Arachnodactyly

One of the rare hereditary connective tissue pathologies is arachnodactyly - deformity of the fingers, accompanied by lengthening of the tubular bones, skeletal curvatures, disorders of the cardiovascular system and visual organs.

The disease was first described by Dr. Williams and French pediatrician Marfan, who called it dolichostenomelia. In world medicine, the term Marfan's syndrome later appeared, and from 1902 they began to use the name arachnodactyly. Pathology refers to congenital disorders of connective tissue, and one of the leading signs are elongated, thinned and curved "spider" fingers. [1]

Epidemiology

Arachnodactyly is considered a hereditary monogenic pathology of connective tissue, with autosomal dominant inheritance, high penetration and varying degrees of expressiveness.

In about 75-80% of cases, the disease is hereditary, and in the remaining cases it occurs as a result of spontaneous mutations (in particular, due to missense point mutations). [2]

It has been proven that the pathogenetic features of arachnodactyly are due to changes in several genes (in 95% of cases):

• in the fibrillin-1 gene (about one thousand mutations studied) on chromosome 15q21.1;
• gene TGFβR1 or TGFβR2 on the ninth and 3p24.2-P25 chromosome.

These changes directly affect the scale of clinical manifestations.

In 5% of patients, mutations in the α-2 chain of type I collagen were described.

The prevalence of arachnodactyly is about 2 cases per 5 thousand people. There is no racial or gender determinism. [3]

Causes arachnodactyly

Arachnodactyly occurs as a result of spontaneous mutation. The disease is not characterized by well-known signs of congenital and hereditary pathologies, and elongated fingers are manifested mainly in Marfan syndrome and homocystinuria.

The disease is rare, and in all the patients detected, a mutation of the FBN1 gene (fibrillin gene) located on chromosome 15 in the q21.1 region was noted. The clinical polymorphism of the syndrome can be explained by the mass of mutations, and about 15% are mutational changes that occurred during conception. [4]

Atypical varieties of arachnodactyly are provoked by mutations from other genes: a relationship was found between the development of pathology and mutations of the LTBP3, R gene localized on chromosome 14 in the q24 region, which transforms the growth factor. 

The overwhelming majority of mutations are referred to as missense mutations (approximately 57%). More than 20% are small deletions with loss of chromosomal parts, about 12% splice site mutations, 8% nonsense mutations, and 2% large-scale rearrangements and deletions. [5]

Congenital contracture arachnodactyly is caused by impaired synthesis of the protein agent fibrillin-2. The problem is caused by a mutation in the FBN2 gene, located on the fifth chromosome in the q23-q31 region. All mutations are predominantly point mutations, switching the codon to coding for another amino acid. [6]

Homocystinuria develops against the background of impaired metabolism of the essential amino acid methionine. The basis of pathology can be the loss of activity or its decrease on the part of such enzyme substances:

• Cystathionine beta synthase enzyme (CBS). The pathology is B ₆  resistant and manifests itself with signs characteristic of the B ₆ -independent form, however, the introduction of a B ₆ -vitamin preparation does not lead to improvement.
• Enzyme N5, N10 methylenetetrahydrofolate reductase (MTHFR). This enzymatic agent is a substrate that causes homocysteine demethylation and its transformation into methionine, an essential amino acid that makes up many protein and peptide substances.
• The enzyme N5 is methylenetetrahydrofolate. This is a B ₆  dependent form of pathology that develops with a deficiency of vitamin B ₆. The introduction of a vitamin preparation into the body improves the patient's condition.
• Homocysteine transmethylase enzyme. It develops against the background of metabolic disorders of cobalamin - vitamin B ₁₂.

Risk factors

Arachnodactyly is a genetically determined disease characterized by systemic damage to the connective tissue. The pathology is associated with changes in the fibrillin 1 gene localized on the short arm of chromosome 15 at locus 21.1.

Arachnodactyly is inherited in an autosomal dominant manner, and is characterized by high penetrance and varying expressiveness. Pathology can manifest itself on both the male and female side.

Pathogenesis

More than 50% of human body weight is connective tissue structures, in particular - the skeleton, skin, vasculature, lymph and blood.

Connective tissue cells are represented by fibroblasts and their subtypes: osteoblasts, chondrocytes, keratoblasts, odontoblasts, as well as macrophages and mast cells.

Embryonic connective tissue is the material for the formation of constitutional, genetic and epigenetic components. Connective tissue diseases are reflected in varying degrees on the entire body as a whole, on its functional ability and constitution.

With arachnodactyly, a substitution of nucleotides in the gene is noted, which contains structural information about the fibrillin-1 peptide. This protein substance belongs to the glycoprotein group, participates in the microfibrillar system and forms the basis for the elastic fibrils of the connective tissue.

The tissue maintains a stable structure, thanks to the extracellular matrix, which contains many growth factors that ensure systematic cellular renewal. Large vessels and ligaments contain numerous elastin fibrils, with the defeat of which the main symptoms of arachnodactyly are observed.

The transforming growth factor β is significantly affected: its inactive form does not bind, which entails an increase in the biological activity of this factor.

Fibrillin disorders entail improper formation of fibers, as a result of which the strength and elasticity of the skin and other structures of the connective tissue is lost.

When collagen structure is disturbed, the primary link of hemostasis is disturbed.

Experts note the involvement of hormonal disorders in the appearance and progression of abnormalities from the connective tissue structures, including arachnodactyly. Thrombotic symptoms are determined by rheological disorders - in particular, a change in blood viscosity in the modified vessels of the brachiocephalic region.

The digestive tract is affected as a result of collagen disorders: hypomotor biliary dyskinesia, hiatal hernia, hepatobiliary anomalies, chronic form of "erased" gastroduodenitis, dolichosigma are noted.

How is arachnodactyly inherited?

Arachnodactyly is inherited in an autosomal dominant manner, but it can also occur as a result of spontaneous mutations. That is, it is not at all necessary that the pathology should manifest itself in any of the close relatives - for example, in parents and grandparents. The mutations underlying the pathology can manifest themselves in a random order.

Symptoms arachnodactyly

In medicine, they share the erased and obvious course of arachnodactyly. With an erased course, changes are present, but they are single and limited to one or two organ systems. A clear course is manifested by multiple visible disturbances with varying intensity of symptoms. At the same time, the patient's condition can be relatively stable over decades, or it can progress steadily, manifesting itself in relation to other organs and systems.

Often, arachnodactyly syndrome can be detected already in the first few days after the birth of the baby.

The main external sign of arachnodactyly is slender and elongated fingers, which, due to short tendons, acquire a typical curvature and resemble spider legs.

Spider fingers or arachnodactyly become clearly visible almost from the neonatal period. But the symptom appears more clearly by about three years of age.

Height indicators are also characteristic: children are usually tall, forearms and legs are long, limbs are disproportionate and thin. The disproportion is especially pronounced in the high localization of the waist and knee caps. [7]

Other skeletal disorders include:

• narrowed and elongated skull shape (dolichocephalic) with an incorrectly formed face area;
• funnel-shaped chest configuration (the so-called "bird");
• curved spinal column;
• congenital hip dislocations;
• habitual knee-shoulder dislocations;
• curvature of the calcaneus;
• osteophytic formations - bone growths;
• flat feet;
• insufficient development of the body fat.

Additional signs of arachnodactyly can be:

• myopia;
• bluish sclera;
• subluxation of the lens;
• disorders of the heart and blood vessels (heart defects, aortic aneurysm);
• pronounced thinness;
• articular hypermobility;
• "Arched" sky.

Arachnodactyly is characterized by the elongation of the tubular bones, causing various skeletal curvatures. In addition, many patients have pyramidal disorders, asymmetry of tendon reflexes, anosocoria and nystagmus against the background of normal mental development.

If we are talking about arachnodactyly, concomitant homocystinuria, then the patient may have the following symptoms:

• periodic seizures;
• secondary glaucoma with subluxation of the lens;
• retinal detachment, astigmatism;
• damage to arterial trunks (including kidneys, brain);
• osteoporosis;
• thrombosis;
• mental disorders.

Arachnodactyly in newborns

In most cases, arachnodactyly can be detected in a child within the first few days of his life. Moreover, in the future, with age, the symptoms tend to aggravate.

The first signs to suspect a disease are usually the following:

• unusually long limbs and fingers;
• lack of weight with an adequate physical condition of the child;
• elongated elongated face;
• deficiency of body fat, poorly developed muscles;
• excess articular flexibility.

From about four years old, against the background of arachnodactyly, the chest begins to change, the spinal column bends, and flat feet develop.

From the side of the organs of vision, myopia, ectopia of the lens, altered corneal configuration, strabismus, hypoplastic processes in the iris and retina are noted. Such violations can be noticed already in the first 2-3 years of a baby's life, although they progress over the years.

The greatest danger is posed by violations of the cardiovascular system. If there are such violations, then against the background of the lack of appropriate treatment, there are high risks of death of the patient even in childhood. Among the most dangerous pathologies, damage to the vascular walls, cardiac malformations, defects of the coronary vessels can be distinguished. Sometimes in children of the first year of life, an increasing failure of cardiac activity is already detected.

Arachnodactyly can be accompanied by damage to other organs - in particular, the nervous system, bronchi and lungs, skin, genitourinary system. Such violations are detected in the course of diagnostic measures.

Complications and consequences

The most common adverse effects of arachnodactyly are heart and respiratory damage. In addition, problems with vision appear, up to and including loss.

Patients with arachnodactyly require complex therapy for all existing pathologies. If such treatment is not carried out, then the life expectancy of patients is significantly reduced: rare patients manage to live up to the age of 40 without medical intervention. Over the years, the problems with the cardiovascular system are aggravated, the risk of extensive hemorrhages with a tragic outcome increases.

People suffering from arachnodactyly should be regularly examined and treated for concomitant pathologies: only under this condition they have every chance to live a long time and without serious complications.

Marfan's syndrome and arachnodactyly require special attention if a female patient becomes pregnant. In such a situation, it is important to regularly and thoroughly examine the patient, medication to maintain the state of her cardiovascular system. This is the only way to guarantee a successful pregnancy and a safe birth of a child.

In order to avoid adverse consequences, patients with arachnodactyly should be regularly examined by doctors, to prevent the development of cardiovascular and musculoskeletal pathologies. They are advised to lead an exceptionally healthy lifestyle, with moderate physical activity.

Diagnostics arachnodactyly

Clinical diagnostics for arachnodactyly includes collection of complaints, hereditary and family history, phenotype assessment, as well as anthropometric and physical studies. It is important to determine the presence of manifestations of connective tissue pathologies in direct relatives: for this, a genealogical study is carried out. [8]

Laboratory diagnostics for arachnodactyly involves the study of the state of certain types of connective tissue, represented by bone and cartilage tissue, blood, lymph. The most informative is the study of the levels of hydroxyproline and glycosoaminoglycans in the daily urine volume. In addition, the content of lysine, proline, hydroxyproline in the blood is assessed. To determine the altered ratios of different types of collagens and structural disorders of collagen fibers, typing is prescribed by the method of indirect immunofluorescence using polyclonal antibodies to collagen and fibronectin. [9] Depending on the indications, the following analyzes are performed, reflecting the quality of connective tissue metabolic processes:

• glycosaminoglycans, fibrillin, fibronectin;
• study of hydroxyproline, markers of collagen type 1 biosynthesis, aminoterminal propeptides of type 1 procollagen, markers of type 1 collagen degradation, galactosyloxylysine, deoxypyridinoline;
• collagen metabolism resolution analysis (study of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases, transforming growth factor);
• analysis for micro and macroelements (content of calcium and magnesium, phosphorus, iron, sulfur and copper, cobalt and selenium, zinc and magnesium, fluorine and vanadium, silicon and boron);
• study of markers of bone tissue formation and the rate of remodeling processes (analysis for the content of osteocalcin, bone alkaline phosphatase, parathyroid hormone, somatotropic hormone, prolactin, vitamin D ₃, pentosidine, homocysteine in urine and blood).

Instrumental diagnostics is aimed at identifying existing developmental defects and assessing the functional state of organs and systems. Cardiovascular disorders with arachnodactyly require mandatory inclusion in the diagnostic list of such procedures as:

• electrocardiography;
• daily ECG monitoring;
• ultrasound examination of the heart and blood vessels.

Vascular abnormalities are examined using computed tomography or magnetic resonance imaging. Additional diagnostic procedures may include:

• Ultrasound of the abdominal organs, genitourinary system;
• X-ray of the chest, hip joints; [10]
• CT or MRI of the spine.

After all the necessary tests, the patient is referred for genetic counseling.

Differential diagnosis

There is a phenotypic similarity between Beals syndrome and arachnodactyly in Marfan syndrome (mutations of the FBN2 and FBN1 genes, respectively), which is due to the almost complete identity of the protein substances fibrillin 1 and fibrillin 2. It is not surprising that the second name for Beals syndrome is contracture arachnodactyly. [11]

Differentiation is carried out with other connective tissue pathologies:

• Stickler syndrome;
• Ehlers-Danlos syndrome;
• homocystinuria;
• arthrogryposis.

Beals syndrome is characterized by a marfanoid phenotype, congenital flexion contractures of large and small joints, carpal and foot arachnodactyly, curvature of the spine, irregular shape of the ears (the so-called "crumpled" auricles). Molecular analysis of the FBN2 gene is performed to confirm the diagnosis.

Arthrogryposis is characterized by multiple articular contractures, low height, and decreased intelligence. The shape of the fingers and ears was normal. [12]

With Ehlers-Danlos syndrome, kyphoscoliosis, funnel-shaped curvature of the chest, pronounced flat feet, and impaired refraction are noted. Increased mobility and articular dislocations, high skin elasticity and sensitivity are typical.

Stickler syndrome is characterized by a change in articular volume and stiffness.

Treatment arachnodactyly

Arachnodactyly belongs to the category of genetic pathologies, and currently medicine does not have methods for correcting gene defects. Therefore, treatment is directed to optimize the patient's condition, prevent the aggravation of pathology, and eliminate symptomatic manifestations. Complex therapy is prescribed, with the involvement of several medical specialists at once, which depends on the belonging of the most pronounced symptomatology: often, in addition, you have to contact an orthopedist, cardiologist, ophthalmologist, gastroenterologist and other doctors. [13]

Among the recommendations for the clinical management of patients, the following are considered as general principles:

• limiting physical activity, but not completely abandoning it (as part of supporting the cardiovascular system);
• drug therapy;
• if necessary, surgical correction of the most affected areas of the heart and blood vessels;
• orthopedic correction;
• spa treatment, physiotherapy, physiotherapy exercises.

The dietary food of patients with arachnodactyly should include a sufficient amount of high-protein foods, enriched with trace elements, vitamins, fatty acids. The use of meat, fish, seafood, beans, nuts is recommended. If arachnodactyly is due to homocystinuria, then the use of animal protein is sharply limited.

Children with a thin physique and tall stature are advised to introduce cottonseed and soybean oil, sunflower seeds, pork fat and lard into the diet from an early age. Additionally, they offer preparations containing polyunsaturated fatty acids of the Omega type, which inhibit the production of somatotropic hormone.

To normalize protein metabolism, B-group vitamins are prescribed. They can also be obtained from food: buckwheat, peas, liver.

It is very important that ascorbic acid enters the patient's body with food. For this purpose, rosehip infusion, bell pepper, cabbage, citrus fruits, as well as sea buckthorn, leeks are necessarily introduced into the diet.

If necessary, patients are offered orthopedic correction necessary to reduce the load on the spinal column and joints. For this purpose, orthopedic shoes, knee and other devices, instep supports, elastic bandages are used.

Surgical treatment is performed according to indications.

Medicines

Drug treatment for arachnodactyly is carried out 1-2 times a year, which depends on the patient's condition and on the severity of pathological symptoms. The duration of the treatment course is determined individually and averages 4 months. [14]

To stimulate the formation of collagen, drugs Piaskledin 300, L-lysine or L-proline are prescribed in combination with complex multivitamin preparations containing ascorbic acid, B vitamins, tocopherol, magnesium, zinc, selenium, copper.

Among chondroprotectors, the most optimal use of chondroitin sulfate and glucosamine sulfate - drugs that are involved in regulating chondrocyte metabolism, suppressing enzyme synthesis, increasing the sensitivity of chondrocytes to enzyme effects, in stimulating anabolic processes, etc. Combined drugs are considered optimal such drugs: Teraflex, Artroflex, Artra etc.

Mineral metabolism is stimulated by drugs that normalize phosphorus-calcium processes. Active forms of vitamin D often become the medicines of choice: Alpha D ₃ -Teva, Oxydevit, Bonviva, etc. At the same time, preparations of phosphorus, calcium, magnesium are used. During treatment, approximately once every 20 days, the level of calcium and phosphorus in the blood or urine is checked, and a blood test for alkaline phosphatase is performed.

To improve the bioenergetic state of the body, it is possible to prescribe Phosphaden, Riboxin, Lecithin, Elkar, Coenzyme Q10.

An approximate therapy regimen may look like this:

• Chondroprotector within the age dose, taken with food and sufficient water. The duration of one treatment course is 3-4 months.
• L-proline in a dosage of 500 mg (for children from 12 years old and adults) is taken half an hour before meals, 1-2 times a day, for six weeks. If indicated, an amino acid complex can be additionally prescribed - L-proline, L-lysine, L-leucine in an amount of 10-12 mg / kg of weight. Reception is carried out 1-2 times a day for two months.
• Vitamin-mineral complex preparations Centrum, or Vitrum, or Unicap, in dosage taking into account age. Duration of admission is 4 weeks.

This treatment regimen is appropriate if a patient with arachnodactyly complains of problems with the musculoskeletal system, and the test results indicate an increased excretion of glycosoaminoglycans in a 24-hour urine study and a decreased content of free amino acids in the blood.

As a rule, the treatment is perceived by patients well enough, without any special side effects. If hypersensitivity reactions are detected, the drugs are replaced, the treatment regimen is adjusted.

Physiotherapy treatment

Physiotherapy procedures for arachnodactyly are prescribed according to indications. For example, with insufficient osteogenesis to improve the healing of bone fractures, or with signs of osteoporosis, electrophoresis with 5% calcium chloride, 4% magnesium sulfate, 2% copper sulfate or 2% zinc sulfate is recommended.

If vegetative vascular disorders are found, use 1% caffeine sodium benzoate, ephedrine hydrochloride or mezaton.

To activate the efficiency of the adrenal cortex, drug electrophoresis with 1.5% etymizole and decimeter therapy are prescribed to the adrenal glands. [15]

To stabilize the vascular tone, water procedures are recommended that promote vascular "gymnastics". Baths such as carbon dioxide, coniferous, hydrochloric, hydrogen sulphide, radon are excellent. They practice rubdowns, douches, contrast showers, foamy and salt baths.

To improve the condition of the cartilage tissue, magnetotherapy, inductotherapy, laser therapy, electrophoresis with dimethyl sulfaxide (Dimexidum) are used.

Surgery

Surgical operations for arachnodactyly are prescribed strictly according to indications. For example, upon detection of pronounced hemodynamic disorders against the background of prolapse of the valve leaflets, massive aortic aneurysm, prosthetics of the valves and the damaged segment of the aorta are performed. [16]

If there are pronounced functional disorders of the respiratory and cardiovascular systems, resulting from a strong curvature of the chest, thoracoplasty is performed.

With progressive pain syndrome caused by a severe form of scoliosis of 3-4 degrees, surgical intervention is also indicated. From an ophthalmological point of view, subluxation of the lens complicated by secondary glaucoma, as well as cataracts and retinal degenerative changes with a high risk of detachment, are considered absolute indications for lens removal.

Any operation for patients with arachnodactyly and other disorders extending to the connective tissue structures is performed only at the stage of relative clinical and biochemical relief. After the intervention, long-term medical supervision and intensive therapy with the use of drugs that improve the exchange of connective tissue are required.

Prevention

Arachnodactyly is an uncommon genetic disorder. Sometimes it occurs spontaneously in apparently healthy parents. Therefore, it is very, very difficult to prevent the appearance of the disease in advance.

If one of the potential parents has a burdened family history - that is, it is known that someone in the family had arachnodactyly - then the spouses should visit genetics and undergo a genetic examination at the stage of planning a child. After confirming the onset of pregnancy, the doctor performs prenatal diagnostics, which includes ultrasound examination of the fetus and a number of biochemical tests:

• analysis of maternal blood;
• analysis of amniotic fluid;
• chorionic biopsy;
• analysis of placental cells and umbilical cord blood.

Patients with arachnodactyly are under medical supervision throughout their lives. Preventive measures in patients are aimed at preventing complications. For this purpose, cardiac surgical correction is performed, drug treatment is prescribed to eliminate the risk of thrombus formation. Antibiotic therapy courses are carried out periodically.

Forecast

The prognosis for the life of patients with arachnodactyly is primarily determined by the severity of concomitant disorders - in particular, diseases of the cardiovascular, musculoskeletal system and organs of vision. Most often, the pathology is complicated by rupture and dissection of the aorta. It is necessary to take this into account and timely carry out cardiac surgery correction, which will help prolong the patient's life and improve its quality.

If the diagnosis was made in a timely manner, then, subject to the recommendations of doctors, the prognosis can be called conditionally favorable. Medical support significantly facilitates the course of arachnodactyly, and patients have the opportunity to live a normal and relatively full life without the development of serious complications.