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Keratinization disorders by M.Y.Abdel_Mawla,MD


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to describe molecular mechanisms of epidermis keratinization and related disorders.

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Keratinization disorders by M.Y.Abdel_Mawla,MD

  1. 1. Keratinization disorders M.Yousry Abdel_Mawla
  2. 2. KERATINOCYTES  Any one of the cells in the skin that synthesize keratin.  Contains actin ,tubulin , intermediate filaments.  Keratin is one of the 6 types of intermediate filaments.
  3. 3. EPIDERMOPOIESIS  Epidermopoiesis Epidermal dynamics Epidermal kinetics
  4. 4. EPIDERMAL DYNAMICS  Epidermal proliferative unit( EPU)  Consists of Single Stem cell Transit amplifying cells Terminally differentiated cells (post mitotic cells)
  5. 5. EPIDERMAL KINETICS  Turn over time Cell cycle Growth fraction
  6. 6.  Turnover time of the germinative epithelium  Epidermal turnover time ( transit time= 14 days) The time taken for a cell to pass from basal layer to the surface of the skin next 14 days Subsequent desquamation
  7. 7. Epidermis Differentiation  Transglutaminase, TGase 1, is localized at the cell membrane.  the proteins form an insoluble structure named “cornified envelope” close to  the cell surface .  Filaggrin (FLG), also encoded in the EDC, is the main component of keratohyalin granules to which the granular layer (stratum granulosum, SG) owes its name.  Upon dephosphorylation and proteolysis of the profilaggrin precursor, filaggrin is dispersed and causes the aggregation of the keratin intermediate filaments  Simultaneously the nucleus is degraded and cell organelles disappear by an unknown mechanism.  Ultimately, keratins remain as the prevailing proteins inside the cornified envelopes strongly contributing to the mechanical resistance of the cornified layer (stratumcorneum, SC).  In addition, keratins can also regulate pathways involved in growth, proliferation, migration and apoptosis of epithelial cells
  8. 8. Epidermal differentiation.  The epidermis is the outermost layer of the skin and is separated from the underlying dermis by the basement membrane.  Keratinocytes, which compose the epidermis, proliferate within the basal cell layer  As differentiation proceeds, keratinocytes progress upwards through the different epidermal layers (the spinous layer, granular layer and cornified layer or stratum corneum),becoming anucleated and increasingly compacted in size, before being eventually lost from the skin surface by desquamation (shedding of the outer layers of skin).  Each stage of epidermal differentiation is characterised by the expression of specific proteins,
  9. 9. 11
  10. 10. Transglutaminases  Transglutaminases cross-link plakins and involucrin.  Other desmosomal proteins are also cross-linked ,forming a scaffold along the entire inner surface of the plasma membrane.  High calcium level increases differentiation.
  11. 11. EPIDERMAL DIFFERENTIATION  8 % of the basal cells -(K-1/K10) undergo differentiation.  Orchestrated expression of keratins and subunits of cornified envelope.  Terminal differentiation (keratinization):  Change in keratin expression .  Formation of corneocyte.
  12. 12. DIFFERENTIATING EPIDERMAL KERATINOCYTES Basal layer as proliferative cells express K-5 and K-14 The process of differentiation starts with the K – 10/K-1 expression (in TA cells) K-2 is expressed at later stages of differentiation( granular layer)
  13. 13. TERMINAL DIFFERENTIATION 1.Formation of keratin 2.Keratin filaments aggregate into bundles with the help of filaggrin. 3.Cornified envelope.
  14. 14. Terminal Differentiation 4.Changes in expression of  Intracellular lipid  Membrane glycoproteins  Growth factor receptors  Adhesion protein  Blood group antigens  Desmosomes.
  15. 15. As keratinocytes are transformed from mitotically active cells in the basal layer to fully differentiated, enucleated squames in the cornified layer. Keratohyalin (profilaggrin- and loricrin-containing) and lamellar (lipid-containing) granules extrude their contents in the granular layer, leading to bundling of keratin filaments and replacement of the plasma membrane with the highly cross-linked, lipid-covered cornified cell envelope
  16. 16. At the beginning of the granular layer1. Keratohyalin granules Formation (KHG) (contains Profilaggrin) 2. Cell envelope proteins cross-linking (Involucrin and Loricrin) In the spinous layer: Formation of 1. Lamellar bodies 2. KIF As the cells enter the spinous layer Switch of keratin synthesis from K5/K14 to K1/K10 Initiation of differentiation
  17. 17. In the transitional zone 1. Filaggrin (keratin bundling protein) acts as a glue matrix that facilitates dense packing of KIF into k. macrofibrils 2.  activity of keratinocytes, 3. Loss of organelles 4. Dehydration 5.  extracelluar Ca++, 6.  activity of transglutaminase, deposition of loricrin, cross linking of involucrin On entering the transitional zone between the granular cell layer and the Cornified layer Profilaggrin is transformed into filaggrin
  18. 18. Corneocytes are shed into the environment In upper stratum corneum 1. Formation of corneocyte bound lipid envelope 2. Plasma membrane and desmosomes become discontinuous, corneodesmosomes are residual intercellular desmosomal interconnections. In lower stratum corneum 1. Dead keratinocytes packed with keratin macrofibrils 2. corneocyte bound protein envelope just beneath the plasma membrane
  19. 19. Desquamation of surface keratinocytes from the stratum corneum is regulated by proteolytic degradation of the cells’ desmosomes.
  20. 20. In response to certain signals probably an increase in calcium concentration during the transition from the granular layers to the SC the lamellar bodies move to the apex of the upper-most granular cells, fuse with the plasma membrane, and secrete their content into the intercellular spaces through exocytosis. Components of the stratum corneum
  21. 21. Stratum corneum proteins • Involucrin • Loricrin • Keratolinin • pro (Filaggrin) • Desmosomal proteins: - desmoplakin - envoplakin
  22. 22. CORNIFIED ENVELOPE  Highly insoluble cell envelope.  Present in stratum corneum.  It’s development is triggered by intracellular calcium.  Involucrin is main envelope precursor.  Others include 1. Loricin 6. Envoplakin 2. Cornifine 7. Periplakin 3. Pancornulin 8. 61KDa protein 4. Elafin 5. Keratolini
  23. 23. Keratins  Keratins are defined as intermediate filament forming proteins with specific physicochemical properties produced in any vertebrate epithelia.  They are multigene family of proteins constituting 85% of the total cellular protein in the cornified cells of the epidermis and encoded by a family of approximately 30 proteins  Each keratin is characterized by a chain of amino acids as the primary structure, which varies in the number and sequence of amino acid as well as in polarity, charge and size.  Keratin filaments have a tripartite secondary structure consisting of an N-terminal head domain, a central α-helical rod domain and C-terminal tail domain and all the proteins are able to self assemble into filaments.
  24. 24. Keratins Functions of keratin in the epidermis: 1. Crucial role in keratinization 2. Integral part of the structural network that make hemidesmosomes, desmosomes, BM (Structural integrity) 3. Maintaining spatial relation between the nucleus and cytoplasmic organelles 4. Transfer of information between the nucleus and cell surface and vice versa i.e. cell signaling.
  25. 25. Type 1 keratins K9,K10 Epidermis(suprabasal) K12 Cornea K13 Oral mucosa K14,K15 Complex epithelia K16,K17 Epithelial appendages K18 Simple epithelia K19 Broad distribution K20 Gut epithelium K23 pancreas K24 unknown K25-28,31-38,39,40 Hair shafts
  26. 26. Type 2 keratins K1,K2 Epidermis (suprabasal) K3 Cornea K4 Oral mucosa K5 Complex epithelia(basal layer) K6a,K6b Epithelial appendages K6c Skin K7,K8 Simple epithelia K71 – 74,75 Hair follicles H76 Oral mucosa K77 Sweat gland ducts K78 tongue
  27. 27. Distribution of keratin in oral epithelium
  28. 28. Distribution of keratin.
  29. 29. Any defect along this pathway leads to DIORDERS OF KERATINIZATION
  30. 30. BASIC K ACIDIC K TISSUE EXPRESSION DISEASE ASSOCITION 1 10 Suprabasal keratinocytes Bullous congenital icthyosiformis erythroderma ; Diffuse non epidermolytic PPK 1 9 Suprabasal keratinocytes (palmo-plantar skin) Epidermolytic PPK 2 10 Upper spinous , granular Icthyosiform bullosa of siemens 3 12 cornea Meesmann’s corneal dystrophy 4 13 Mucosal epithelium White sponge nevus 5 14 Basal keratinocytes Epidermolytic bullosa complex 6a 16 Outer root sheath,hyperproliferative, palmo-plantar keratinocytes Paronychia congenita type 1 ; Focal non-epiderdermolytic PPK 6b 17 Nail bed ,epidermal appendages Paronychia congenita type II, Steatocystoma multiplex 8 18 Simple epithelium Cryptogenic cirrhosis
  31. 31. DISTURBANCE IN EPIDERMAL KINETICS 1. ACANTHOSIS Enhanced cell proliferation Enlargement of the germinative cell Increased mitotic rates Broadening of epidermis
  32. 32. DISTURBANCE IN EPIDERMAL DIFFERENTIATION PARAKERATOSIS Incomplete differentiation in post mitotic phase Faulty and accelerated cornification Retension of of pyknotic nuclei of epidermal cells Leads to gap between cells Loss of barrier function of the epidermis
  33. 33. DYSKERATOSIS  Morphologic presentaion of apoptosis of keratinocytes  Eosinophilic cytoplasm ,pyknotic nucleus  Cells are packed with keratin filaments Cell will tent to round up Loose it’s attachment with surrounding cells
  34. 34. DISORDERS OF KERATINIZATION 1. Icthyosis 2. Palmoplantar keratodermas / Erythrokeratoderma 3. Porokeratosis 4. Peeling skin syndromes 5. Discrete keratotic disorders 6. Miscellaneous circumscribed keratotic disorders 7. Filiform keratoses 8. Confluent and reticulate papillomatosis
  35. 35. Keratinocytes and keratinization disorders
  36. 36. Ichthyotic skin disorders   Ichthyotic skin disorders are classified into the following groups  • Noncongenital ichthyoses develop 4 weeks after birth and spare flexures,  palms and soles.  • Congenital ichthyoses present with collodion membrane or ichthyosiform  erythroderma at birth or manifest within 4 weeks.  Variants in which the skin lesions are but one facet of a more sinister  systemic illness (syndromic ichthyosis).
  37. 37. Ichthyosis vulgaris  Ichthyosis vulgaris is characterized by deficiency of profilaggrin, a major constituent  of the keratohyalin granules.  Ultrastructurally, the keratohyalin granules are reduced, spongy or crumbly and associated with decreased amounts of filaggrin.  Reflecting a defective epidermal synthesis of filaggrin  Filaggrin aggregates keratin intermediate filaments in the lower stratum corneum and is subsequently proteolyzed  to form free amino acids including urocanic and pyrrolidone carboxylic acids critical as water-binding compounds in the stratum corneum.  the epidermal differentiation complex on chromosome 1q21 has identified mutations in the gene encoding filaggrin  Since the filaggrin gene is a major susceptibility gene for atopic dermatitis, mutations have also been shown in atopic dermatitis  Ichthyosis vulgaris is characterized by mild to moderate orthohyperkeratosis associated with a hyperplastic, atrophic or normal epidermis. The key feature is a thin or absent granular cell layer  
  38. 38. Ichthyosis vulgaris  Commonest form and also the mildest.  Autosomal-dominantly inherited  Inherited disorder of keratinization associated with decreased conversion of profilaggrin to filaggrin that is characterized by fine scaling predominantly affecting the extensor surfaces of the extremities with sparing of the flexures and tendency towards improvement in the summer months.  Filaggrin is an epidermal protein which is needed for aggregation of keratin intermediate filament and retention of moisture in the stratum corneum.  Onset : early childhood (in between 3-12 months of age)
  39. 39. Ichthyosis Vulgaris
  40. 40. Ichthyosis vulgaris (association with)  Ichthyosis vulgaris is frequently associated with keratosis pilaris and atopic dermatitis so their C/F are found with it, accounting keratotic lesions on on palmer creases (keratosis punctata), Follicular hyperkeratoses on shoulders, buttocks, thighs and upper arms as in case of KP and hay fever, asthma, eczema or urticaria may be presented as a manifestation of AD.
  41. 41. Ichthyosis vulgaris ( D/D)  Xerosis/Asteatotic eczema  X-Linked ichthyosis  Acquired ichthyosis  Atopic dermatitis  KID syndrome  Netherton syndrome Associations • Atopic dermatitis • Keratosis pilaris
  42. 42. X-Linked ichthyosis  Ichthyosis seen only in men as a result of steroid sulfatase deficiency.  X-Linked recessive inheritance.  Males are affected and females are asymptomatic carrier.  Onset : usually before 3 months of age.  The children are commonly born via C/S, with failure of progression of labor owing to a placental sulfatase deficiency and low maternal urinary estrogen level.
  43. 43. X-Linked ichthyosis(C/F)  Large dark polygonal scales divided by wide splits prominently on trunk and extensor extremities. The palms and soles are nearly always spared.  The sides of the neck usually are involved giving rise to a unwashed look (dirty neck)  Ocular involvement : Corneal opacity.  Cryptorchidism, testicular carcinoma.
  44. 44. X-linked Ichthyosis
  45. 45. Histopathology of Icthyosis vulgaris
  46. 46. Histopathology of I .Vulgaris
  47. 47. The disease is associated with a deficiency of the microsomal enzyme, steroid sulfatase/STS (sterol sulfate sulfohydrolase/arylsulphatase C). This is a membrane-bound enzyme, which hydrolyses the 3-â-sulfate esters of cholesterol and the sulfated steroid hormones It is characterized by a raised serum cholesterol sulfate. The corneocytes contain excess cholesterol 3-sulfate and diminished free sterol. Steroid sulfatase deficiency possibly results therefore in persistence of the lipid contents of the membrane-coating granules and hence increased or persistent adhesion between adjacent keratin plates in the stratum corneum. Increased amounts of cholesterol sulfate may inhibit the epidermal serine protease activity, which results in retention of corneodesmosomes leading to less shedding of scales and retention hyperkeratosis. The gene locus for recessive X-linked ichthyosis is within the Xp22.3 region of the X chromosome Lesions show non-specific features of compact hyperkeratosis and slight acanthosis associated with a granular cell layer, which may be normal or increased in thickness
  48. 48. X-Linked ichthyosis(D/D)  Ichthyosis vulgaris  Lamellar ichthyosis  Asteatotic eczema  Atopic dermatitis  Netherton syndrome  Nonbullous congenital ichthyosiform erythroderma Associations • Androgenetic alopecia • Kallmann syndrome • Multiple sulfatase deficiency
  49. 49. Lamellar Ichthyosis  Present at birth or appears soon after.  Usually involves the entire cutaneous area.  Autosomal-Recessive inheritance.  It is a severe form of Ichthyosis and also is very uncommon.  Decreased or absent transglutaminase-1 activity.  Onset : Birth- collodion baby.
  50. 50. Lamellar Ichthyosis (C/F)  H/O a collodion-like (a colourless or yellow syrupy liquid) membrane encasing the baby at birth which desquamates over the first 2/3 weeks.  Scales : Thick dark (grayish-brown), strikingly quadrangular, free at edges and adherent at centre; tend to be largest at extremities where these large plate-like scales are separated by superficial fissuring (similar to a dry river bed).  Involvement of palm and soles : Ranges from minimal hyper- linearity to severe keratoderma.  Ectropion and eclabium : Ectropion is the turning out of the eyelid so that the inner surface is exposed. Eclabium is eversion of a lip. Tautness of facial skin is responsible for these.
  51. 51. Lamellar Ichthyosis
  52. 52. Lamellar Ichthyosis
  53. 53. Ectropion
  54. 54. Collodion Baby  A number of forms of ichthyosis present at birth with infant encased in a tight membrane of adherent keratinocytes, which has been compared to parchment or collodion.  Kollodes is the Greek word for glutinous or glue-like.  The membrane is then shed, leaving either normal skin (lamellar exfoliation of newborn) or, more often, one of the forms of nonbullous congenital ichthyosiform erythroderma or lamellar ichthyosis.
  55. 55. Collodion baby
  56. 56. Nonbullous congenital ichthyosiform erythroderma  Rare severe ichthyosis presenting at birth.  All three enzymes have autosomal recessive inheritance have mutations:  Tranglutaminase-1 (TGM1) at 14q11.2; also involved in lamellar ichthyosis.  Two lipoxygenases at 17p13.1 (ALOX12B and ALOXE3).  Clinical features:  Frequently born as collodion baby.  Fine white scales and erythroderma. Also ectropion and scarring alopecia.  Nail dystrophy, short stature, cardiac malformations.
  57. 57. Harlequin Fetus  Evolve of the word ‘Harlequin’ : Harlequin or Arlecchino in Italian or Arlequin in French is the most popularly known of the comic servant characters from the Italian Commedia dell'arte and its descendant, the Harlequinade. In French passion plays Hellequin, a black-faced emissary of the devil, is said to have roamed the countryside with a group of demons chasing the damned souls of evil people to Hell.  Synonym: Ichthyosis congenita gravis.  A severe disorder that affects the skin in utero, causing thick, horny, armor- like plates covering the entire surface.  Ears are rudimentary or absent, eclabium and ectopion are severe.  Abnormalities of profilaggrin, K6 and K16 expression have been reported.  Recessive inheritance has been favoured and is supported by reports of consanguinity.  Usually the child is stillborn or dies soon after delivery; although there are reports of a few survivors, with lifelong systemic retinoids.
  58. 58. Harlequin Fetus
  59. 59. Harlequin Fetus
  60. 60. Bullous Ichthyosiform Erythroderma (Borcq)  Synonym: Epidermolytic hyperkeratosis.  Uncommon generalized disorder with blisters and hyperkeratotic lesions.  Autosomal-dominantly inherited.  Mutations in keratin1 and 10 genes.  There is altered assembly process of cornified cell envelopes.  It has been described as an incidental finding in normal skin, skin adjacent to epidermal tumor (both benign and malignant) and normal oral mucosa.
  61. 61. Epidermolytic hyperkeratosis (C/F)  At birth, widespread blisters and erosions; child looks as if burned.  Then development of distinctive dirty, spiny, hyperkeratotic lesions, often scattered on an erythematosus background; most often in flexures.  Palmoplantar keratoderma common.  Epidermolytic hyperkeratosis skin is usually has a characteristic pungent odor, thought to be related to super- infection by mixed flora.
  62. 62. Investigation findings 1) Ichthyosis vulgaris : Histology reveals mild hyperkeratosis with an reduced/absent granular layer; normal thickness of spongy layer, normal dermis. Electron microscopy : keratohayalin granules. 2) X-linked Ichthyosis : Elevated plasma cholesterol sulfate level or lipoprotein electrophoresis showing increasing motility of low- density lipoproteins (LDLs). 3) Lamellar Ichthyosis : The transglutaminase-1 can be stained in frozen sections of skin; histology shows orthokeratotic hyperkeratosis and mild to moderate acanthosis. 4) Epidermolytic hyperkeratosis : H/E shows compact hyperkeratosis. Granular layer is markedly thickened and contains coarse keratohyaline granules. Electron microscopy : Perinuclear haloes.
  63. 63. Features of different types of Ichthyosis Features IV X-linked Ichthyosis Lamellar Ichthyosis EK Inheritance AD X-linked AR AD Severity Mild Moderate Severe Becomes less severe with age Defect Flaggrin protein Steroid sulphatase enzyme Transglutamina se 1 Abnormal distribution of keratinocytes Distribution All over body All over body Only men All over body, very severe, involves flexure, neck, face, scalp, scaly palms and sole All over body, bullae and hyperkeratotic lesions over knee, elbows; keratoderma
  64. 64. Features of different types of Ichthyosis (contd.) Features IV X-linked Ichthyosis Lamellar Ichthyosis EK Onset 3-12 months of age Before 3 months of age Birth- collodion baby Birth- bullae, erythroderma. Spared areas Flexures and face Palms and soles None None Other features Fine scales, improves in summer Scales are black and brown, eye involvement, cryptorchidism Scales are large and quadrangular, ectropion and eclabium Erythroderma Treatment Emollients Emollients Retinoids- acitretin Systemic and oral retinois + antibiotics Prognosis Good Good Causes serious disability Tends to become less severe with age
  65. 65. Ichthyosis Linearis Circumflexa  Inherited autosomal-recessive disorder.  Migratory annular and polycyclic patches occur.  May first appear as generalized exfoliative erythroderma; later lesions predominate on trunk and extrimities, appear as polycyclic patches characterized by constantly changing patterns.
  66. 66. Congenital reticular ichthyosiform erythroderma (ichthyosis ‘en confettis’ /ichthyosis variegata)  The patients are born with congenital ichthyosiform erythroderma.  During childhood the integument clears gradually so that enlarging patches of normal skin appear to be enclosed by erythrokeratotic and hyperpigmented areas in a reticular arrangement.  Associated features : hypertrichosis, and palmoplantar hyperkeratosis, hypogonadism, growth retardation, hepatomegaly, keratoacanthoma or squamous cell carcinoma.
  67. 67. Congenital reticular ichthyosiform erythroderma (ichthyosis ‘en confettis’ /ichthyosis variegata)  Histologically: there is psoriasiform hyperplasia.  The horny layer is thickened and parakeratotic.  The parakeratotic corneocytes have enlarged nuclei.  keratinocytes of the upper layers : prominent perinuclear vacuolation and contain few keratohyalin granules.  Their cell borders are well defined an intracytoplasmic eosinophilic granules are absent. Some of the vacuolated keratinocytes are binucleated.  keratin 2e is missing, the other epidermal keratins are regularly expressed.
  68. 68. Ichthyosis variegata: There is hyperkeratosis and well-developed psoriasiform hyperplasia.
  69. 69. There is parakeratosis with prominent nuclei. Note the cytoplasmic vacuolation. Eosinophilic intracytoplasmic inclusions are absent
  70. 70. Syndromes associated with Ichthyosis
  71. 71. Sjögren–Larsson syndrome  Sjögren–Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, mental retardation, and spastic paresis  long-chain fatty alcohol is deposited in cultured fibroblasts, whin blood cells, and serum in SLS  mutations in the fatty aldehyde dehydrogenase (FALDH) gene (ALDH3A2) were responsible for the development of SLS. However, the exact pathomechanisms of this ichthyosis in SLS is not fully understood.  
  72. 72. (A) Histopathology of ichthyotic skin lesion of S L syndrome. Orthohyperkeratosis with mild hypergranulosis was observed. (B) Ultrastructurally, at the stratum granulosum/stratum corneum interface, abnormal apparently empty lamellar granules (white arrowheads) were seen in the granular cells and lipid vacuoles (white arrows) were observed in the cornified cells. (C–E) Vacuoles, presumably lipid droplets (white arrows) and irregularly shaped abnormal intercellular materials (black arrows) were apparent in the stratum corneum layers. Scale bars=50 (A) and 0.3 m (B–E).
  73. 73. Netherton syndrome  Ichthyosiform skin changes  Trichorrhexis invaginata (bamboo hair)  Atopic dermatitis. Difficult to manage; keratolytics for ichthyotic lesions; topical tacrolimus, acitretin.
  74. 74. Refsum Syndrome  Autosomal recessive inherited ichthyosis, resembling ichthyosis vulgaris.  Atypical retinitis pigmentosa.  Peripheral neuropathy.  Cerebellar ataxia.  Nerve deafness.  ECG changes.
  75. 75. KID Syndrome  Keratitis-Ichthyosis-Deafness syndrome.  Other name : Senter syndrome.  Vascularization of cornea, deafness, hyperkeratotic palms and soles, hypotrichosis, partial anhydrosis, nail dystrophy and tight heel cords are the characteristic features.  Treatment with acitretin (isotretinoin exacerbate corneal vascularization), cyclosporin A eye drop.
  76. 76. CHILD Syndrome  Congenital hemidysplasia with ichthyosiform erythroderma and limd defects.  Unilateral inflammatory nevi and ipsilateral limb defect.  X-linked dominant and lethal in hemizygous male.  H/E : presence of foamy macrophages in dermal papillae.
  77. 77. Acquired Ichthyosis  Vitamin deficiency: Vitamin A, vitamin B6, and nicotinic acid deficiency.  Infections: Leprosy, tuberculosis, syphilis.  Medications: nicotinic acid (most common), triparanol, clofazemine.  Systemic diseases : Sarcoidosis, hypothyroidism, lupus erythromatosus, AIDS.  Malignancy : lymphoma specially Hodgkin’s lymphoma; also occurs in NHL, mycosis fungoids, multiple myeloma. Caution: Whenever ichthyosis appears in adult life for the first time, exclude an underlying malignancy.  Severe xerosis in the elderly.
  78. 78. Pityriasis rotunda (pityriasis circinata)  Patients present with persistent, very sharply defined, circular or oval areas of hyper- or hypopigmentation associated with a fine scale.  The sex incidence : equal  Lesions: multiple and frequently numerous, ,characteristically noninflammatory and asymptomatic ,often, confluent, measuring 0.5–28 cm in diameter , located on the trunk and limbs&sometimes associated with gradual remission during the summer months and relapse in winter.  Acutaneous marker of severe internal disease:tuberculosis, cancer (particularly hepatoma), leukemia,cirrhosis, ovarian and uterine disease.  The histological features :hyperkeratosis with a diminished or absent granular cell layer and loss of the epidermal ridge pattern
  79. 79. Pityriasis rotunda Pityriasis rotunda: characteristic lesion showing circumscription, scaling, and hyperpigmentation.
  80. 80. 93
  81. 81. Peeling skin syndrome  characterized by a spontaneous, lifelong peeling of the stratum corneum without bleeding or pain. The mode of inheritance is autosomal recessive.  Three types can be distinguished: 1. type A a generalized continued shedding or peeling of the entire skin without signs of inflammation or other symptoms is present from birth or develops during childhood 2. Type B appears, resembles and is characterized by isolated erythematous lesions which then peel, leaving burning superficially denuded red patches with a peripheral collarette. A mutation of corneodesmosin has been identified.
  82. 82. Peeling skin syndrome 3-In type C (acral peeling skin syndrome), involvement is confined to the backs of the hand and feet  A homozygous missense mutation in the gene of transglutaminase-5 has been identified.
  83. 83. Histological features of peeling skin syndrome  Type A: a plane of separation either within the lower part of an otherwise normal horny layer or above the granular cell layer. an intracellular splitting is within the corneocytes.  Type B: epidermis is psoriasiform with an absent or reduced granular cell layer and marked parakeratosis. The split is at the level of the granular cell layer.  Type C peeling skin syndrome: the horny layer is detached from the stratum granulosum
  84. 84. Peeling skin syndrome: the biopsy is taken from the edge of the lesion. the stratum corneum is clearly separated from the underlying epidermis.
  85. 85. Erythrokeratoderma variabilis  Lesions usually present soon after birth or during the first year of life and are of two types, typically present simultaneously:  • Type 1 lesions : ymmetrically distributed, discrete figurate, and often bizarre patches of erythema, which vary in size, shape, number, and location over periods of hours and days . These are sometimes temperature or stress related.  Type 2 lesions : well-defined, fixed geographical, reddish-yellowbrown greasy, hyperkeratotic plaques arising either within the erythematous lesions or, more often, independently.,asymptomatic, mild pruritus or burning sensations  The condition particularly affects the face, buttocks, and extensor surfaces of the extremities.  Occasionally associated with high estrogen levels ,Hypertrichosis (of vellus hairs) and mildkeratoderma of the palms and soles  Erythrokeratoderma variabilis harbor s connexin(Cx) 31 or Cx30.3 mutations  The histopathological features : not specific, orthohyperkeratosis, variable parakeratosis, irregular acanthosis, and papillomatosis with an undulating skin surface. Dyskeratotic cells with pyknotic nuclei reminiscent of the grains of Darier .The granular cell layer appears normal. A perivascular lymphohistiocytic inflammatory cell infiltrate may be present in the superficial dermis.
  86. 86. Erythrokeratoderma variabilis: in these lesions there is more pronounced scaling.
  87. 87. Progressive symmetric erythrokeratodermia(Gottron's syndrome)  Inherited as an autosomal dominant with incomplete penetrance.Both sexes are equally affected  Presents in the first year of life with fixed symmetrical, and sometimes pruritic, erythematous scaly plaques lacking transient migratory erythema .  On the extensor surfaces including the elbows, knees, buttocks, dorsal surfaces of the feet and hands, and head.  The face, chest, and abdomen are typically unaffected.  Additional features : palmoplantar keratoderma and pseudoainhum(constriction bands on the fingers and toes).
  88. 88. Pathogenesis and histological features  A mutation in the loricrin gene on chromosome 1q21  A connexin gene disorder(?).  Histologically:marked basket-weave hyperkeratosis with focal parakeratosis hypergranulosis, and psoriasiform hyperplasia. 1. Paranuclear vacuolation :in the granular cell layer. 2. A perivascular lymphocytic infiltrate is present in the superficial dermis. 3. loricrin-rich intranuclear granules in the granular cell layer. 4. Lamellar granules are increased in number 5. lipid droplets may be evident in the cornified cells
  89. 89. Pachyonychia congenita type I  Focal (nonepidermolytic) palmoplantar keratoderma with oral hyperkeratosis (Jadassohn-Lewandowsky syndrome, focal palmoplantar keratoderma with oral hyperkeratosis, palmoplantar ectodermal dysplasia type I) :an autosomal dominant mode of inheritance  The features : massive hyperkeratosis of the distal nail beds of the fingers and toes, resulting in elevation and apparent thickening of the nail plate.  Associations :Palmoplantar keratoderma, hyperhidrosis follicular keratosis, xerosis, and verrucous lesions on the elbows, knees, and lower legs.  Mutations :in keratin K16 and K6a genes.
  90. 90. Pachyonychia congenita type 1: there is gross nail deformity with transverse arching of the distal portion.
  91. 91. the subungual hyperkeratosis
  92. 92. Pachyonychia congenita type 1 Follicular lesion showing keratin plugging of the ostium with adjacent hyperkeratosis and associated acanthosis.
  93. 93. Pachyonychia congenita type 1 Massive hyperkeratosis, hypergranulosis, and acanthosis.
  94. 94. Pachyonychia congenita type II  Pachyonychia congenita type II (palmoplantar ectodermal dysplasia type II, Jackson-Lawler syndrome, Jackson-Sertoli syndrome) :an autosomal dominant.  Mild focal palmoplantar keratoderma over pressure areas, subungual hyperkeratosis, epidermal cysts, steatocystoma multiplex, abnormal eyebrows and body hair (pili torti), natal teeth, angular cheilosis, and hoarseness.  Mutations in kerat in 17 and keratin 6b genes.  mutations in keratin 17 may also result in steatocystoma multiplex in isolation
  95. 95. Acrokeratosis verruciformis of Hopf  An autosomal dominant mode of inheritance.  In infancy or early childhood as dry, rough, brownish or skin-colored verrucoid, keratotic papules.  located particularly on the backs of the hands and feet, and on the knees and elbows.  Loss of function of the sarco- (endo-) plasmic reticulum Ca2+ ATP ase2 mutant in acrokeratosis verruciformis provides evidence that acrokeratosis verruciformis and Darier's disease are allelic disorders.  The lesions are acanthotic with a prominent granular cell layer, typically showing a ‘church spire’ appearance
  96. 96. Acrokeratosis verruciformis Hyperkeratosis and church-spire papillomatosis.
  97. 97. Hyperkeratosis lenticularis perstans((Flegel's disease)  Equal sex incidence in fourth or fifth decade.  large numbers of 1–5-mm discrete, gray, graybrown or red- brown, circular scaly papules.  Initial lesions :on the dorsum of the foot, the lower legs, upper arms, and pinnae,buttocks, trunk, and dorsal aspects of the hands with punctate keratoses on the palms and soles.  Asymptomatic or mildly pruritic.  Early lesions :lamellar hyperkeratosis, focal parakeratosis, and an essentially normal epidermis.  An established lesion: hyperkeratosis &parakeratosis, inconspicuous or absent granular cell cell, intercellular edema , foci of basal cell degeneration and a chronic inflammatory cell infiltrate a perivascular or lichenoid distribution
  98. 98. Flegel's disease: Lesions are small, multiple and covered by a well-developed scale.
  99. 99. Flegel's disease: (A) scanning view of an established lesion showing focal hyperkeratosis, parakeratosis, and a superficial bandlike chronic inflammatory cell infiltrate
  100. 100. Flegel's disease hyperkeratosis, focal epidermal atrophy and basal cell liquefactive degeneration. Note the cytoid bodies
  101. 101. Flegel's disease: high-power view showing spongiosis with microvesiculation, cytoid bodies, and a predominantly lymphocytic infiltrate.
  102. 102. Flegel's disease  The lymphocytes are an admixture of CD4+ T-helper cells and, less frequently CD8+ T-suppressor cells.. Sézary-like forms have been described. Langerhans cells are highly reduced  In the atrophic areas: 1. cytokeratin 1 &10 , filaggrin, and loricrin are absent. 2. Rudimentary keratohyalin granules, absence, 3. vacuolation or abnormally lamellated membrane coating (Odland) bodies, 4. failure to form a compact keratin, and cornified envelope in the corneocytes
  103. 103. Granular parakeratosis  It affects the axillae intertriginous areas including submammary and intermammary skin, groins, vulva, perianal region and, lower back, buttocks, and flanks.  In women than males. the middle aged to elderly; children are rarely involved.  It presents as pruritic or burning erythematous, hyperpigmented, and hyperkeratotic patches, papules, or plaques.  As a result of a contact reaction to an antiperspirant or creams, shampoos, and soaps.  A failure to transform profilaggrin to filaggrin with the resultant failure in degradation of keratohyalin granules.
  104. 104. Histopathology  A massive hyperkeratosis with parakeratosis and retention of keratohyalin granules in the stratum corneum .  The underlying epidermis :acanthosis or even some degree of thinning. Hair infundibula are occasionally affected.  Necrotic areas with invasion of neutrophils or perforation of the epidermis are rarely found.  The superficial dermis contains a sparse perivascular lymphocytic
  105. 105. Granular Parakeratosis (A) there is marked thickening of the horny layer with parakeratosis (B) high-power view showing retention of the keratohyalin granules.
  106. 106. Porokeratoses Hereditary disorder of keratinization characterized by expanding atrophic anular patch(es) surrounded by prominent keratotic ridge called the cornoid lamella Autosomal dominant
  107. 107. Porokeratoses 1. Porokeratosis of Mibelli (PM) 2. Disseminated superficial actinic Porokeratosis (DSAP) 3. Disseminated superficial Porokeratosis (DSP) 4. Linear Porokeratosis (LP) 5. Porokeratosis palmaris et plantaris disseminata (PPPD) 6. Punctate porokeratosis
  108. 108. Porokeratosis of Mibelli: A classical lesion showing an annular plaque with normal or atrophic centers surrounded by a keratotic ridge
  109. 109. hyperkeratotic border (arrows) limits the lesion and accounts for the roughness slightly hypopigmented and atrophic center
  110. 110. Disseminated superficial actinic Porokeratosis (DSAP)
  111. 111. Porokeratosis palmaris et plantaris disseminata (PPPD)
  112. 112. Punctate porokeratosis
  113. 113. Histopathology of Porokeratosis
  114. 114. Histopathology of Porokeratosis
  115. 115. Acquired palmoplanter keratodermas
  116. 116. Acquired keratoderma due to psoriasis
  117. 117. Acquired keratoderma due to chronic eczema
  118. 118. Acquired PPK NOT inherited as a primary genetic condition. They may occur as part of a generalised skincondition(some of which may be inherited) or as a result of another illness
  119. 119. Acquired PPK  More likely to present in adulthood
  121. 121. References  McKee's Pathology of the Skin. – 4th ed. (2012)Calonje, Eduardo. III. McKee,Phillip H. Pathology of the skin.  Leopold Eckhartetal (2013):Cell death by cornification, Biochimica et Biophysica Acta (2013): 3471–3480.  Presland R(2009):Function of Filaggrin and Caspase-14 in Formation and Maintenance of the Epithelial Barrier, Dermatol Sinica 27: 1-14,  Lorenzo Alibardi(2003):Immunocytochemistry and Keratinization in the Epidermis Zoological Studies 42(2): 346-356.  Lorenzo Alibardi, Mattia Toni(2006):Cytochemical, biochemical and molecular aspects of the process of keratinization in the epidermis, Progress in Histochemistry and Cytochemistry 40 : 73–134
  122. 122. References (continued)  Shibani Shetty, Gokul S.(2012):Keratinization and its Disorders, Oman Medical Journal (2012) Vol. 27, No. 5: 348-357.  Norle´n(2006) Stratum corneum keratin structure, function and formation, International Journal of Cosmetic Science, 2006, 28, 397–425  Akemi Ishida-Yamamoto et al(1998):Iherited disorders of keratinization, Journal of Dermatological Science 18 (1998) 139- 154.  Matthias Schmuth,etal(2013):Inheritedichthyoses/g eneralized Mendelian disorders of cornification, European Journal of Human Genetics (2013) 21, 123–133. 
  123. 123. THANK YOU