to the floor without bending your knees (1 point)	1

Maximum points - 9

The degree of joint mobility has a normal distribution in the population. Joint hypermobility is observed in approximately 10% of people, only in a small part of them it is pathological. The presence of hypermobility can often be established in blood relatives (mainly with similar problems). In 75% of cases, the onset of clinical manifestations occurs at school age, the most common variant in this case is arthralgia of the knee joints. Increased range of motion reduces joint stability and increases the frequency of dislocations.

Hypermobility is the result of weakness and extensibility of ligaments, which are hereditary. Of particular importance in this regard are genes encoding the synthesis of collagen, elastin, fibrillin and tenaskin. Clinical significance is determined by frequent dislocations and subluxations, arthralgia, and autonomic dysfunctions. Thus, the formula of R. Graham (2000) helps to understand the relationship between joint hypermobility and joint hypermobility syndrome:

Joint hypermobility + Symptoms = Hypermobility syndrome.

With mechanical overload against the background of reduced resistance of cartilage and other connective tissue structures, areas of micronecrosis and inflammation (arthritis with synovitis or bursitis), load-bearing arthropathy with dysplasia of the osteochondral apparatus may occur. Most patients suffer from non-inflammatory joint diseases (arthrosis, chronic diseases of the spine).

Characteristic signs of load-bearing arthropathy:

• familial forms of early osteoarthritis or osteochondrosis;
• history of injuries and ruptures of ligaments, joints, subluxations, joint and bone pain;
• the relationship between pain syndrome and physical activity;
• low inflammation activity, its subsidence as the load decreases, rapid pain relief and restoration of movement;
• damage to one or two joints along the axis;
• limited effusion;
• presence of local joint pain;
• the presence of osteoporosis, joint hypermobility and other signs of connective tissue dysplasia.

However, patients with "vague" signs of UCTD are encountered more often. Identification of phenotypic signs of UCTD in combination with the above-mentioned manifestations should prompt the physician to consider the possibility of a clinically significant systemic defect of connective tissue.

Diagnostic signs of connective tissue dysplasia revealed during examination

Anamnesis	Slow healing of wounds and scars Joint pain Back pain Cardialgia Feeling short of breath Increased fatigue Bruising, nosebleeds, vascular-platelet type bleeding
General inspection	Body length >95th centile Arm span to body length ratio >1.03 Hernias, muscle diastasis Asthenic physique Hypoplasia of muscle and adipose tissue
Leather	Atrophic striae, visible vascular network Increased skin elasticity Depigmentation foci Pigment spots Hypertrichosis Hemangiomas, angioectasias Ecchymosis, positive pinch test Dry wrinkled skin Transverse folds on the abdomen
Head	Dolichocephaly, skull asymmetry Long or short neck Anomalies of the auricles (low position and asymmetry; abnormal development of the helices; small or fused earlobes; large, small or protruding ears) High or gothic palate Split tongue Anomalies of bite Striations of the tongue Disturbed growth of teeth and their anomalies Deviated septum
Torso	Deformation of the chest (funnel-shaped, keel-shaped, decrease in the anterior-posterior size) Scoliosis due to dysplasia of the ligamentous apparatus Thoracic lordosis
Face	Wide-set or close-set eyes Short or narrow palpebral slits Eye pathology (lens dislocations, keratoconus, anisocoria, blue sclera, colobomas) Slanting chin Small or large mouth
Hands	Joint hypermobility (hyperextension, positive thumb symptom) Long fingers, positive thumb symptoms Thickening of the nail phalanges, syn-, polydactyly, impaired nail growth Short or crooked little fingers The fourth finger is shorter than the second.
Legs	Increased foot length, flat feet Joint hypermobility (hyperextension of the knee joints, flexion of the foot >45') Varicose veins, venous valve insufficiency Habitual dislocations and subluxations of joints Sandal-shaped gap X- and O-shaped curvature of the legs

Note. Each phenotype is assessed from 0 to 3 points depending on its severity (0 - no phenotype; 1 - minor; 2 - average; 3 - significant severity of the phenotypic feature). Children with a score of more than 30 have a diagnostically significant complex of CTD signs. When calculating, only the points obtained during an objective examination are assessed. A score of more than 50 allows us to think about differentiated CTD.

The most numerous complaints were related to cardiac and vegetative symptoms. The structure of disease symptoms was dominated by headaches (28.6%), recurrent bronchial obstruction (19.3%), cough (19.3%), difficulty in nasal breathing (17.6%), abdominal pain (16.8%), skin rashes (12.6%), joint pain (10.9%), increased fatigue (10.9%), subfebrile temperature (10.1%).

In the structure of the main diagnoses, attention is drawn to the high frequency of allergic diseases, identified in 25.2% of children (the majority was bronchial asthma - 18.5% of the group); the second most frequent was neurocirculatory dysfunction - 20.2%. In third place were diseases of the musculoskeletal system and connective tissue, identified in 15.1% (CTD made up 10.9% of the group). Diseases of the digestive system were detected in 10.1% of children. All children had concomitant diagnoses, the vast majority - more than one. Diseases of the musculoskeletal system and connective tissue appeared in 37.0%, NCD was diagnosed in 19.3%, infectious diseases of the respiratory system - in 27.7%, allergic - in 23.5%, gastrointestinal diseases - in 20.2%, nervous system - in 16.8%.

ECG features were detected in 99.1% (on average 2.2 ECG phenomena per child). Metabolic disorders - in 61.8%, rVica bundle branch block - in 39.1%, sinus arrhythmia - in 30.1%, ectopic rhythm - in 27.3%, electrical position shift - in 25.5%, early ventricular repolarization syndrome - in 24.5%, electrical axis shift to the right - in 20.0%. Minor cardiac anomalies were detected on echocardiography in 98.7% (on average 1.8 per child). The most common anomalies were the presence of chords in the left ventricular cavity (60.0%), grade I mitral valve prolapse (41.9%), grade I tricuspid valve prolapse (26.7%), pulmonary valve prolapse (10.7%), and dilation of the sinuses of Valsalva (10.7%), which significantly exceeds the population frequency of findings on echocardiography.

Ultrasound examination of the gastrointestinal tract revealed changes in 37.7% (an average of 0.72 findings per patient). Deformation of the gallbladder - in 29.0%, accessory lobes of the spleen - in 3.5%, increased echogenicity of the pancreas and gallbladder wall, dyskinesia, hypotension of the gallbladder - in 1.76% each, respectively, other changes - in 7.9%. Ultrasound examination of the kidneys diagnosed disorders in 23.5% of children (an average of 0.59 findings). Hypermobility of the kidneys was detected - in 6.1%, pyelectasis - in 5.2%. Doubling of the renal pelvis and calyceal system and nephroptosis - in 3.5% each, hydronephrosis - in 2.6%, other changes - in 7%.

Neurosonography abnormalities were detected in 39.5% (0.48 per examined): bilateral dilation of the lateral ventricles - in 19.8%, their asymmetry - in 13.6%, unilateral dilation - in 6.2%, other changes - in 8.6%. Radiography and ultrasound revealed a high frequency of abnormalities in the cervical spine (81.4%, an average of 1.63 per examined): instability was detected in 46.8%, cervical scoliosis - in 44.1%, cranial subluxation of C, C2 _- in 22.0%, hypoplasia of C1 - in 18.6%, Kimmerle anomaly - in 15.3%, other changes - in 17.0% of children. Ultrasound Dopplerography of the main vessels of the head revealed abnormalities in 76.9% (1.6 findings per one examined person). Blood flow asymmetry in the vertebral arteries was revealed in 50.8%, in the internal carotid arteries - in 32.3%, in the common carotid arteries - in 16.9%, outflow asymmetry in the jugular veins - in 33.8%, and other abnormalities - in 23.1%. When registering the platelet aggregation function, abnormalities were revealed in 73.9% of children, the average values for the group were below the reference values.

Thus, the examination results can be characterized as multiple organ disorders, most often from the cardiovascular, nervous, musculoskeletal systems. In addition to the complex of phenotypic signs of CTD, each child had signs of several disorders from organs and systems: ECG changes, minor heart anomalies, changes in the cervical spine and blood flow asymmetry, structural features of internal organs, decreased BMD. On average, a child has more than 8 of these or those features (4 - from the heart; 1.3 - from the abdominal organs; 3.2 - from the cervical vertebrae and vessels). Some of them can be classified as functional (ECG changes, presence of blood flow asymmetries on ultrasound Doppler, instability of the cervical spine, gallbladder deformations), others are morphological in nature (hypoplasia and subluxation of the cervical vertebrae, minor cardiac anomalies, decreased BMD).

A decrease in BMD may be important in the development of early osteochondrosis, scoliosis, and cervical vascular disorders. UCTD plays a major etiologic role in the genesis of neurocirculatory dysfunction in children. The initial background for its development is the weakness of the subendothelial layer of blood vessels, developmental anomalies, and weakening of the ligamentous apparatus of the vertebrae. As a result, hemorrhages and injuries to the cervical spine are common during childbirth. Bone remodeling and bone formation processes are 75-85% under genetic control. Urgent attempts to reduce the avalanche of bone fractures in old age (2/3 of which are vertebral and femoral at this age) should begin in adolescence and pursue the prevention of late osteoporosis.