to describe molecular mechanisms of epidermis keratinization and related disorders.

1. Keratinization disorders
M.Yousry Abdel_Mawla

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. EPIDERMOPOIESIS
 Epidermopoiesis
Epidermal dynamics Epidermal kinetics

4. EPIDERMAL DYNAMICS
 Epidermal proliferative
unit( EPU)
 Consists of
Single Stem cell
Transit amplifying cells
Terminally differentiated
cells
(post mitotic cells)

5. EPIDERMAL KINETICS
 Turn over time
Cell cycle Growth fraction

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. 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. 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. 11

11. 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.

12. 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.

13. 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)

14. TERMINAL DIFFERENTIATION
1.Formation of keratin
2.Keratin filaments aggregate into bundles with the help
of filaggrin.
3.Cornified envelope.

15. Terminal Differentiation
4.Changes in expression of
 Intracellular lipid
 Membrane glycoproteins
 Growth factor receptors
 Adhesion protein
 Blood group antigens
 Desmosomes.

16. 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

21. 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

22. 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

23. 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

24. Desquamation of surface keratinocytes from the
stratum corneum is regulated by proteolytic
degradation of the cells’ desmosomes.

25. 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

27. Stratum corneum proteins
• Involucrin
• Loricrin
• Keratolinin
• pro (Filaggrin)
• Desmosomal proteins:
- desmoplakin
- envoplakin

28. 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

29. 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.

30. 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.

31. 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

32. 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

33. Distribution of keratin in oral
epithelium

34. Distribution of keratin.

36. Any defect along this pathway
leads to
DIORDERS OF KERATINIZATION

37. 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

38. DISTURBANCE IN EPIDERMAL KINETICS
1. ACANTHOSIS
Enhanced cell proliferation
Enlargement of the germinative cell
Increased mitotic rates
Broadening of epidermis

39. 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

41. 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

42. 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

43. Keratinocytes and keratinization disorders

44. 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).

45. 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



46. 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)

47. Ichthyosis Vulgaris

48. 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.

49. Ichthyosis vulgaris ( D/D)
 Xerosis/Asteatotic eczema
 X-Linked ichthyosis
 Acquired ichthyosis
 Atopic dermatitis
 KID syndrome
 Netherton syndrome
Associations
• Atopic dermatitis
• Keratosis pilaris

50. 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.

51. 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.

52. X-linked Ichthyosis

53. Histopathology of Icthyosis vulgaris

54. Histopathology of I .Vulgaris

55. 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

57. 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

59. 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.

60. 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.

61. Lamellar Ichthyosis

62. Lamellar Ichthyosis

63. Ectropion

64. 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.

65. Collodion baby

66. 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.

67. 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.

68. Harlequin Fetus

69. Harlequin Fetus

70. 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.

71. 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.

72. 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.

73. 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

74. 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

75. 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.

76. 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.

77. 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.

78. Ichthyosis variegata:
There is hyperkeratosis and well-developed psoriasiform
hyperplasia.

79. There is parakeratosis with prominent nuclei. Note the cytoplasmic
vacuolation. Eosinophilic intracytoplasmic inclusions are absent

80. Syndromes associated
with Ichthyosis

81. 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.



82. (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).

83. Netherton syndrome
 Ichthyosiform skin changes
 Trichorrhexis invaginata (bamboo hair)
 Atopic dermatitis.
Difficult to manage; keratolytics for
ichthyotic lesions; topical tacrolimus, acitretin.

84. Refsum Syndrome
 Autosomal recessive inherited ichthyosis, resembling
ichthyosis vulgaris.
 Atypical retinitis pigmentosa.
 Peripheral neuropathy.
 Cerebellar ataxia.
 Nerve deafness.
 ECG changes.

85. 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.

86. 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.

87. 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.

88. 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

89. Pityriasis rotunda
Pityriasis rotunda: characteristic
lesion showing circumscription,
scaling, and
hyperpigmentation.

91. 93

92. 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.

93. 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.

94. 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

95. Peeling skin syndrome: the biopsy is taken from the edge of the lesion. the stratum
corneum is clearly separated from the underlying epidermis.

96. 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.

97. Erythrokeratoderma
variabilis: in these lesions
there is more pronounced
scaling.

98. 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).

99. 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

100. 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.

101. Pachyonychia congenita type 1: there is gross nail deformity with transverse arching of the distal portion.

102. the subungual hyperkeratosis

103. Pachyonychia congenita
type 1
Follicular lesion
showing keratin
plugging
of the ostium
with
adjacent
hyperkeratosis
and associated
acanthosis.

104. Pachyonychia congenita
type 1
Massive
hyperkeratosis,
hypergranulosis,
and
acanthosis.

105. 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

106. 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

107. Acrokeratosis verruciformis
Hyperkeratosis
and church-spire
papillomatosis.

108. 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

109. Flegel's disease:
Lesions are small, multiple
and covered by a well-developed
scale.

110. Flegel's disease:
(A) scanning view of an
established lesion showing
focal
hyperkeratosis, parakeratosis, and
a superficial bandlike chronic
inflammatory
cell infiltrate

111. Flegel's disease
hyperkeratosis, focal epidermal
atrophy and basal cell
liquefactive degeneration. Note the
cytoid bodies

112. Flegel's disease:
high-power view showing
spongiosis with microvesiculation,
cytoid bodies, and a
predominantly lymphocytic
infiltrate.

113. 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

114. 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.

115. 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

116. Granular Parakeratosis
(A) there is marked thickening of the
horny layer with parakeratosis
(B) high-power view showing retention
of the keratohyalin granules.

117. Porokeratoses
Hereditary disorder of keratinization
characterized by expanding atrophic anular
patch(es) surrounded by prominent
keratotic ridge called the cornoid
lamella
Autosomal dominant

119. 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

121. Porokeratosis of
Mibelli:
A classical
lesion showing
an annular
plaque with
normal or
atrophic centers
surrounded by a
keratotic ridge

122. hyperkeratotic
border (arrows)
limits the lesion and
accounts for the
roughness slightly
hypopigmented and
atrophic center

123. Disseminated superficial actinic Porokeratosis (DSAP)

126. Porokeratosis palmaris et plantaris disseminata (PPPD)

130. Punctate porokeratosis

131. Histopathology of Porokeratosis

132. Histopathology of Porokeratosis

134. Acquired palmoplanter
keratodermas

135. Acquired
keratoderma
due to
psoriasis

136. Acquired keratoderma due to
chronic eczema

138. 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

139. Acquired PPK
 More likely to present in adulthood

140. CAUSES OF ACQUIRED KERATODERMA
I. INFLAMMATORY SKIN CONDITIONS
II. INFECTIONS
III. CIRCULATORY PROBLEMS
IV. 2ry TO INHERITED CONDITIONS THAT MAY
NOT USUALLY RESULT IN PPK
V. DRUGS AND TOXINS
VI. INTERNAL DISORDERS
VII. MISCELLANEOUS

142. 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

143. 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.
 www.expertconsult.com

144. THANK YOU