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Disorders of keratinization

This document provides information on disorders of keratinization. It begins with an introduction to abnormal keratinization and cell cohesion in the epidermis. Specific conditions discussed include ichthyosis vulgaris, recessive X-linked ichthyosis, keratosis pilaris, and palmoplantar keratoderma. Ichthyosis vulgaris is caused by filaggrin gene mutations and results in dry, scaling skin. Recessive X-linked ichthyosis is caused by steroid sulfatase deficiency and is characterized by fine scaling that develops in the first months of life. The document provides details on pathogenesis, clinical features, complications, investigations, and treatment for several disorders of keratinization.

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Disorders Of Keratinization Dr. Kavindya Fernando JMJ 1
Contents ■ Introduction ■ Ichthyosis vulgaris ■ Keratosis pilaris ■ Keratosis follicularis (Darier’s disease) ■ Palmoplantar keratoderma ■ Knuckle pads ■ Callosities and corns JMJ 2
Introduction ■ Abnormality is found in – Keratinization – Cell cohesion & proliferation within epidermis ■ Shedding of corneocyte  balanced procedure – Thickness of horny layer does not alter ■ If  keratinization & cell cohesion become abnormal – horny layer  thick – Skin surface  dry & scaly JMJ 3 Living keratinocyte (deeper epidermis) Dead corneocytes (horny layer) Impairs barrier function
Mendelian disorder of cornification (MeDOC) ■ Characterized by – Hyperkeratosis or – Visible scaling or – Both ■ Molecular mechanisms underlying JMJ 4 Abnormal genetic coding for Keratins Enzymes Involed in cell cohesion in horny layer Molecules Critical in signalling pathway governing cell cohesion in spinous layer
Classification Dx of Keratinization Ichthyosis Keratoderma of palms & soles Keratosis follicularis Keratosis pilaris Knuckle pads Callosities & corns JMJ 5
ICHTHYOSIS Greek meaning “FISH” JMJ 6
Ichthyosis ■ Main features – Dry, rough skin with marked scaling – No inflammation ■ There are 36 form of inherited ichthyosis including, – Conditions primarily affecting the skin & – Rarer ‘syndromic’ associations involving the organs ■ Over 25 genes of mutations+ JMJ 7
Ichthyosis ■ Pathophysiological aspects of ichthyosis – Abnormal differentiation and/or – Abnormal desquamation (retention hyperkeratosis) or – Accelerated keratinocyte production (epidermal hyperplasia/ hyperproliferative hyperkeratosis) JMJ 8
Ichthyosis – classification JMJ 9 Ichthyosis Inherited Acquired Non-syndromic Syndromic Common ichthyosis Autosomal recessive congenital ichthyosis Keratinopath ic ichthyosis Others X –linked ichthyosis syndromes Autosomal ichthyosis forms with prominent Hair abnormalities Neurological signs Deafness Transient neonatal respiratory distress
Ichthyosis – classification JMJ 10 Non-syndromic Common ichthyosis Autosomal recessive congenital ichthyosis Keratinopathic ichthyosis Others • Ichthyosis vulgaris • Non-syndromic RXLI • Harlequin ichthyosis • Lamellar ichthyosis • Congenital ichthyosiform erythroderma • Self-healing collodion baby • Acral self-healing collodion baby • Bathing suit ichthyosis • Epidermolytic ichthyosis
Ichthyosis – classification JMJ 11 Syndromic • Recessive X-linked ichthyosis X –linked ichthyosis syndromes Autosomal ichthyosis forms with prominent Hair abnormalities Neurological signs Deafness Transient neonatal respiratory distress • Netherton syndrome • Refsum syndrome • KID syndrome • MEDNIK syndrome • Ichthyosis- premature syndrome
Non- syndromic forms JMJ 12
Inherited ichthyois – non-syndromic forms Disease Mode of inheritance Genes Common Ichthyosis Ichthyosis vulgaris Semidominant FLG Non-syndromic recessive x-linked ichthyosis (RXLI) XR STS JMJ 13
Inherited ichthyois – non-syndromic forms Disease Mode of inheritance Genes Autosomal Recessive Congenital Ichthyosis Harlequin ichthyosis AR ABCA12 Lamellar ichthyosis AR TGM1, NIPAL4, ALOX12B, ABCA12, PNPLA1, CERS3, LIPH Congenital ichthyosiform erythroderma AR ALOXE3, ALOX12B, ABCA12, CYP4F22, NIPAL4, TGM1 Self-healing collodion baby (SHCB) AR TGM1, ALOXE3, ALOX12B Acral self-healing collodion baby AR TGM1 Bathing suit ichthyosis AR TGM1 JMJ 14
Inherited ichthyois – non-syndromic forms Disease Mode of inheritance Genes Keratinopathic Ichthyosis (KPI) Epidermolytic ichthiosis AD KRT1, KRT10 Superficial epidermolytic ichthyosis AD KRT2 Congenital reticular ichthyosiform erythroderma AD KRT10 Annular epidermolytic ichthyosis AD KRT1, KRT10 Ichthyosis Curth-Mackin AD KRT1 Autosomal recessive epidermolytic ichthyosis AR KRT10 Epidermolytic naevi Somatic mutations KRT1 KRT10 JMJ 15
Inherited ichthyois – non-syndromic forms Disease Mode of inheritance Genes Other Non-Syndromic forms Loricin Keratodrma AD LOR Erythrokeratodermia viriabilis AD (AR) GJB3, GJB4 Inflammatory peeling of skin (PSS type B) AR CDSN Exfoliative ichthyosis AR CSTA Keratosis linearis-ichthyosis congenita-keratoderma AR POMP JMJ 16
Syndromic forms JMJ 17
Inherited ichthyois – syndromic forms Disease Mode of inheritance Genes X-linked Ichthyosis syndromes Recessive X-linked ichthyosis XR STS (and others) Ichthyosis follicularis alopecia photophobia XR MBTPS2 Conradi-Hunermann-Happle syndrome AD EBP JMJ 18
Inherited ichthyois – syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with prominent hair abnormalities Netherton syndrome AR SPINK5 Severe dermatitis- multiple allergies-metabolic wasting (SAM) AR DSG1 Ichthyosis with hypotrichosis AR ST14 Neonatal ichthyosis-sclerosing cholangitis AR CLDN1 JMJ 19
Inherited ichthyois – syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with prominent neurological signs Refsum syndrome AR PHYH, PEX7 Multiple sulphate deficiency AR SUMF1 Gauchers syndrome type 2 AR GBA Sjogren-Larsson syndrome AR ALDH3A2 Natural lipid storage disease with ichthyosis AR ABHD5 Trichothiodystrophy AR C7ORF11, ERCC2, XPD, ERCC3, XPB, GTF2H5, TTDA Cerebral dysgenesis-neuropathy – ichthyosis-palmoplantar keratoderma (CEDNIK) AR SNAP29 Arthrogryposis-renal dysfunction- cholestasis (ARC) AR VPS33BJMJ 20
Inherited ichthyois – syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with DEAFNESS Keratitis-ichthyosis-deafness (KID) AD GJB2 (GJB6) ELOVL4 deficiency AR SUMF1 Mental retardation – enteropathy – deafness – neuropathy – ichthyosis – keratodermia (MEDNIK) AR AP1S1 JMJ 21
Inherited ichthyois – syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with transient neonatal respiratory distress Ichthyosis- prematurity syndrome (IPS) AR SLC27A4 JMJ 22
ICHTHYOSIS VULGARIS JMJ 23
Ichthyosis vulgaris ■ Cause – Mild scaling disorder – Common in human – Autosomal semi-dominant disorder – Affect 1 in 250 people in UK ■ FLG gene mutation – 2/3rd of ichthyosis patients ■ 2 FLG mutation ■ Clear cut clinical phenotype – 1/3rd ■ Only 1 FLG mutation ■ Disease expression is milder JMJ 24 2FLG genes 1 FLG gene FLG GENE MUTATION
Ichthyosis vulgaris ■ Filaggrin mutation results in – Impaired epidermal barrier formation – Marked reduction in natural moisturizing factors (NMF) ■ FLG mutations predispose to – Atopic eczema – Allergic rhinitis – Asthma – Food allergies – Hand eczema – Nickel sensitization – Eczema herpeticatum in atopic eczema JMJ 25
Cause ■ Mutant alleles of filaggrin gene – 4% in European population ■ Heterozygotes  have milder disease ■ Compound heterozygotes ■ Homozygotes JMJ 26 Filaggrin gene Mutation Loss / reduction in profilaggrin Major component of keratohyalin granules More marked disease
JMJ 27 Major component of keratohyalin granule Cleaved Breakdown of fillagrin Produce filaggrin degradation products Reduce tran-sepidermal water loss
Clinical course ■ Not present at birth ■ Develop during 1st months of life ■ Wells & Kerr study – Demonstratable scaling in 40% of patients develop at the age of 3 months ■ Some improve in adult life, ■ Particularly during warm weather & in high humidity – Seasonal variation (improve during summer) ■ But seldom clears completely JMJ 28
Presentation ■ Dryness – Usually mild & symptoms free ■ Scales – Light grey – Small & branny – Covering mainly extensor surfaces of extremities & trunk ■ Groin & larger flexures  always spared ■ Smaller scales compared to RXLI ■ Accentuated palmar creases  almost all IV – Found in almost all IV – Not influenced by humidity or seasonal variation JMJ 29
JMJ 30 Ichthyosis vulgaris : fine scaling
JMJ 31 Ichthyosis vulgaris : accunuated palmar creases
Presentation ■ Keratosis pilaris – may often present ■ Few experience – hypohydrosis ■ Other frequent features – Keratosis follicularis – Mind concomitant atopic eczema – Allergic rhinitis JMJ 32 As mutation in filaggrin gene strong predisposing factor for atopic eczema
Complications ■ Dry skin chaps in winter and ■ Easily irritated by degreasing agents JMJ 33
Differential diagnosis ■ Xerosis of atopic eczema JMJ 34
Investigations ■ Immunohistochemical studies – Absent or markedly reduced filaggrin signal ■ Ultrastructure – Scarce & crumbly keratohyalin granules – These defects correlate well with number of FLG mutations in its severity JMJ 35 Investigations Immunohistochemistry Ultrastructure Histology
Investigations ■ Histology – Orthohyperkeratosis – With a diminished or absent granular layer JMJ 36
Treatment ■ Palliative ■ Dryness can be helped by – Regular use of emollients – Best applied after a shower ■ Can use – Emulsifying ointments – Soft white paraffin – E45 – Unguentum Merck JMJ 37 • Bath oils & creams containing humectants • Glycerin • Urea • Lactic acid
Recessive X- linked Ichthyosis JMJ 38
Cause ■ Less common than IV ■ Complete form seen only in males ■ Female carries  may show mild scaling ■ In UK – affects 1 in 600 males ■ Cause by mutations in STS gene ■ Associate with deficiency of enzyme STEROID SULFATASE – Which hydrolyses cholesterol sulfate JMJ 39
JMJ 40 Impaired hydrolyzation of cholesterol sulphate Steroid sulfatase deficiency Inhibit proteases Kallikrein 5 Kallikrein 7 In skin Marked reduction in serene protease activity Decrease desquamation Hyperkeratosis Example for retention hyperkeratosis
Cause ■ Responsible gene is in end in short arm of X chromosome – Xp 22.3 ■ Sometimes gene deletion may extend – Adjacent genes may also delete – Result in Kallmann syndrome – With the recessive form of X linked chondrodysplasia punctata – Or with brain abnormalities ■ Mental retardation ■ Unilateral polymicroglia ■ Retinitis pigmentosa ■ Disease severity may be enhanced by concomitant filaggrin mutations JMJ 41
Presentation & course ■ Soon after birth – Very fine scaling or peeling of skin – Often goes unnoticed & soon resolves ■ Scales – at age of 2-6 months – Larger & browner – Involves the neck, – to the lesser extent the popliteal and antecubital areas, – as well as the skin generally ■ Palms & soles are normal ■ About 30% have light grey scales  easily misdiagnose as IV ■ No association between atopy or keratosis pilaris ■ Condition persist throughout life JMJ 42
Presentation & course ■ Dark hyperkeratosis in lateral aspects of trunk & back of neck – Leaving “dirty look” – Characteristic appearance ■ Deep stromal corneal opacities – Frequent finding – Does not affect visual acuity ■ RXLI have association with – Cryptorchidism – ADHD – Autism JMJ 43
JMJ 44 Recessive X-linked ichthyosis : scaling on the arm
JMJ 45 Recessive X-linked ichthyosis : scaling on the legs
JMJ 46 Recessive X-linked ichthyosis : scaling on the trunk
JMJ 47 Recessive X-linked ichthyosis : patient with light grey scaling
Complications ■ Affected babies may be born after a prolonged labour – Presence of the enzyme defect in placenta (placental sulfatase deficiency) – insufficienct cervical dialation ■ Kallaman’s syndrome – Hypogonadotrophic hypogonadism & anosmia – Caused by deletion of a part of X chromosome – That included the gene for X-linked ichthyosis ■ Neurological defects may occur JMJ 48
Investigations ■ None usually needed ■ Drawing pedigree tree – Shoes mode of inheritance ■ Fluorescence in situ hybridization – To detect steroid sulfatase gene deletions ■ Electron microscopy – Retained corneo-desmasomes within the stratum corneum – This is a typical feature of retention hyperkeratosis ■ Histology – Orthohyperkeratosis & a well maintained, often thickened stratum granulosum – Marked follicular plugging (although no obvious keratosis follicularis) JMJ 49
Treatment ■ Dryness can be helped by – Regular use of emollients best applied after a shower ■ Oral aromatic retinoids  best avoided JMJ 50
Autosomal recessive congenital ichthyoses JMJ 51
Autosomal recessive congenital ichthyoses Many types Lamellar Ichthyosis Congenital ichthyosiform erythroderma Harlequin ichthyosis JMJ 52 ■ Bizarre skin changes are seen at birth ■ Term “COLLODION BABY” is often used
Autosomal recessive congenital ichthyoses ■ Mutation in plethora genes, which encodes proteins involved – in lipid transport such as ABCA12, – in lipid biosynthesis such as CERS3, – in fatty acid metabolism or – have a role in assembling supra-structures such as the cornified envelope JMJ 53
Autosomal recessive congenital ichthyoses ■ Initially stratum corneum is smooth & shiny – Skin looks as it is covered with cellophane or collodion – Tight skin  ectropion & feeding difficulty ■ Shiny outer surface is shed within a few days – Leaving behind red scaly skin ■ Collodion babies may have problems with – Temperature regulation – High water loss JMJ 54 Best dealt with by high humidity incubators
JMJ 55 Autosomal recessive congenital ichthyosis : shedding of collodion membrane after 1 week
Lamellar ichthyosis & CIE ■ Rare condition ■ Inherited as autosomal recessive trait ■ Skin changes at birth in both  collodion baby ■ Later they can be distinguished by ■ Both last for life ■ Cause disfigurement JMJ 56 Lamellar ichthyosis • Plate-like scales Congenital ichthyothiform erythroderma • Finer scaling • More obvious redness
Lamellar ichthyosis & CIE ■ Mutation in transglutaminase 1 gene – Chromosome 14q11.2 ■ Transglutaminase-1 – Major cross linking enzyme in stratum corneum ■ Lamellar ichthyosis shows genetic heterogenicity JMJ 57
JMJ 58 Autosomal recessive congenital ichthyosis : congenital ichthyosiform erythroderma
JMJ 59 Autosomal recessive congenital ichthyosis : Lamellar ichthyosis
Acral peeling skin syndrome ■ Milder disorder ■ Due to mutation in transglutaminase -5 gene ■ Persistent sun-burn like peeling is limited to the hands & feet JMJ 60
Bathing suit ichthyosis ■ Confined to axillae, trunk & scalp ■ Self healing collodion baby – Completely resolves by 3 months of age JMJ 61
Bathing suit ichthyosis JMJ 62
Self healing collodion baby ■ Completely resolves by 3 months of age JMJ 63 (a) Collodion baby at birth (b) mild ichthyosis and minimal erythroderma at the age of 21 montha
Harlequin fetus ■ Results from null mutation in ABCA12 gene – On chromosome 2q35 – Member of ABC transporter superfamily – Normal function – forming a skin lipid barrier ■ Affected babies – Preterm – Covered with an armor-like collodion membrane – When it sheds  reveals thick fissured hyperkeratosis – Ectropion & eclabium (outward turning of lips) – Extreme cases - die JMJ 64
Harlequin fetus ■ Need neonatal ICU care ■ Infants that do survive develop – Very severe hyperkeratotic erythroderma ■ Missense mutations in ABCA12 gene – May have milder repercussions – Resulting in lamellar ichthyosis JMJ 65
JMJ 66 Harlequin ichthyosis : at birth : 6 weeks on retinoid therapy : 6 months
Keratinopat hic ichthyosis ■ All of these results from mutation in keratin genes JMJ 67
Epidermolytic ichthyosis ■ Previously known as – Bullous ichthyosiform erythroderma ■ Rare condition ■ Autosomal dominant ■ Socially disturbing  secondary infection resulting foul odor ■ Mutation of the genes (on chromosomes 12q13 and 17q21) – Controls the production of keratins 1 & 10 JMJ 68
Epidermolytic ichthyosis ■ Clinical course – shortly after birth  skin become – Generally red – Show numerous blisters – Redness fades over few months – Tendency to blister also lessens ■ During childhood – Gross brownish warty hyperkeratosis – Sometimes roughly linear or annular form – Usually worst in flexures JMJ 69
Epidermolytic ichthyosis ■ Diseased skin – May become secondary infected and painful – May develop foul odor ■ Histology – Thickened granular cell layer – Contains large granules – Clefts may be seen in upper dermis ■ Few with localized lesions with same histology – Have gonadal mosaicism – Therefore their children  risk of developing generalized disorder JMJ 70
Epidermolytic ichthyosis ■ Treatment  symptomatic ■ Antibacterial washes & masking fragrances ■ Antibiotics may need ■ Acitretin  in severe cases ■ Superficial epidermolytic ichthyosis – Milder – Autosomal dominant – Resulting from defect in keratin 2 gene JMJ 71
Superficial epidermolytic ichthyosis ■ Milder ■ Autosomal dominant ■ Resulting from defect in keratin 2 gene JMJ 72
Other ichthyosifor m disorders JMJ 73
Other ichthyosiform disorders ■ Ichthiosiform skin changes  may result as a part of multisystem disease ■ Refsum’s syndrome – Autosomal recessive – Deficiency of a single enzyme concerned in the break down of phytanic acid – Phytanic acid then accumulates in tissues – Retinal degeneration – Peripheral neuropathy – Ataxia JMJ 74
Other ichthyosiform disorders ■ Rud’s syndrome – Ichthyosiform erythroderma in association with – Mental retardation – Epilepsy ■ Netherton’s syndrome – Brittle hair (bamboo deformity) – Curious gyrate – Erythromatous hyperkeratotic eruption (ichthyosis linearis circumflexa) JMJ 75
Other ichthyosiform disorders ■ MEDNIK syndrome – M Mental retardation – E Enteropathy – D Deafness – N Neuropathy – I Ichthyosis – K Keratoderma ■ KID syndrome – K Keratitis – I Ichthyosis – D Deafness JMJ 76
Acquired ichthyosis JMJ 77
Acquired Ichthyosis ■ Similar to ichthyosis vulgaris ■ Arises in adulthood ■ Rare ■ Histology – Epidermis show compact hyperkeratosis – With a thinned or absent granular cell layer ■ Improve with treatment for the systemic disease JMJ 78
Acquired Ichthyosis Neoplasia • Hodgkin’s lymphoma • Mycosis fungoides • Multiple myeloma • Kaposi & other sarcoma • CA lung • CA breast • CA ovary • CA cervix Infections • Leprosy • TB • HIV • HTLV-1 associated myelopathy Endocrinopathies • DM • Thyroid Dx • Hyperparathyroidi sm • Hypopituirism Chronic metabolic derangements • Malabsorption Xn • Essential fatty acid deficiency • Pancreatic insufficiency (shwohman Xn) Medication • Statins • Nicotinic acid • Cimetidine • Clofazimine Autoimmune conditions • Dermatomyositis • SLE • Scleradorma Anorexia nervosa Others • Sarcoidosis • Bone marrow transplant • Chronic renal failure JMJ 79
Keratosis Pilaris JMJ 80
Cause ■ Common ■ Affect 50% of adolescent population ■ Autosomal dominant ■ Caused by mutation in a gene lining on the short arm of chromosome 18 ■ Heterozygous carriers with abnormal profilaggrin gene – Often have keratosis pilaris ■ Abnormality is in – Keratinization of hair follicle – Which become filled with horny plugs JMJ 81
Presentation & course ■ Skin changes – begin in childhood – Less obvious in adulthood ■ Most common type – Greyish horny follicular plugs – Sometimes with red areolar – Confined to the outer aspect of thighs & upper arms – Skin feels rough ■ Less often – Affects the sides of face – Perifollicular erythema – Loss of eyebrow hair ■ There is an association with ichthyosis vulgaris JMJ 82
Complications ■ Involvement of cheeks – May cause ugly pitted scaring ■ Follicles in the eyebrows may damage – Hair loss in eyebrows JMJ 83
Differential diagnosis ■ In severe vitamin deficiency – Widespread follicular keratosis (phynoderma) occurs ■ None are needed JMJ 84 Investigations
Treatment ■ Not usually needed ■ Keratolytic – Salicylic acid – Urea ■ UV radiation – Temporary benefit ■ Moving to more humid climate JMJ 85
KERATOSIS FOLLICULARIS Darier’s disease JMJ 86
Cause ■ Rare ■ Autosomal dominant ■ New mutations common ■ Characterized by – Chronic eruption of keratotic papules – Histology of which shows acantholysis & dyskeratosis ■ Abnormal gene – ATP2A2 on chromosome 12q24 – Encodes for SERCA2, calcium pump (keeps high concentration of calcium in endoplasmic reticulum) JMJ 87
Presentation ■ Signs appear in mid teens – Usually after overexposure to sunlight ■ Characteristic lesion – Small pink or brownish papules with – Greasy scale – These coalesce into warty plaques in a seborrheic distribution ■ Early lesions seen on – Sternal area – Interscapular area – Behind the ears JMJ 88
Presentation ■ Severity varies ■ Abnormalities remain for life ■ Other skin changes – Plane warts on the backs of the hands – Punctate keratoses or pits on the palms & soles – Cobblestone-like irregularities of the mucus membranes in the mouth – Distinctive nail dystrophy – White or pinkish lines or ridges run longitudinally to the free edge of the nail , where they end in triangular nicks JMJ 89
Complications ■ Some are stunted ■ Some families  Darier’s disorder runs with bipolar mood disorder ■ Personality disorder  including antisocial behaviour ■ Over half of patients have major psychiatric condition at some point in their life ■ Impairment of delayed hypersensitivity – High tendency to develop widespread herpes simplex & bacterial infections JMJ 90
Differential diagnosis ■ Lesions are similar to seborrheic eczema – This lacks warty papules of Darier’s disease ■ Acanthosis nigricans – Mainly flexural ■ Keratosis pilaris – Favors outer upper arms and thighs ■ Other forms of folliculitis ■ Grover’s disease JMJ 91
Investigations ■ Skin biopsy – Confirms diagnosis – Characteristic clefts in epidermis & dyskeratotic cells JMJ 92
Treatment ■ Severe and disturbing disease – Long term acitrecin – Ablative laser treatment – Varied strengths of topical 5-fluorouracil ■ Milder cases – Only topical keratolytics (salicylic acid) – Control of infection JMJ 93
KERATODERMA OF PALMS & SOLES Inherited types Acquired types JMJ 94
Inherited types ■ Many genodermatoses share keratoderma of the palms & soles ■ Clinical patterns & modes of inheritance vary from family to family ■ Punctate ■ Striate ■ Diffuse ■ Mutilating ■ Sometimes in association with metabolic disorders such as tyrosinaemia or with changes elsewhere JMJ 95
Inherited types ■ Punctate type – Due t mutation of keratine 16 gene – On chromosome 17 – 17q12-q21 ■ Epidermolytic type – By mutation of keratin 9 gene – Found only on palms and soles ■ Diffuse type – Most common type – Also known as tylosis – Inherited as autosomal dominant trait linked to changes in chromosome region 12q11-q13 – Which harbours the type 11 keratin gene cluster – Few have association with oesophageal carcinoma JMJ 96
JMJ 97 Epidermolytic palmoplantar keratoderma caused by a mutation in KRT9 encoding keratin 9
Inherited types ■ Treatment – Unsatisfactory – Higher concentrations of keratolytics ■ Salicilic acid ■ Urea – Systemic retinoids JMJ 98
Acquired types ■ Some healthy people may have few punctate keratoses on palms, ■ & this is no longer thought as a cause for internal malignancy ■ However palmar keratosis cause by arsenic may have association between malignancy ■ Block people are prone to keratotic papules along their palmar creases ■ Sometimes K of Palms and soles may be part of generalized skin diseases – Pitiryasis rubra pilaris – Lichen planus JMJ 99
Acquired types ■ Keratoderma climacterium – Seen in over-weight middle aged women – At about the time of menopause – Most marked around the border of hals – Where painflul fissures form – & interfere with walking ■ Treatment – Regular paring – Use of keratolytic ointments – Many improve with application of 40% urea in cream or ointment bases JMJ 100
KNUCLE PADS JMJ 101
Cause ■ Sometimes familial (usually not) JMJ 102
Presentation ■ Fibromatous hyperkeratoric areas – Appear on the backs of many finger joints ■ Usually begins in late childhood ■ Persisting thereafter ■ Can have an association wit Dupuytren’s contracture JMJ 103
Differential diagnosis ■ Occupational callosities ■ Granuloma annular ■ Viral warts JMJ 104
Investigation & treatment ■ Investigations – Biopsy ■ May be helpful in few cases ■ Treatment – None JMJ 105
CALLOSITIES AND CONES JMJ 106
Callosities and cones ■ Both are responses to pressure JMJ 107
Callocities ■ More diffuse type of thickening of ■ Keratin layer ■ Seems to be a protective response to – Repeated friction & pressure ■ Often occupations; ■ Painless ■ No therapy needed JMJ 108
Cones ■ Has a central cone of hard keratin ■ They hurt when forced inward ■ Appear, where there is local pressure – Often between bony prominences and shoes ■ Favourite areas – Under surface of toe joints – Under prominent metatarsals JMJ 109
Cones ■ Soft cones – Arise in 3rd & 4th toe clefts – When toes are squeezed together by tight shoes – Such are often macerated ■ Main DD – Hyperkeratotic warts ■ These have tiny bleeding points pared down or ■ Pinpoint blood vessels – when examined with dermatoscope – Corn ■ Has only its hard compacted avascular core surrounded by ■ More diffuse thickening of opalescent keratin JMJ 110
Cones ■ Treatment – Eliminate pressure – Regular paring reduces the symptoms temporary – Well fitting shoes are essential – Cones under metatarsals ■ Helped by soft spongy sikes or orthotic shoe inserts – Special care needed for corns on ischemic or diabetic feet ■ Which has greater risk of infection & ulceration JMJ 111
■ Chromosome 14 – Ichthyosis - AR - transglutaminase 1 gene ■ Chromosome 12 – Epidermolytic ichthyosis - keratin gene 1-12q13 – Tylosis - keratin 11 gene - 12q11-q13 ■ Chromosome -17 – Epidermolytic ichthyosis - keratin gene 10-17q21 – Keratoderma punctate type - keratin 16 gene 17q12-q21 ■ Chromosome 18 – Keratosis pilaris JMJ 112
Thank You! JMJ 113

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Disorders of keratinization

  • 1.
  • 2.
    Contents ■ Introduction ■ Ichthyosisvulgaris ■ Keratosis pilaris ■ Keratosis follicularis (Darier’s disease) ■ Palmoplantar keratoderma ■ Knuckle pads ■ Callosities and corns JMJ 2
  • 3.
    Introduction ■ Abnormality isfound in – Keratinization – Cell cohesion & proliferation within epidermis ■ Shedding of corneocyte  balanced procedure – Thickness of horny layer does not alter ■ If  keratinization & cell cohesion become abnormal – horny layer  thick – Skin surface  dry & scaly JMJ 3 Living keratinocyte (deeper epidermis) Dead corneocytes (horny layer) Impairs barrier function
  • 4.
    Mendelian disorder ofcornification (MeDOC) ■ Characterized by – Hyperkeratosis or – Visible scaling or – Both ■ Molecular mechanisms underlying JMJ 4 Abnormal genetic coding for Keratins Enzymes Involed in cell cohesion in horny layer Molecules Critical in signalling pathway governing cell cohesion in spinous layer
  • 5.
    Classification Dx of Keratinization Ichthyosis Keratoderma of palms& soles Keratosis follicularis Keratosis pilaris Knuckle pads Callosities & corns JMJ 5
  • 6.
  • 7.
    Ichthyosis ■ Main features –Dry, rough skin with marked scaling – No inflammation ■ There are 36 form of inherited ichthyosis including, – Conditions primarily affecting the skin & – Rarer ‘syndromic’ associations involving the organs ■ Over 25 genes of mutations+ JMJ 7
  • 8.
    Ichthyosis ■ Pathophysiological aspectsof ichthyosis – Abnormal differentiation and/or – Abnormal desquamation (retention hyperkeratosis) or – Accelerated keratinocyte production (epidermal hyperplasia/ hyperproliferative hyperkeratosis) JMJ 8
  • 9.
    Ichthyosis – classification JMJ9 Ichthyosis Inherited Acquired Non-syndromic Syndromic Common ichthyosis Autosomal recessive congenital ichthyosis Keratinopath ic ichthyosis Others X –linked ichthyosis syndromes Autosomal ichthyosis forms with prominent Hair abnormalities Neurological signs Deafness Transient neonatal respiratory distress
  • 10.
    Ichthyosis – classification JMJ10 Non-syndromic Common ichthyosis Autosomal recessive congenital ichthyosis Keratinopathic ichthyosis Others • Ichthyosis vulgaris • Non-syndromic RXLI • Harlequin ichthyosis • Lamellar ichthyosis • Congenital ichthyosiform erythroderma • Self-healing collodion baby • Acral self-healing collodion baby • Bathing suit ichthyosis • Epidermolytic ichthyosis
  • 11.
    Ichthyosis – classification JMJ11 Syndromic • Recessive X-linked ichthyosis X –linked ichthyosis syndromes Autosomal ichthyosis forms with prominent Hair abnormalities Neurological signs Deafness Transient neonatal respiratory distress • Netherton syndrome • Refsum syndrome • KID syndrome • MEDNIK syndrome • Ichthyosis- premature syndrome
  • 12.
  • 13.
    Inherited ichthyois –non-syndromic forms Disease Mode of inheritance Genes Common Ichthyosis Ichthyosis vulgaris Semidominant FLG Non-syndromic recessive x-linked ichthyosis (RXLI) XR STS JMJ 13
  • 14.
    Inherited ichthyois –non-syndromic forms Disease Mode of inheritance Genes Autosomal Recessive Congenital Ichthyosis Harlequin ichthyosis AR ABCA12 Lamellar ichthyosis AR TGM1, NIPAL4, ALOX12B, ABCA12, PNPLA1, CERS3, LIPH Congenital ichthyosiform erythroderma AR ALOXE3, ALOX12B, ABCA12, CYP4F22, NIPAL4, TGM1 Self-healing collodion baby (SHCB) AR TGM1, ALOXE3, ALOX12B Acral self-healing collodion baby AR TGM1 Bathing suit ichthyosis AR TGM1 JMJ 14
  • 15.
    Inherited ichthyois –non-syndromic forms Disease Mode of inheritance Genes Keratinopathic Ichthyosis (KPI) Epidermolytic ichthiosis AD KRT1, KRT10 Superficial epidermolytic ichthyosis AD KRT2 Congenital reticular ichthyosiform erythroderma AD KRT10 Annular epidermolytic ichthyosis AD KRT1, KRT10 Ichthyosis Curth-Mackin AD KRT1 Autosomal recessive epidermolytic ichthyosis AR KRT10 Epidermolytic naevi Somatic mutations KRT1 KRT10 JMJ 15
  • 16.
    Inherited ichthyois –non-syndromic forms Disease Mode of inheritance Genes Other Non-Syndromic forms Loricin Keratodrma AD LOR Erythrokeratodermia viriabilis AD (AR) GJB3, GJB4 Inflammatory peeling of skin (PSS type B) AR CDSN Exfoliative ichthyosis AR CSTA Keratosis linearis-ichthyosis congenita-keratoderma AR POMP JMJ 16
  • 17.
  • 18.
    Inherited ichthyois –syndromic forms Disease Mode of inheritance Genes X-linked Ichthyosis syndromes Recessive X-linked ichthyosis XR STS (and others) Ichthyosis follicularis alopecia photophobia XR MBTPS2 Conradi-Hunermann-Happle syndrome AD EBP JMJ 18
  • 19.
    Inherited ichthyois –syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with prominent hair abnormalities Netherton syndrome AR SPINK5 Severe dermatitis- multiple allergies-metabolic wasting (SAM) AR DSG1 Ichthyosis with hypotrichosis AR ST14 Neonatal ichthyosis-sclerosing cholangitis AR CLDN1 JMJ 19
  • 20.
    Inherited ichthyois –syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with prominent neurological signs Refsum syndrome AR PHYH, PEX7 Multiple sulphate deficiency AR SUMF1 Gauchers syndrome type 2 AR GBA Sjogren-Larsson syndrome AR ALDH3A2 Natural lipid storage disease with ichthyosis AR ABHD5 Trichothiodystrophy AR C7ORF11, ERCC2, XPD, ERCC3, XPB, GTF2H5, TTDA Cerebral dysgenesis-neuropathy – ichthyosis-palmoplantar keratoderma (CEDNIK) AR SNAP29 Arthrogryposis-renal dysfunction- cholestasis (ARC) AR VPS33BJMJ 20
  • 21.
    Inherited ichthyois –syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with DEAFNESS Keratitis-ichthyosis-deafness (KID) AD GJB2 (GJB6) ELOVL4 deficiency AR SUMF1 Mental retardation – enteropathy – deafness – neuropathy – ichthyosis – keratodermia (MEDNIK) AR AP1S1 JMJ 21
  • 22.
    Inherited ichthyois –syndromic forms Disease Mode of inheritance Genes Autosomal ichthyosis syndromes with transient neonatal respiratory distress Ichthyosis- prematurity syndrome (IPS) AR SLC27A4 JMJ 22
  • 23.
  • 24.
    Ichthyosis vulgaris ■ Cause –Mild scaling disorder – Common in human – Autosomal semi-dominant disorder – Affect 1 in 250 people in UK ■ FLG gene mutation – 2/3rd of ichthyosis patients ■ 2 FLG mutation ■ Clear cut clinical phenotype – 1/3rd ■ Only 1 FLG mutation ■ Disease expression is milder JMJ 24 2FLG genes 1 FLG gene FLG GENE MUTATION
  • 25.
    Ichthyosis vulgaris ■ Filaggrinmutation results in – Impaired epidermal barrier formation – Marked reduction in natural moisturizing factors (NMF) ■ FLG mutations predispose to – Atopic eczema – Allergic rhinitis – Asthma – Food allergies – Hand eczema – Nickel sensitization – Eczema herpeticatum in atopic eczema JMJ 25
  • 26.
    Cause ■ Mutant allelesof filaggrin gene – 4% in European population ■ Heterozygotes  have milder disease ■ Compound heterozygotes ■ Homozygotes JMJ 26 Filaggrin gene Mutation Loss / reduction in profilaggrin Major component of keratohyalin granules More marked disease
  • 27.
    JMJ 27 Major componentof keratohyalin granule Cleaved Breakdown of fillagrin Produce filaggrin degradation products Reduce tran-sepidermal water loss
  • 28.
    Clinical course ■ Notpresent at birth ■ Develop during 1st months of life ■ Wells & Kerr study – Demonstratable scaling in 40% of patients develop at the age of 3 months ■ Some improve in adult life, ■ Particularly during warm weather & in high humidity – Seasonal variation (improve during summer) ■ But seldom clears completely JMJ 28
  • 29.
    Presentation ■ Dryness – Usuallymild & symptoms free ■ Scales – Light grey – Small & branny – Covering mainly extensor surfaces of extremities & trunk ■ Groin & larger flexures  always spared ■ Smaller scales compared to RXLI ■ Accentuated palmar creases  almost all IV – Found in almost all IV – Not influenced by humidity or seasonal variation JMJ 29
  • 30.
  • 31.
    JMJ 31 Ichthyosis vulgaris: accunuated palmar creases
  • 32.
    Presentation ■ Keratosis pilaris– may often present ■ Few experience – hypohydrosis ■ Other frequent features – Keratosis follicularis – Mind concomitant atopic eczema – Allergic rhinitis JMJ 32 As mutation in filaggrin gene strong predisposing factor for atopic eczema
  • 33.
    Complications ■ Dry skinchaps in winter and ■ Easily irritated by degreasing agents JMJ 33
  • 34.
    Differential diagnosis ■ Xerosisof atopic eczema JMJ 34
  • 35.
    Investigations ■ Immunohistochemical studies –Absent or markedly reduced filaggrin signal ■ Ultrastructure – Scarce & crumbly keratohyalin granules – These defects correlate well with number of FLG mutations in its severity JMJ 35 Investigations Immunohistochemistry Ultrastructure Histology
  • 36.
    Investigations ■ Histology – Orthohyperkeratosis –With a diminished or absent granular layer JMJ 36
  • 37.
    Treatment ■ Palliative ■ Drynesscan be helped by – Regular use of emollients – Best applied after a shower ■ Can use – Emulsifying ointments – Soft white paraffin – E45 – Unguentum Merck JMJ 37 • Bath oils & creams containing humectants • Glycerin • Urea • Lactic acid
  • 38.
  • 39.
    Cause ■ Less commonthan IV ■ Complete form seen only in males ■ Female carries  may show mild scaling ■ In UK – affects 1 in 600 males ■ Cause by mutations in STS gene ■ Associate with deficiency of enzyme STEROID SULFATASE – Which hydrolyses cholesterol sulfate JMJ 39
  • 40.
    JMJ 40 Impaired hydrolyzationof cholesterol sulphate Steroid sulfatase deficiency Inhibit proteases Kallikrein 5 Kallikrein 7 In skin Marked reduction in serene protease activity Decrease desquamation Hyperkeratosis Example for retention hyperkeratosis
  • 41.
    Cause ■ Responsible geneis in end in short arm of X chromosome – Xp 22.3 ■ Sometimes gene deletion may extend – Adjacent genes may also delete – Result in Kallmann syndrome – With the recessive form of X linked chondrodysplasia punctata – Or with brain abnormalities ■ Mental retardation ■ Unilateral polymicroglia ■ Retinitis pigmentosa ■ Disease severity may be enhanced by concomitant filaggrin mutations JMJ 41
  • 42.
    Presentation & course ■Soon after birth – Very fine scaling or peeling of skin – Often goes unnoticed & soon resolves ■ Scales – at age of 2-6 months – Larger & browner – Involves the neck, – to the lesser extent the popliteal and antecubital areas, – as well as the skin generally ■ Palms & soles are normal ■ About 30% have light grey scales  easily misdiagnose as IV ■ No association between atopy or keratosis pilaris ■ Condition persist throughout life JMJ 42
  • 43.
    Presentation & course ■Dark hyperkeratosis in lateral aspects of trunk & back of neck – Leaving “dirty look” – Characteristic appearance ■ Deep stromal corneal opacities – Frequent finding – Does not affect visual acuity ■ RXLI have association with – Cryptorchidism – ADHD – Autism JMJ 43
  • 44.
    JMJ 44 Recessive X-linkedichthyosis : scaling on the arm
  • 45.
    JMJ 45 Recessive X-linkedichthyosis : scaling on the legs
  • 46.
    JMJ 46 Recessive X-linkedichthyosis : scaling on the trunk
  • 47.
    JMJ 47 Recessive X-linkedichthyosis : patient with light grey scaling
  • 48.
    Complications ■ Affected babiesmay be born after a prolonged labour – Presence of the enzyme defect in placenta (placental sulfatase deficiency) – insufficienct cervical dialation ■ Kallaman’s syndrome – Hypogonadotrophic hypogonadism & anosmia – Caused by deletion of a part of X chromosome – That included the gene for X-linked ichthyosis ■ Neurological defects may occur JMJ 48
  • 49.
    Investigations ■ None usuallyneeded ■ Drawing pedigree tree – Shoes mode of inheritance ■ Fluorescence in situ hybridization – To detect steroid sulfatase gene deletions ■ Electron microscopy – Retained corneo-desmasomes within the stratum corneum – This is a typical feature of retention hyperkeratosis ■ Histology – Orthohyperkeratosis & a well maintained, often thickened stratum granulosum – Marked follicular plugging (although no obvious keratosis follicularis) JMJ 49
  • 50.
    Treatment ■ Dryness canbe helped by – Regular use of emollients best applied after a shower ■ Oral aromatic retinoids  best avoided JMJ 50
  • 51.
  • 52.
    Autosomal recessive congenital ichthyoses Manytypes Lamellar Ichthyosis Congenital ichthyosiform erythroderma Harlequin ichthyosis JMJ 52 ■ Bizarre skin changes are seen at birth ■ Term “COLLODION BABY” is often used
  • 53.
    Autosomal recessive congenital ichthyoses ■Mutation in plethora genes, which encodes proteins involved – in lipid transport such as ABCA12, – in lipid biosynthesis such as CERS3, – in fatty acid metabolism or – have a role in assembling supra-structures such as the cornified envelope JMJ 53
  • 54.
    Autosomal recessive congenital ichthyoses ■Initially stratum corneum is smooth & shiny – Skin looks as it is covered with cellophane or collodion – Tight skin  ectropion & feeding difficulty ■ Shiny outer surface is shed within a few days – Leaving behind red scaly skin ■ Collodion babies may have problems with – Temperature regulation – High water loss JMJ 54 Best dealt with by high humidity incubators
  • 55.
    JMJ 55 Autosomal recessivecongenital ichthyosis : shedding of collodion membrane after 1 week
  • 56.
    Lamellar ichthyosis &CIE ■ Rare condition ■ Inherited as autosomal recessive trait ■ Skin changes at birth in both  collodion baby ■ Later they can be distinguished by ■ Both last for life ■ Cause disfigurement JMJ 56 Lamellar ichthyosis • Plate-like scales Congenital ichthyothiform erythroderma • Finer scaling • More obvious redness
  • 57.
    Lamellar ichthyosis &CIE ■ Mutation in transglutaminase 1 gene – Chromosome 14q11.2 ■ Transglutaminase-1 – Major cross linking enzyme in stratum corneum ■ Lamellar ichthyosis shows genetic heterogenicity JMJ 57
  • 58.
    JMJ 58 Autosomal recessivecongenital ichthyosis : congenital ichthyosiform erythroderma
  • 59.
    JMJ 59 Autosomal recessivecongenital ichthyosis : Lamellar ichthyosis
  • 60.
    Acral peeling skinsyndrome ■ Milder disorder ■ Due to mutation in transglutaminase -5 gene ■ Persistent sun-burn like peeling is limited to the hands & feet JMJ 60
  • 61.
    Bathing suit ichthyosis ■Confined to axillae, trunk & scalp ■ Self healing collodion baby – Completely resolves by 3 months of age JMJ 61
  • 62.
  • 63.
    Self healing collodionbaby ■ Completely resolves by 3 months of age JMJ 63 (a) Collodion baby at birth (b) mild ichthyosis and minimal erythroderma at the age of 21 montha
  • 64.
    Harlequin fetus ■ Resultsfrom null mutation in ABCA12 gene – On chromosome 2q35 – Member of ABC transporter superfamily – Normal function – forming a skin lipid barrier ■ Affected babies – Preterm – Covered with an armor-like collodion membrane – When it sheds  reveals thick fissured hyperkeratosis – Ectropion & eclabium (outward turning of lips) – Extreme cases - die JMJ 64
  • 65.
    Harlequin fetus ■ Needneonatal ICU care ■ Infants that do survive develop – Very severe hyperkeratotic erythroderma ■ Missense mutations in ABCA12 gene – May have milder repercussions – Resulting in lamellar ichthyosis JMJ 65
  • 66.
    JMJ 66 Harlequin ichthyosis: at birth : 6 weeks on retinoid therapy : 6 months
  • 67.
    Keratinopat hic ichthyosis ■ All ofthese results from mutation in keratin genes JMJ 67
  • 68.
    Epidermolytic ichthyosis ■ Previouslyknown as – Bullous ichthyosiform erythroderma ■ Rare condition ■ Autosomal dominant ■ Socially disturbing  secondary infection resulting foul odor ■ Mutation of the genes (on chromosomes 12q13 and 17q21) – Controls the production of keratins 1 & 10 JMJ 68
  • 69.
    Epidermolytic ichthyosis ■ Clinicalcourse – shortly after birth  skin become – Generally red – Show numerous blisters – Redness fades over few months – Tendency to blister also lessens ■ During childhood – Gross brownish warty hyperkeratosis – Sometimes roughly linear or annular form – Usually worst in flexures JMJ 69
  • 70.
    Epidermolytic ichthyosis ■ Diseasedskin – May become secondary infected and painful – May develop foul odor ■ Histology – Thickened granular cell layer – Contains large granules – Clefts may be seen in upper dermis ■ Few with localized lesions with same histology – Have gonadal mosaicism – Therefore their children  risk of developing generalized disorder JMJ 70
  • 71.
    Epidermolytic ichthyosis ■ Treatment symptomatic ■ Antibacterial washes & masking fragrances ■ Antibiotics may need ■ Acitretin  in severe cases ■ Superficial epidermolytic ichthyosis – Milder – Autosomal dominant – Resulting from defect in keratin 2 gene JMJ 71
  • 72.
    Superficial epidermolytic ichthyosis ■Milder ■ Autosomal dominant ■ Resulting from defect in keratin 2 gene JMJ 72
  • 73.
  • 74.
    Other ichthyosiform disorders ■Ichthiosiform skin changes  may result as a part of multisystem disease ■ Refsum’s syndrome – Autosomal recessive – Deficiency of a single enzyme concerned in the break down of phytanic acid – Phytanic acid then accumulates in tissues – Retinal degeneration – Peripheral neuropathy – Ataxia JMJ 74
  • 75.
    Other ichthyosiform disorders ■Rud’s syndrome – Ichthyosiform erythroderma in association with – Mental retardation – Epilepsy ■ Netherton’s syndrome – Brittle hair (bamboo deformity) – Curious gyrate – Erythromatous hyperkeratotic eruption (ichthyosis linearis circumflexa) JMJ 75
  • 76.
    Other ichthyosiform disorders ■MEDNIK syndrome – M Mental retardation – E Enteropathy – D Deafness – N Neuropathy – I Ichthyosis – K Keratoderma ■ KID syndrome – K Keratitis – I Ichthyosis – D Deafness JMJ 76
  • 77.
  • 78.
    Acquired Ichthyosis ■ Similarto ichthyosis vulgaris ■ Arises in adulthood ■ Rare ■ Histology – Epidermis show compact hyperkeratosis – With a thinned or absent granular cell layer ■ Improve with treatment for the systemic disease JMJ 78
  • 79.
    Acquired Ichthyosis Neoplasia • Hodgkin’s lymphoma •Mycosis fungoides • Multiple myeloma • Kaposi & other sarcoma • CA lung • CA breast • CA ovary • CA cervix Infections • Leprosy • TB • HIV • HTLV-1 associated myelopathy Endocrinopathies • DM • Thyroid Dx • Hyperparathyroidi sm • Hypopituirism Chronic metabolic derangements • Malabsorption Xn • Essential fatty acid deficiency • Pancreatic insufficiency (shwohman Xn) Medication • Statins • Nicotinic acid • Cimetidine • Clofazimine Autoimmune conditions • Dermatomyositis • SLE • Scleradorma Anorexia nervosa Others • Sarcoidosis • Bone marrow transplant • Chronic renal failure JMJ 79
  • 80.
  • 81.
    Cause ■ Common ■ Affect50% of adolescent population ■ Autosomal dominant ■ Caused by mutation in a gene lining on the short arm of chromosome 18 ■ Heterozygous carriers with abnormal profilaggrin gene – Often have keratosis pilaris ■ Abnormality is in – Keratinization of hair follicle – Which become filled with horny plugs JMJ 81
  • 82.
    Presentation & course ■Skin changes – begin in childhood – Less obvious in adulthood ■ Most common type – Greyish horny follicular plugs – Sometimes with red areolar – Confined to the outer aspect of thighs & upper arms – Skin feels rough ■ Less often – Affects the sides of face – Perifollicular erythema – Loss of eyebrow hair ■ There is an association with ichthyosis vulgaris JMJ 82
  • 83.
    Complications ■ Involvement ofcheeks – May cause ugly pitted scaring ■ Follicles in the eyebrows may damage – Hair loss in eyebrows JMJ 83
  • 84.
    Differential diagnosis ■ Insevere vitamin deficiency – Widespread follicular keratosis (phynoderma) occurs ■ None are needed JMJ 84 Investigations
  • 85.
    Treatment ■ Not usuallyneeded ■ Keratolytic – Salicylic acid – Urea ■ UV radiation – Temporary benefit ■ Moving to more humid climate JMJ 85
  • 86.
  • 87.
    Cause ■ Rare ■ Autosomaldominant ■ New mutations common ■ Characterized by – Chronic eruption of keratotic papules – Histology of which shows acantholysis & dyskeratosis ■ Abnormal gene – ATP2A2 on chromosome 12q24 – Encodes for SERCA2, calcium pump (keeps high concentration of calcium in endoplasmic reticulum) JMJ 87
  • 88.
    Presentation ■ Signs appearin mid teens – Usually after overexposure to sunlight ■ Characteristic lesion – Small pink or brownish papules with – Greasy scale – These coalesce into warty plaques in a seborrheic distribution ■ Early lesions seen on – Sternal area – Interscapular area – Behind the ears JMJ 88
  • 89.
    Presentation ■ Severity varies ■Abnormalities remain for life ■ Other skin changes – Plane warts on the backs of the hands – Punctate keratoses or pits on the palms & soles – Cobblestone-like irregularities of the mucus membranes in the mouth – Distinctive nail dystrophy – White or pinkish lines or ridges run longitudinally to the free edge of the nail , where they end in triangular nicks JMJ 89
  • 90.
    Complications ■ Some arestunted ■ Some families  Darier’s disorder runs with bipolar mood disorder ■ Personality disorder  including antisocial behaviour ■ Over half of patients have major psychiatric condition at some point in their life ■ Impairment of delayed hypersensitivity – High tendency to develop widespread herpes simplex & bacterial infections JMJ 90
  • 91.
    Differential diagnosis ■ Lesionsare similar to seborrheic eczema – This lacks warty papules of Darier’s disease ■ Acanthosis nigricans – Mainly flexural ■ Keratosis pilaris – Favors outer upper arms and thighs ■ Other forms of folliculitis ■ Grover’s disease JMJ 91
  • 92.
    Investigations ■ Skin biopsy –Confirms diagnosis – Characteristic clefts in epidermis & dyskeratotic cells JMJ 92
  • 93.
    Treatment ■ Severe anddisturbing disease – Long term acitrecin – Ablative laser treatment – Varied strengths of topical 5-fluorouracil ■ Milder cases – Only topical keratolytics (salicylic acid) – Control of infection JMJ 93
  • 94.
    KERATODERMA OF PALMS &SOLES Inherited types Acquired types JMJ 94
  • 95.
    Inherited types ■ Manygenodermatoses share keratoderma of the palms & soles ■ Clinical patterns & modes of inheritance vary from family to family ■ Punctate ■ Striate ■ Diffuse ■ Mutilating ■ Sometimes in association with metabolic disorders such as tyrosinaemia or with changes elsewhere JMJ 95
  • 96.
    Inherited types ■ Punctatetype – Due t mutation of keratine 16 gene – On chromosome 17 – 17q12-q21 ■ Epidermolytic type – By mutation of keratin 9 gene – Found only on palms and soles ■ Diffuse type – Most common type – Also known as tylosis – Inherited as autosomal dominant trait linked to changes in chromosome region 12q11-q13 – Which harbours the type 11 keratin gene cluster – Few have association with oesophageal carcinoma JMJ 96
  • 97.
    JMJ 97 Epidermolytic palmoplantarkeratoderma caused by a mutation in KRT9 encoding keratin 9
  • 98.
    Inherited types ■ Treatment –Unsatisfactory – Higher concentrations of keratolytics ■ Salicilic acid ■ Urea – Systemic retinoids JMJ 98
  • 99.
    Acquired types ■ Somehealthy people may have few punctate keratoses on palms, ■ & this is no longer thought as a cause for internal malignancy ■ However palmar keratosis cause by arsenic may have association between malignancy ■ Block people are prone to keratotic papules along their palmar creases ■ Sometimes K of Palms and soles may be part of generalized skin diseases – Pitiryasis rubra pilaris – Lichen planus JMJ 99
  • 100.
    Acquired types ■ Keratodermaclimacterium – Seen in over-weight middle aged women – At about the time of menopause – Most marked around the border of hals – Where painflul fissures form – & interfere with walking ■ Treatment – Regular paring – Use of keratolytic ointments – Many improve with application of 40% urea in cream or ointment bases JMJ 100
  • 101.
  • 102.
    Cause ■ Sometimes familial(usually not) JMJ 102
  • 103.
    Presentation ■ Fibromatous hyperkeratoricareas – Appear on the backs of many finger joints ■ Usually begins in late childhood ■ Persisting thereafter ■ Can have an association wit Dupuytren’s contracture JMJ 103
  • 104.
    Differential diagnosis ■ Occupationalcallosities ■ Granuloma annular ■ Viral warts JMJ 104
  • 105.
    Investigation & treatment ■Investigations – Biopsy ■ May be helpful in few cases ■ Treatment – None JMJ 105
  • 106.
  • 107.
    Callosities and cones ■Both are responses to pressure JMJ 107
  • 108.
    Callocities ■ More diffusetype of thickening of ■ Keratin layer ■ Seems to be a protective response to – Repeated friction & pressure ■ Often occupations; ■ Painless ■ No therapy needed JMJ 108
  • 109.
    Cones ■ Has acentral cone of hard keratin ■ They hurt when forced inward ■ Appear, where there is local pressure – Often between bony prominences and shoes ■ Favourite areas – Under surface of toe joints – Under prominent metatarsals JMJ 109
  • 110.
    Cones ■ Soft cones –Arise in 3rd & 4th toe clefts – When toes are squeezed together by tight shoes – Such are often macerated ■ Main DD – Hyperkeratotic warts ■ These have tiny bleeding points pared down or ■ Pinpoint blood vessels – when examined with dermatoscope – Corn ■ Has only its hard compacted avascular core surrounded by ■ More diffuse thickening of opalescent keratin JMJ 110
  • 111.
    Cones ■ Treatment – Eliminatepressure – Regular paring reduces the symptoms temporary – Well fitting shoes are essential – Cones under metatarsals ■ Helped by soft spongy sikes or orthotic shoe inserts – Special care needed for corns on ischemic or diabetic feet ■ Which has greater risk of infection & ulceration JMJ 111
  • 112.
    ■ Chromosome 14 –Ichthyosis - AR - transglutaminase 1 gene ■ Chromosome 12 – Epidermolytic ichthyosis - keratin gene 1-12q13 – Tylosis - keratin 11 gene - 12q11-q13 ■ Chromosome -17 – Epidermolytic ichthyosis - keratin gene 10-17q21 – Keratoderma punctate type - keratin 16 gene 17q12-q21 ■ Chromosome 18 – Keratosis pilaris JMJ 112
  • 113.