disorders of epidermal differentiation and keratinization

8/12/2019 Disorders of Epidermal Differentiation and Keratinization

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Disorders Of EpidermalDifferentiation And Keratinization

THE ICHTHYOSIS


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Ichthyoses

Ichthys (Greek) meaning fish A heterogenous group of skin diseases

characterized by generalized scaling and,often, areas of thickened skin . Most types areinherited , and these usually present at birth.However, some forms are acquired

Scales may vary in size, color, and body site


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ICHTHYOSIS May be accompanied by erythema,

abnormalities in other parts of skin, and adnexalstructured

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 exceptionof epidermolytic hyperkeratosis , neutral lipidstorage disease. Refsum disease, and acquiredichthyosis associated w sarcoidosis


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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


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Clinical presentation

Visible scaling may be seen in some patients,w. flakes of stratum corneum varying in sizefrom fine to coarse.

There may be thickening of the skin w./wo.visible scale

A family pedigree may clarify the pattern ofinheritence. (the presence of consanguinitymay suggest autosomal recessive inheritance)


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Etiologi & Pathogenesis Ichthyosis Fully differen. end products of the epidermis is the

stratum corneum, with is composed of terminallydifferen. keratinocytes, corneocytes (bricks ),surrounded by intercellular matrix (mortar ).

Corneocytes bricks are protein enriched , and theintercellular mortar is composed of hydrophobic, lipid-enriched membrane bilayers

The keratin-laden corneocytes are thought to beprimarily responsible for the resilience and waterretention properties of the stratum corneum, while thematrix forms most of the permeability barrier to waterloss.


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Etiology & Pathogenesis


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Etiology & Pathogenesis The normal stratum corneum undergoes

desquamation in an organized and invisible manner,with individual corneocytes separating from eachother and shedding as single cells.

Ichthyotic skin has an abn. Quality and quantity ofscale, the barrier function of the str. Corneum iscompromised and there may be alterations in thekinetics of epidermal cell proliferation

The str. Corneum can be viewed as a compartmentwith thickening of the str.corneum being the result ofcells entering the compartment at an increased rate, orleaving (corneocytes desquamation) too slowly or both


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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 beenidentified. For examp. mutations in the genes that encodethe suprabasal epidermal keratins, keratin-1 and -10 causeepidermolytic hyperkeratosis

Mutations in the gene encoding transglutaminase 1 , an

enzyme that catalyzes the cross linking of proteins andattachment of ceramides during the formation ofcorneocytes cause lamellar ichthyosis one form of A.R.C.I


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Etiology & Pathogenesis Steroid sulfatase controls the hydrolysis of

cholesterol sulfate in corneocytes and is thoughtto be important in the regulation of corneocytesdesquamation

Deficiency of steroid sulfatase causes X-linkedrecessive ichthyosis

The observation that several drugs that lowerserum cholesterol (nicotinic acid, triparanol ) caninduce ichthyotic skin changes indicates theimportant the lipid homeostasis in normalkeratinization


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Further evidence is the identification ofmutations in the genes encoding cholesterolbiosynthetic enzymes as a cause of x-linkeddominant chondrodysplasia punctata andcongenital hemidysplasia with ichthyosiformerytroderma and limb defects (CHILD)

syndrome and genes encoding the otheraspects of lipid biosynthesis in the autosomalrecessive congenital ichthyosis


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Etiology & Pathogenesis The recent identification of mutations in SPINK-5

(serine protease inhibitor, Kazel type 5), encodinga serine protease inhibitor, confirms a role forprotease inhibitor in normal epidermaldifferentiation

The discoveries of connexin abnormalities ascauses for erythrokeratodermia variabilis;keratitis, ichthyosis, & deafness (KID) syndrome ;& other disorders involving ectodermal tissueshighlight the role of intercellular communicationfor properly functioning skin.


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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 areoften the most severely involved area,

The scale may be centrally attached w. cracking (Superficial fissuring through the str. corneum) atthe edges

).


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Other findings commonly associatedwith 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


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ICHTHYOSIS VULGARIS

The disease was thought to be autosomaldominant.

Recently, Mutations in the gene encodingprofilaggrin (FLG) have been found to causeichthyosis vulgaris. This finding clarifies theinheritance pattern as semi-dominant.


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Mild Ichthyosis vulgaris Vs simple dryskin (Xerosis)

Evolving understanding of this very commoncondition is beginning to clarify how aspectrum of underlying mutations can causethe diverse clinical severity of dry skin fromxerosis to severe ichthyosis vulgaris. Inaddition, on the basis of skin findings alone,

males w. severe ichthyosis vulgaris may bedifficult to differentiate from those affected w.X-linked recessive ichthyosis.


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The histopathologic findings of ichthyosisvulgaris may be distinctive in specimens takenfrom homozygotes, showing mild

hyperkeratosis & absent granular layer. In heterozygotes, even when the granular

layer is present on light microscopy,examination by electron microscopy can showkeratohyalin granules that are small,abnormally shaped, & crumbly in appearance


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Biochemical studies of epidermis frompatients w. ichthyosis vulgaris have shownabsence or decrease of filaggrin and itsprecursor, profilaggrin


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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 inaffected pregnancies

Gene: STS Steroid sulfatase Lipid metab.-abn cholesterol metab. W. Accuumulationof cholesterol sulfate Hyperkeratosis, may have hypergranulosis ; nonspecific.


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X-linked Recessive Ichthyosis (X-LRI)

Syndrome of placental steroid sulfatasedeficiency was described in pregnancies w.failure to initiate labor in asso. W. lowmaternal urinary estrogens.

Because the majority of maternal urinaryestrogens are derived from the fetal adrenal &are metabolized by the placenta, low levelscan reflect fetal abnormalities or death.


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However, in this condition, low levels do notindicate severe fetal morbidity.

The asso. Between failure to initiate orprogress labor & ichthyosis in the maleoffspring was not appreciated until later.

Steroid sulfatase hydrolizes sulfate esters,,which include cholesterol sulfate & sulfatedsteroid hormones.


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Sulfated fetal adrenal hormones undergodesulfation to estrogen, which are excreted inmaternal urine.

the absence of steroid sulfatase enzyme inthe fetal placenta leads to low maternalurinary estrogens &, in some pregnancies, to a

failure of labor to initiate or to progressnormally.


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continue In males w. XLRI, stroid sulfatase enzyme activity

is decreased or absent in many tissues, includingepidermis, str. Corneum, & leukocytes, and in

cultured fibroblasts. In addition, cholesterol sulfate, an enzymesubstrate, accumulates in serum and in scale.

Carrier females have been found to haveleukocyte steroid sulfatase levels intermediatebetween those observed in normal individuals &those in affected males


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Lamellar Ichthyosis(autosomalrecessive 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


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EPIDERMOLYTIC HYPERKERATOSIS

Autosomal dominant Birth Heterogenous. May have verrucous, firm,

hyperkeratotik (hystric)spines, often linearly arrrayed inflexural creases; blister; may have erythroderma &/orpalmar/plantar keratoderma

Skin infection; characteristic pungent odor Gene : KRT1, KRT10 ; in Vrner type (confined to

palms/soles) KRT9


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Protein: keratin1or keratin10; in V rner type,keratin9

Structural protein abn. Leading to keratinintermediate filament dysfunction- epidermalfragility

Hyperkeratosis; vacuolar degeneration of theepidermal granular (& often deeper layer);large irregular keratohyalin granules


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ACQUIRED ICHTHYOSIS

Adult hood Can be manifest. Of systemic disease

Has been described in asso. w. Malignancy,drug and metabolic disease, HIV and otherinfections and autoimmune condition


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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)


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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.

disorders of epidermal differentiation and keratinization

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