Ectodermal dysplasia

A relatively rare disease - ectodermal dysplasia - is a genetic disorder, accompanied by a disorder in the functionality and structure of the derived elements of the outer layer of the skin. Usually hair, nail plates, teeth, glandular system (mucous, sweat and sebaceous) are affected. The disease is complex, it can take several forms. The treatment is mainly corrective, symptomatic: unfortunately, we are not talking about complete recovery. [1]

Epidemiology

Variations of ectodermal dysplasia are the Christ-Siemens-Touraine syndrome, as well as the Clawston, Rapp-Hodgkin and EEC syndromes. Pathology was first described in the middle of the 19th century by Dr. Touraine. In 1913 and 1929 this description was supplemented, respectively, by the dentist Christ and the dermatologist Siemens, in 1968 by Rapp and Hodgkin, in 1970 by Rudiger.

In the medical literature, the disease is more often found under the name ectodermal dysplasia and corresponds to the international coding Q82.4 (ICD-10).

To date, doctors cannot voice the exact incidence rate. However, it is believed that the syndrome occurs in about one case in 5-10 thousand. [2]

The etiological heterogeneity of the disease with three genetic types of hereditary transmission is precisely known: autosomal recessive, dominant and X-linked recessive (the latter is the most common). [3]

At the moment, three genes have been identified on different chromosomes, which make it possible to identify this disease using genetic molecular techniques. The number of possible mutations is over sixty.

Ectodermal dysplasia is more common in boys, which is associated with sex-linked inheritance. Girls often have a mild form of pathology, or asymptomatic.

Pathology is registered in different countries of the world in representatives of any race. It can appear sporadically in clinically healthy couples, or manifest in a familial form (especially often if the parents are closely related).

Causes ectodermal dysplasia

The only reason for the development of ectodermal dysplasia lies in the mutation of a certain hereditary gene factor. In particular, the most common disorder is the EDA gene located on the X chromosome. This gene is responsible for the coding of the protein substance ectodisplasin-A, the incorrect structure of which entails a violation of the formation of ectoderm elements. Currently, the exact characteristics of the protein substance and the mechanism of development of mutational disorders have not been clarified.

The disease linked to the X chromosome has its own characteristics: the problem is found more often in men, but women are also able to act not only as carriers, but also to have individual signs of the syndrome, albeit to a mild degree. For example, in patients with ectodermal dysplasia, excessive dryness of the skin, wrinkling, thinning and dry hair, and dental deformation can be observed. Problems with the breasts and nipples are possible. Such signs indicate the possibility of incomplete dominance of EDA gene mutations.

Among other types of mutations, one can distinguish changes in the EDAR gene, which is responsible for encoding a receptor for tumor necrosis factor. This gene is localized on chromosome II, inheritance is autosomal recessive. The exact process of the development of pathology has not been clarified.

If we are talking about rare variants of ectodermal dysplasia, then they arise under the influence of gene mutations in TDARADD, which is responsible for the encoding of the receptor protein for exodisplasin-A, localized on chromosome I. The pathogenetic mechanisms are not fully understood. [4]

Risk factors

The most significant risk factors leading to the birth of a child with ectodermal dysplasia are defects:

• the EDA gene encoding ectodisplasin-A, mapped to chromosome Xq12-q13.1;
• the EDAR gene encoding the tumor necrosis factor receptor, a member of the EDAR superfamily, mapped to chromosome 2q11-q13;
• gene TDARADD, encoding ectodisplasin-A, a receptor-associated protein, mapped to chromosome 1q42.2-q43.

One can suspect a hereditary predisposition to ectodermal dysplasia by examining family history.

Complex genetic molecular diagnostics allows to assess the genetic risk of developing this syndrome in a child.

Pathogenesis

The pathogenetic features of the development of this disease are poorly understood. It is known that ectodermal dysplasia appears as a result of mutational changes in certain genes. The cause of the most common form of pathology is damage to the EDA gene located on the X chromosome. This gene is responsible for encoding a protein agent called ectodisplasin-A. Pathological changes in its structure cause abnormal development of ectodermal derivatives. Unfortunately, to date, both the functional side of this protein agent and the pathogenesis of changes in the mutation of the EDA gene have been insufficiently studied.

The main distinguishing feature of ectodermal dysplasia is that clinical disorders are found not only in male patients, but also in women: carriage is manifested by milder pathological changes. In particular, there is dry hair and skin, early wrinkling, curvature and other disorders of the teeth.

In addition, the causes of the typical Christ-Siemens-Touraine syndrome are mutational changes in the EDAR gene, which is responsible for encoding one of the receptors for tumor necrosis factor. This gene is localized on chromosome II, inheritance occurs in an autosomal recessive manner. The pathogenetic features have not been studied in this case either. [5]

There is also a more rare type of anhydrotic type of ectodermal dysplasia, with an autosomal dominant mode of inheritance. The cause is mutational changes in the TDARADD gene, which encodes a protein substance-receptor for exodisplasin-A and is localized on chromosome I. Most likely, the pathogenetic characteristics in this case are identical with the more common type of sex-linked disease.

For your information: ectoderm is one of three germ layers (two more are represented by mesoderm and endoderm). Ectoderm is the outer layer that forms during the third week of embryonic development and determines the formation of the skin and appendages (hair, nails), rectal and oral epithelium, tooth enamel, lens and cornea, sweat glands. In people with ectodermal dysplasia, some or all of the structures of the ectoderm are either absent or insufficiently functioning.

Symptoms ectodermal dysplasia

The clinical picture in ectodermal dysplasia is determined by a number of numerous disorders affecting the ectoderm and sweat glands. The sebaceous and apocrine glands are also affected, but these defects are less pronounced. Other glandular systems - in particular, lacrimal, digestive, nasal, bronchial - show signs of atrophy. Typical signs: atrophic processes, hypoplasia of the skin, hypoplasia of the mammary glands and nipples.

In the face area, wrinkles, thinning of the eyelids, periorbital pigmentation disorders, papules, eczematous rashes, palmar hyperkeratosis are found. The frontal tubercles and superciliary arches clearly protrude forward, the bridge of the nose is smoothed, the nose is small saddle-shaped, the nasal wings are hypoplastic, the lips are full and prominent, the cheeks are sunken.

The hair is sparse, often with receding hairline, dry and light shades.

The teeth are irregular, often tapered and pointed. Some teeth are completely absent (canines are always present).

The auricles are also deformed: they are usually small, set high, and the ear curl is irregular.

On the part of the organs of vision, there may be a clouding of the lens, myopia, blepharoconjunctivitis, decreased tear production, and a liquid vitreous body.

Some patients are completely deaf. There is a tendency to infectious diseases, thermoregulation disorders.

First signs

The first manifestations of ectodermal dysplasia are often found already in the neonatal period. However, this can happen later, since the clinical picture in young children is not always pronounced and worsens over the years.

The basic symptoms by which one can suspect the presence of pathology are often the following:

• growth retardation against the background of a relatively large head;
• dryness, thinness of hair, mainly "vellus" hair with slow growth and low pigmentation, shortened and rare eyelashes and eyebrows, or their complete absence;
• early alopecia, up to complete loss of hair;
• typical appearance of the "old man's face", protruding frontal region, brow ridges and tubercles, dilated cheekbones, retraction of the bridge of the nose, small saddle nose and hypoplastic wings, sunken cheeks, protruding lips like "fish", "heavy" chin, irregular shape auricles;
• delayed teething (from one to three years), violation of the usual sequence of teething, long period of preservation of milk teeth, the absence of some teeth;[6]
• conical dental configuration, pointed incisal edges, smoothed molar surface;
• violations of the dentition and occlusion;
• underdeveloped salivary glands, poor salivation, dry mouth, hoarseness;
• excessive dryness of the skin, early wrinkling, which is especially noticeable on the face;
• pigmentation disorders, improper functioning of the sebaceous glands, papular rash;
• conjunctivitis, traffic phobia;
• underdeveloped mammary glands, or their absence;
• insufficiently developed mucous glands in the respiratory and digestive systems, which causes frequent bronchitis, rhinitis, sinusitis, gastrointestinal pathologies;
• periodic sharp increase in temperature associated with improper heat transfer due to disruption of the sweat glands;
• less often - mental retardation, oligophrenia (more often the development of intelligence corresponds to the norm);
• impaired social adaptation and orientation, stiffness and isolation;
• speech problems associated with improper dental growth and dryness of the mucous membranes of the oronosopharynx;
• impaired vision;
• little or no sweating.

Triad for anhydrotic ectodermal dysplasia

Anhydrotic variant of ectodermal dysplasia is manifested by a triad of basic signs:

• rare body hair like atrichosis or hypotrichosis; [7], [8]
• incorrect configuration of teeth (often conical, pointed), or underdevelopment and absence of teeth;
• violations of sweating of the type of hypo and anhidrosis, which is often due to the absence of sweat glands as such.

Due to the presence of anhidrosis, the patient has such auxiliary signs as high-temperature hypersensitivity and regular relapses of hyperthermia, which is a real danger to human life. The skin is thinned, dry. Many patients suffer from chronic blepharoconjunctivitis, dry eye syndrome, asthma-like conditions. [9]

Forms

Different cumulative manifestations and their intensity determine the subdivision of ectodermal dysplasia into several types, which can be called independent forms of pathology. The main such types are: Christ-Siemens-Touraine syndrome, Clostone syndrome, Rapp-Hodgkin syndrome and EEC syndrome.

The Christ-Siemens-Touraine syndrome, or anhydrotic ectodermal dysplasia, is characterized by complete dysfunction of the sweat glands, as well as a peculiar phenotype of the structure of the facial area: the child has a prominent anterior forehead, thin and thin eyebrows, rare short eyelashes, wrinkles. Typically periorbital pigmentation disorder, saddle-like bridge of the nose, jaw hypoplasia. Hair is either depigmented or lightly pigmented.

Some experts considered that full-scale anhidrosis in patients is still rarely found, and in most patients the perspiration system is weak, but still functioning. This opinion was taken into account and led to the fact that doctors over time began to use a more correct name: the hypohydrotic form of the disease. Hypohydrotic ectodermal dysplasia is a genetic disorder of the formation of the ectodermal layer. Pathology is characterized by disturbances in the formation of such elements of the ectoderm as skin and hair, glands (sweat, sebaceous) and teeth. The disease consists of three subtypes, which practically do not differ symptomatically, since impaired sweating (mainly hypohidrosis) becomes the main clinical sign. We are talking about the Christ-Siemens-Touraine syndrome itself with an X-linked type of inheritance, as well as autosomal recessive and autosomal dominant ectodermal dysplasia. There are several more less common subtypes, accompanied by a pronounced deficiency of immunity - the so-called congenital anhydrotic ectodermal dysplasia with an immunodeficiency state.

Closton's syndrome is a hydrous type of ectodermal dysplasia. The defining symptoms of the pathology are all the same lesions of the teeth, hair and the perspiration system, but to a somewhat lesser extent. Hypodentia is found in the lower incisors, second molars, and upper canines. Nail lesions are manifested in the form of hypoplasia, dystrophy, aplasia with paronychia. The number of sweat glands is reduced, with unchanged sebaceous glands. Hypotrichosis, baldness is possible. The mode of inheritance is autosomal and autosomal dominant.

The Repp-Hodgkin syndrome is otherwise called hypohydrotic ectodermal dysplasia, accompanied by a cleft lip, alveolar ridge, soft and hard palate. Distinctive manifestations are the following: hypohidrosis and hypotrichosis, pathological changes in nails, hypodentia or oligodentia in conjunction with a cleft of the upper lip, alveolar ridge, soft and hard palate. Common symptoms are also confluence of the bridge of the nose, narrowing of the nose, micrognathia of the upper jaw, a small mouth, and diminished genitals. The syndrome is inherited in an autosomal dominant manner.

The EEC syndrome has only recently been isolated as an independent disease, better known as the cumulative syndrome of ectrodactyly, ectodermal dysplasia with a cleft palate and upper lip. Distinctive symptoms are defects in the feet and hands, a cleft upper lip, and sometimes a cleft tongue. These signs are present against the background of impaired perspiration, hypotrichosis and alopecia, nail hypoplasia, dryness and hypopigmentation of the skin, conjunctivitis, light phobia, etc. Dental anomalies, late eruption, multiple caries are also typical. Against the background of physical defects, mental development is usually adequate. The mode of inheritance is autosomal dominant, but there are also recessively inherited variants.

Ectodermal dysplasia in children

Despite the fact that ectodermal dysplasia is a congenital disease, it is not always possible to diagnose it in a newborn baby: often the diagnosis is made only after a few years (often by 2-3 years). Practicing doctors note the need for early diagnosis, since not only the further lifestyle, but sometimes the patient's life itself may depend on this. Symptoms of pathology are diverse, but not always noticeable. However, some of them are more common, while others are less common. [10]Both parents and doctors should be alerted by the following signs:

• hypoplasia of the sweat glands with hypo or anhidrosis, thermoregulatory disturbances, frequent episodes of hyperthermia, unreasonable fever, regular overheating;
• hypotrichosis phenomena, rarity, depigmentation and thinness of hair, shortening of eyebrows and eyelashes (or their absence);
• persistent or transient baldness (complete or focal);
• late dental eruption in violation of its sequence;
• lack of number of teeth, violation of their configuration (often - cone-shaped, spike-like shape with a pointed edge), or the absence of teeth;
• malocclusion, sometimes - tooth mobility, large interdental spaces;
• low attachment of the supralabial frenulum, sharp expression of the buccal cords, small oral vestibule;
• underdeveloped maxillary alveolar process;
• on the roentgenogram - shortened dental roots, widened periodontal fissures, flattened condylar mandibular processes;
• hypoplasia of the mucous glands in the mouth, as a result - insufficient salivation, hoarseness;
• tendency to fungal stomatitis, cheilitis;
• a typical "old man's face" with a prominent frontal region, sunken nose bridge, small saddle nose, sunken cheeks, full fuzzy convex lips, irregularly shaped auricles;
• thinned dry wrinkled skin, sometimes with papular rash;
• insufficient function of the lacrimal glands, frequent inflammatory diseases (keratitis, blepharitis, etc.);
• lip and palate defects;
• nail lesions, paronychia;
• defects of the feet and / or hands, hyperkeratosis of the palms and feet;
• insufficient development of the mammary glands and nipples (sometimes their absence);
• immunodeficiency, eczema;
• tendency to respiratory and digestive diseases, as well as nosebleeds.

Different combinations of signs and their intensity determine individual variants of the course of ectodermal dysplasia.

Complications and consequences

Patients with ectodermal dysplasia should avoid any uncontrolled thermal effects in every possible way. Infants require constant monitoring of body temperature. Older children should be provided with the necessary preventive and cooling measures - in particular, regularly drink cool drinks, moisturize clothes, use air conditioners.

Care of the oral cavity and teeth should be started as early as possible - to maintain their functional fitness and optimize their appearance. The help of an orthodontist often consists in the setting of corrective plates and sinus lifting followed by dental implantation. Supportive dentures are possible. [11]

For the hypohydrotic form of ectodermal dysplasia with immunodeficiency, it is required to take medications to support the immune system, as well as intensive therapy for infectious diseases, or hematopoietic stem cell transplantation.

If the pathological syndrome is not detected in early childhood, then impaired thermoregulation can cause damage in the brain, which will ultimately lead to death. With adequate and timely diagnosis and competent treatment, patients have the opportunity to lead a normal life without negatively affecting its duration. [12]

Diagnostics ectodermal dysplasia

The diagnosis of ectodermal dysplasia is often established after periodic cases of fever, or with late teething. Dysfunction and absence of sweat glands are confirmed by skin biopsy or non-invasive confocal microscopy. It is also possible to study graphite imprints of palmar surfaces and feet.

The quality of the function of the sweat system is assessed by numerical assessment of pilocarpine-induced sweating. To confirm the diagnosis, genetic tests are performed, a hereditary history is examined.

Genetic assessment consists of direct sequencing of the EDA gene sequence to detect mutations. [13]

Assessment of the hereditary history is carried out along with the determination of the objective status of the mother. Often, she has certain signs indicating the carriage of pathology. Such signs include dry skin, thinning, weakened hair, and underdeveloped breasts.

Genetic studies of the carriage of a disturbed form of the EDA gene are often problematic due to frequent false negative indicators. Therefore, to prove carriage, other methods of genetic research are used - in particular, multiplex ligase reaction.

Instrumental diagnostics, which are carried out in patients with suspected ectodermal dysplasia, may include the following procedures:

• ultrasound and electrocardiography;
• skin biopsy to assess the condition of the sweat glands;
• microscopy of the hair structure;
• X-ray of the jaws to determine the quality of the tooth germs.

Laboratory examinations in the form of a general blood test may indicate a shift in eosinophil parameters, anemia, but such changes are nonspecific for ectodermal dysplasia.

Differential diagnosis

Anhydrotic ectodermal dysplasia is distinguished primarily from the hydrotic variant of the disease (Cluston's syndrome). The symptomatology of the two pathologies has much in common, but in the hydrotic form, the sweat glands function, therefore, xeroderma and hyperthermia may be absent. Also, differentiation is carried out between all existing types of ectodermal dysplasia and certain forms of ichthyosis. [14]

Treatment ectodermal dysplasia

The treatment regimen for ectodermal dysplasia is determined, depending on the existing disorders, and involves the use of symptomatic agents against the background of lifelong special care, which is prescribed to the patient as a lifestyle and includes avoiding overheating and physical exertion. Therapeutic tactics also depend on the patient's age. [15]

The basic direction of systemic therapy is the use of second-generation H1-antihistamine blockers, since they are not able to penetrate the blood-brain membrane, are suitable for long-term administration, and are convenient to use (once a day). In early childhood, first-generation H1-antihistamine blockers can be used, which is due to the slight sedative properties of these drugs. [16]

With ectodermal dysplasia, external therapeutic agents are required to soften and protect the skin. The drugs of choice can be:

• emollients with a hydrophilic base and 5% urea;
• creams based on ciramides or petroleum jelly with a frequency of use at least 2 times a day (with the onset of the remission period, they switch to use 1 time in 1-2 days);
• medical and cosmetic products intended for the care of dry and irritated skin.

Patients with an increased SCORAD index (from 20 to 40 and more than 40) are externally prescribed active corticosteroids:

• mometasone furoate ointment 0.1% daily at night for 21 days;
• can be replaced with 0.005% fluticasone propionate.

If there is no reaction to topical application of corticosteroids, topical calcineurin inhibitors are prescribed - for example, tacrolimus ointment 0.1% twice a day for three months, or until symptoms are resolved.

Among vitamin preparations, it is appropriate to take only vitamin D ₃  (cholecalciferol), and only after assessing the content of calcidiol in the blood. Cholecalciferol is prescribed at 1000-1600 IU daily for 1-2 months.

Physiotherapy involves the use of phototherapy:

• UVA1 (340-400 nm) in the acute period, with relapse or severe stage up to 5 times a week for 1.5-3 months;
• Narrowband UVB (311-313 nm) in chronic pathology.

Patients with ectodermal dysplasia are additionally prescribed symptomatic medications in consultation with other doctors of narrow specializations: dentist, gastroenterologist, pulmonologist, etc.

Medicines are used in combination with the regular application of topical dermatological moisturizers, such as:

• Radevit is a dermatoprotective agent that improves trophism and tissue regeneration. It has anti-inflammatory, emollient, moisturizing properties. Radevit is not used in the presence of allergies and hypervitaminosis A, E, D.
• Lipikar is a cosmetic lipid-reducing agent that softens and nourishes the skin. It can be used at any age, even in the neonatal period.
• Emolium is a complex emollient that moisturizes even the deepest layers of the skin, restoring the protective lipid layer. Contains sodium hyaluronate, urea, shea butter and macadamia oil. It can be used from birth if there is no allergy to the composition of the drug.
• La Cree is an effective remedy containing natural plant oils and extracts, lecithin and allantoin. The cream effectively softens, eliminates itching, redness, flaking of the skin, prevents the appearance of inflammatory elements.

Since the condition of patients with ectodermal dysplasia worsens in the summer, which is associated with an increase in ambient temperature and increased solar activity, then during these months

Prevention

It is almost impossible to prevent the development of hereditary ectodermal dysplasia: it is only possible to alleviate the symptoms of pathology. In many cases, the life of patients with a gene mutation can be made as comfortable as possible, since the severity of the clinical picture largely depends not only on the hereditary factor, but also on its combination with the external conditions and the patient's lifestyle. At the same time, the fundamental point is love and participation on the part of relatives and parents. After consulting with a doctor, it is necessary to think over the child's rehabilitation system: make adjustments to nutrition, consult a dentist and a dental technician, balance the main points that affect the quality of treatment and adaptation of the patient in society.

It is also important to determine the presence of the syndrome as early as possible in order to assess the risks to the child. This can be done by cryotyping - the study of the chromosome set of a newborn baby using the analysis of umbilical cord blood.

The likelihood of having a sick baby can be determined with the help of medical geneticists, using a DNA test, when the baby is still in the womb. Probability factors are not only cases of the birth line syndrome, but also certain stresses before or during gestation.

The use of in vitro fertilization allows you to avoid the development of the disease in a child even at the stage of fertilization. IVF method involves obtaining several embryos: before they are "implanted" into the mother's body, the risks of hereditary pathology are checked.

Forecast

Unfortunately, patients with ectodermal dysplasia cannot be cured: only a symptomatic effect on the manifestations of the syndrome is available. Patients of early childhood may die due to violations of thermoregulation and the addition of a secondary infection. The disease, as a rule, does not affect the life expectancy of adult patients.

It is very important to identify the disease at an early age in order to immediately begin treatment. This will prevent the development of complexes, phobias in the baby, and improve social adaptation. In general, a complex and rather complex treatment is prescribed, with the involvement of specialists from different medical profiles.

It is equally important to adhere to all the recommendations of doctors. If everything is carefully planned and adjusted, then the patient will be able to lead a normal life, despite the pathology. It should be borne in mind that a more favorable course of the disease is noted when the patient lives in cool and humid climatic conditions.

Ectodermal dysplasia is a rare but complex disease that cannot be cured. But timely diagnosis and high-quality symptomatic and complex correction allows patients to get rid of most painful manifestations, to ensure an adequate and full life.

Disability for ectodermal dysplasia

Children with ectodermal dysplasia, manifested by multiple dental disorders in combination with disorders of other anatomical structures of ectodermal origin, are usually recognized as childhood invalids. However, with small pathological changes, an uncomplicated and mild course of the disease, the assignment of a disability group may be refused, since the diagnosis of ectodermal dysplasia itself is not an unconditional basis for recognizing a child as disabled.

The assessment of the patient's ability to work is carried out no earlier than 12 months after the diagnosis, after the necessary medical and rehabilitation measures have been taken. If, after the treatment course, doctors confirm a persistent violation of the body's functionality due to congenital developmental defects, then in this case one can count on assigning a disability group corresponding to the severity of the existing pathologies.

How do people live with ectodermal dysplasia?

The fight against the manifestations of ectodermal dysplasia continues in patients throughout their lives. The patient is monitored by doctors of various specialties: pediatrician, orthodontist, therapist and orthopedist, speech therapist, psychologist, neuropathologist, medical geneticist, otolaryngologist and dermatologist. If necessary, seek help from maxillofacial surgeons.

Based on numerous clinical studies and observations, experts have identified a list of the most important recommendations for patients with ectodermal dysplasia:

• Regularly monitor the body temperature indicators, stabilize them with wipes with a damp and cool towel, shower procedures, cool drinks, air conditioning in the stay area. When performing physical activity, wear moist, light clothing. If indicated, take antipyretic medications.
• Systematically visit doctors, depending on the symptoms and disorders. If there is a lack of lacrimal secretions, use special eye drops. Apply moisturizers regularly to relieve dry skin.
• Eat only liquid food, if necessary, use artificial saliva preparations, avoid hot and dry foods and foods.
• Provide dental prosthetics.
• Family planning should be done only after genetic counseling.
• Observe caries prevention measures, carry out early remineralizing therapy and fluoridation.

Patients who adhere to these recommendations live quite normal lives, create families, and are socially active. At the same time, understanding and participation on the part of loved ones is of considerable importance.