Atopic dermatitis (AD) is a hereditary disease that has a
chronically relapsing course with a certain age-related dynamics, characterized
by impaired cell membrane activation, hypersensitivity to many immune and non-
immune stimuli, and skin vascular dysfunction. The clinical picture is
manifested by itchy inflammatory skin changes with true rash polymorphism and
lichenification , a certain symmetrical topography, depending on age
characteristics, often combined with functional disorders of the nervous
system, immune disorders and atopic lesions of the respiratory organs.
The history of the nosological identification of atopic dermatitis is complex
and has ancient origins. Itchy inflammatory skin lesions that began in
childhood, accompanied by suppuration, lymphadenitis, nervousness, were called
“benign scrofulides “, “complex lichen “, ” scrofulous
lichen with eczema, etc.
At the end of the XIX century. Attention was drawn to three features of the disease:
- diathetic , familial and constitutional character
- polymorphism of the clinical picture, including eczematous and lichenoid rashes
- originality of age evolution of manifestations.
E. Besnier (1892) substantiated the independence of this form, tracing
these features in a number of families. Presenting a demonstration called
“polymorphic dermatitis, puriginous , chronic, aggravated, with winter
paroxysms, in a predominantly eczematous -lichenoid form”, he emphasized
that this disease, having begun in infancy, “infantile rash” in the
form of “infantile erythema”, eczematization , pseudolichens , then
it can go into a mild form or long-term remission; later, the disease “sets”
and manifests itself as lichenified foci, periodically complicated by paroxysms
of eczematization and widespread impetiginization . Seasonality, familiality,
the possibility of combination with asthma, hay catarrh, gastrointestinal
diseases were noted. L. Brocq , emphasizing the importance of isolating a new
form of the disease with its “double clinical picture”, manifested by eczema
and lichenification , mentioned the similarity of one of its components, namely
lichenification , with the neurodermatitis he studied earlier. After this
discussion at the French Dermatological Society, the isolated form came to be
referred to in the literature as ” Besnier ‘s diathetic prurigo “.
Along with this, there was a tendency to consider these lesions within the
framework of symptomatic skin manifestations of childhood diathesis, and later
– allergic conditions. However, in the works of Soviet pediatricians, diathesis
has always been considered as anomalies of the constitution, and not
nosological forms of diseases [Maslov MS, 1939, 1949; Akhmina N. I. et al.,
1983, etc.].
In the 20-30s of the 20th century, the concept of atopic diathesis appeared, a
“strange” familial hypersensitivity that differed from acquired allergies in
the absence of a mandatory dependence on sensitization, a reaction to many
provoking factors that are harmless to others. Skin disease of this type was
called “atopic dermatitis” [ Weis T., Sulzberger M., 1933; Hill L.,
Sulzberger M., 1935], atopic neurodermatitis, atopic eczema. The presented
descriptions of atopic dermatitis corresponded to the presentation of the
clinical picture of Besnier ‘s diathetic prurigo . However, if earlier this
disease was considered rare, then since the 40-50s of our century, atopic
dermatitis has been considered one of the most common dermatoses in many
countries. According to the summary data of B. T. Glukhensky , S. A. Grando
(1985), it makes up 5-30% of all skin diseases. According to V. A. Grebennikov,
M. V. Khristyuk (1980), atopic dermatitis accounts for 20% of childhood skin
diseases. Apparently, different numbers of the population frequency of atopic
dermatitis in the surveyed contingents are also associated with age differences
in incidence – from 0.5 to 7%.
Over the past 50 years, the nosological clarification of atopic dermatitis has
been supplemented by numerous studies of its pathogenesis and a discussion of
its diagnostic criteria. In clinical studies, atopic dermatitis has been
distinguished from seborrheic dermatitis, chronic Vidal lichen simplex (limited
neurodermatitis), nummular eczema, strophulus , diaper dermatitis, and other
dermatoses. Despite the incompleteness of modern knowledge about pathogenesis,
the accumulated observations about its symptoms, course, epidemiology are
considered sufficient grounds for interpreting it as a well-defined nosological
form. The genetic heterogeneity of atopic dermatitis is not excluded, although
the diversity of its clinical forms does not contradict the general pattern of
clinical polymorphism of multifactorial diseases.
Etiology and pathogenesis
According to genealogical studies, atopic dermatitis is classified as a multifactorial pathology, which is considered from the standpoint of the hypothesis of polygenic additive inheritance with a threshold effect [ Vogel F., 1970; Rajka G., 1975]. Identification of a burdened family history reaches 70% [ Leung D., Geha R., 1981]. B. T. Glukhenky , S. A. Grando (1985) noted atopic diseases in 38.9% of probands with atopic dermatitis, T. A. Garina (1979) – in 53.7%. Most often, active atopic dermatitis is detected in sibs of sick children. There is also significant family accumulation among parents, but atopic dermatitis is recorded in them more according to anamnestic data. In relatives of the II degree of kinship, the frequency of the disease differs little from the population. T. A. Garina (1979) established, according to strict criteria, active manifestations of atopic dermatitis in 37.5% of sibs of affected children (7 times more often than in the control group), in 5.26% of mothers and only in 0.5% of relatives II degree of relationship.
genetic component
in the etiology of atopic dermatitis is high, as evidenced by a
significant excess of concordance for atopic dermatitis in monozygotic twins
compared to dizygotic twins – 0.86 and 0.21, respectively [ Schultz F. et al .,
1985].
The polygenic system assumes the presence of the main gene that determines the
damage to skin structures, and additional genes. The threshold effect leading
to the manifestation of the disease is achieved with their additive action, as
well as the additional influence of environmental risk factors. Exogenous
factors involved in the implementation of genetic information in the patient’s
phenotype provoke exacerbations and contribute to the chronic course of the
disease. Susceptibility to environmental influences depends on the age of the
patient, his endogenous constitutional features, such as the morphological and
functional characteristics of the gastrointestinal tract, endocrine, nervous
system, etc. In infancy and early childhood, disturbances in nutrition,
digestion and absorption predominate. An important role belongs to an excess of
foods rich in histamine liberators , food allergies, immaturity of enzyme
systems, staphylococcal intestinal infections, liver diseases, vitamin
metabolism disorders, which is reflected in detail in many works [Zverkova F.
A., 1974; Toropova N. P., 1979, 1981, 1983; Zelentsova V. JI., 1982, etc.].
At an older age, an increasing place is occupied by psycho-emotional stress,
overwork, and an irrational regimen. Their action is enhanced with
post-infectious asthenia , neuroses, in children against the background of
residual microsymptomatics of a congenital nature, hydrocephalic syndrome,
diencephalic pathology. The importance of neurogenic factors has always been
emphasized in the works of domestic researchers. A deep theoretical basis for
these studies was created by the study of brain reflexes by I. M. Sechenov, the
reflex theory of pathology by I. P. Pavlov, and the reflection of the ideas of
nervism in the works of prominent clinicians. In many Soviet works [Skripkin
Yu. K., 1965, 1967; Berenbein B. A., 1971; Chebotarev K. S., 1975;
Mashkilleyson A. JI. et al., 1976, and others] and foreign authors present the
role of disorders of the central and autonomic nervous system, changes in the
exchange of mediators of nervous processes, and neurocirculatory disorders.
The development of atopic dermatitis is also facilitated by constitutional
features of immunity, immunodeficiency states, chronic focal infections, and
constitutional metabolic disorders.
Despite the multifaceted study of the factors contributing to the development
of atopic dermatitis, the initial stages of its pathogenesis are not entirely
clear, and the primary gene products have not been identified. There have been
attempts to consider the defect of suppressor T-lymphocytes as primary lesions
[ Jensen J. et al ., 1981], increased activity of cAMP – dependent
phosphodiesterase [ Hani – fin J. M. et al ., 1985], an anomaly of the enzyme
that catalyzes the desaturation of linoleic acid [ Whright St., 1985], defects
that cause generalized dysfunction of vasoactive mediators [Ring J., 1979],
protein kinase disorders . But none of the assumptions has universal acceptance
and definitive evidence.
It is assumed that the functional disorders of cyclic nucleotides and membrane
activation revealed in atopy are close to the basic defects. Over the past 20
years, many works have been published on disturbances in membrane reception and
intracellular regulation. This was reflected in the theory of blockade of β-
adrenergic receptors [ Szentivanyi A., 1968], based on evidence of weakening
the activation of 0-adrenergic receptors with a reduced level of cyclic
adenosine monophosphate ( cAMP ).
When studying membrane reception, it turned out that in patients with atopic
dermatitis, cellular responses to stimulation of histamine H2 receptors and
prostaglandin EI receptors, which perform their functions through the adenylate
cyclase and cAMP system, are defective . Thus, the idea arose of a more general
defect in membrane reception with suppression of not only p – adrenergic
receptors , but also other receptors, the activation of which stabilizes the
cell [Parker C. W. et al ., 1977; Bus – se W., Lands S., 1979; Kragballe K.,
Herlin T., 1981]. In addition, data have appeared indicating hypersensitivity
of a – adrenergic receptors and cholinergic receptors [Ring J. et aL , 1981].
On this basis, it became possible to explain the hypersensitivity of patients
with atopic dermatitis to many irritants as a result of increased reactivity of
the skin, basophils and mast cells infiltrating it, with excessive sensitivity
to signaling substances that cause cell destabilization, and reduced activity
in response to signals necessary for their stabilization. Under such a
situation, it is clear that various factors that change the kinetics of
neurotransmitters, adrenaline, and other hormones can contribute to outbreaks
of atopic dermatitis. In the same series of stimuli are allergens, toxins,
reagins , biologically active substances released from cells in response to
immune and non- immune stimuli directed to target cells.
Subsequent links in the pathogenesis of atopic dermatitis, arising from
impaired membrane reception, are diverse and include primarily functional
changes in skin vessels based on dysfunction of vasoactive mediators,
functional disorders of cells involved in immunological reactions, disorders of
cholinergic and a-adrenergic tone. It has long been noted that manifestations
of atopic dermatitis, in addition to erythema and increased vascular
permeability of the skin, include a number of other vascular changes, such as
white dermographism, facial pallor or congestive hyperemia, acrocyanosis and
prolonged cold erythema, delayed white phenomenon with paradoxical
vasoconstriction on the introduction of acetylcholine, abnormal
vasoconstriction with the introduction of nicotinic acid esters. The tendency
to release vasoactive mediators both on immune and non- immune stimulation was
emphasized [Ring J., O’Connor R., 1979].
A number of other autonomic disorders in patients with atopic dermatitis can
also be associated with increased a-adrenergic and cholinergic tone; enhanced
pilomotor reflex, hyperesthesia, paroxysmal itching, impaired motility of
smooth muscle organs, poor sleep, motor restlessness, obsession, etc. Such
connections may facilitate the conditioned reflex fixation of painful reactions
against the background of pathological inertia of nervous processes. Therefore,
in neurotic reactions to a traumatic situation, attacks of itching and erythema
occur without the participation of immune stimuli. V. D. Topolyansky and M. V.
Strukovskaya (1986), emphasizing pseudo-allergic manifestations, attribute atopic
dermatitis to psychosomatic disorders.
Many patients with atopic dermatitis have a number of disorders of cellular and
humoral immunity, including a decrease in the reaction of lymphocyte blast
transformation to plant mitogens , a skin reaction to DNCB, some bacterial
antigens, a decrease in neutrophil and monocyte chemotaxis, monocyte
cytotoxicity, impaired phagocytosis, and a decrease in the subpopulation of
T-lymphocytes suppressors, a tendency to a transient decrease in IgA
(neutralizing food allergens), an increased level of IgE in 50-80% of patients,
the presence of specific IgE to food, fungal, pollen, household allergens, a
decrease in the activity of natural killers, etc. [Skripkin Yu. K. et al.,
1975; Kochergin N. G. et al., 1977; Shatilova N. V. et al., 1979; Shutsky I. V.
et al., 1980; Shakhtmeis – ter I. Ya. et al., 1983; Gorlanov I. A., 1985;
Potekaev N. S., Sergeev Yu. V., 1985; Turner M. W. et al ., 1980; Leung D.,
Geha R., 1981; Wuthrich B., 1983, 1984; Kurz K., 1984; Klene U. et al ., 1986].
An increase in the level of IgE is associated not only with strong and early
antigenic stimulation, but also with a defect in the regulatory function of
T-lymphocytes-suppressors [Gorlanov IA, 1980; Armitste – ad J. et al ., 1983;
Chandra R., Baker M., 1983].
Immunological dysfunctions also contribute to a decrease in resistance to skin
infection, increased colonization of Staphylococcus aureus on the skin and
yeast forms of Pityrosporon. orbiculare [ Glo – or M. et al ., 1982; Amblard P.
et al ., 1985; Waersted A., Hjorth N., 1985; White MS, Nobel WC, 1986, etc.],
causing inflammatory lesions and increased itching. In atopic dermatitis
complicated by severe secondary infection, a decrease in the chemotaxis of
neutrophils and monocytes is especially pronounced, which is associated with
stimulation of membrane Ho receptors by histamine (at its high level) . Some
patients have decreased production of interferon and lysozyme.
The versatility of the pathogenetic spectrum of atopic dermatitis, apparently,
is the basis of such a complex symptom complex. Membrane reception disorders
are not complete, but partial blocks and are aggravated under the influence of
intercurrent factors. This can explain the long-term remission or weakening of
the manifestation of the pathological process with the age of patients. The
histopathology of atopic dermatitis does not differ in pathognomonic features.
In addition to the usual inflammatory changes, there is a high proliferative
activity of epidermocytes and round cells in dermal infiltrates. Clusters of
Langerhans cells are found in the epidermis of biopsy specimens from chronic
lesions , which are believed to be involved in immunological reactions and
inhibition of epidermal cell proliferation. There are many mast cells near the
adventitial cells of the vessels, and degranulated basophils in the dermis.
Expansion of superficial venous vessels, demyelination of nerve fibers,
perineural fibrosis, slight edema of collagen fibers, proliferative and
exudative changes in the area of hair follicles were revealed.
Clinic
The disease begins more often at the 3rd month, it is never congenital.
Cases of a later onset are not uncommon, but always in childhood. Usually in
childhood, the lesions are more common and recur more often: many adults are
localized on the hands or heal. However, recent work on the study of catamnesis
and long-term follow-up show that the disease continues in adults in 80% [Van
Hecke E., Leyes G., 1981] – 40% of cases [ Rystedt I., 1985]. With long-term
remissions, the possibility of relapse is not ruled out even in old age.
Relapses are often associated with periods of physiological and emotional
stress: by the age of 7, graduation from school, the onset of menstruation,
pregnancy, etc. In childhood , there is usually a summer improvement, in many
adults seasonality is lost. Prognostically for a child with atopic dermatitis,
early onset, female sex, combination with respiratory atopy , other hereditary
pathology, early allergization , persistent diseases of the gastrointestinal
tract, and focal infections are considered unfavorable.
There are 3 age phases of the disease: the first – up to two years, the
second – from 2 years to adolescence, the third – adolescence and adulthood.
The main differences in the clinic according to age phases are the localization
of lesions and the ratio of exudative and lichenoid components.
In the first age phase
Lesions are more exudative , and their localization is confined to areas of the skin in which there is an accumulation of histamine. The initial lesions are represented by erythema, progressive edema, often vesiculation , mokutia with the formation of massive serous crusts. Lichenoid lesions, trophic skin changes with severe dryness appear later (after a few weeks). Against this background, some children subsequently develop small puriginous papules. Localization of lesions is most often on the cheeks, chin, on the outer parts of the legs, extensor surfaces of the upper limbs, on the buttocks. In the future, lesions may appear on the chest, abdomen, back, or erythroderma develops (Hill’s atopic erythroderma). The boundaries of the lesions are usually indistinct. However, children with staphylococcal intestinal infection develop multiple raised, well-demarcated, bright red, edematous crusted lesions. Some children with minimal cerebral insufficiency develop lichenification early , dry, wrinkled skin, excruciating itching, and poor sleep.
In the second age phase
Acute inflammatory phenomena are less pronounced or they are short-lived, but erythema and some swelling in the lesions always persist. Eruptive elements include lichenoid flat polygonal papules, numerous follicular papules, with exacerbations – papulovesicles , vesicles. Secondary elements are represented by hemorrhagic crusts, scales, lichenification , cracks, erosions. The boundaries of the lesions are indistinct; they are most often located in large folds (elbow, popliteal), on the neck, on the hands and in the wrist area. Many patients have a diffuse lesion of the skin with the presence of dryness, pityriasis peeling, small excoriations, numerous hemispherical, rounded follicular papules. These papules are pale, usually skin-colored, and only briefly red in color when exacerbated. In many patients, especially towards the end of the second phase, Perioral licheni – fication and cheilitis. A. L. Mashkilleyson (1983) distinguishes atopic cheilitis among cheilitis and indicates that for some time it may be the only manifestation of atopic dermatitis. P. Schudel , V. Wiithrich (1985) among micromanifestations found in 17% of patients with cheilitis without other classical manifestations of atopic dermatitis.
In the third age phase
The activity of inflammatory manifestations decreases, but the phenomena
of lichenification and vascular dysfunctions increase. Localization loses
confinement to folds, selectivity of rashes in the area of the upper half of
the body with diffuse lesions of the face, neck, and upper limbs becomes
noticeable.
Itching, often very severe and paroxysmal, is a constant symptom in all age
phases. It intensifies at night, with excitement, eating that the patient
cannot tolerate, etc. In a chronic course, many patients, especially in the 2nd
phase, have pronounced dyschromia on the trunk, shoulders in the form of
large-focal pigmentation and hypopigmentation .
With a severe and prolonged process, signs of an “atopic face” are formed,
including pseudo -Hertoge symptom (rarefaction of the lateral part of the
eyebrows due to constant friction and scratching), Morgan’s folds, Denis lines
(deep folds on the lower eyelids), swelling and cyanosis of the lower eyelids,
peeling upper and lower eyelids, facial pallor or congested reddish coloration
with pastiness, perioral lichenification and cheilitis.
White dermographism is noted in many, but not all patients: sometimes there is
no dermographic reaction or it is pale pink. The pilomotor reflex is increased.
In adolescence, marbling of the skin, livedo , acrocyanosis , and hyperhidrosis
of the palms and soles are common. When the fingers are affected with cracks
and vesiculation , the nails become dystrophic with deep furrows. Hair becomes
dull during exacerbations.
Recurrent secondary skin infection is so characteristic that it can be included
in the main picture of atopic dermatitis. There is erythematous -squamous
streptoderma , folliculitis, purulent crusts, boils, microbial paronychia,
yeast lesions.
Infected foci with cracks and crusts in the behind-the-ear folds are frequent.
Less commonly, impetigo or eczema herpetiformis occurs. With persistent or
irrationally treated pyogenic infection, lymphadenitis appears, especially in
the chin area, on the neck, the temperature rises.
Among the associated lesions, urticarial rashes and Quincke’s edema,
measles-like erythema, vasomotor rhinitis, bronchitis with an asthmatic
component, conjunctivitis, sometimes bronchial asthma or pollinosis, and even
less often, atopic cataract should be noted.
In connection with the wide phenotypic range, it is advisable to identify a
number of clinical forms of atopic dermatitis: erythematosquamous ,
papulo-vesicle-crustous , lichenoid (“true Besnier prurigo ” ), purigiform and
mixed forms. The latter – erythematous -squamous with slight lichenification is
the most common. Naturally, this division is conditional, since with
evolutionary age-related changes, the clinical picture changes gradually.
Differences in individual forms of atopic dermatitis are in a different ratio
of primary eruptive elements ( lichenoid polygonal papules, follicular papules,
papulovesicles ). The predominance of certain elements of the rash reflects
some connection with exogenous risk factors. So, in the lichenoid form, the
influence of psychogenic factors is more noticeable, obsessive neurosis is
revealed; with prurigo-like forms, chronic colitis, hypersensitivity to
domestic akaro fauna are often detected, with eczematoid forms – food or
microbial allergies.
According to the size of the area of the involved skin in the pathological
process, local (usually folds, brushes or perioral lichenification ), common
and erythro – dermic forms.
There are three types of atopic dermatitis [ Wut – rich B., Schudel P., 1983].
In the first type, recovery occurs up to two years, in the second, the
manifestation of rashes is expressed up to 2 years, followed by remissions,
sometimes long-term, the third type is characterized by a continuous course.
When predicting and prescribing treatment, it is advisable to take into account four degrees of process activity:
- minimal with local lesions, moderate itching, without deviation of laboratory parameters (hemograms, proteinograms )
- moderate with more widespread and severe lesions, severe pruritus, increased lichenification or inflammation, secondary infection, with slight laboratory abnormalities
- high degree , characterized by an increase in the severity of inflammation, edema, generalization of rashes, significant lichenification with pruriginous rashes, intense paroxysmal itching, severe bacterial complications, severe laboratory abnormalities ( eosinophilia , anemia, leukopenia or leukocytosis, monocytosis or monocytopenia , increased ESR, dysproteinemia , pathological liver tests, etc.)
- the maximum degree of activity of the pathological process is characterized by a universal skin lesion, accompanied by severe inflammation, masking lichenification , painful constant itching, secondary infection, lymphadenopathy , fever, poor health and severe general condition, significant changes in laboratory parameters.
Severe outcomes occur with complications such as anaphylactoid shock,
disseminated vascular coagulation syndrome, Kaposi’s eczema herpetiformis,
long-term and widespread pyogenic infection with fever and lymphadenopathy .
The diagnosis of atopic dermatitis is based on:
- anamnesis, which primarily focuses on age evolution, seasonality, localization of previous rashes, the multiplicity of provoking factors, especially emotional, nutritional, etc.,
- detailed analysis of eruptive elements and their localization in comparison with age phases and clinical forms, taking into account the intensity of itching, true polymorphism of eruptive elements, a combination of inflammatory and lichenified foci, characteristic complications, dysfunction of skin vessels and autonomic dystonia.
Differential diagnosis should be carried out with seborrheic dermatitis,
Vidal’s simple chronic lichen, symptomatic lichenification in mental and
endocrine diseases, with microbial eczema. In addition to true polymorphism and
lichenification without concentric zones characteristic of Vidal’s lichen, it
is very important to analyze the evolutionary features of localization, which
are not present in any of these diseases. V. Jates and co-authors (1983)
consider the localization features to be the most important diagnostic sign of
atopic dermatitis when differentiating it from seborrheic dermatitis in
children.
The disease atopic dermatitis is often combined with monogenic dermatoses,
especially with autosomal dominant ichthyosis vulgaris. In order not to confuse
dryness and flaking of the skin that occurs in patients with atopic dermatitis
due to trophic disorders with ichthyosis vulgaris, it should be remembered that
the latter necessarily has follicular keratosis with horny plugs and damage to
the palms and soles in the form of rough folding and thickening.
Treatment and prevention
The treatment of atopic dermatitis is multifaceted and individualized. In severe cases, intensive therapy is carried out using infusion and symptomatic agents (eufillin, diuretics), according to indications, heparin, chimes, stugeron , antibiotics are prescribed. In milder cases, conventional anti-inflammatory and antitoxic agents are used (antihistamines, calcium, rutin, ascorbic acid, sodium hyposulfite, calcium pantothenate , sodium salicylate ). Some patients are helped by zaditen , glycyram , histaglobulin. According to the indications, they are mainly used in adult patients with pyrilene [ Mashkilleyson A. L. et al., 1985] or other ganglion blockers , sedative herbs, pyrroxane , electrosleep or other soothing physiotherapeutic procedures. In some cases, it is necessary to prescribe short courses of treatment with tranquilizers, antipsychotics or antidepressants. Vitamin E or papaverine is recommended to stabilize membranes or influence cellular regulation [ Baer R., 1985]. To increase immunity and improve trophism, vitamins A, B1, B2, Be, phytin, iron preparations, calcium glycerophosphate, aloe, dimocyphon , splenin , etc. are prescribed. In infancy and early childhood, the appointment of enzymes that improve digestion and eubiotics is especially important . In adult patients, sedative effects come first. Adequate external therapy is of particular importance. It should include the use of anti-inflammatory and absorbable agents (pastes and ointments with ASD – III fraction, tar, naftalan oil), agents that epithelialize and improve skin trophism ( solcoseryl , vulnuzan ), certainly antibacterial agents ( lincomycin ointment, levosin , levomekol , rivanol ointment , dermatological compress with rivanol lotion, etc.)
There are two ways to prevent atopic dermatitis:
- elimination of environmental risk factors and treatment of intercurrent diseases that provoke or aggravate atopic dermatitis;
- medical genetic counseling for families.
Families of patients with atopic dermatitis more often than with other multifactorial dermatoses ask questions about the role of heredity and genetic prognosis for offspring. The empirical risk of inheritance for relatives of the first degree of kinship is 16% [Kozlova S.I., Prytkov A.N., 1981]. With genetic counseling, the diagnosis must be absolutely reliable. Atopic dermatitis must be differentiated from hereditary diseases such as Knapp – Comrover syndrome, hyperimmunoglobulinemia E syndrome, accompanied by itchy skin lesions and recurrent deep skin infection, Wiskott -Aldrich syndrome, phenylketonuria, etc. To differentiate with them in a medical genetic consultation, it may be provided laboratory assistance.