This document provides information on various types of palmoplantar keratoderma (PPK). It describes the clinical patterns, genetic causes, histopathological findings, and management options for different syndromic and non-syndromic forms of PPK, including epidermolytic, punctate, striate, and transgradient PPK as well as disorders associated with PPK like pachyonychia congenita and Naxos syndrome. The document discusses the characteristic features, genetic defects, and treatment approaches for these PPK subtypes.

1. PALMOPLANTAR
KERATODERMA
MAJ TEGHVEER SINGH
RESIDENT DERMATOLOGY

2. INTRODUCTION
• Excessive epidermal thickening of palms & soles
• Acquired or heriditary
• Syndromic or non syndromic
• Genes Implication
1. Structure proteins
2. Cornified envelop
3. Cohesion
4. Cell to cell communications
5. Transmembrane signal transduction

3. CLINICAL PATTERNS
• Diffuse – complete palmar or planar surface
centripalmar or insteps , uniform thickening
• Focal,areate or annular – pressure points are disproportionately thickened
• Striate keratoderma – focal keratoderma , conspiciously longitudinal lesions on
fingers overlying flexor tendons
• Punctate , papular or disseminated – multiple scattered discrete round lesions
• Transgradient – extends beyond palmo plantar skin contiguously or as
callosities at pressure points
• Confluent – cover whole digits
• Cicatrizing keratoderma (mutilating) – constriction bands appear around digits

4. EPIDERMOLYTIC PPK
• Voerne’r disease
• AD
• KRT 9 or KRT 1
• Diffuse
• Disruption of intermediate filament integrity – blistering & hyperkeratosis
epidermolysis with tonofilament clumping to minor trauma
• Infants – diffuse kerotoderma
• Adults – confluent , even ,thick yellowish hyperkeratosis with sparing of
dorsal surface, sharp demarcation with erythematous edges

6. EPIDERMOLYTIC PPK
• Epidermolysis in suprabasal keratinocytes
• Hyperkeratosis , acanthosis & papillomatosis
• Round or ovoid eosinophilic inclusions with large tonofilament
aggregates
• Whorls of keratins containing tubular structure – tono tubules
• MANAGEMENT
1. Mechanical debridement
2. Mild keratolytics
3. Oral retinoids
4. Topical calcipotriol

7. Non – epidermolytic palmoplantar
keratoderma
• Diffuse keratoderma
• No cytolysis in upper spinous or granular layer
• Bothnia type , kimonis type, nagashima type
• AQP5 gene

8. Non – epidermolytic palmoplantar
keratoderma
• Present in the 1st few months of life
• Obvious > 2yrs age
• Variably thick , yellow hyperkeratosis occurs on the whole surface of
foot
• Starting on the heel & anterior arch
• Spreading to palms
• Hyperhidrosis ,dermophytic infections & pitted keratolysis is
common

11. Non – epidermolytic palmoplantar
keratoderma
• Keratolytic therapy
• Systemic acitretin ( 0.2 – 0.5 mg /kg )
• Erythromycin – bothnia type
• Tacrolimus – nagashima type

12. PACHYONYCHIA CONGENITA
• AD
• KRT6 A-C , 16 or 17
• PC type 1 ( Jadassohn-Lewandowsky) – 6A/16
• PC type 2 ( Jackson-Lawler ) – 6B/17
• Nail bed , oral mucosa , palmoplantar skin , teeth & pilosebaceous
unit

13. PACHYONYCHIA CONGENITA
• Toe nail dystrophy + plantar kerotoderma + plantar pain in > 3yr old
• Thickened toenail occur within 1st yr to 9yrs of life
• KRT6A mutation carriers manifest in early age
• Not all 20nails are involved
• Plantar keratoderma manifest as calluses , fissures & thickened skin
• Thick yellow keratosis
• Friction blisters
• Plantar pain

14. PACHYONYCHIA CONGENITA
• Follicular hyperkeratoses on knees & elbows
• Oral leukokeratosis
• Palmoplantar hyperhydrosis
• Natal teeth
• Patchy white thickened areas on tongue & oral mucosa
• Oral lesions resembling candidiasis
• Hoarseness of voice & fatal respiratory obstruction in infancy
• Steatocystoma or pilosebacious cyst

16. PACHYONYCHIA CONGENITA
• Tonofilament aggregates demonstrate intermediate filament disorder
• Gross hyperkeratosis
• Alternating ortho & parakeratosis
• Acanthosis with patchy hypergranulosis – large & malformed
keratohyaline granules
• Cyst may be keratinous epidermoid cyst, eruptive vellous cyst or
true steatocyst

17. PACHYONYCHIA CONGENITA
• Mechanical reduction of hyperkeratosis & nails
• Proper footware & orthotics to reduce blistering & callosities
• Cyst – surgical excision
• Emollients & keratolytics
• Treatment of hyperhidrosis

18. MAL DE MELEDA
• AR
• Transgradient keratoderma
• Croatian island of meleda
• SLURP1 – transmembrane signal transduction , cell activation &
adhesion

19. MAL DE MELEDA
• Early childhood
• Hyperkeratosis is preceded by erythema
• Patches of waxy ivory-yellow hyperkeratosis extend across the
glove & stocking distribution
• Insular lesions of knees & elbows – key feature
• Eythema persists in central palms & soles
• Hyperhidrotic maceration & maladour – fungal superinfection

20. MAL DE MELEDA
• Circumferential hyperkeratosis of fingers – sclerodactyly & digital
constriction
• Nail changes – hypercurvature , thickening & koilonychia
• Angular cheilitis
• Ridged tongue
• High arched palate

23. MAL DE MELEDA
• Greatly thickened corneal layer
• Increased stratum lucidum
• Marked acanthosis
• Papillomatosis is a typical feature

24. MAL DE MELEDA
• Oral retinoids – hyperkeratosis responds better than erythema
• Excision of keratoses
• Split – thickness skin graft

25. LORICRIN KERATODERMA
• Diffuse transgradient
• LOR gene – loricrin
• Glycine rich cornefied envelope protein
• Mutant protein is transported to the nucleus
• Interfares with regulation of cornification

26. LORICRIN KERATODERMA
• Generalised desquamation at birth
• Collodion babies
• Icthyosis is mild
• Rugose keratoderma – childhood
• Confluent honeycomb pattern
• Edges are diffuse & cicatricial bands (psuedo– ainhum)
• Knuckle pad & warty keratoses

28. LORICRIN KERATODERMA
• Hyperkeratosis with hypergranulosis & parakeratosis
• Intranuclear granules in granular cells and a thin corneified cell
envelope in the lower cornified layers with abnormal extracellular
lamellae
• Immunoelectron microscopy – presence of loricrin in the nucleus

29. LORICRIN KERATODERMA
• Isotreninoin
• Inhibitors of VEGF receptor 2

30. STRIATE PPK
• AD
• Keratinocytic disadhesion
• Desmosomal defects
• Haploinsufficiency for desmoglein 1 – mutation in DSG1
• Mutation in desmoplakin

31. STRIATE PPK
• Linear pattern of thickening on the palms & flexor aspect of fingers
• Soles – confluent
• Mechanical stress
• Pain , hyperhidrosis & mild hyperkeratosis of knees
• Woolly hairs

34. STRIATE PPK
• Disadherence of the keratinocytes with widening of intercellular
space
• DSG 1 – size of desmosomes are reduced
• DSP – abnormal keratin filament with loss of desmosomal
connections
• Management :
1. Systemic acetretin
2. Urea cream

35. PUNCTATE PPK
• AD
• Small rounded papular lesions on the palms & soles that tend to
coalesce over pressure points
• AAGAB gene – codes for p34
• Increase in epidermal growth factor signalling-keratinocyte
proliferation

36. PUNCTATE PPK
• Early adoloscence but also upto 6th decade of life
• Pinpoint keratotic papules, initially translucent with a depression in
the centre but later opaque and warty
• Enviromental factors and personal skincare regimes may affect the
degree of hyperkeratosis
• Lesions are more florid in manual workers
• There is no involvement of the dorsum of the hands or legs, knees
or elbows

38. PUNCTATE PPK
• Orthohyperkeratotic with compact acanthosis & hypergranulosis with
a depression in the centre
• Cornoid lamella
• Hypogranulosis and focal parakeratosis
• Management :
1. Pumice stone
2. Oral retinoids (0.5 – 1 mg/kg/day)
3. Tyrosine kinase receptor inhibitors

39. Cole Disease
• Punctate keratoderma & pigmentary anomaly
• Congenital or early onset
• Defective melanosome transfer from melanocytes to keratinocytes
• Relatively mild focal or punctuate keratoderma
• Sharply demarcated irregular macules with varying degrees of
hypopigmentation
• located over the extremities
• There might be an early onset calcific tendinopathy or calcinosis cutis

41. Cole Disease
• Histology shows hyperorthokeratosis, hypergranulosis and
acanthosis
• Ultrastructure confirms a reduction of the melanin content of
keratinocytes with disproportionately large melanosomes of
melanocytes

42. SPINY KERATODERMA
• Fine 1–2 mm papules that project from the palmoplantar surface
• filiform, spiked, prickly, minute digitate or music box‐like spines
• start in early childhood and gradually increase in number, i.e. they
appear in the first up to the fifth decade

43. SPINY
KERATODERA
• Dense columns of parakeratosis above
a hypogranular epidermis
• Management :
• Mechanical debridement -
dermabrasion, topical keratolytics
• Etretinate or actitretin have a temporary
effect
• Topical 5‐fluorouracil

44. MARGINAL PAPULAR
KERATODERMA
• Acrokeratoelastoidosis with
elastorrhexis
• Focal acral hyperkeratosis
• characterized by papules, plaques and
nodules
• located at the junction between the
palmar and dorsal skin of the hands or
feet along the thenar and hypothenar
eminences
• Focal orthohyperkeratosis
• Massive elastosis

45. TRANSIENT AQUAGENIC
KERATODERMA
• Mainly palmar, disorder represents a mild keratoderma
• Triggered or exacerbated by contact with water or sweat
• acquired but autosomal recessive or dominant
• cyclo‐oxygenase 2 inhibitor

46. TRANSIENT AQUAGENIC
KERATODERMA
• 6–45 years, more often women
• Subtle keratoderma appearing after a few minutes of immersion of their
hands in water or after sweating
• Soles
• Characteristic sign might be that patients bring with them a vessel to
immerse their hands in water (‘hands in the bucket’ sign)
• The painful, burning or itching, whitish papular lesions are associated
with dilated acrosyringeal ostia which can be seen by dermoscopy
• Lesions subside shortly after drying the hands, leaving minimal
hyperkeratosis in the centre of the palms

48. TRANSIENT AQUAGENIC
KERATODERMA
• 20% aluminium chloride hexahydrate followed by urea cream or
botulinum toxin.

49. NAXOS SYNDROME
• PPK + Arrythmogenic right ventricle cardiomyopathy + woolly hairs
• gene encoding plakoglobin - a cell junction protein found in desmosomes in
the epidermis and cardiac muscle
• Different mutations of JUP show a large phenotypic spectrum
• Expression of altered plakoglobin may show mild skin fragility, keratoderma
and woolly hair only
• Autosomal dominant JUP mutations underlie isolated arrhythmogenic right
ventricular cardiomyopathy and a Naxos variant with leukonychia and
oligodontia
• Complete loss of plakoglobin due to homozygous nonsense mutations may
lead to acantholytic epidermolysis bullosa

50. NAXOS SYNDROME
• Woolly hair develops from birth while diffuse or striate hyperker-
atoses of the palms and soles appear during the first year of life
when the skin starts to become mechanically stressed
• Cardiomyopathy manifests by adolescence and shows 100%
penetrance

51. CARVAJAL–HEURTA SYNDROME
• Cardiocutaneous syndrome with NEPPK
• Woolly hair and dilated cardiomyopathy
• Recessive desmoplakin (DSp) mutations producing a premature stop codon
leading to a truncated protein
• Dominant negative effect on desmosomal assembly has been found to be
associated with cardiomyopathy and mild hyperkeratosis of the elbows and
knees
• Heterozygous carriers of the missense mutation p.S299R showed isolated
arrhythmogenic right ventricular cardiomyopathy without cutaneous phenotype
• Complete loss of the tail domain of desmoplakin presents as
acantholytic epidermolysis bullosa

52. CARVAJAL–HEURTA SYNDROME
• Striate lichenoid keratoses of flexures, follicular keratoses of elbows & knees
• Presents at a younger age with bilateral predominantly left ventricular
involvement leading to early heart failure with cardiac enlargement and
disrupted cardiac contraction
• Large intercellular spaces of supra basal keratinocytes (keratinocytic
disadhesion)
• Reveal clumping of desmosomes or signs for intermediate filament disruption
such as perinuclear localization of keratin in suprabasal keratinocytes
• On resting electrocardiogram, affected patients exhibit repolarization and or
depolarization abnormalities
• structural/functional abnormalities of the ventricles

53. CARVAJAL–HEURTA SYNDROME
• Investigate cardiac function in patients with striate keratoderma as
early diagnosis and intervention may improve outcome
• Depending on the myocardial symptoms, implantation of an
automatic cardioverter defibrillator with/without antiarrhythmic drugs
• Heart transplantation
• Screening of possibly affected family members should be initiated
considering dominant as well as recessive inheritance

54. VOHWINKEL SYNDROME
• AD
• Hereditary keratoderma with hearing loss
• Defective connexin function
• Maternal inheritance - rare mitochondrial type of keratoderma
• connexin 26 is expressed in the cochlea where it may permit the
recycling of potassium to endolymph
• In skin, the protein is found in palmoplantar epidermis and sweat
glands

55. VOHWINKEL SYNDROME
• Palmoplantar keratoderma begins in childhood as shiny or translucent papular
hyperkeratosis, gradually becoming confluent of the hands and feet
• Striate lesions may be seen
• Warty papules on the knuckles and other extensor sites coalesce into the
pathognomonic ‘starfish’ keratoses
• The edge of the keratoderma at the wrists and Achilles tendon consists of spiky
digitate hyperkeratotic projections onto normal skin
• Multiple keratoses on the digits produce circumferential hyperkeratosis, which
predisposes to the formation of cicatricial bands and autoamputation
• The little finger and fifth toe are commonly affected
• A high tone sensorineural hearing loss is probably present from birth

57. BART –PUMPHREY SYNDROME
• knuckle pads (similar to the focal keratoses of Vohwinkel syndrome)
• Diffuse PPK in childhood
• Leukonychia
• Mixed sensorineural and conductive deafness – at birth

58. HURIEZ SYNDROME
• AD
• Onset – early infancy
• Accentuated scleroatrophy of palms & soles
• Hyperkeratosis & dry skin
• Absent dermatoglyphics
• Risk of squamous cell carcinoma of the affected skin is increased by
around 100‐fold
• The disease is characterized by a triad of diffuse scleroatrophy of the
hand, mild PPK and hypoplastic nail change

60. TYLOSIS EOSOPHAGIAL
CANCER/HOWEL-EWANS
SYNDROME
• 42.5‐kb segment of chromosome 17q23
• commonly deleted in oesophageal carcinoma
• Mutant RHBDF2 increase signalling through EGFR resulting in
hyperproliferation and dysregulation of wound repair which might
stimulate the subsequent development of precancerous lesions
• AD focal keratoderma associated with later development of
oesophageal cancer – 5th decade
• Pressure points of the sole are predominantly affected and less so the
palms
• There is variable oral leukokeratosis and follicular accentuation.

62. Clouston syndrome (hidrotic ectodermal
dysplasia type 2)
• Combination of small dystrophic nails developing in early infancy
with hypotrichosis in conjunction with papillomatous and fissured
transgredient keratoderma
• Clubbing
• Polydactyly , syndactyly
• Eye brows sparse or absent
• Mutations in the gap junction β‐6 ( GJB6) gene encoding
connexin30

66. Odonto‐onycho-dermal dysplasia
• Dental anomalies in association with PPK and nail dystrophy
• WnT10A gene encoding a signalling molecule expressed in skin
critical for the development of ectodermal appendages
• Hypotrichosis, nail fragility, early loss of deciduous teeth,
hydrocystomas of the eyelids or other follicular and adnexal tumours
occurring in older patients
• Diffuse PPK may develop due to multiple palmoplantar eccrine
syringofibroadenoma

67. Papillon–Lefevre and Haim–Munk
syndrome
• Homozygous mutations in the CTSC gene encoding the lysosomal protease cathepsin C
• Expressed in various tissues - cells of the immune system such as nuclear leukocytes, in the lung, kidney
and other epithelial tissues
• Functions are protein degradation and proenzyme activation
• Activity of several critical proteases is decreased
• Neutrophil phagocytosis and reactivity to T and B cell mitogens are impaired explaining the
predisposition to pyogenic infection, which may also involve internal organs
• Also high levels of oxidative stress markers have been confirmed and natural killer (NK) cell cytotoxicity
seems to be impaired
• Severe gingivitis and periodontitis affect both deciduous and permanent dentition leading to loss of teeth
• Unless treated Virulent Gram‐negative organisms invade the alveolar socket, usually including
Actinobacillus actinomycetemcomitans

68. Papillon Lefevre Syndrome
• AR
• Redness and thickening of the palms and soles is associated with
periodontitis and pyoderma
• Hyperkeratotic lesions can also affect the elbows and knees
• Pseudo‐ainhum

71. Haim Munk syndrome
• onychogryphosis, arachnodactyly and acroosteolysis
• a single family of Jews of South Indian origin (so‐called ‘Cochin
Jews’)
• Retinoids

75. Olmsted syndrome
• Severe mutilating transgredient keratoderma with prominent
periorificial hyperkeratosis
• gain‐of‐function mutations in the transient receptor potential vanilloid
3 gene (TRp V3)
• TRPV3 encodes a critical element for a member of the TRP cation
selective ion channels that are involved in the regulation of skin
barrier formation, hair growth, epidermal differentiation (through
TGF‐α /EGFR signalling), skin inflammation, pain and pruritus

76. Olmsted syndrome
• First year of life with symmetrical sharply defined palmar and plantar
keratoderma surrounded by erythema and flexion deformities,
constriction or spontaneous amputation of the digits
• Disease tends to have a slow but progressive course
• The keratotic lesions are pruritic and mildly painful with pressure
• Periorificial plaques present with erythema and warty hyperkeratosis
involving the mouth and perianal regions.

77. Olmsted syndrome
• Massive hyperkeratosis and/or fissuring of the gluteal cleft may
cause pain and considerable discomfort
• Keratoses extending to the flexor sites of the forearms or knees may
show a follicular and striate aspect
• Alopecia, nail and tooth anomalies, joint laxity and corneal dystrophy
recurrent skin infections
• Squamous cell carcinoma or malignant melanoma
• High IgE levels with eosinophilia, erythromelalgia and deafness

79. Olmsted syndrome
• etretinate or acitretin
• Topical keratolytics, emollients and corticosteroid as well as
calcineurin inhibitors may offer temporary relief of hyperkeratosis,
pain or itching
• Excision and skin grafting of severe keratoderma showed favourable
long‐term clinical results in some patients
• Erlotinib (an EGFR inhibitior) led to thinning of
keratoderma,resolution of perioral plaques within 3 weeks

80. Oculocutaneous tyrosinaemia
(tyrosinaemia type II)
• Herpetiform corneal ulcers and painful palmoplantar keratoses with
progressive mental impairment
• Biallelic mutations in TAT encoding tyrosine aminotransferase
tyrosine aminotransferase deficiency impacts on the degradation
pathway of tyrosine and phenylalanine
• The keratinocytic ultrastructure reveals clumped tonofilaments with
adherent globoid keratohyalin granules suggesting enhanced
microfilament aggregation due to an excessive amount of
intracellular tyrosine

81. Oculocutaneous tyrosinaemia
(tyrosinaemia type II)
• First year of life, photophobia and corneal ulcers
• A year or two later, erythematous crusts appear on the pressure bearing areas
of the soles followed by painful circumscribed hyperkeratosis typically making
the child walk on the toes
• The keratoses vary from gross keratoderma to patchy hyperkeratotic
yellow‐white papules
• Bullous lesions and hyperhidrosis
• In incomplete forms, keratoderma may be the presenting feature although
conversely keratoderma may be delayed until the second decade
• Unless correctly treated, behavioural problems arise within a few years and
progressively worsen, ending in inanition or death

82. Oculocutaneous tyrosinaemia
(tyrosinaemia type II)
• Elevated tyrosine levels in newborn screening by tandem mass
spectrometry and analysis of the tyrosine aminotransferase gene
can confirm the diagnosis
• In urine high levels of tyrosine and its metabolites are present
• Slit lamp examination may reveal tyrosine crystals in ocular lesions
Histology shows acanthosis with hyperkeratosis with thickening of
the granular layer

83. Oculocutaneous tyrosinaemia
(tyrosinaemia type II)
• Reduction of plasma tyrosine can be achieved by restricting the
intake of natural protein
• To avoid deficiency of essential amino acids a phenylalanine and
tyrosine free amino‐acid formula is used (plasma tyrosine level
below 600 μmol/L)
• Early initiation of diet causes prompt resolution of the ocular and
cutaneous symptoms and prevents the development of mental
manifestation

84. Keratoderma climactericum
(haxthausen disease)
• A strong association with obesity and hypertension
• Pressure areas of the heel and the forefoot are involved first
• Erythema and heavy hyperkeratosis with fissuring makes walking
painful
• The hyperkeratotic areas slowly extend to become confluent
• Later the central palms may be affected
• Symptoms may be worse in winter

86. TREATMENT
• Topical 0.05% oestradiol in a water‐in‐oil base
• Keratolytics and emollients
• Etretinate, acitretine may be the treatment of choice

87. Inflammatory dermatoses
• In psoriasis both diffuse, gross and centripalmar hyperkeratosis
A scalloped margin (‘festonné’),Caro–Senear lesions (depressed
plaques) on the sides of the fingers and involvement of the knuckles
may suggest the diagnosis
• The lesions of reactive arthritis are compact, heaped up and resemble
the heads of nails (keratoderma blenorrhagica)
• Extensive hyperkeratotic eczema may be difficult to distinguish on
clinical and histological grounds but marked itching may indicate
eczema
• The even orange hyperkeratosis of pityriasis rubra pilaris is associated
with an acute follicular eruption in adults and by lesions on the knees
and elbows in children

88. Inflammatory dermatoses
• Lupus erythematosus may show dry and atrophic, hypertrophic or
ulcerative palmar lesions
• Keratoderma is also reported in association with acrocyanosis and
livedo reticularis
• Antidesmocollin 3 antibodies were found in a patient with an
immunobullous disorder and acquired diffuse PPK
• In lichen planus, warty lesions may be mistaken for viral warts
• Lichen planus and other lichenoid erup-tions such as lichen nitidus
may mimic punctate keratoderma

89. Infections
• Trichophyton rubrum, may be unilateral and lacking inflammatory
signs
• Keratoderma may be seen in crusted scabies
• The tendency of secondary syphilis lesions to involve the palms is
well known and hyperkeratotic late syphilides may be warty or focal
• Tropical diseases such as late yaws may be complicated by
keratoderma
• In immunocompromised patients, viral warts may be confluent on
the palms or soles

91. Myxoedema and Lymphoedema
• Palmoplantar hyperkeratosis with myxoedema, improving with treatment
• Hypothyroidism must be suspected in patients with acquired PPK
• In chronic lymphoedema, the skin overlying the lymphoedematous area first becomes diffusely
thickened, and then develops into a velvety papillomatous surface, which is ultimately covered by
large irregular warty projections (lymphostatic verrucosis; mossy foot)
• The condition may simulate chromoblastomycosis
• Lymphoedematous keratoderma occurs most characteristically in filariasis, but may develop in
the context of chronic lymphoedema of any origin
• Histologically, there is hyperkeratosis, acanthosis and papilloma-tosis. The dermis is oedematous
with dilated lymphatics, conspic -uous new‐vessel formation, some sclerosis and a variable
infiltrate of inflammatory cells
• Hyperkeratotic component and the lymphoedema improved in three cases given etretinate
0.6 mg/kg/day

92. MALIGNANCY & DRUGS
• In addition to ‘tripe palms’ and Bazex acrokeratosis paraneoplastica
acquired diffuse PPK has been observed with cancer of the bronchus
and filiform PPK has been reported with cancer of the breast, colon and
kidney
• An increased incidence of keratoses in patients with lung or bladder
cancer
• Hypersensitivity to drugs such as iodine
• Keratoderma may result from tegafur, glucan, lithium and halogenated
weed‐killers, and dioxin
• Arsenical‐induced irregular warty keratoses, or more even glassy
lesions are seen

93. KERATODERMA & PSEUDO-AINHUM
1. Vohwinkle syndrome & Bart – Pumphrey syndrome
2. Clouston syndrome
3. Mal de Meleda
4. Papillon-lefevre syndrome
5. Olmsted syndrome
6. Loricrine keratodema