Diagnosis of undifferentiated connective tissue dysplasia

There are no generally accepted diagnostic algorithms for undifferentiated connective tissue dysplasia. The complexity of diagnostics is aggravated by the lack of an accurate definition of the nature and number (specificity) of the signs. The peak of diagnostics occurs in senior school age. Prognostic factors of the genealogical history for the formation of undifferentiated connective tissue dysplasia are signs of CTD in relatives of the 1st and 2nd degree (chest deformities, heart valve prolapses, joint hypermobility, hyperextensibility and thinning of the skin, spinal pathology, myopia). Pedigree data indicate the accumulation of pathology related to CTD in families: osteochondrosis, polyarthritis, varicose veins, hernias, hemorrhagic diseases. The presence of joint hypermobility can often be established in blood relatives.

Certain combinations of external signs allow us to assume a particular syndrome or phenotype. Joint phenotypes and joint hypermobility have the lowest specificity and diagnostic sensitivity, as they can be detected in almost all dysplastic syndromes and phenotypes. Myopia, scoliosis, and asthenic physique also have low specificity. Skin phenotypes, arachnodactyly, and chest deformities have the highest diagnostic sensitivity. Minor cardiac anomalies are most closely associated with external and internal phenotypes of DST.

Joint hypermobility syndrome is diagnosed in the presence of 2 major criteria, 1 major and 2 minor criteria, or 4 minor criteria. Two minor criteria are enough if there is a close relative suffering from this disease. Joint hypermobility syndrome is excluded in Marfan or Ehlers-Danlos syndromes (except for the hypermobility type). Joint hypermobility syndrome is a common and benign variant of UCTD, on the other hand, it can be a symptom of a more serious and clinically significant disease. When detecting signs of joint hypermobility syndrome, the presence and severity of skeletal and skin dysplasia phenotypes and signs of cardiovascular and visual involvement should be assessed.

Revised diagnostic criteria for benign joint hypermobility syndrome (Grahame R. et Al., 2000)

Big criteria

Minor criteria

Beighton score 4/9 or higher (both at time of examination and in the past) Arthralgia of 4 or more joints for more than 3 months

Beighton Index 1.2 or 3/9 Arthralgia (>3 months) in 1-3 joints or back pain, spondylosis, spondylosis/spondylolithesis Dislocation/subluxation of more than one joint or one joint with repeated occurrence Inflammation of the soft tissues around the joint. Three or more lesions (eg, epicondylitis, tenosynovitis, bursitis) Marfanoid appearance Skin abnormalities: banding, hyperextensibility, thin skin, tissue paper scarring Signs related to the organs of vision: epicanthus, myopia, antimongoloid eye shape Varicose veins or hernia, uterine/rectal prolapse

The diagnosis of undifferentiated connective tissue dysplasia, suspected during examination, requires instrumental examination. Diagnostic signs of DCT, revealed during examination:

• cardiovascular system: systolic murmur, valve prolapse, aneurysms of the interatrial septum and sinuses of Valsalva, false chords, papillary muscle dystonia, dilation of the aortic root;
• respiratory system: tracheobronchial dyskinesia, hyperventilation syndrome, bronchial hyperreactivity;
• digestive system: tendency to inflammatory diseases of the mucous membranes of the stomach and intestines, persistent kinks and deformations of the gallbladder, excessively long hypoplastic intestine, visceroptosis;
• urinary system: nephroptosis, atony of the renal pelvis and calyces, increased mobility of the kidneys, duplication of the kidneys or urinary tract, orthostatic proteinuria, excretion of increased amounts of oxyproline;
• CNS: thermoregulation disorders, asymmetry of tendon reflexes, pyramidal disorders, spina bifida, juvenile osteochondrosis;
• musculoskeletal system: instability of the cervical spine, scoliosis of the thoracic and cervical spine, subluxations of the cervical vertebrae, decreased BMD.

For diagnosis, it is advisable to use the criteria of the above 10 dysplastic syndromes and phenotypes.

Marfan-like appearance suggests signs of predominant involvement of the skeletal system (the presence of four or more skeletal phenomena).

The Marfan-like phenotype includes a wide range of conditions from "incomplete Marfan syndrome" to relatively milder conditions that are diagnosed when there is evidence of involvement of at least three systems: skeletal, cardiovascular, and at least one of the two - pulmonary or visual. The following is a list of visceral signs:

• cardiovascular system: aortic dilatation, minor cardiac anomalies (except mitral valve prolapse), pulmonary artery dilation, mitral valve calcification;
• pulmonary system: tracheobronchial dyskinesia, history of spontaneous pneumothorax;
• visual system: myopia, abnormally flat cornea.

The MASS phenotype is recognized by:

• in case of mitral valve prolapse;
• expansion of the aorta within 2a;
• skin involvement (hyperextensibility, striae);
• involvement of the skeletal system.

Primary (isolated) mitral valve prolapse:

• EchoCG signs of mitral valve prolapse, including with myxomatous degeneration of the valves;
• signs of involvement of the skin, skeletal system and joints;
• no signs of aortic dilation.

The Ehlers-like phenotype (classic) includes a wide range of conditions from “incomplete” EDS to very mild and clinically less significant conditions that are diagnosed with signs of involvement of the skin, muscular system, and blood vessels.

Ehlers-like hypermobility phenotype:

• joint hypermobility (up to 4 points according to Beighton);
• pain for less than 3 months in 1-3 joints, rare subluxations, spondylosis;
• complications of hypermobility (sprains, dislocations and subluxations, flat feet);
• signs of skin and/or skeletal involvement.

Benign joint hypermobility:

• signs of joint hypermobility (4 or more points according to Beighton);
• there is no arthralgia or involvement of the skeletal system and skin.

Unclassifiable phenotype of undifferentiated connective tissue dysplasia:

• detect 6 or more of any external DST phenotypes;
• there are not enough signs to diagnose the above-mentioned dysplastic phenotypes.

Increased dysplastic stigmatization:

• 3-5 external DST hair dryers;
• various combinations of bone-skeletal, skin and joint factors;
• There are no significant minor cardiac anomalies or other visceral signs of CTD.

Increased dysplastic stigmatization with predominantly visceral manifestations:

• isolated external dysplasia phenomena;
• 3 or more minor anomalies of the heart and/or connective tissue framework of other internal organs.

Reliable differences in clinical symptoms of individual dysplastic syndromes and phenotypes with different prognostic value were revealed. Unclassified phenotype and increased dysplastic stigmatization have minimal clinical manifestations of dysplasia and are close to normal variants. Phenotypes 1-4 partially coincide in clinical manifestations with Marfan syndrome, 5-7 - with classical and hypermobile types of EDS. In the case of the last 3 types, we can talk about unclassified DCT. In children, it is somewhat more difficult to differentiate undifferentiated connective tissue dysplasia by syndromes and phenotypes due to the incomplete formation of organs and systems.

Clinically differentiated and undifferentiated forms cannot always be clearly distinguished; often the diagnosis is formulated only by quantitatively counting the symptoms.

Molecular genetic diagnostics of congenital CTD is promising. However, most biochemical and molecular genetic methods are labor-intensive and require expensive equipment. That is why clinical-anamnestic and functional examination methods are most accessible for screening children. Such children are often observed by various narrow specialists, each of whom prescribes their own treatment, sometimes untimely and without the desired effect. The child is given many diagnoses, while there is no understanding of the pathology of the body as a whole. It is necessary to single out such patients in a special high-risk group with multiple organ pathology.

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