History

In 1880, Thost described a family with diffuse non-transgrediens PPK. This was followed by Unna’s description of a clinically identical, autosomal dominant PPK in two families. Although “Unna–Thost type” has been used to designate non-epidermolytic PPK (NEPPK), in 1992, Küster et al. reviewed the family described by Thost and found the histologic features of epidermolytic hyperkeratosis, which characterize the “Vörner type” of PPK. Subsequently, after keratin mutations were reported in epidermolytic PPK (EPPK), identical mutations were found in the descendants of the family studied by Thost . This confusion underscores the need for careful histologic examination and sometimes multiple biopsy specimens to identify epidermolytic hyperkeratosis.

Epidemiology

EPPK is likely the most common form of diffuse keratoderma, with an estimated incidence of ≥4.4 per 100 000 in Northern Ireland .

Pathogenesis

Mutations in KRT1 and KRT9 underlie diffuse EPPK. The expression of keratin 9 is limited to the suprabasal cell layers of palmar and plantar skin. In patients with diffuse EPPK, the majority of keratin 9 mutations are localized to a very small area within this gene that encodes the helix initiation motif in the 1A domain (see Ch. 56 ). Such mutations are highly disruptive to keratin filament assembly, causing tonofilament clumping and cytolysis that result in blistering as well as hyperkeratosis.

Within palmoplantar skin, keratin 9 is thought to partner with keratin 1. Of note, mutations in keratin 1 and 10 are associated with epidermolytic ichthyosis (EI; formerly bullous congenital ichthyosiform erythroderma), in which epidermolytic hyperkeratosis is seen histologically (see Ch. 57 ). PPK in EI is predictive of a mutation in keratin 1, which is the only type II keratin expressed in palmoplantar skin. In contrast, EI due to keratin 10 mutations rarely has involvement of palmoplantar skin, likely reflecting compensation by keratin 9, which is also a type I keratin. The majority of mutations in EI patients are in the critical 1A and 2B domains of the keratin molecule . However, when keratin 1 defects underlie diffuse EPPK alone, including the “tonotubular“ subtype, the mutations are typically in the beginning of the 1B domain . Although keratin 1 mutations have been reported in some families with the Greither type of EPPK, other Greither variants with NEPPK not associated with keratin 1 mutations have also been described. Of note, keratin 1 mutations have also been identified in patients with focal PPK (see below).

Clinical features

The palmoplantar skin is initially red, followed by the appearance of thick, yellow hyperkeratosis by 3–4 years of age. In adults, there is confluent hyperkeratosis with a smooth, waxy surface and sharply demarcated erythematous border, sparing the dorsal aspects of the palms and soles ( Fig. 58.5 ). Blistering and fissuring are not common but may occur during childhood or during oral retinoid therapy. Knuckle pads and thickened nails are occasionally present . Disabling pain, especially of the palms, can occur in the “tonotubular” EPPK subtype . The Greither type (PPK transgrediens and progrediens) presents with limited transgredient lesions, e.g. overlying the Achilles tendon, elbows, and knees.

Diffuse epidermolytic palmoplantar keratoderma (Vörner–Unna–Thost).

Diffuse, hyperkeratosis with waxy surface on the palm (A) and soles (B, C) , with sharp demarcation. Note the red borders (A, C) .

C, Courtesy, Alfons Krol, MD, and Dawn Siegel, MD.

Pathology

EPPK shows the typical pattern of epidermolytic hyperkeratosis, which is characterized by vacuolated suprabasal keratinocytes with round or ovoid eosinophilic inclusions that represent large tonofilament aggregates at an ultrastructural level . In the “tonotubular” subtype, electron microscopy shows whorls of keratin containing tubular structures . Histologic findings also include coarse keratohyalin granules, acanthosis, and marked orthohyperkeratosis. Intraepidermal blistering and a mild superficial dermal inflammatory infiltrate may result from keratinocyte cytolysis ( Fig. 58.6A ). The findings of epidermolytic hyperkeratosis are often subtle and patchy, requiring a careful search and often multiple biopsy specimens to enable their identification.

Histologic features of palmoplantar keratoderma.

A In epidermolytic hyperkeratosis, suprabasal keratinocytes show vacuolated cytoplasm, intracytoplasmic eosinophilic granules, and coarse keratohyalin granules. B In non-epidermolytic keratoderma, an extremely thick orthohyperkeratotic horny layer and acanthotic epidermis are seen.

Courtesy, Luis Requena, MD.

Differential diagnosis

EI can be distinguished clinically by the cutaneous involvement beyond the palms and soles. EPPK and NEPPK can be differentiated histologically by the absence of epidermolytic hyperkeratosis in the latter; they are not distinguishable clinically, although the erythematous border of EPPK tends to be more pronounced.

Management

Factors to consider when selecting treatment for diffuse PPK include the severity of symptoms, degree of hyperkeratosis, and age of the patient. Mechanical debridement with a blade or dental drill is useful for troublesome areas, followed by application of a keratolytic agent to help avoid fissure formation. Options for keratolytic therapy include 50% propylene glycol in water under plastic occlusion several nights per week, lactic acid- and urea-containing creams and lotions, and salicylic acid 4–6% in petrolatum; the latter should not be applied to large areas in young children to avoid salicylism from systemic absorption (see Ch. 129 ). Oral retinoids may improve the hyperkeratosis, but even low doses can lead to excessive peeling and increased fragility of volar skin in EPPK . Topical calcipotriene (calcipotriol) has reportedly been helpful .

Epidemiology and pathogenesis

An autosomal dominant form of NEPPK described in a family from Bothnia in Northern Sweden and three English pedigrees is due to heterozygous missense mutations in AQP5 , which encodes aquaporin 5. Aquaporins are transmembrane proteins that allow the osmotic movement of water across the cell membrane. Aquaporin 5 is expressed by keratinocytes in the granular layer, and the gain-of-function mutations that cause Bothnia-type NEPPK lead to increased keratinocyte water uptake rather than transepidermal water loss .

The form of NEPPK described by Kimonis is caused by a heterozygous mutation in a highly conserved lysine residue in the V1 domain of keratin 1 that does not result in epidermolytic hyperkeratosis .

Nagashima -type NEPPK, an autosomal recessive disorder almost exclusively observed in Asia, is caused by biallelic nonsense mutations in SERPINB7. This gene encodes the ser ine p rotease in hibitor family B member 7, which has an unknown protease target in the skin .

Mal de Meleda is an autosomal recessive condition that was first described in inhabitants of the island of Mljet (Meleda) off the Dalmatian coast. It is caused by biallelic mutations in SLURP1 ( s ecreted l eukocyte antigen-6/ u rokinase-type plasminogen activator related p rotein 1 ), which is expressed in the granular layer of the epidermis . SLURP1 acts as a ligand of the α7-nicotinic acetylcholine receptor and plays a role in epidermal differentiation. Heterozygous female carriers may have a mild clinical phenotype.

Clinical features

The clinical findings and time course of the different types of NEPPK are overall similar to those of EPPK (see above). The hyperkeratosis is variably thick and hyperhidrosis is common, with frequent dermatophyte infections and pitted keratolysis. The Bothnia type features a characteristic white spongy appearance upon exposure to water .

In Mal de Meleda, progressive transgredient hyperkeratosis begins during early infancy and becomes severe, impairing the mobility of hands and resulting in hyperhidrotic maceration, severe malodor, and fissures ( Fig. 58.7 ). Fungal superinfection is common, and hyperkeratosis of the fingers may lead to sclerodactyly and digital constrictions (pseudoainhum). The elbows, knees, wrists, and ankles as well as the dorsal surfaces of the hands and feet can be involved, and the nails show thickening, koilonychia, and subungual hyperkeratosis. Angular cheilitis and involvement of the lips and perioral skin may be observed . Hyperpigmented macules, melanoma, and Bowen disease within the keratotic areas have been reported .

Mal de Meleda.

Diffuse, yellow hyperkeratosis characterized by maceration, erythema in areas with reduced hyperkeratosis, progression beyond the palmar area (transgrediens), and a well-defined red border.

Differential diagnosis

In addition to diffuse EPPK, exfoliative ichthyosis and aquagenic palmoplantar keratoderma may be diagnostic considerations.

Pathology

Histologically, palmoplantar skin shows orthohyperkeratosis, hypergranulosis or normogranulosis, and acanthosis ( Fig. 58.6B ). A moderate perivascular lymphocytic infiltrate may be present. In Mal de Meleda, papillomatosis is a characteristic finding. PAS staining should be performed to exclude infection by dermatophytes.

Management

Stronger keratolytic therapy may be helpful, such as 5–10% salicylic acid in white soft paraffin, or 5–6% salicylic acid in 70% propylene glycol gel; occlusion for a few nights per week enhances efficacy, and mechanical debridement can also be performed. Low-dose acitretin (0.2–0.5 mg/kg daily) may be considered, especially for patients with functional impairment. Fungal superinfection and bacterial overgrowth should be treated. Responses to oral erythromycin and topical tacrolimus have been described in the Bothnia and Nagashima types, respectively . Excision of hyperkeratotic skin with split-thickness skin grafting represents an option to relieve functional impairment .