Connective tissue dysplasia: main clinical syndromes, diagnosis, treatment

District gynecologist, Gynecologist-surgeon (SOD)

Fedina

Tatyana Leonidovna

Obstetrician-gynecologist of the highest category

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Dysplasia is a pathology that manifests itself in the form of atypical changes in the epithelial cells of the vaginal part of the cervix. Gynecologists consider the disease as a precancerous process. In the early stages, dysplasia is reversible: timely initiation of treatment can prevent the formation of a malignant neoplasm. The risk group includes women aged 25–35 years. Every year, doctors record 1.5 cases of the disease for every thousand patients of a given age interval. Diagnosis and treatment of cervical dysplasia is carried out by a gynecologist. If there are appropriate indications, the doctor may refer the patient to an oncologist and surgeon.

Reasons for development

In 95% of cases, the disease develops against the background of infection of the patient with oncogenic types of human papillomavirus. Within 12–18 months after contact with the vaginal mucosa, the viral infection provokes changes in the structure of flat epithelial cells. Other causes of cervical dysplasia may include:

• suppression of the patient’s immune function while taking immunosuppressants;
• systematic smoking in active or passive forms;
• chronic infectious diseases of the genitourinary system;
• endocrine disorders caused by pregnancy, premature menopause or taking hormonal drugs;
• early pregnancy and childbirth.

The risk of developing pathological changes in the epithelium of the cervix increases with traumatic damage to adjacent tissues.

Postoperative period

Recommendations in the postoperative period depend on the type and volume of intervention that was performed. The woman should be at rest, which will promote faster tissue healing.

Doctors recommend that within 2-3 months after surgery you avoid:

• Moving heavy objects.
• Physical education classes.
• Visits to baths, saunas.
• Sexual contacts.

To monitor the healing process, it is important for a woman to regularly visit a gynecologist after each menstrual cycle. If bleeding does not stop within 6 weeks after the intervention, an unpleasant odor, itching and burning are observed, this indicates the presence of complications. In this case, the recovery period may be delayed, and the uterine cavity will become scarred.

Kinds

The cervix is ​​a narrow cylindrical body, inside of which the cervical canal is located. The external os of the organ is located in the vagina, the internal - in the uterine cavity. The inner surface of the cervical canal is lined with epithelium consisting of columnar cells. There are glands on the walls of the cervix: the mucus they produce prevents pathogenic microflora from entering the uterus from the vagina. In normal condition, the epithelium of the cervical canal is bright red. Dysplasia leads to disruption of the structure of the mucous membrane: atypical cells have an increased size and an atypical shape.

The dysplastic process can affect various layers of squamous epithelium. Gynecologists distinguish three degrees of pathology based on the depth of formation of atypical cells. Mild cervical dysplasia (CIN I according to the international classification) is characterized by minor changes in the morphology of cellular structures. The pathology affects the upper third of the stratified epithelium.

Moderate dysplastic process (CIN II) develops in the upper and middle third of epithelial tissues. Severe dysplasia (CIN III) affects the entire thickness of the epithelium and is considered by gynecologists as a non-invasive cancer. The pathology does not spread to adjacent muscles, blood vessels and nerve endings (invasive cervical cancer affects all of these structures).

Connective tissue dysplasia in the practice of a pediatrician

Translated from Greek as “deviation in formation”

“Medical Bulletin” has touched upon the topic of DST more than once.
But so far only isolated manifestations of this congenital pathology have been described. Thus, in “MV” No. 21 for 2010, Professor L.M. Makarov spoke about primary channelopathies, often leading to sudden cardiac death in children and caused by mutations of genes expressed in the myocardium. In “MV” No. 4 for 2011, Professor I.V. Viktorova described joint hypermobility syndrome, and in No. 17-18 for 2011, Professor E.A. Gallyamov spoke about the most important pathogenetic factor of gastroesophageal reflux disease - congenital hiatal hernias, formed due to the increased elasticity of the tissues limiting this hole.

These publications already show how widespread and significant diseases caused by CTD are. However, many years of research by Z.V. Nesterenko and the world science data that she analyzes indicate that DST affects not three, but much more body systems, and this problem is incomparably wider and more acute than it was thought about in 1989, when the Scottish doctor R. Beighton first proposed to designate the congenital pathology of TS, manifested by a decrease in its strength, by the term dysplasia, which translated from Greek means “deviation in formation.”

If proline changes to arginine

The frequency of detection of CTD (according to various authors) is quite high - from 26 to 80% for all ages and from 74 to 85% among children.

In the development of such dysplasias, mutations of genes encoding the synthesis and spatial structure of collagen and responsible for the formation of matrix components are of key importance. Accordingly, according to one of the first classifications of DST, they were divided into diseases caused by impaired synthesis or catabolism of the fibrous components of DST or its main substance.

But in the 1990s, a classification that is more common today was adopted. The first group of dysplasias includes fairly rare differentiated dysplasias (DDSDs), which have a monogenic and specific type of inheritance, more often autosomal dominant, and clearly defined clinical symptoms. These are Marfan syndrome, Ehlers-Danlos syndrome, osteogenesis imperfecta and several others.

To get acquainted with DDST, let's turn to the most common (frequency of occurrence among newborns is 5:100,000) of their representative - Marfan syndrome (MS). All proven cases of this syndrome are a consequence of a mutation in the fibrillin gene. It is localized in the long arm of chromosome 15, field 21 (15ql5-q21.3). The essence of the mutation is the replacement of the amino acid proline with arginine in the fibrillin protein. As a result, the synthesis of collagen type 3 increases and the content of collagen type 1 decreases. If normally the ratio of collagen-1:collagen-3 is 6:4, then with SMA it drops to 3:7.

The clinical picture in a typical case of SMA is manifested by a characteristic triad of signs related to the musculoskeletal and cardiovascular systems, as well as the visual organs.

Changes in the musculoskeletal system include: tall stature, asthenic physique (the length of the limbs is disproportionate to the length of the body), arachnodactyly (long thin fingers), chest deformity, high arched palate, kyphoscoliosis, ligamentous weakness. Lesions of the cardiovascular system include: dilatation of the aortic root, aortic regurgitation, dissecting aortic aneurysm, mitral valve prolapse, blood regurgitation due to insufficiency of this valve. A characteristic pathology of the visual organs is iridodenesis (tremor of the lens due to weakness of the ligament of Zinn), subluxation of the lens, a high risk of retinal detachment and high myopia.

Before the widespread use of surgical correction of cardiovascular pathology, almost all patients with SMA died before the age of 30-35 years. Moreover, the main group is still in childhood. However, in the 21st century, with adequate therapy, the life expectancy of most patients with SMA is only slightly inferior to this indicator in the general population.

Tall, freckled, stooped

The second group of DST, which makes up the disorders most often encountered by practical pediatricians, includes disorders united by the term undifferentiated dysplasia (UDTD). Unlike differentiated dysplasias, UCTD are genetically heterogeneous pathologies. The main characteristic of such dysplasias is a wide range of clinical manifestations without clear symptoms. That is, UCTD is not a nosological entity, and there is no place for it in ICD-10 yet. In turn, UCTDs are divided into 2 groups: diseases with an established and unidentified (and this is the vast majority of UCTDs) gene defect.

UCTD in a child can be diagnosed already at the stage of physical examination with a comprehensive assessment of the so-called phenotypic markers. External and visceral markers are distinguished, the predominance of which depends on what type of TS lesion occurs - dense or loose. The critical number of external markers that allows one to make a conclusion about the presence of UCTD is now considered to be 3-6. Based on the diagnostic significance of individual signs of UCTD, diagnostic tables are proposed with a score of external and visceral markers, as well as biochemical parameters.

For example, external changes in the skin in children with UCTD usually indicate damage to loose connective tissue and are characterized by the presence of hyperelasticity, increased extensibility, stretch marks, keloid scars, a pronounced subcutaneous venous network, characteristic pigment spots of the “café au lait” color, or depigmentation, a large number nevi.

But lesions of dense TS are manifested by changes in the skeleton: poor posture in the form of kyphosis and scoliosis, stooping, chest deformities, and flat feet. Such children, as a rule, are tall and asthenic in build.

All children with UCTD exhibit so-called minor developmental anomalies, or dysmorphia. The most common dysmorphias include: fair skin, fused eyebrows, wide bridge of the nose, hyper- and hypotelorism, blue sclera, epicanthus, abnormal tooth growth, deformed auricle, fused lobe, curved little fingers, incomplete syndactyly of the fingers, light or red hair color. Diagnostically significant for identifying UCTD is the presence of 6 or more dysmorphias in a child.

Markers external and internal

Let us now turn to the internal markers of UCTD, and we emphasize that there is a direct correlation between the number of external and internal markers.

If we talk about the integral indicators of internal UCTD markers detected by biochemical methods, then the most informative is determining the level of molecules formed during the breakdown of collagen. These are hydroxyproline and glycosaminoglycans in daily urine, and in blood serum - lysine and proline. A change in the ratio of collagens of different types in UCTD allows the use of the indirect immunofluorescence method according to Sternberg LA (1982) in diagnosis.

On the membranes of leukocytes, an increased representation of HLA histocompatibility antigens is usually detected - A28, B35, Cw5, Cw52, and on the other hand, a reduced number of antigens such as A2, B12, Cw3. The most promising, of course, are molecular genetic diagnostic methods that identify specific gene mutations. However, in cases of UCTD, these assays are still at an early stage of development.

One of the most often involved in the pathological process in UCTD in children is the cardiorespiratory system.

This leads to serious pediatric errors

With UCTD in children, the formation of the elastic framework of the lungs is disrupted at the beginning of life, which causes the valve mechanism of bronchial obstruction and the formation of emphysematous bullae due to rupture of morphologically incompetent interalveolar septa. The consequence of subpleurally located bullae can be spontaneous pneumothorax. A congenital defect in the cartilaginous and connective tissue framework of the trachea and bronchi leads to their increased mobility, the occurrence of bronchiectasis, and pneumosclerosis. Dyskinesia of the trachea and bronchi leads to the development of broncho-obstructive syndrome (BOS).

There is a high correlation between the severity of bronchial asthma in children and the manifestations of dysplasia. And the more common and severe the latter are, the earlier the child develops pulmonary hypertension and pulmonary fibrosis in addition to bronchial asthma.

Anomalies in the structure of the bronchopulmonary system in UCTD lead to a deterioration in the elimination of pathogenic agents in conditions of altered immune reactivity and contribute to the long-term persistence of bacteria and the formation of a recurrent course of pneumonia. It is also noteworthy that the level of atypical childhood pneumonia is growing, caused by intracellular pathogens - chlamydia and mycoplasma, with a predominant lesion of the interstitium of the lungs, with a recurrent course of which progresses, as in cases of asthma, pneumofibrosis, pulmonary hypertension.

With UCTD, congenital defects are often diagnosed: tracheobronchomegaly, tracheobronchomalacia, cystic hypoplasia of the lungs. Against the background of dysplasia, the listed diseases are especially often accompanied by the development of severe complications in the form of pneumofibrosis, pulmonary hypertension, bronchiectasis, and spontaneous pneumothorax.

Unfortunately, in contrast to the above-mentioned pronounced manifestations of UCTD in children, subclinical variants are usually not diagnosed. This often leads to incorrect interpretation of the pathological process and serious pediatric errors.

Truly small heart

Since 1987, the classification of diseases of the cardiovascular system of the New York Heart Association has identified the syndrome of connective tissue dysplasia of the heart (CDS), which accompanies both differentiated and undifferentiated dysplasia. In turn, cardiac dysplasia includes several syndromes.

Valvular syndrome combines isolated and combined heart valve prolapses and myxomatous valve degeneration. In approximately 70% of cases, the syndrome is represented by prolapse of the mitral valve, less often - tricuspid or aortic, enlargement of the aortic root and pulmonary trunk; ectopically located chordae, aneurysms of the sinuses of Valsalva. In some cases, such changes are accompanied by regurgitation phenomena, which is reflected in the indicators of myocardial contractility and volumetric parameters of the heart.

With thoradiaphragmatic syndrome, we are talking about the asthenic shape of the chest or its deformation, spinal deformities (scoliosis, kyphoscoliosis, hyperkyphosis, hyperlordosis), changes in standing and excursion of the diaphragm. Among children with CTD, the most common deformity of the chest is pectus excavatum, and the second most common is keeled. Deformations of the sternum, ribs, spine and the associated high position of the diaphragm reduce the chest cavity, increase intrathoracic pressure, disrupt the inflow and outflow of blood, and contribute to the occurrence of arrhythmias.

Vascular syndrome involves damage to elastic arteries, in which their walls expand and saccular aneurysms appear. Arteries of both muscular and mixed types are affected. As a result, bifurcation-hemodynamic aneurysms appear, as well as pathological tortuosity of vessels up to looping.

Thoradiaphragmatic heart syndrome (THDS) is formed in parallel with the progression of deformation of the chest and spine, against the background of valvular and vascular syndromes. In children with a typical asthenic constitution, the asthenic variant of STDS is more often manifested. In this case, the size of the heart chambers decreases, but while maintaining their normal thickness. In a word, a “true small heart” is being formed, functioning without serious deviations.

Unfortunately, in some children with chest deformation due to displacement of the heart, when it “moves away” from the mechanical influences of the chest bone, rotating and accompanied by “torsion” of the main vascular trunks, the so-called false stenotic variant of TDS is formed, which is especially severe.

Metabolic cardiomyopathy syndrome combines cardialgia, arrhythmias, and disorders of repolarization processes. The development of metabolic cardiomyopathy is determined by the influence of cardiac factors (valvular syndrome, variants of CVD) and extracardiac conditions (autonomic dysfunction, deficiency of micro- and macroelements, etc.). Cardiomyopathies with DST usually do not have specific symptoms.

Arrhythmic syndrome includes ventricular and atrial extrasystoles, paroxysmal tachyarrhythmias, pacemaker migrations, atrioventricular and intraventricular blocks, anomalies of impulse conduction along additional pathways, ventricular preexcitation syndrome, and QT interval prolongation syndrome.

A practical pediatrician should remember that in children suffering from CTD, cardiomyopathies and arrhythmic syndrome are very common (in 60-64% of patients). And it is they who determine the increased risk of sudden cardiac death in such children.

A universal remedy has not yet been found

A universal remedy that restores connective tissue for all forms of dysplasia has not yet been found. An individual treatment program is selected for each child with CTD. Its three main tasks are: improving the metabolic processes of connective tissue, eliminating existing complications and preventing new ones.

In any case, we are talking about the actually coordinated work of a team of pediatricians of several specialties. And about a very complex, complex treatment that affects the entire childhood period of life (in the Russian Federation - up to 18 years). We will have time to give only one example of such therapy, related to Marfan syndrome.

Non-drug therapy includes strict adherence to the child’s diet, including nutrition, where the emphasis is on the consumption of complete proteins and foods containing polyunsaturated fatty acids; and physical activity, certain types of which are prohibited for such patients. There is a list of professions for which schoolchildren suffering from CTD cannot be trained.

Drug treatment includes symptomatic administration of b-blockers. In the case of aortic dilatation, and especially in the presence of regurgitation, they reduce the ejection into the aorta and, accordingly, the load on its walls, correcting concomitant hypertension. It is believed that these cardiotropic drugs reduce the risk of sudden death in children with cardiac damage due to SMA and any other CTD.

Since it has been proven that the progression of skeletal pathologies in Marfan syndrome slows down when the deficiency of microelements (calcium, magnesium, zinc, copper) necessary for the formation of TS is eliminated, nutritional supplements containing the above substances, as well as hyaluronic acid, synthetic analogues of vitamins K and D3. In the blood of patients with SMA, there is often an increased level of somatotropic hormone. Therefore, to reduce its secretion, high-fat Omega-3 enzymes are prescribed in the diet from early childhood.

Let us now turn to therapy affecting connective tissue. It includes ascorbic acid in the form of special children's milkshakes, as well as correctors for impaired synthesis and catabolism of glycosaminoglycans - chondroitin sulfate and succinic acid. Another drug recommended as a corrector of bioenergetic processes is carnitine chloride.

What surgeons can do

For aortic aneurysm, dissecting aneurysm, aortic valve defect with symptoms of heart failure, and children with Marfan syndrome, only surgical treatment can help. Clear indications for prosthetics have been developed. For example, an aneurysmally dilated aorta must be replaced with an endo- or exoprosthesis. In case of mitral valve prolapse accompanied by “stable” regurgitation, valve replacement is not performed. However, with the rapid progression of regurgitation, up to the addition of left ventricular failure, valve replacement becomes necessary.

Surgical treatment of deformities of the chest and spine is an extremely traumatic procedure, carried out in several stages, often complicated by pleurisy, pericarditis, and pneumonia. The question of its feasibility was discussed many times at symposiums dedicated to DST. Specialists from various countries adopted a common position denying the advisability of such operations for any DST.

Symptoms

Symptoms of cervical dysplasia are nonspecific. Every fourth clinically registered case of changes in squamous epithelium is detected by chance. Often the course of the pathology is complicated by secondary infections, the symptoms of which are similar to colpitis or cervicitis. Patients experience the following symptoms:

• severe itching;
• acute pain syndrome;
• systematic vaginal discharge with an atypical odor and color.

Dysplastic lesions of the cervix can regress on their own after eliminating the underlying inflammation. In 80% of cases this does not happen - the pathology is characterized by a progressive course. The complicated course of dysplasia is accompanied by the formation of genital warts of the vagina, vulva and anus. Often the disease develops against the background of chlamydia or gonorrhea.

Symptoms

The main part of the risk group are women from 25 to 35 years old who have had sexual intercourse early. At an early stage, the disease is practically asymptomatic. In this case, dysplasia is diagnosed only during a planned examination in gynecology.

As the disease progresses, the following signs of a problem appear:

• Itching, burning sensation.
• Painful sensations in the vagina during sexual intercourse.
• Drainage of blood upon palpation.
• Signs of vaginitis and adnexitis with associated pain.
• The presence of an unpleasant odor.
• Unstable menstrual cycle.
• Significant increase in temperature.
• The patient experiences nagging pain in the lower abdomen.

The symptoms of the disease are similar to the manifestations of PMS in the initial stages. During visual inspection, changes may not be observed. Pathology is often diagnosed against the background of other processes of infection by viruses, bacteria, and microbes. Often the pathology is accompanied by signs of cervicitis, colpitis, itching, burning and other manifestations of the inflammatory process. The appearance of symptoms cannot be ignored and it is important to consult a doctor as soon as possible. If left untreated, the disease begins to progress rapidly and can turn into a squamous cell tumor.

At the third stage, changes can affect almost the entire layer of the epithelium, in which case a diagnosis of non-invasive cancer is made. This disease is also characterized by the absence of manifestations and a long stay in a latent form. Therefore, for the earliest possible diagnosis of oncology, it is important to undergo timely examinations by a gynecologist.

Diagnostic measures

Diagnosis of cervical dysplasia consists of several stages. At the first stage, the patient will have to undergo an examination of the external os of the cervical canal. The procedure is performed by a gynecologist using a vaginal speculum. During the examination, the doctor will be able to detect changes in the color of the mucous membrane, atypical growths of the epithelium and other signs of morphological changes in cellular structures.

The next stage of diagnosis is colposcopy and diagnostic tests. Using an optical apparatus, the doctor examines the surface of the cervix and applies iodine or a weak solution of acetic acid to it. Areas of dysplasia will not display the color characteristic of healthy tissue.

Laboratory tests are carried out through microscopy of scrapings from different parts of the external os of the cervical canal. Signs of malignant degeneration of epithelial cells become an indication for a biopsy. The gynecologist takes a biopsy sample - a small piece of tissue affected by the dysplastic process. Subsequent cytological examination will establish the degree of dysplasia and study the structure of atypical cells.

The presence of markers indicating the presence of oncogenic types of papillomavirus in a woman’s body is determined during a PCR test. Based on these data and the symptoms identified in the patient, the gynecologist develops a treatment strategy for cervical dysplasia.

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Medication method

When the disease is diagnosed early, drug treatment is effective. It is aimed at eliminating the effects of HPV and other factors that could trigger the development of dysplasia. Treatment is mainly aimed at:

• Improving the condition of epithelial tissue.
• Elimination of the inflammatory process.
• Boosting immunity.
• Restoration of vaginal microflora.

Influence tactics are selected taking into account whether the woman plans to have children. Therapy is carried out using:

• Immunostimulants.
• Vitamins.
• Interferon alpha, Isoprinosine.

Additionally, folic acid may be prescribed to strengthen the immune system and accelerate cell regeneration.

Surgical intervention

If drug treatment is ineffective, there are contraindications or a number of other factors confirming its advisability, destruction of the affected area or its removal is carried out.

Destruction of the affected area can be performed in the form of:

• Cryodestruction. The epithelial layer is frozen using liquid nitrogen.
• Effects of radio waves. High-frequency waves are applied to the lesions. The procedure does not lead to scarring.
• Photodynamic therapy. A new highly effective method of treating cervical dysplasia, which provides for a number of strict restrictions during the rehabilitation period.
• Laser excision. The doctor removes the affected area using a laser, while controlling the depth of penetration of the beam.
• Electroconization. Using a diathermocoagulator loop, the damaged area is removed.

In particularly difficult cases, removal of the entire cervix – amputation – may be indicated. Each of the surgical techniques used has its own advantages and disadvantages, and therefore it is best to start treatment in the initial stages.

Therapeutic course

When prescribing treatment, the doctor takes into account the degree of cervical dysplasia diagnosed in the patient. Detection of first-degree dysplasia allows you to choose a wait-and-see approach. Successful treatment of the cause of the development of the dysplastic process allows one to count on independent regression of atypical changes in the epithelium. In such cases, girls are recommended to undergo quarterly cytological examinations, through which the condition of the cervix is ​​monitored.

The drug course is based on immunomodulatory drugs. These drugs can be prescribed to women who have experienced relapses of pathology after previous treatment.

Surgical interventions are performed when there is a risk of malignancy of the dysplasia focus. Low-traumatic methods can prevent malignant degeneration of atypical cells: cryodestruction, electrocoagulation, radio wave or laser therapy. Third degree dysplasia becomes an indication for amputation of the cervix or excision of the tissue affected by the pathological process.

How to cure vaginal dysplasia

Because of the term “precancerous condition,” patients, faced with vaginal or cervical dysplasia, become depressed. But in reality everything is not so scary!

Treatment depends on the degree of dysplasia:

• Mild dysplasia does not require treatment until the condition worsens. If the doctor notices changes, the modified cells are destroyed with a laser, chemicals or modern radio wave method. Genital warts are removed using the same method, as they can develop into cancer.
• In case of deep dysplasia or the onset of cancerous degeneration, vaginectomy is indicated - removal of dysplasia areas. If the process has gone too far, then to save the organ, skin is transplanted from the buttocks or thighs.

Preventive measures

Prevention of cervical dysplasia requires patients to comply with a set of recommendations. Girls need:

• undergo regular gynecological examinations;
• use barrier methods of contraception;
• stop smoking and drinking alcohol;
• promptly treat genitourinary tract infections;
• include foods containing vitamins A and B in your daily diet.

Preventive measures are addressed to patients with a family history of oncological pathologies of the reproductive system.