Atlas of Genetic Diagnosis and Counseling || Epidermolytic Palmoplantar Keratoderma

Epidermolytic Palmoplantar Keratoderma

Epidermolytic palmoplantar keratoderma (EPPK), first

described by Vorner in 1901, may be the most common

form of diffuse keratoderma and is characterized by

keratosis restricted to the palms and soles. The disease

is also known as keratosis palmaris et plantaris

familiaris. The estimated incidence is at least 4.4 per

100,000 in Northern Ireland (Covello et al. 1998)

Synonyms and Related Disorders

Keratosis of Greither; Keratosis palmaris et plantaris;

Localized epidermolytic hyperkeratosis; Vorner type

plamoplantar keratoderma

Genetics/Basic Defects

1. Inheritance:

a. Autosomal dominant

b. Highly penetrant

2. Cause

a. Keratin 9 (K9)

i. A type 1 keratin gene (KRT9, located at

17q12-q21), a type 1 keratin expressed exclu-

sively in the suprabasal keratinocytes of

palmoplantar epidermis

ii. Nearly 20 distinct pathogenic mutation in

KRT9 have been identified in various ethnic

kindreds with EPPK (Chen et al. 2009)

b. Mutations in keratin 1 gene (KRT1) underlies mild

EPPK (Terron-Kwiatkowski et al. 2002, 2006)

Clinical Features

1. Characteristic hyperkeratosis (Covello et al. 1998)

a. Early onset: present at birth or during the first

months of life

b. Diffuse thick yellowish hyperkeratosis, dis-

tinctly limited to the palms and soles, with

sharply bordered erythematous margins (virtu-

ally diagnostic of EPPK)

c. Absence of associated features

2. Differential diagnosis (Lee et al. 2008)

a. Diffuse hereditary PPK without associated

features (Hatsell et al. 2001)

i. Diffuse nonepidermolytic PPK (NEPPK)

a) NEPPK: an autosomal dominant disorder

b) Clinically difficult to distinguish between

EPPK and NEPPK

c) Histologically, EPPK shows

epidermolysis of keratinocytes in the

suprabasal layers, a characteristic not

observed in NEPPK

d) In mild cases of EPPK, diagnosis can

still be problematic as detection of

epidermolysis can be difficult

ii. Progressive PPK

a) Hyperkeratosis extends onto the dorsa of

the hands and the feet with characteristic

involvement of the Achilles tendon

b) Hyperhidrosis common

c) Intrafamilial phenotypic variation

common

d) Course of the disease: worsen during

childhood, static after puberty, and

improves in the fifth decade of life

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_82,# Springer Science+Business Media, LLC 2012

749

iii. Gamborg-Nielson PPK

a) An autosomal recessive disorder

b) Severe form of PPK delineated in two

families with six patients in Sweden

c) Thick, diffuse keratoderma with knuckle

pads

d) Occasional keratosis on the dorsa of the

hands

e) Mutilating changes due to constricting

bands surrounding the fingers have been

described

b. Diffuse hereditary PPK with associated features

i. Mal de Meleda

a) Described initially in inhabitants of the

Adriatic Island of Meleda (Miljet)

b) An autosomal recessive disorder

c) Diffuse, thick keratoderma with promi-

nent erythematous border extending

onto the dorsa of the hands and the feet

d) Constricting bands around digits

resulting in spontaneous amputation

e) Well-circumscribed psoriasis-like plaques

or lichenoid patches on the knees and the

elbows

f) Hyperhidrosis

g) Periorbital erythema and hyperkeratosis

h) Nail changes (koilonychias, subungual

hyperkeratosis)

i) Other associated features (lingua plicata,

syndactyly, hair on the palms and the

soles, high arched palate, left handedness)

ii. Vohwinkel PPK mutilans

a) An autosomal dominant disorder

b) Honeycomb-like keratosis of the palms

and soles in infancy

c) Constricting fibrous bands on the digits,

leading to progressive strangulation and

autoamputation

d) Starfish-shaped keratosis on the dorsa of

the fingers and the knees

e) Other associated features (alopecia,

deafness, spastic paraplegia, myopathy,

ichthyosiform dermatosis, and nail

abnormalities)

iii. Olmsted mutilating PPK with periorificial

keratotic plaques (Olmsted syndrome)

(Da Rosa Santos et al. 1997; Tao et al. 2008)


b) Onset in the first year of life

c) Symmetric, sharply circumscribed PPK,

surrounded by erythema with flexion

deformities of the digits, leading to con-

striction and spontaneous amputation

(Poulin et al. 1984)

d) Presence of hyperkeratotic plaques with

a periorificial pattern (Atherton et al.

1990; Lucker and Steijlen 1994)

e) Onychodystrophy

f) Universal congenital alopecia

g) Oral leukokeratosis

h) Joint hyperlaxity

iv. PPK with sclerodactyly


b) Sclerodactyly

c) Diffuse keratoderma more marked on

the soles than the palms

d) Nail abnormalities

e) Hypohidrosis

f) Associated with squamous cell

carcinoma

v. PPK with periodontitis

a) An autosomal recessive disorder

b) Diffuse trangrediens palmoplantar

dermatosis

c) Periodontosis, unless treated, results

in severe gingivitis and loss of teeth by

age 5 years

d) Increased susceptibility to infection

e) Scaly, erythematous lesions often obser-

ved over the knees, the elbows, and the

interphalangeal joints

f) Hyperhidrosis with malodor

vi. Clouston hidrotic ectodermal dysplasia

a) Diffuse, papillomatous PPK

b) Nail dystrophy

c) Universal sparsity of hair

d) Other associated features (sensorineural

deafness, polydactyly, syndactyly, finger

clubbing, mental retardation, dwarfism,

photophobia, and strabismus)

vii. Diffuse NEPPK and sensorineural deafness


b) Diffuse palmoplantar hyperkeratosis

c) Associated with a slowly progressive,

bilateral, high-frequency hearing loss

d) Deafness precedes the skin changes

750 Epidermolytic Palmoplantar Keratoderma

c. Focal (nummular) PPK without associated

features

i. Focal NEPPK


b) Palmar keratosis with a nummular, linear,

membranaceous, fissured, or periungual

configuration

c) Plantar keratosis with a nummular

appearance, localized to pressure points

ii. Focal epidermolytic PPK


b) Nummular keratotic lesions,located

mainly on plantar pressure points

c) Painful lesions

iii. Siemens PPK areata/striata


b) Marked variable phenotypic expression

c) Marked erythema initially, followed by

islands of linear hyperkeratosis

d. Focal (nummular) hereditary PPK with associ-

ated features

i. Oculocutaneous tyrosinemia (tyrosinemia

type II)

a) Focal, painful PPK

b) Bilateral, pseudoherpetic corneal ulceration,

leading to corneal scarring and glaucoma

c) Mental retardation

d) Occasional hyperkeratotic lesions on the

elbows, knees, and tongue

e) Hyperhidrosis

f) Occasional bullous lesions

ii. Pachyonychia congenita

a) Autosomal recessive disorder

b) Localized areas of hyperkeratosis on the

palms and the soles

c) Discoloration and thickening of the nails

iii. Keratosis palmaris and plantaris with carci-

noma of the esophagus

a) Autosomal dominant disorder

b) Age of onset: 5–15 years

c) Focal PPK

d) Increased susceptibility to developing car-

cinoma of the esophagus (38-fold increase)

e) Variable oral leukokeratosis and follicu-

lar keratosis

iv. Focal palmoplantar and oral mucosa

hyperkeratosis


b) Focal PPK, especially on weight-bearing

areas

c) Oral hyperkeratosis

d) Increased severity with age

e) Subungual and circumungual

hyperkeratosis

e. Papular PPK without associated features

i. Keratosis palmoplantaris punctata


b) Asymptomatic, tiny hyperkeratotic pap-

ules present on the palmoplantar surface

c) Absence of associated features in most

patients

d) Spastic paralysis, ankylosing spondylitis,

facial sebaceous hyperplasia reported

e) Possible association with gastrointestinal

malignancy

ii. Acrokeratoelastoidosis


b) Round or oval, yellowish, hyperkeratotic

papules that can appear umbilicated

c) Distribution of the lesions: along the

border of the palms and the soles

d) Associated hyperhidrosis

iii. Focal acral hyperkeratosis


b) Condition similar to acrokeratoelastoidosis

c) Insidious onset in childhood, reaching

maximum in early life

d) Race: African origin

f. Papular PPK with associated features

i. Rare single-pedigree syndromes

a) Syndrome of cystic eyelids, punctate

PPK, hypotrichosis, and hypodontia

(Schopf–Schulz–Passarge syndrome)

b) Punctate PPK with ankylosing spondylitis

c) Punctate PPK with facial sebaceous

hyperplasia

d) Punctate PPK with spastic paralysis

e) PPK with lipomata

ii. Punctate PPK and cancer

g. Acquired palmoplantar keratoderma

i. Inflammatory and reactive dermatoses

a) Hyperkeratotic eczema

b) Psoriasis

c) Reiter syndrome

d) Lichen planus

e) Pityriasis rubra pilaris

Epidermolytic Palmoplantar Keratoderma 751

f) Lupus erythematosus

g) Callosities

h) Darier disease

ii. Infective causes

a) Dermatophytes

b) Viral (human papilloma virus) warts

mimicking keratoderma

c) AIDS-related psoriasis with discrete

keratotic pustular keratoderma

d) Late secondary syphilis in patients

with HIV with diffuse, symmetric

keratoderma or papular PPK

e) Yaws

f) Leprosy

iii. Drugs

a) Chronic arsenic exposure with multiple,

irregular, warty keratosis

b) Lodine: manifestation of drug

hypersensitivity

iv. Cutaneous features of systemic disease

a) Myoedema with hyperkeratosis

b) Diabetes with discrete plantar keratosis

c) Cutaneous T-cell lymphoma with

subungual hyperkeratosis

v. Haxthausen keratoderma climactericum

a) Onset in the 40s

b) Initial lesion: pressure areas on the soles

c) Erythema and hyperkeratosis with fissur-

ing making walking painful

d) Minimal pruritus

e) Discrete and centrally confined palmar

involvement

vi. Keratoderma associated with internal

malignancy

a) Keratoderma as a paraneoplastic phenom-

enon, such as acrokeratosis

paraneoplastica of Bazex associated with

squamous cell carcinoma of the upper gas-

trointestinal tract and acanthosis palmaris

associated with gastric or pulmonary

malignancy in 90% of cases

b) Keratoderma as evidence of predisposi-

tion to malignancy such as late-onset

punctate keratoderma associated with

cutaneous and internal malignancy

h. Syndromes with PPK as an associated features

i. Basal cell nevus syndrome

ii. Congenital bullous ichthyosiform

erythroderma

iii. Congenital nonbullous ichthyosiform

erythroderma

iv. Darier disease

v. Epidermodysplasia verruciformis

vi. Epidermolysis bullosa herpetiformis

vii. Ichthyosis vulgaris

viii. Incontinentia pigmenti

ix. Keratitis, ichthyosis, and deafness (KID)

syndrome

x. Lamellar ichthyosis

Diagnostic Investigations

1. Histology and ultrastructures: cytolysis of

keratinocytes and abnormal aggregation of

tonofilaments in the suprabasal layers of the

epidermis

2. Molecular genetic analysis

a. KRT9 mutations analysis

i. Sequencing of entire coding region

ii. Sequencing of select exons

iii. Targeted mutations analysis

b. KRT1 mutation analysis for patients with no

mutations in KRT9

Genetic Counseling

1. Recurrence risk

a. Patient’s sib: not increased unless a

parent is affected in which case there is a 50%

risk

b. Patient’s offspring: 50%

2. Prenatal diagnosis

a. Not usually requested because of mild nature of

the disease

b. Possible to pregnancy at-risk, provided the

disease-causing mutation has been identified in

the proband

c. Accomplished in a Chinese kindred affected by

EPPK for detection of c. T470C (p.M157T) of

the keratin 9 gene from fetal DNA obtained by

amniocentesis (Chen et al. 2009)

3. Management

a. Topical keratolytics

b. Topical retinoids such as tretinoin


References

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palmoplantar keratoderma with periorificial keratotic

plaques. British Journal of Dermatology, 122, 245–252.Chen, X. L., Xu, C. M., Cai, S. R., et al. (2009). Prenatal

diagnosis of epidermolytic palmoplantar keratoderma caused

by c.T470C (p.M157T) of the keratin 9 gene in a Chinese

kindred. Prenatal Diagnosis, 29, 922–923.Christiano, A. M. (1997). Frontiers in keratodermas: Pushing the

envelope. Trends in Genetics, 13, 227–233.Coleman, C. M., Munro, C. S., Smith, F. J., et al. (1999).

Epidermolytic palmoplantar keratoderma due to a novel

type of keratin mutation, a 3-bp insertion in the keratin 9

helix termination motif. British Journal of Dermatology,140, 486–490.

Corden, L. D., & McLean, W. H. I. (1996). Human keratin

diseases: Hereditary fragility of specific epithelial tissues.

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Mutations in keratin K9 in kindreds with epidermolytic

palmoplantar keratoderma and epidemiology in Northern

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palmoplantar keratoderma. British Journal of Dermatology,150, 647–651.

Lee, R. A., Yassaee, M., Bowe, W. P., et al. (2008). Keratosispalmaris et plantaris. Medscape Reference. Retreived July

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drome: Mutilating palmoplantar and periorificial

keratoderma. Journal of the American Academy of Derma-tology, 31, 508–509.

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and classification. British Journal of Dermatology, 131,1–14.

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tions in two families with epidermolytic palmoplantar

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syndrome – congenital palmoplantar and periorificial

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a b c

Fig. 1 (a–c) A 47-year-old woman with epidermolytic

palmoplantar keratoderma showing diffuse keratoderma affect-

ing both the palms and the soles. The keratoderma had erythem-

atous border at the margins of both palms and soles and was

completely restricted to the palms and soles. The dorsa of the

hands and soles were spared. This patient has multiple affected

relatives in several generations

Fig. 2 This 17-year-old girl was seen for hyperkeratosis of the

palms and soles associated with severe nail hyperplasia of

the toes. She has mental retardation and short stature. Clinically

she has type IV epidermolytic palmoplantar keratoderma with

pachyonychia congenita Fig. 3 She has marked midfacial hypoplasia


Fig. 4 Diffuse thickyellowish hyperkeratosis was

noted on her palms. Her soles

also have same thick yellowishhyperkeratosis

Fig. 5 Her toe nails show

subungual keratinous mass

pushing the nail bed upward


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Atlas of Genetic Diagnosis and Counseling || Epidermolytic Palmoplantar Keratoderma