Chapter 50. Inherited Palmoplantar Keratodermas

Inherited palmoplantar keratodermas are individually rare; the prevalence of epidermolytic keratoderma in Northern Ireland was 4.4 per 100,000.9 Autosomal recessive keratodermas may occur with locally high prevalence in sequestered populations or communities amongst whom consanguineous union is common.

Palmoplantar skin is structurally specialized,10 with absence of hair and increased epidermal thickness and rugosity, features necessary to cope with increased friction and mechanical stress. Dermatoglyphics together with eccrine sweat also enhance grip. Localized palmoplantar hypertrophy (callus) is a physiological response to sustained friction, for example, from ill-fitting footwear or manual work. In the inherited PPKs, excessive epidermal thickening is the result of a broad range of pathogenic pathways.

Many keratodermas are associated with defects of keratinocyte structure. The major structural component of keratinocytes is the 10-nm (intermediate) filament cytoskeleton. Keratins are a family of rod-like proteins, expressed in pairs in a tissue and differentiation specific manner, which initially dimerize then assemble to form multimeric intermediate filaments.7 Defects in individual keratins affect skin in a distribution corresponding to the expression pattern of the particular keratin.3 Keratin 9 (K9) is specific to palmoplantar skin, although its likely partner in these sites, keratin 1, is also expressed in hair-bearing skin. Other keratins constitutively or facultatively expressed in palmoplantar skin include K6, K16 (also found in mucosa, hair follicles, and nail bed), and K17 (hair follicles and nail bed11). There are multiple K6 isoforms,12,13 and defects in K6a, K6b, and K6c as well as all the other keratins named above can result in keratoderma. The majority of pathogenic mutations in keratins occur in the highly conserved boundary peptides of the α-helical rod domain regions, which are thought vital for end-to-end overlap interactions during the elongation phase of filament assembly.3 Typically, keratin defects result in a disrupted intermediate filament cytoskeleton. The intermediate filament network is attached to desmosomes, intercellular junctions which in turn form paired plaques with the corresponding structures in adjacent keratinocytes. Defects in desmosomal proteins such as desmoglein 1, desmoplakin 1, plakoglobin, and plakophilin 1 also cause PPK.6 Structural weakness due to keratin and desmosome defects has the potential to cause epidermolysis or acantholysis of keratinocytes, of which hyperkeratosis may be an indirect consequence, but nonmechanical mechanisms are also probable. Keratins, for example, are also involved in the regulation of proliferation, apoptosis, and skin pigmentation.14,15 Moreover, cell stress as a nonspecific response to an accumulation of misfolded proteins may contribute to pathogenesis. Mechanically stressed keratinocytes containing mutant keratins of the type which cause severe epidermolysis bullosa simplex show greater resistance to apoptosis than wild-type keratinocytes; the increased resistance was dependant on an increase in extracellular signal-regulated kinase (ERK) and Akt signaling.16 Keratoderma in tyrosinemia type II may be also due to tonofilament accumulation secondary to excessive intracellular tyrosine.17

Another large group of PPK syndromes are due to defects in connexins, the proteins that make up gap junction communication channels between cells.5 Gap junctions are assembled in plaques containing multiple connexon units, each of which consists of a pair of hemichannels with a central channel through which small molecules (<1 kDa) can pass between the cytoplasm of adjacent cells. Each hemichannel in turn contains six homomeric or heteromeric connexin proteins. The 21 human connexin proteins, like keratins, are expressed in a tissue and differentiation specific manner and the phenotype of gap junction diseases in part reflects their expression pattern. For example, most mutations in the gene (GJB2) encoding connexin 26 (Cx26) cause impaired hearing because the gene is expressed in the inner ear where it is necessary for the circulation of endolymph. Cx26 is also expressed in skin, and some Cx26 defects also cause a cutaneous phenotype, such as PPK. PPK is also found in syndromes due to mutations affecting connexin 30 (Cx30, associated with hidrotic ectodermal dysplasia18,19) and connexin 43 (Cx43; oculo-dental digital dysplasia20). However, point mutations in a single connexin can cause a range of phenotypes depending on the specific amino acid affected. While some pathogenic mutations interfere with the formation of functional gap junctions, others exhibit defects in trafficking to the cell membrane and the connexins instead accumulate within organelles.21 Recent evidence in erythrokeratoderma variabilis (EKV) suggests that accumulation of mutant proteins causes the unfolded protein response.22 In the case of connexin mutations associated with palmoplantar keratoderma, this endoplasmic reticulum stress may be responsible for hyperkeratosis and inflammation.

Other mechanisms of PPK are extremely varied. In loricrin keratoderma, a barrier abnormality is associated with a defective CE scaffold that results in increased extracellular permeability defect.23 The C-terminal peptide of the mutant loricrin includes polybasic nuclear recognition signals which cause the aberrant protein to accumulate in the nucleus, which is likely to interfere with terminal differentiation.24–26 In Papillon–Lefèvre syndrome (PLS), in which PPK is associated with predisposition to pyogenic infection, the cysteine protease cathepsin C is inactive.27 This lysosomal enzyme is important in intracellular protein degradation28 and in the activation of neutrophil serine proteases.29 Its absence may have consequences for the regulation of inflammation,30 but the mechanism of keratoderma may also relate to aberrant desmosomal cleavage. In Mal de Meleda, a secreted nicotinic acetylcholine receptor ligand, SLURP-1, is deficient. The normally expressed protein may act by modulating keratinocyte behavior or inflammatory responses.31–33 Keratoderma is a feature of rare neurodevelopmental syndromes due to defective intracellular vesicle trafficking,34,35 and of keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome where there is a defect in proteasome production.36

Known gene defects causing keratoderma are listed in Table 50-1.

Clinical findings vary between different genetic forms of PPK. The hyperkeratosis may present as multiple papular lesions (punctate PPK), as callosities localized to points of particular stress (focal/areate, or striate PPK) or may extend over the whole palm or sole (diffuse PPK). The distinction between focal, striate, and diffuse forms is not always easy to make, and the severity of PPK may vary, even within a family. Hyperhidrosis is a common complaint amongst patients with focal or diffuse keratodermas. Corynebacterial overgrowth leading to keratolysis and malodor, and secondary dermatophyte infection, is common. Transgredient keratoderma extends onto the dorsa of the hands and other cutaneous sites; circumferential keratoderma of digits is associated with the formation of constricting bands (“pseudoainhum,” see Chapter 68) and sometimes autoamputation (cicatrizing or mutilating keratoderma). It may also cause tapering of the digits (sclerodactyly) with bony atrophy and nail dystrophy. A number of keratoderma syndromes, in particular Huriez and Olmsted syndromes (see below) are characterized by the frequency of squamous cell carcinoma in affected skin; melanoma has also been reported in various PPKs.

Approach to the Patient with Keratoderma

In the history, early age of onset is usual. Punctate keratodermas present in adulthood, but new presentations of diffuse PPK at this age are more likely to be papulosquamous disorders (see Section “Differential Diagnosis”). In inherited PPKs, hyperhidrosis is commonly reported. Pain is a particular feature of focal keratodermas, but in all forms of keratoderma functional, occupational, or social disability should be recorded. A family history, including consanguinity, may be helpful but it is unwise to draw firm conclusions about either clinical type or inheritance patterns without having examined all available members of a pedigree, even if said to be affected. Family history of early onset systemic malignancy or skin cancer should be noted.

The distribution of keratoderma (punctate, focal, striate, or diffuse) is not an absolute guide. Feet tend to be more markedly and diffusely involved, so that in severe cases the underlying pattern may be more obvious on the hands. The appearance of the hyperkeratosis—for example, honeycomb patterned, waxy, or fissured—may be significant. Sharp, livid margins or the presence of transgredient hyperkeratosis on dorsa of hands, feet, and digits should be noted. The possibility of secondary fungal or bacterial infection, and of the development of malignancy, should be considered. It is important to examine the whole skin for signs of other skin diseases such as eczema, psoriasis, and lichen planus. In inherited PPK, mild acral hyperkeratosis may indicate a generalized cutaneous disorder that is locally severe on palms and sole; fissures at the oral commissures and follicular hyperkeratosis are also common. Mild ichthyosis seen in loricrin PPK may be missed if not specifically sought. Many PPKs involve mucosa, including genital mucosa. The presence of other ectodermal abnormalities should be documented, i.e., abnormalities of nails, teeth, hair and hair follicles, sweat glands, and sweating. Finally, specific features associated with syndromic keratoderma should be elicited by history and examination. These include hearing impairment (which may be subtle), neuropathy, and cardiac disease (conduction defects or cardiomyopathy).

A pathway to aid diagnosis (Fig. 50-1) is provided, but is neither comprehensive nor absolute. Individual presentations are discussed in more detail below.

Keratodermas with Mainly Cutaneous Features

Punctate Keratoderma

Punctate keratoderma (Buschke–Fischer–Brauer syndrome; MIM 146800) is usually inherited as an autosomal dominant trait.37 Unlike most other inherited PPKs, punctate PPK presents in adult life as multiple keratinizing papules (Fig. 50-2A). It may be an incidental finding, although plantar lesions can produce significant disability and also cause secondary focal keratoderma. From the gradual accumulation of discrete individual lesions it may be inferred that there is a defect in one inherited allele, and the disease is expressed when the remaining allele is damaged. An association with malignancy of kidney, stomach, breast, and colon, has been reported in a few pedigrees,38,39 but has not been generally substantiated. In any case, the condition is probably genetically heterogeneous. The size of the papules in different families varies from a few millimeters to tiny filiform lesions (music-box spine keratoderma) (see eFigs. 50-2.1 and 50-2.2). Similarly, histology of the lesions may show orthokeratotic or parakeratotic hyperkeratosis. At least two genetic loci have been suggested40,41 although that at 15q22.2–15q22.31 is most certain. Other clinically similar conditions include punctate keratoderma of the palmar creases, and focal acral hyperkeratosis of the margins of palms and soles, with or without elastoidosis. Papular palmoplantar lesions may be seen in other genodermatoses, notably Darier disease (see Chapter 51), in which the pitted lesions common in younger cases become papular with age. Acquired causes of punctate palmoplantar lesions include dioxin toxicity and chronic arsenicism.

Epidermolytic Keratoderma

An example of uncomplicated diffuse keratoderma is epidermolytic PPK (EPPK; Vörner syndrome; MIM 144200). EPPK is probably the commonest PPK,9 and is an autosomal dominant trait due to defects in keratin 9, the one keratin specific to palmoplantar skin.42 It presents in childhood as diffuse PPK with a sharp, livid transition to normal skin at the edge of palms and soles (Fig. 50-2C; see also eFig. 50-2.3). Severe cases may be accompanied by blistering, although in adults the epidermal weakness is more commonly manifested by fissuring. Histology of the stratum spinosum shows vacuolated keratinocytes with keratin filament aggregates at electron microscopic level, accompanied by orthohyperkeratosis of the stratum corneum. Defects in keratin 1, the presumed partner of keratin 9 in palmoplantar skin, also cause diffuse transgredient keratoderma with epidermolytic hyperkeratosis at other cutaneous sites, but extrapalmoplantar involvement may be subtle (see eFig. 50-2.4). A specific defect of the 1B domain of keratin 1 causes tubular tonofilament structures to form in some pedigrees.43 Keratoderma may also be a feature of epidermolysis bullosa of the severe Dowling–Meara type (MIM 131760; 44) due to mutations in the basal layer keratins 5 and 14 (see Chapter 62). The mechanism(s) by which keratin gene defects may give rise to the palmoplantar hyperkeratosis are discussed above.

Nonepidermolytic Diffuse PPK

Nonepidermolytic diffuse PPK restricted to palmoplantar skin is heterogeneous. The term Unna–Thost syndrome (MIM 600962) should probably be discarded, as even the original Thost family in fact had epidermolytic PPK.45 In one pedigree a diffuse nonepidermolytic phenotype was due to a defect in the variable region of the keratin 1 gene,46 and in another was mapped to a locus including the type II keratin gene cluster.47 Another locus proximal to the type II keratin gene cluster has been identified.48

Focal PPK

Focal PPK (see Fig. 50-2 and eFig. 50-2.5) may complicate punctate PPK on the feet, or may occur in isolation; in the latter situation it may be difficult to distinguish from physiological callosities, and indeed the tendency to these may have a genetic basis.49 Early onset focal keratoderma of whatever cause leads to disability (“hereditary painful callosities”), and patients may be so severely affected as to become wheelchair bound. Autosomal dominant pedigrees of focal PPK are commonly associated with nail dystrophy and mucosal features as part of the pachyonychia spectrum, but even in the absence of nail dystrophy may be due to mutation in keratin 16.50 In the majority of cases of focal PPK in isolation, genetic causes have not been identified, but in three pedigrees it has been ascribed to mutations in keratin 6c.49 Painful focal PPK is also found in tyrosinemia type II (see below and Chapter 131).

Striate PPK

Striate PPK (SPPK; MIM 148700) is a distinct variant of focal PPK in which there is prominent linear involvement of the volar surfaces of the digits (see Fig. 50-2B) and less distinctly of corresponding areas of the soles. Histology of autosomal dominant inherited striate PPK shows subtle widening of the intercellular spaces (see Fig. 50-5C). 51,52 Most cases are due to defects in gene encoding desmosomal plaque proteins of which desmoglein 1 (DSG1) is most commonly implicated, but mutations in desmoplakin 1 are also reported.53,54 Keratoderma due to defects in these genes is believed to be due to haploinsufficiency, i.e., reduced amounts of the relevant structural protein expressed in the desmosomal plaque result in mechanical weakness which manifest at points of greatest stress. However, as with keratins, demosomal components are implicated in intracellular signaling and growth regulation. Striate PPK may also be seen with some mutations in keratin 1,55 and indeed striate accentuation is a nonspecific component of milder diffuse keratodermas. Most cases of autosomal dominant SPPK are simple, but defects in desmoplakin also give rise to syndromes of cardiomyopathy and wooly hair (see below).

Loricrin Keratoderma

Loricrin keratoderma (syn. Camisa syndrome; MIM 640117) was described as a variant of Vohwinkel syndrome (VS).56 It is characterized by a similar “honeycomb” patterned and transgredient keratoderma (Fig. 50-3A; see also eFig. 50-3.1), leading to circumferential digital involvement, cicatrizing bands, and sometimes autoamputation. However, there is also a mild generalized ichthyosis, and collodion babies or generalized desquamation at birth are reported.57,58 Compared with true VS, due to mutations in Cx26, the edge of the keratoderma at the wrists is diffuse, and deafness is not a feature. Multiple mutations are reported of which the most frequent mutation, 730insG, has been found in families from the United Kingdom, Japan, Germany, and Italy.24,57,59–64 In all cases they are single nucleotide insertions resulting in a shift of the reading frame and a termination codon delayed by 22 amino acids. In the elongated carboxyl-terminal domain many of the glycine residues are replaced by arginine, drastically altering the properties of the loricrin polypeptide by producing nuclear recognition signals (see above).

Huriez Syndrome

Huriez syndrome (PPK with scleroatrophy, sclerotylosis; MIM 181600), an autosomal dominant disorder, is characterized by diffuse PPK that affects mainly palmar skin (Fig. 50-3C).65–70 The underlying gene defect is unknown but linkage to chromosome 4q23 has been reported.71 Sclerodactyly, brachydactyly, and cutaneous erythema and/or atrophy are typical, as are various nail changes; hypohidrosis is also reported. A deficiency of Langerhans cells in affected skin has been identified.72 The condition predisposes to squamous cell carcinomas of affected skin, occurring in the third to fourth decade, which are unusually prone to metastasis.67,68 Causal treatment is not available, but benefit from oral retinoids is recorded.67

Mal de Meleda

Mal de Meleda (MIM 248300) is a rare autosomal recessive disorder originally described in communities of the Mediterranean littoral. The transgredient (i.e., it extends over the lateral margin of the palms and proximally over the wrists) hyperkeratosis has a waxy ivory to yellow appearance and is typically inflamed or macerated, with a livid margin.73 Dermatophyte superinfection, to which many keratodermas are prone, may mimic these appearances. Knuckle pads, similar waxy lesions on acral sites, angular cheilitis, and circumferential sclerosing and cicatrizing lesions of the digits are typical (Fig. 50-3D; see also eFig. 50-3.2B); not surprisingly nails are often dystrophic. The typical Mediterranean disorder is due to mutations in the ARSB gene encoding SLURP-1, an acetylcholine receptor analog.31,74,75

Other Transgredient Keratodermas

Recessive transgredient and/or mutilating disorders with phenotypes resembling Mal de Meleda are reported,76,77,78,79,80 but appear to be genetically distinct. A very rare autosomal recessive disorder (KLICK syndrome) has been described in which a cicatrizing PPK is associated with ichthyosis and a bizarre striate hyperkeratosis of flexures.81,82 This has recently been shown to be due to defects in POMP which encodes a protein which is a chaperone for proteasome maturation.36 Similarly, pedigrees of autosomal dominant transgredient PPKs have been described. The term Greither syndrome has been used,2,83,84 but may not be a single entity.85 Some autosomal dominant transgredient keratodermas within this spectrum are due to mutations in keratin 1 (Fig. 50-4A),86 but other such pedigrees, for example, Sybert syndrome87 appear not to be keratin disorders.

Keratodermas with Ectodermal Dystrophy

Pachyonychia Congenita

Pachyonychia congenita (PC) is a spectrum of dominantly inherited disorders associated with focal PPK. In addition to painful focal PPK and hypertrophic dystrophy of the distal nail, there are numerous reported associations88 (see eFig. 50-4.1). Two main syndromes are recognised clinically,89 in which various associated features can cause significant additional morbidity and disability. PC-1 (Jadassohn–Lewandowsky; MIM 167210) is associated with follicular keratoses, oral leukokeratosis and hoarseness. Severe oral lesions can resemble mucosal candidiasis90 and laryngeal involvement may produce infantile respiratory obstruction.91 The rarer PC-2 (Jackson–Lawler; MIM 167210) is distinguished by multiple pilosebaceous cysts, teeth present at birth, and hair changes such as protuberant eyebrows. Extensive and infected flexural, vulval or scrotal cysts can present as hidradenitis suppurativa.92 PC-1 is typically associated with mutations in KRT6A or KRT16 and PC-2, with mutations in KRT6B or KRT17, reflecting the expression patterns of the relevant keratins3: for example K16 is a major secondary keratin in orogenital epithelia. Severity varies within and between families, and incomplete phenotypes such as PPK without nail dystrophy or steatocystoma multiplex without PPK may be caused by mutations in the same genes. However, detailed analysis of patients with KRT16 mutations suggests that mutations which predict a more disruptive effect on K16 protein structure produce a more severe phenotype.93 A recent large study casts doubt on the consistency of the association of clinical syndrome and mutated keratin94 and it has been proposed instead that PC be designated according to the affected keratin—PC-6a, PC-6b, etc. and PC-U (unknown).95 Genotypic classification has the aim of individualising targeted molecular therapy, already promising in this disorder.8

Schöpf–Schulz–Passarge Syndrome

Schöpf–Schulz–Passarge syndrome (SSPS96; MIM 227450) appears to be allelic with onycho-odonto-dermal dysplasia (OODD; MIM 257980), a spectrum of autosomal recessive ectodermal dysplasias with a core phenotype of abnormal nails, oligodontia with abnormal teeth, and hypotrichosis.97 Dental anomalies may occur in heterozygotes. Features in addition to palmoplantar keratoderma (see eFig. 50-4.2) include erythematous facial lesions and atrophic lingual papillae. In SSPS, patients commonly develop benign adnexal tumors. Apocrine hydrocystoma, presenting as eyelid cysts is characteristic of SSPS: eccrine poroma and syringofibroadenoma also occur.98 Squamous and basal cell carcinomas and porocarcinomas are reported in affected skin. Disorders within the OODD spectrum are due to mutations in WNT10a97,99–101; the protein encoded by this gene is a member of a family of secreted signaling molecules which inhibit degradation of the β-catenin complex and hence allow it to modulate gene expression. WNT signaling is important in many developmental pathways, and WNT10a is implicated in dental and hair follicle morphogenesis, and the formation of ectodermal ridges.

Olmsted Syndrome

Olmsted syndrome (mutilating palmoplantar keratoderma with periorificial plaques,102–105) is a severe disorder. Congenital diffuse, sharply demarcated, and progressive keratoderma of palms and soles causes flexion deformities, constrictions, autoamputation, and obliteration of digits. Periorificial keratoses are characteristic but associated symptoms include a variety of nail dystrophies and hypotrichosis. The disease usually manifests within the first 6 months of life and is progressive. A number of patients have developed squamous cell carcinoma in affected skin. The genetic basis is unknown. Most cases are sporadic but it may be autosomal dominant. In children, the disorder must be distinguished from recessive transgredient PPKs including Mal de Meleda and, because of the periorificial keratoses, acrodermatitis enteropathica.

Other Ectodermal Syndromes with Keratoderma

PPK is found in the Naegeli–Franceschetti–Jadassohn syndrome (MIM 161000) and dermatopathia pigmentosa reticularis (MIM 125595), allelic syndromes due to dominant mutations in the nonhelical E1/V1 domains of keratin 14.106 Other features include absent dermatoglyphics, reticulate pigmentary anomalies, hypohidrosis, and other subtle ectodermal defects. PPK also occurs with keratin 5 and 14 defects in the severe Dowling–Meara form of epidermolysis bullosa simplex44 in Kindler syndrome, due to mutations in FERMT1 encoding kindlin-1, a cell adhesion molecule involved in signaling via the actin filament network,107 and in ectodermal dysplasia with skin fragility due to defects in the desmosomal protein plakophilin 1.54 PPK is found in hidrotic ectodermal dysplasia (Clouston syndrome, MIM 129500), due to mutations in GJB6 encoding connexin 30 (Cx30, see Chapter 142),18 which can mimic PC,108 and in oculo-dento-digital-dyplasia (ODDD; MIM 164200) due to mutations in GJA1 encoding Cx43.20 Similarly, PPK may be part of the presentation of erythrokeratoderma variabilis (MIM 133200; Chapter 49) which is due to mutations in GJB3 or GJB4.4

Other Keratodermas with Oral or Mucosal Features

Howel–Evans Syndrome

Howel–Evans syndrome [Tylosis and (o)esophageal cancer, TOC; MIM 148500] is an exceptionally rare autosomal dominant disorder; only a few families are known. In the original report by Howel–Evans et al,109 18 of 48 individuals who had PPK developed squamous cell carcinoma of the esophagus at an average age of 43 years. Palmoplantar hyperkeratosis appeared on average 30 years earlier. The keratoderma is characterized by thick yellow focal hyperkeratosis most prominent on the pressure sites (Fig. 50-4C; see also eFig. 50-4.3).110 Pain is not a major feature, and the palms are only involved in manual workers. Confluent hyperkeratoses over pressure sites on the feet may lead to more diffuse involvement. Oral leukoplakia precedes plantar lesions in children. Follicular hyperkeratosis also occurs and the major differential distinction to be made is with PC or focal PPK with oral leukokeratosis. In the latter disorders, nail abnormalities are usually present, although sometimes subtle. The disorder has long been mapped to chromosome 17q25.111 Causative mutations have recently been found in RHBDF2.112 This inactive member of the rhomboid family of intramembrane serine proteases may normally inhibit an active rhomboid protease; mutations may interfere with epidermal growth factor and EphrinB3 signalling.

Papillon–LefèVre Syndrome

PLS (PPK with periodontitis, MIM 245000) is an autosomal recessive disorder caused by mutations in the CTSC gene coding for the proteolytic enzyme cathepsin C.27,113 PLS is characterized by a diffuse palmoplantar erythematous and fissured hyperkeratosis (Fig. 50-4B) with transgredient erythema, and peridontitis.114 If untreated, deciduous teeth may be lost by the age of 4–5 years, and subsequently, permanent dentition may also be lost. Redness and thickening of the palms and soles usually occur in the first years of life, coincidental with eruption of the deciduous teeth.115 Typically, PLS patients show scaly erythematous psoriasiform lesions over knees, elbows, and interphalangeal joints. Transverse ridging of nails, onychogryphosis, sheeted follicular hyperkeratosis and a subtle, generalized white opalescence of oral mucosa, and dural calcification, have also been reported. Associated plantar hyperhidrosis can cause malodor. Patients are susceptible to skin infections (with Staphylococcus aureus) and pyogenic liver abscesses.116 Loss of permanent dentition will lead to improvement of the periodontitis, but patients benefit greatly from adequate dental hygiene and care. Haim–Munk syndrome (HMS, MIM 245010) is allelic with PLS,117 but is a distinct disorder which appears to have arisen in the Jewish population of Kochi, Kerala, India. In HMS, the features are more severe and extensive, and there are additional manifestations of arachnodactyly, acroosteolysis, atrophic nails, and pes planus. The recently described autosomal dominant hypotrichosis–acro-osteolysis–onychogryphosis–palmoplantar keratoderma–periodontitis (HOPP) syndrome combines periodontitis, acro-osteolysis, and psoriasiform skin lesions with a unique focal or reticular keratoderma and progressive scarring alopecia118,119; CTSC mutations have been excluded in the three reported cases.

Keratodermas with Cardiac Disease

Naxos Disease

Naxos disease (MIM 601214), first reported in pedigrees from the eponymous Greek island, is an autosomal recessive disorder.120 Patients have a diffuse, gray–yellow fissuring but nonepidermolytic keratoderma, wooly hair, and arrhythmogenic right ventricular cardiomyopathy (ARVC) causing heart failure and sudden death. The disease is due to homozygosity for a deletion mutation in the gene for the desmosomal plaque protein junctional plakoglobin (JUP), which causes a frameshift and premature termination of the protein.121 More than 90% of homozygous individuals have electrocardiographic abnormalities (mostly T wave inversion in V1–V3 leads), associated with arrhythmias, syncope, heart failure, and sudden death,122–125 but heterozygotes show no overall increased cardiac morbidity or mortality. Another mutation in JUP caused dominant ARVC without cutaneous features.126 Conversely, in two pedigrees with keratoderma, skin fragility and wooly hair in the absence of cardiac disease, homozygosity for novel recessive mutations in JUP has recently been reported.127

Carvajal–Huerta Syndrome

Carvajal–Huerta syndrome (MIM 605676) is the association of striate keratoderma, wooly hair, and dilated left ventricular cardiomyopathy.128 It is a recessive disorder due to truncating mutations in the desmoplakin gene (DSP) which cause the protein to lose its C-terminus.129 Affected family members present with striate PPK, with some extravolar involvement at sites of pressure. The associated dilated left ventricular cardiomyopathy, developing in teenage years, is characterized by cardiac enlargement and disrupted cardiac contraction.123 A range of phenotypes with right, left, or biventricular arrthymogenic cardiomyopathy in isolation or combined with wooly hair and other ectodermal features including keratoderma, are due to dominant or recessive mutations in desmoplakin.125,130–132 Larger truncations in DSP give rise to lethal acantholytic ectodermal dysplasia.133

Mild PPK with ARVC and wooly hair due to recessive mutation in desmocollin-2 has been reported.134

Keratodermas with Impaired Hearing

Many autosomal dominant palmoplantar keratoderma syndromes with sensorineural hearing loss are caused by mutations in the gap junction genes GJB2 or GJB6, encoding the gap junction proteins Cx26 and Cx30, respectively.4,19,135–138 Mutations in GJB2, encoding Cx26, usually cause nonsyndromic deafness, but a minority are responsible for most of the PPK-deafness syndromes. There is a wide range of overlapping phenotypes, and almost every Cx26 mutation associated with PPK has a clinically distinct phenotype.139,140 Amongst these, VS is most dramatic, with honeycomb patterned keratoderma, “starfish” acral keratoses, constricting bands, and autoamputation141–143 (Fig. 50-3B; see also eFig. 50-4.4). Even in this syndrome the PPK may be focal, papular, or diffuse. Acral hyperkeratosis is found in other Cx26 PPKs; in the case of Bart–Pumphrey syndrome as knuckle pads. Constricting bands around the fingers and autoamputation occur when there is confluent transgredient PPK. The genotype–phenotype correlation is poorly understood, but mutations that cause PPK and deafness tend to cluster in the extracellular domains of Cx26.5,140 Other mutations in GJB2 give rise to more severe syndromes in which PPK is part of a generalized oculo-cutaneous disorder: keratitis ichthosis and deafness (KID; MIM 148210) and hystrix ichthyosis and deafness (HID; MIM 602540).144,145 These disorders are described in Chapter 49.

A specific mutation in mitochondrial DNA, A7,445G, has been reported as causing the combination of hearing loss and a variable keratoderma (Fig. 50-4E) with matrilineal inheritance in pedigrees from New Zealand, Scotland, Japan, Portugal, and Hungary.146–149 This segment of the mitochondrial genome encodes a serine transfer RNA, MTTS1. Penetrance of both features is incomplete, and the same mutation has been reported as a familial cause of impaired hearing in the absence of observed keratoderma.

Keratodermas with Neuropathy or Mental Retardation

Two autosomal recessive syndromes with the combination of neuropathy and mental retardation have been documented genetically. CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma; MIM 609528) is due to a 1-bp deletion in SNAP29, which encodes a SNARE protein involved in vesicle fusion.34,150 MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is due to a splicing defect in the AP1S1 gene, encoding a subunit of one of the adaptor protein complexes which regulate vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles.35 The similarities between the disorders may be explained by the fact that the AP1 complex interacts with the SNAP29 gene product in the transport vesicles. In other reported pedigrees, PPK was combined with spastic paraplegia or motor and sensory neuropathy,151–153 but as yet causative mutations have not been identified.

Tyrosinemia Type II

Tyrosinemia type II (Richner–Hanhart syndrome, MIM 276600) is a very rare autosomal recessive disorder154,155 due to deficiency of tyrosine aminotransferase, leading to accumulation of tyrosine and phenolic acid metabolites156 (see Chapter 131). Clinical characteristics include painful focal palmoplantar hyperkeratosis, photophobia, and corneal erosions that may cause scarring or glaucoma.154–159 Eye lesions precede the skin phenotype but the latter may occur in the absence of ocular involvement. Histopathological examination shows eosinophilic inclusions in the basal layer of the epidermis and increased keratohyaline granules. It is suggested that excess tyrosine enhances cross-links between aggregated tonofilaments and stabilizes microtubules.17 The untreated syndrome causes psychomotor retardation, but a diet low in phenylalanine and tyrosine will both ameliorate cutaneous symptoms and prevent further mental deterioration.

Histologically, keratodermas are characterized by definition by increased stratum corneum thickness often with hypergranulosis but acanthosis, papillomatosis, and increased stratum lucidum vary. Where vacuolar degeneration and epidermolysis are present, it suggests keratin 9 defects (Fig. 50-5A), but it may be necessary to biopsy weight-bearing sites to maximize the chance of finding it. Normal palmoplantar skin contains increased numbers of tonofilaments on electron microscopy.10 Abnormal aggregated keratin intermediate filaments in EPPK160 and tonotubular structures in a rare variant form43,161 are identifiable. Overt epidermolysis is not a major feature of PPK due to defects of other keratins, but prominent eosinophilic cytoplasm and keratin aggregates can be identified in most cases of PC (Fig. 50-5B52; Zamiri, unpublished data). Increased tonofilaments and microtubules are also reported in tyrosinemia type II.17

In desmosomal disorders, there is increased separation between keratinocytes, although frank acantholysis is unusual with desmoglein mutations (Fig. 50-5C).51,52 Ultrastructurally, desmosomal plaques may be reduced in number or poorly formed, and keratin aggregation and compaction has also been noted with desmoplakin mutations.51,162,163 In loricrin keratoderma, retained nuclei may be seen in the stratum corneum in which the mutant loricrin is detectable.164 In Mal de Meleda, and in PLS, perivascular inflammation may be prominent, although this is a nonspecific finding in other keratodermas. The pathologist should also look for fungal spores or hyphae.

Punctate keratoderma may be orthokeratotic or parakeratotic. The latter in two dimensions resembles the coronoid lamella of porokeratosis, but nonannular lesions are not true porokeratoses. Whether these variations are of nosological significance remains to be determined.

The cysts of PC include epidermoid and vellus hair cysts as well as true steatocysts, and indeed a single cyst may vary in its histology in different sections. The periodontal lesions of PLS show pockets of epithelium with ulceration and a mixed inflammatory cell infiltrate.

It is important to bear in mind the possibility of the development of squamous cell carcinoma or melanoma within keratoderma, and any changing or suspicious area should be biopsied.

Further investigation will be determined by the clinical syndrome; for example, audiometry, cardiac, or esophageal studies. In Olmsted syndrome, acrodermatitis enteropathica should be excluded by measuring serum zinc. Skin scraping for mycology remains the most useful investigation for many patients with keratoderma.

It is increasingly possible to obtain confirmation of the gene defect in familial keratodermas, particularly those involving connexins, by sending DNA to specialist commercial, or academic laboratories, but a reasonably strong clinical suspicion of the gene responsible is usually needed. Molecular diagnosis is particularly useful to distinguish focal PPKs with oral lesions, due for example, to keratin 16 mutations, from Howel–Evans syndrome.

See Box 50-1 and eFig. 50-5.1.

Management of Keratoderma

Many patients with PPK, particularly those with diffuse varieties, tolerate the condition without specific treatment. Patient-led self-help groups catering for rare and orphan disorders offer valuable support, but the rarity of individual conditions means that specific advice is difficult to obtain. An important exception is the Pachyonychia Congenita Project (www.pachyonychia.org).

For patients with focal keratoderma, which is often painful and sometimes disabling, regular paring by a podiatrist or the patient him/herself helps to control hyperkeratosis. Topical keratolytic agents such as salicylic acid ointment (5%–20%) or benzoic acid compound ointment help to soften the hyperkeratosis prior to abrasion. Propylene glycol (40%–60% in aqueous cream under occlusion at night) can also soften hyperkeratosis and aid reduction of callosities.

Many patients complain of hyperhidrosis for which simple measures such as topical aluminum chloride hexahydrate may be used. Suitable ventilated footwear, insoles, and “wicking” socks (available from suppliers of outdoor walking equipment) may offer some relief. Botulinum toxin has been successfully used to reduce plantar pain but requires regional anesthesia.165 Malodor due to keratolytic corynebacterial infection of macerated hyperkeratosis, and fungal superinfection are also common. Where present, topical or systemic antimicrobials produce worthwhile benefit, but need to be repeated.

Oral retinoids are frequently tried but there are few systematic studies. Acitretin (10 mg/day or more), etretinate, or isotretinoin may all help, particularly in keratin, loricrin, or connexin disorders; successful use in PLS and Mal de Meleda is also reported. However, individual dosimetry may need to be adjusted carefully as excessive shedding of hyperkeratosis can cause palmar and plantar skin to become tender. In conditions with painful callosities such as PC, retinoids may reduce the thickness of the hyperkeratoses but aggravate the pain. If successful, lifelong treatment is required, with its associated risks. Oral retinoids have also been used to rescue impending autoamputation due to circumferential constricting bands.166–168 A few reports suggest topical (or systemic) 5-fluorouracil may benefit punctate or filiform keratoderma.169–171 Surgical treatment, including excision and grafting, has been reported,172 most commonly used to prevent permanent contracture in Olmsted syndrome.173–176 Surgical release of constricting bands has had poor outcomes and asymptomatic lesions are probably best left alone.177

For severe disorders where the genetic etiology is known, prenatal diagnosis is technically possible as a preventive strategy. Specific gene therapy is an exciting but still distant prospect for disorders of known etiology. However, a recent study in PC has shown that inhibition of mutant gene expression by repeated injection of a specific small interfering RNA (siRNA) was effective in reducing hyperkeratosis.8