Disorders Of Epidermal Differentiation And Keratinization

THE ICHTHYOSIS

Ichthyoses
Ichthys (Greek) meaning fish A heterogenous group of skin diseases characterized by generalized scaling and, often, areas of thickened skin. Most types are inherited, and these usually present at birth. However, some forms are acquired Scales may vary in size, color, and body site

ICHTHYOSIS
May be accompanied by erythema, abnormalities in other parts of skin, and adnexal structured May be asso.w systemic findings, such as failure to thrive, increased susceptibility to infection, atopic dermatitis, neurosensoris deafness, neurologic and other disease Pathology is usually non-specific w. the exception of epidermolytic hyperkeratosis, neutral lipid storage disease. Refsum disease, and acquired ichthyosis associated w sarcoidosis

Clinical presentation
Several features are useful in distinguishing different forms of icthyosis: Age of onset Presence of collodion membrane at birth Quality of scale Presence/absence of erythroderma Abn. in other parts of the skin (e.g., palms & soles, ectropion, eclabium) & adnexal structures (e.g., alopecia, hair follicle / shaft abn) Involvement of other organ system

Clinical presentation
Visible scaling may be seen in some patients, w. flakes of stratum corneum varying in size from fine to coarse. There may be thickening of the skin w./wo. visible scale A family pedigree may clarify the pattern of inheritence. (the presence of consanguinity may suggest autosomal recessive inheritance)

Etiologi & Pathogenesis Ichthyosis

Fully differen. end products of the epidermis is the stratum corneum, with is composed of terminally differen. keratinocytes, corneocytes (bricks), surrounded by intercellular matrix (mortar). Corneocytes bricks are protein enriched, and the intercellular mortar is composed of hydrophobic, lipidenriched membrane bilayers The keratin-laden corneocytes are thought to be primarily responsible for the resilience and water retention properties of the stratum corneum, while the matrix forms most of the permeability barrier to water loss.

Etiology & Pathogenesis

Etiology & Pathogenesis

Etiology & Pathogenesis

The normal stratum corneum undergoes desquamation in an organized and invisible manner, with individual corneocytes separating from each other and shedding as single cells. Ichthyotic skin has an abn. Quality and quantity of scale, the barrier function of the str. Corneum is compromised and there may be alterations in the kinetics of epidermal cell proliferation The str. Corneum can be viewed as a compartment with thickening of the str.corneum being the result of cells entering the compartment at an increased rate, or leaving (corneocytes desquamation) too slowly or both

Etiology & Pathogenesis

The process of epidermal differentiation is complex and not completely understood. Defects in many different aspects and steps of this process can lead to a similar end result: abn. str. corneum and scale. In some of these disorders the underlying abn. Has been identified. For examp. mutations in the genes that encode the suprabasal epidermal keratins, keratin-1 and -10 cause epidermolytic hyperkeratosis Mutations in the gene encoding transglutaminase 1, an enzyme that catalyzes the cross linking of proteins and attachment of ceramides during the formation of corneocytes cause lamellar ichthyosis one form of A.R.C.I

Etiology & Pathogenesis

Steroid sulfatase controls the hydrolysis of cholesterol sulfate in corneocytes and is thought to be important in the regulation of corneocytes desquamation Deficiency of steroid sulfatase causes X-linked recessive ichthyosis The observation that several drugs that lower serum cholesterol (nicotinic acid, triparanol) can induce ichthyotic skin changes indicates the important the lipid homeostasis in normal keratinization

Etiology & Pathogenesis

Further evidence is the identification of mutations in the genes encoding cholesterol biosynthetic enzymes as a cause of x-linked dominant chondrodysplasia punctata and congenital hemidysplasia with ichthyosiform erytroderma and limb defects (CHILD) syndrome and genes encoding the other aspects of lipid biosynthesis in the autosomal recessive congenital ichthyosis

Etiology & Pathogenesis

The recent identification of mutations in SPINK-5 (serine protease inhibitor, Kazel type 5), encoding a serine protease inhibitor, confirms a role for protease inhibitor in normal epidermal differentiation The discoveries of connexin abnormalities as causes for erythrokeratodermia variabilis; keratitis, ichthyosis, & deafness (KID) syndrome; & other disorders involving ectodermal tissues highlight the role of intercellular communication for properly functioning skin.

ICHTHYOSIS VULGARIS
Onset: infancy / childhood The scale is most prominent on the extensor surfaces of the extremities, w. flexural sparing. The diaper area tends to be spared. There may be fine, white scale over large areas. Particularly on the lower extremities, which are often the most severely involved area, The scale may be centrally attached w. cracking (Superficial fissuring through the str. corneum) at the edges ).

Other findings commonly associated with ichthyosis vulgaris

Hyperlinear palms Palmar/plantar thickening approaching a keratoderma Keratosis pilaris Atopy (can manifest as hay fever, eczema, or asthma) Hypohidrosis with heat intolerance The condition usually worsens in climates that are dry & cold & improves in warm, humid environments, where the disease may clear dramatically

ICHTHYOSIS VULGARIS
The disease was thought to be autosomal dominant. Recently, Mutations in the gene encoding profilaggrin (FLG) have been found to cause ichthyosis vulgaris. This finding clarifies the inheritance pattern as semi-dominant.

Mild Ichthyosis vulgaris Vs simple dry skin (Xerosis)

Evolving understanding of this very common condition is beginning to clarify how a spectrum of underlying mutations can cause the diverse clinical severity of dry skin from xerosis to severe ichthyosis vulgaris. In addition, on the basis of skin findings alone, males w. severe ichthyosis vulgaris may be difficult to differentiate from those affected w. X-linked recessive ichthyosis.

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The histopathologic findings of ichthyosis vulgaris may be distinctive in specimens taken from homozygotes, showing mild hyperkeratosis & absent granular layer. In heterozygotes, even when the granular layer is present on light microscopy, examination by electron microscopy can show keratohyalin granules that are small, abnormally shaped, & crumbly in appearance

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Biochemical studies of epidermis from patients w. ichthyosis vulgaris have shown absence or decrease of filaggrin and its precursor, profilaggrin

X-linked Recessive Ichthyosis

birth / infancy Fine large scales; comma shape corneal opacities on posterior capsule Crytorchidism; female carriers may have corneal opacities & delay of onset / progression of labor in affected pregnancies Gene: STS Steroid sulfatase Lipid metab.-abn cholesterol metab. W. Accuumulation of cholesterol sulfate Hyperkeratosis, may have hypergranulosis; nonspecific.

X-linked Recessive Ichthyosis (X-LRI)

Syndrome of placental steroid sulfatase deficiency was described in pregnancies w. failure to initiate labor in asso. W. low maternal urinary estrogens. Because the majority of maternal urinary estrogens are derived from the fetal adrenal & are metabolized by the placenta, low levels can reflect fetal abnormalities or death.

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However, in this condition, low levels do not indicate severe fetal morbidity. The asso. Between failure to initiate or progress labor & ichthyosis in the male offspring was not appreciated until later. Steroid sulfatase hydrolizes sulfate esters, ,which include cholesterol sulfate & sulfated steroid hormones.

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Sulfated fetal adrenal hormones undergo desulfation to estrogen, which are excreted in maternal urine. the absence of steroid sulfatase enzyme in the fetal placenta leads to low maternal urinary estrogens &, in some pregnancies, to a failure of labor to initiate or to progress normally.

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In males w. XLRI, stroid sulfatase enzyme activity is decreased or absent in many tissues, including epidermis, str. Corneum, & leukocytes, and in cultured fibroblasts. In addition, cholesterol sulfate, an enzyme substrate, accumulates in serum and in scale. Carrier females have been found to have leukocyte steroid sulfatase levels intermediate between those observed in normal individuals & those in affected males

Lamellar Ichthyosis(autosomal recessive congenital ichthyosis)

Autosomal recessive Birth (often collodion presentation) Large, plate-like, brown scales over of the most of the body; accentuated on lower extremities ectropion; eclabium;alopecia. Palmar/plantar involement varies. Heat intolerance Gene: various (TGM1) Protein: Transglutaminase1 (Cornified Envelope formation) Hyperkeratosis, acanthosis, may show parakeratosis. nonspecific

EPIDERMOLYTIC HYPERKERATOSIS
Autosomal dominant Birth Heterogenous. May have verrucous, firm, hyperkeratotik (hystric)spines, often linearly arrrayed in flexural creases; blister; may have erythroderma &/or palmar/plantar keratoderma Skin infection; characteristic pungent odor Gene: KRT1, KRT10; in Vrner type (confined to palms/soles) KRT9

 Protein: keratin1or keratin10; in Vrner type, keratin9 Structural protein abn. Leading to keratin intermediate filament dysfunction- epidermal fragility Hyperkeratosis; vacuolar degeneration of the epidermal granular (& often deeper layer); large irregular keratohyalin granules

ACQUIRED ICHTHYOSIS
Adult hood Can be manifest. Of systemic disease Has been described in asso. w. Malignancy, drug and metabolic disease, HIV and other infections and autoimmune condition

Acquired Ichthyosis
Hodgkin disease HIV (30%) Sarcoidosis SLE Dermatomyositis, Mixed connective tissue disease, eosinophilic fasciitis G.V.H D Cholesterol lowering agent Butirofenon (antipsychotic) Dixyrazine (major transquilizer) Nafoxidine (estrogen antagonist) Kava (psychoactive beverage)

Therapy
Simptomatik Fokus pada hidrasi lubrikasi keratolitik Topikal retinoid dan vitamin D preparations (hati-hati) Systemic retinoid (isotretinoin dan acitretin) can induced dramatic improvement, particulary useful in lamellar ichth.