Ichthyosis vulgaris (OMIM 146700) is the most common disorder of keratinization (incidence 1 : 250), with an onset in early childhood and an autosomal dominant inheritance.^{27. and 37.} Heterozygotes show a very mild phenotype with incomplete penetrance (semidominant); such cases may be misdiagnosed as dry skin.^{11. and 41.} The disorder is lifelong. It is characterized by fine, whitish scales involving particularly the extensor surfaces of the arms and legs, as well as the scalp. Flexures are spared. There may be accentuation of palmar and plantar markings, keratosis pilaris, and features of atopy.

In ichthyosis vulgaris, there is a deficiency in profilaggrin which is converted into filaggrin, the major protein of keratohyalin.^{17. and 42.} There are quantitative decreases in filaggrin, related to the severity of the disease. ⁴³ This results from loss-of-function mutations in the gene encoding filaggrin (FLG), located at 10q21.11.^{44.45. and 46.} The gene is unusually large and repetitive, making analysis of it difficult. ¹¹ Mutations in the FLG gene occur in approximately 9% of individuals from European populations. ⁴⁷ Childhood eczema is strongly associated with these common European mutations.^{48. and 49.} A previously unreported genetic locus for ichthyosis vulgaris has been identified in two Chinese families on chromosome 10q22.3–q24.2. ⁵⁰ No specific gene has, as yet, been identified.

The treatment of ichthyosis vulgaris will depend on the severity of the disease. In mild cases emollients and keratolytics may suffice. Hydration can be achieved with 12% ammonium lactate cream or lotion and keratolysis with a 6% salicylic acid gel. Many products on the market contain urea or propylene glycol and benefit these patients. ⁵¹ Topical retinoids may also be beneficial. Future therapy may be directed towards compounds that increase filaggrin expression in keratinocytes, such as oleanolic acid and ursolic acid, and other products in medicinal herbs and plants. ⁴⁷

This form of ichthyosis (OMIM 308100), which is inherited as an X-linked recessive trait, is present at birth or develops in the first few months of life. It is characterized by large polygonal scales which are dirty brown in color and adherent. X-linked ichthyosis may involve the entire body in varying degree, although there is sparing of the palms and soles. The preauricular region is characteristically involved in this variant of ichthyosis; in contrast, this site is usually spared in ichthyosis vulgaris. ⁵³ Corneal opacities and mental retardation may also occur in X-linked ichthyosis.^{54.55.56. and 57.} Other rare associations include congenital dislocation of the hip, ⁵⁸ Poland’s syndrome (unilateral absence of the pectoralis major muscle – OMIM 173800) ⁵⁹ and Kallmann’s syndrome (hypogonadism, renal agenesis, anosmia and synkinesis – OMIM 308700). ⁶⁰ Interestingly, X-linked ichthyosis and Kallmann’s syndrome result from abnormalities in contiguous genes. ⁶⁰ It has also been associated with the oculo-auriculo-vertebral spectrum (Goldenhar syndrome – OMIM 164210). ⁶¹ Ichthyosis vulgaris and X-linked ichthyosis have been reported in the same family. ⁶² Male-pattern baldness does occur, despite earlier claims to the contrary.^{63. and 64.}

Its incidence is approximately one in 5000–6000 males, but occasionally female heterozygotes have mild scaling of the legs. ⁵⁷ Full expression of the disease has only been reported in a few females. ⁶⁵

This condition is characterized by a deficiency of steroid sulfatase in a wide range of tissues, including leukocytes and fibroblasts. As a result there is an accumulation of cholesterol sulfate in the pathological scales and in serum and leukocytes.^{16.66.67.68. and 69.} Accumulation in the skin interferes with normal barrier function^{70. and 71.} and with proteases involved in the dissolution of desmosomes required for desquamation of the stratum corneum. ²⁰ There are elevated levels of cholesterol sulfate and dehydroepiandrosterone in the serum. ⁷² The deficiency in placental sulfatase which is also present results in decreased maternal urinary estrogens and a failure to initiate labor in some cases. ⁵⁴ The steroid sulfatase (STS) gene is on the distal short arm of the X chromosome (Xp22.3). ⁵⁵ Most cases involve complete or partial deletion of the STS gene and flanking sequences.^{73.74.75.76.77.78.79. and 80.} The defect is usually inherited and it is not due to a de novo mutation. ⁸¹ In most cases, there appears to be paternal transmission of the affected X chromosome. ⁸⁰ FISH analysis is best performed for an accurate diagnosis of the female carrier state. ⁸²

Treatment regimens similar to those for ichthyosis vulgaris can be used.

In recent years there has been an attempt to reclassify the autosomal recessive ichthyoses previously known as lamellar ichthyosis (LI) and non-bullous congenital ichthyosiform erythroderma (CIE) as ichthyosis congenita on the basis of ultrastructural findings suggesting that there are at least four types.^{86.87. and 88.} It has an estimated prevalence of one in 300 000 newborns and most of the infants are born as ‘collodion babies’. ⁸⁹ This new classification has not yet been widely accepted by clinicians; furthermore, inheritance and ultrastructure have not always proven to be a reliable basis for classifications. A defect in keratinocyte transglutaminase has been detected in about 50% of the families studied. ⁹⁰

To date, six genes have been identified for autosomal recessive congenital ichthyosis. They include TGM1 on chromosome 14q11, ABCA12 on chromosome 2q34–q35, ⁹¹ichthyin on chromosome 5q33, ALOXE3 and ALOX12B on chromosome 7p13, and CYP4F22 (FLJ39501) on chromosome 19p12–q12.^{89. and 92.} Two additional loci have been identified, the first on chromosome 19p13.2–p13.1 (? CYP4F22) and the second on chromosome 12p11.2–q13. ⁸⁹ In addition, mutations in CG1-58/ABHD5 on chromosome 3p21 have been found to underlie Chanarin–Dorfman syndrome (OMIM 275630). ⁸⁹ Another syndromic congenital ichthyosis is hypotrichosis, caused by a mutation in ST14 on 11q24.3–q25. The gene encodes the serum protease matriptase. ⁹³ The genes in the LOX cluster are involved in the subset of congenital ichthyosis known as (non-bullous) congenital ichthyosiform erythroderma. ⁸⁹

The four subtypes of ichthyosis congenita are discussed below. This classification may need to be modified or abandoned as overlapping ultrastructural features have been reported between some of the types. ⁹⁴

The term ‘bullous ichthyosis’ is preferred to bullous congenital ichthyosiform erythroderma (OMIM 113800), and to epidermolytic hyperkeratosis (which merely describes a histological reaction pattern).^{138.139. and 140.} Despite this confusion in terminology there is a resurgence in the use of the term epidermolytic hyperkeratosis.^{141. and 142.} Bullous ichthyosis is a rare, autosomal dominant condition which is usually severe and characterized at birth by widespread erythema and some blistering. ²⁸ Coarse, verrucous scales, particularly in the flexures, develop as the disposition to blistering subsides during childhood. Annular plaques, of late onset, have been reported. ¹⁴³ It has been associated with hypocalcemic vitamin D-resistant rickets. ¹⁴⁴

Bullous ichthyosis is a clinically heterogeneous condition.^{145.146.147.148.149. and 150.} Six subtypes were recently defined, the presence or absence of palmoplantar keratoderma being used as a major feature in defining the subtypes. ¹⁵¹ There is some evidence to suggest that cases with severe palmoplantar keratoderma (type PS-1) have abnormalities in KRT1, while those without have abnormalities in KRT10.^{142.152.153. and 154.} In cases of palmoplantar keratoderma without diffuse cutaneous lesions, defects in KRT9 are usual. The commonest abnormality in KRT10 involves an arginine to histidine substitution at one point.^{155. and 156.} Other substitutions have been reported.^{157.158. and 159.} No abnormality in KRT1 or KRT10 has been detected in some cases, suggesting that other genes may be involved. Keratin 1 and 10 are coexpressed to form keratin intermediate filaments in the suprabasal layers of the epidermis.^{149.151.160.161.162. and 163.} The KRT1 and KRT10 genes are located on chromosome 12 in the type II keratin cluster. Approximately 50% of cases involve spontaneous mutations in either gene. ¹⁶⁴ Clinical variants of bullous ichthyosis include a rare acral group (not included in the six subtypes mentioned above), ¹⁰ an annular form (due in one case to a KRT10 mutation),^{161.165. and 166.}ichthyosis hystrix of Curth–Macklin (OMIM 146590) due to mutations in the keratin 1 (KRT1) gene at 12q13, and characterized ultrastructurally by perinuclear shells of unbroken tonofilaments), ¹⁶⁷ichthyosis hystrix of Lambert,^{168. and 169.} and ichthyosis bullosa of Siemens.^{170.171.172.173.174.175.176.177.178. and 179.} Ichthyosis bullosa of Siemens (OMIM 146800) is due to mutations in the keratin 2e gene (KRT2) at 12q11–q13, in contrast to the mutations in keratin 1 or 10 in patients with epidermolytic hyperkeratosis/bullous congenital ichthyosiform erythroderma.^{180. and 181.} It is autosomal dominant. The hyperkeratosis is usually limited to the flexural areas and there is no erythroderma. ¹⁸² There is circumscribed shedding of the stratum corneum over hyperkeratotic skin (the Mauserung phenomenon).^{182.183. and 184.}Ichthyosis exfoliativa (exfoliative ichthyosis – OMIM 607936) is said to have a similar genetic defect and clinical features to ichthyosis bullosa of Siemens, but one report has suggested that there is no epidermolytic hyperkeratosis on histology.^{185. and 186.} It also appears to be autosomal recessive with linkage to 12q13.^{187. and 188.}

Prenatal diagnosis can be made at approximately 19 weeks by fetal skin biopsy examined by light and electron microscopy; ¹⁸⁹ it can be made earlier (10–11 weeks’ gestation) by direct gene sequencing of chorionic villus samples.^{190. and 191.}

Retinoid therapy is particularly effective in patients with KRT10 mutations, but not in patients with KRT1 mutations. ¹⁹² The mosaic form of this disease has been successfully treated with topical maxacalcitol, a vitamin D3 analogue with approximately 10 times greater efficacy at suppressing keratinocyte proliferation in vitro than calcipotriol. ¹⁹³

Netherton’s syndrome (OMIM 256500) is a rare autosomal recessive disease characterized by the triad of ichthyosis, trichorrhexis invaginata (bamboo hair), and an atopic diathesis with elevated levels of IgE.^{198.199.200.201.202.203.204.205. and 206.} Infants are usually born with ichthyosiform erythroderma which may persist, ²⁰⁷ or eventually become a milder, migratory and polycyclic ichthyosis known as ichthyosis linearis circumflexa (ILC). Patches of ILC do not usually appear until after the first year of life, sometimes delaying the diagnosis.^{208.209.210. and 211.} Other clinical manifestations include intermittent aminoaciduria, elevated serum levels of interleukin 18 (IL-18), mental retardation, enteropathy, and hemihypertrophy.^{212. and 213.}

Netherton’s syndrome is due to mutations of SPINK5 on chromosome 5q32.^{214. and 215.} It is telomeric to the cytokine gene cluster at 5q31. ²¹⁶SPINK5 encodes the lymphoepithelial-Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor which has a crucial role in epidermal growth and differentiation.^{209.214.215.217. and 218.} An immunohistochemical test for the presence of LEKTI in skin has been developed. It is absent in Netherton’s syndrome. ²¹⁹ There is some correlation between the mutations and the phenotype. ²²⁰

Other hair shaft abnormalities such as pili torti, trichorrhexis nodosa, and monilethrix have also been reported in Netherton’s syndrome.^{221. and 222.} The hair shaft abnormalities are more common in eyebrow than scalp hair. ²²³ Hair shaft changes may not appear until 18 months of age. ²²⁴ The diagnosis has been made by dermoscopy of the hairs in one suspected case; trichorrhexis invaginata was present. ²²⁵

Disturbances in the immune system have been reported in several patients with Netherton’s syndrome. ²²⁶ This may be the explanation for the finding of infections, including HPV infection, superimposed on the ichthyotic lesions.^{227. and 228.} Squamous cell carcinomas may develop. ²²⁹ CD30⁺ T-cell lymphoma developed in one patient with Netherton’s syndrome who underwent a heart transplant for idiopathic cardiomyopathy. ²¹⁷ Cases with phenotypic overlap with the peeling skin syndrome (see p. 278) have been reported.^{230. and 231.} The keratin filaments from the scales in Netherton’s syndrome are composed of reduced amounts of high molecular subunits and increased amounts of low molecular subunits. ¹⁹⁸ Some patients may have ichthyosis linearis circumflexa in the absence of features of Netherton’s syndrome.

Various treatments have been used with variable success. Emollients are useful adjuncts with other therapies. Topical corticosteroids are moderately effective, but their long-term use is contraindicated. Topical retinoids may eventually result in aggravation of the condition. Topical calcipotriol, PUVA, cyclosporine (ciclosporin), and ammonium lactate 12% lotion have also been used. ²³² Good control was obtained with tacrolimus and pimecrolimus in one report, ²³² but another found no benefit from tacrolimus. ²⁰⁶

Erythrokeratodermia variabilis (EKV – OMIM 133200) is a rare, usually autosomal dominant form of ichthyosis that develops in infancy; uncommonly it is present at birth. ²³⁵ A rare autosomal recessive variant is now recognized. ²³⁶ There are transient erythematous patches and erythematous hyperkeratotic plaques which are often polycyclic or circinate.^{27.32.237. and 238.} Lesions may resemble erythema gyratum repens. ²³⁹ A targetoid appearance is seen in the rare cocarde variant.^{240. and 241.} Follicular hyperkeratosis has been described. ²⁴² There is retention hyperkeratosis associated with a basal cell type of keratin. ²⁴³

The disorder has been mapped to chromosome 1p35.1, but is genetically heterogeneous. EKV may be caused by mutations in one of two neighboring connexin genes, GJB3 and GJB4, encoding the gap junction proteins Cx31 and Cx30.3 respectively.243.^{244.245.246.247. and 248.} Sporadic cases also occur. Cases with no identifiable gene defect have been reported. ²⁴⁹ Cx31 is expressed predominantly in the stratum granulosum in normal skin. ²⁵⁰ The ‘new’ type of erythrokeratoderma reported by van Steensel et al²⁵¹ has subsequently been reclassified as KLICK syndrome (OMIM 601952).^{252. and 253.}

Progressive symmetric erythrokeratodermia (OMIM 602036), thought at one time to be the same condition, appears to be a variant with its own specific abnormality, a mutant loricrin gene.^{26. and 254.} Loricrin and connexin gene mutations were absent in one case. ²⁵⁵ It differs from EKV by a greater incidence of palmoplantar keratoderma and the absence of migratory erythematous lesions. ²⁵⁶ As the name suggests, the symmetry of the lesions in this variant is more striking. ²⁵⁶ Profilaggrin N-terminal domains are aggregated with mutant loricrin within condensed nuclei. These nuclei persist in the cornified layer as parakeratosis. ²⁵⁷ The ichthyotic variant of Vohwinkel’s syndrome also has this abnormality. Progressive symmetric erythrokeratodermia could well be reclassified in the future as Vohwinkel’s syndrome or under the simplistic title of loricrin keratoderma (OMIM 604117). ²⁵⁸ Heterogeneous phenotypes of loricrin keratoderma may be the result of genetic heterogeneity of loricrin mutations. ²⁵⁹

EKV is said to be one of the most responsive genodermatoses to oral retinoids, although their use in children remains controversial. ²⁶⁰ Relapse usually occurs on cessation of the treatment. ²⁵⁶ Topical tretinoin 0.05% cream has also been used. Others have reported a lack of response to retinoids, but success with tazarotene gel. ²⁶¹ Topical tacalcitol has also been used. ²⁴⁹ As for all keratotic diseases, emollients and keratolytics should be used first, or as adjuvants.

Harlequin ichthyosis (OMIM 242500) is a severe disorder of cornification. It is usually incompatible with extrauterine life and is of autosomal recessive inheritance.^{28. and 263.} There appears to be genetic heterogeneity.^{264.265. and 266.} It is characterized by thick, plate-like scales over the entire body with deep fissures. ²⁶⁷ Ectropion, eclabium, and flattened ears are other features of the disease. ²⁶⁸ It has been reported in association with hypothyroidism and juvenile rheumatoid arthritis in one patient. ²⁶⁹

The gene responsible has recently been identified as ABCA12, a member of the adenosine triphosphate-binding cassette (ABC) superfamily of active transporters.^{270. and 271.} The gene maps to chromosome 2q34. ²⁷² The ABCA12 protein is involved in the transportation of key lipids to the stratum corneum and the formation of lamellar granules.^{270. and 273.} Now that DNA diagnosis is available, it allows for robust prenatal and preimplantation testing without the need for fetal skin biopsies.^{270. and 274.} Prenatal skin biopsy was previously carried out at about 19 weeks.^{275. and 276.} In countries where DNA testing is not readily available, a fetal skin biopsy is best done at around 23 weeks, because of pitfalls in making the diagnosis at an early stage. In some countries terminations of the pregnancy are only allowed until 20 or 21 weeks gestation. ²⁶⁸

Harlequin ichthyosis is a disorder of epidermal keratinization in which there are altered lamellar granules and a variation in the expression of keratin and filaggrin.^{265. and 277.} Lipid levels may be increased in the stratum corneum. ²⁷⁸ In some cases, a defect of protein phosphatase has been demonstrated. ²⁶⁶ This enzyme may alter the processing of profilaggrin to filaggrin. ²⁶⁶

Patients who survive the neonatal period develop a severe exfoliative erythroderma consistent with non-bullous congenital ichthyosiform erythroderma (CIE). ²⁷⁹ Survival beyond the neonatal period has been enhanced by the use of oral retinoids. ²⁷²

Follicular ichthyosis (ichthyosis follicularis – OMIM 308205) is a rare, distinctive form of ichthyosis in which the abnormal epidermal differentiation occurs mainly in hair follicles.^{287. and 288.} Clinically there are spiny follicular papules. ²⁸⁹ Its onset is at birth or in early childhood. It is an X-linked recessive condition, but two female patients have now been reported. ²⁹⁰ The involved gene has not been characterized. The hyperkeratosis is more prominent on the head and neck. Photophobia and alopecia are often present, ²⁹¹ leading to the eponym IFAP (ichthyosis follicularis, alopecia, atrichia, photophobia). ²⁸⁹ Three of the patients reported have also had acanthosis nigricans-like lesions. ²⁸⁷ The case reported as ‘ichthyosis cribriformis’ had keratotic cones and not spiny keratin excrescences, ²⁹² but it may be a related condition.

A moderate response to retinoid therapy has been recorded. ²⁹³

Acquired ichthyosis, which occurs in adult life, is similar to ichthyosis vulgaris both clinically and histologically. ²⁹⁴ The subject was reviewed in 2006. ²⁹⁵ It is usually associated with an underlying malignant disease, particularly a lymphoma, ²⁹⁶ but it usually appears some time after other manifestations of the malignant process. Ichthyosis has also been associated with malnutrition, sympathectomy, ²⁹⁷ hypothyroidism, ²⁹⁸ leprosy, HIV infection, ²⁹⁹ HTLV-1 infection, ³⁰⁰ sarcoidosis,^{301. and 302.} diabetes mellitus, ³⁰³ eosinophilic fasciitis³⁰⁴ and drugs such as clofazimine, pravastatin, ³⁰⁵ allopurinol, hydroxyurea,^{295. and 306.} cimetidine, ²⁹⁵ fenofibrate, nicotinic acid, and nafoxidine. ³⁰⁷ Many of the drugs interfere with lipid metabolism. An ichthyosiform contact dermatitis may follow the repeated application of antiseptic solutions containing cetrimide. ³⁰⁸ There is compact orthokeratosis and/or parakeratosis without spongiosis. Cetrimide appears to act on the lipids and enzymes of the lamellar bodies. ³⁰⁸ Acquired ichthyosis is sometimes seen in the recipients of bone marrow transplants.^{309. and 310.} Acquired ichthyosis must be distinguished from asteatosis (dry skin). It may be related to an essential fatty acid deficiency in some cases. ³⁰²

In acquired ichthyosis, there is compact orthohyperkeratosis with a reduced or absent granular layer. ²⁹⁵

Pityriasis rotunda, which is manifested by sharply demarcated, circular, scaly patches of variable diameter and number, is probably a variant of acquired ichthyosis. It is more common in black and oriental patients than in whites. An underlying malignant neoplasm or systemic illness is often present.^{311.312.313.314.315. and 316.} Pityriasis rotunda may also occur as a familial disease, suggesting that there are two types with significant prognostic differences.^{317.318. and 319.} It is particularly common on the island of Sardinia, where familial cases are not uncommon, suggesting that it is a genodermatosis. ³²⁰ Immunohistochemical studies have shown a marked reduction in filaggrin and loricrin expression in lesional skin and a reduction, on light microscopy, ³²¹ in keratohyaline granules, beneath a layer of compact orthokeratosis. ³²¹

Refsum’s disease (OMIM 266500), a rare autosomal recessive disorder, is characterized by ichthyosis, cerebellar ataxia, peripheral neuropathy, and retinitis pigmentosa. ²⁸ The skin most resembles ichthyosis vulgaris but the onset of scale is often delayed until adulthood. There is an inability to oxidize phytanic acid, and improvement occurs when the patient adheres to a diet free from chlorophyll, which contains phytol, the precursor of this fatty acid. ²⁸ It is caused by a mutation in the gene encoding phytanoyl-CoA hydroxylase (PAHX, or PHYH) at 10pter–p11.2, or the gene encoding peroxin-7 (PEX7) at 6q22–q24. ³²² Decreased phytannic acid oxidation is also observed in cells lacking PEX7, so the two genes have a related function.

There are a number of rare syndromes in which ichthyosis is a feature. As their histopathology resembles one of the already described forms of ichthyosis, they will be discussed only briefly.

The palmoplantar keratodermas are a heterogeneous group of congenital and acquired disorders of keratinization, characterized by diffuse or localized hyperkeratosis of the palms and soles, sometimes accompanied by other ectodermal abnormalities.^{422. and 423.} Another classification system has also been proposed: the four major categories include diffuse, focal/circumscribed, and punctate palmoplantar keratodermas, and the palmoplantar ectodermal dysplasias. More than 20 subtypes have now been described in this latter category. ⁴²⁴ In one Indian study, the focal/circumscribed group was the most common type of palmoplantar keratoderma. ⁴²⁵ Categorization has been made on the basis of their mode of inheritance, sites of involvement, and associated abnormalities. ⁴²⁶ The autosomal recessive types are usually the most severe and include mal de Meleda, Papillon–Lefèvre syndrome, some mutilating variants, and a variant associated with generalized ichthyosis. ⁴²⁷ The other hereditary forms are autosomal dominant, although sporadic cases of most syndromes occur. ⁴²⁸

Another feature used to distinguish the various subtypes of keratoderma is the presence of hyperkeratosis beyond the palms and soles. These ‘transgrediens’ lesions occur in the Olmsted, Greither, Vohwinkel, and mal de Meleda types. ⁴²⁹ Onset of most keratodermas is at birth or in early infancy, but later onset is seen in the punctate and acquired forms. New syndromes continue to be reported or recognized.^{430. and 431.} In one of these, palmoplantar keratoderma is associated with large ears, hypopigmented hair, and frontal skull bossing. ⁴³² In another type, the Bothnian type (OMIM 600231), found in northern Sweden, the gene maps to 12q11–q13. ³⁹⁰ In yet another, a non-epidermolytic palmoplantar keratoderma is associated with sensorineural deafness and a mutation in the mitochondrial genome (mtDNA).^{433. and 434.} There are at least two genotypic variants of palmoplantar keratoderma with deafness. One is due to a mutation in the connexin 26 gene (GJB2) at 13q11–q12 (OMIM 148350) and the other is due to the mitochondrial mutation just mentioned. It has consistently involved an A7445G point mutation (OMIM *590080). ⁴³⁴ In palmoplantar keratoderma with anogenital leukokeratosis, an absence of K6 and K16 has been detected. ⁴³⁵ No keratin or genetic studies were done on the case with oral leukokeratosis and recurring cutaneous horns of the lip. ⁴³⁶ In the Schöpf–Schulz–Passarge syndrome (OMIM 224750) there are associated apocrine hidrocystomas, hypodontia, hypotrichosis, and hypoplastic nails.^{437. and 438.}

Brief mention will be made of the important clinical features of the various keratodermas.

Oculocutaneous tyrosinosis (OMIM 276600), also known as tyrosinemia II and the Richner–Hanhart syndrome, is an extremely rare, autosomal recessive genodermatosis caused by a deficiency of hepatic tyrosine aminotransferase (tyrosine transaminase).^{657.658.659.660.661. and 662.} The gene is located at 16q22.1–q22.3. It is usually characterized by corneal ulcerations and painful keratotic lesions on the palms and soles, but ocular lesions have been absent in some kindreds. ⁶⁶³ The palmoplantar lesions vary from fine 1–2 mm keratoses to linear or diffuse keratotic thickenings.^{661. and 664.} Erosions and blisters have also been reported.^{665.666. and 667.} Mental retardation is often present. The condition is treated by a dietary restriction of tyrosine and phenylalanine. If started early, mental retardation may be avoided. ⁶⁶⁶

Acrokeratoelastoidosis (Costa’s papular acrokeratosis – OMIM 101850) ⁶⁷¹ is a rare variant of palmoplantar keratoderma which occurs both sporadically and as an autosomal dominant genodermatosis.^{672.673. and 674.} No gene has been implicated although early linkage studies suggested the ACP1 gene; another study suggested a gene on chromosome 2. ⁶⁷⁵ This has never been confirmed. There appears to be some variability in the morphological expression of the disease.^{676. and 677.} Its onset is in childhood or early adult life and there is a female predominance. There are multiple, small (2–5 mm in diameter), firm, translucent, asymptomatic papules which are most numerous along the junction of the dorsal and palmar or plantar surfaces of the hands and feet respectively.^{678. and 679.} Larger plaques also develop by coalescence of the papules. ⁶⁸⁰ They may be localized to the sides of the fingers, particularly the inner side of the thumb and the adjoining index finger. In this situation, they resemble clinically the lesions seen in collagenous and elastotic plaques of the hands (see p. 343), an acquired entity which is found predominantly in males over the age of 50 and which results from trauma and actinic damage. ⁶⁷¹ In acrokeratoelastoidosis there may also be a mild diffuse hyperkeratosis of the palms and soles; this was a prominent feature in one report. ⁶⁸¹ There may also be isolated lesions over interphalangeal joints and elsewhere on the dorsum of the hands and feet. ⁶⁸² A variant of acrokeratoelastoidosis has been found on the palms in systemic scleroderma. ⁶⁸³

The treatment is a matter of debate. No curative treatment has been reported to date. ⁶⁸⁴ Options include topical keratolytics, retinoids, or corticosteroids. Systemic immunosuppressive therapy with prednisone or methotrexate has also been used. ⁶⁸⁴ Cryosurgery has been unsuccessful while the erbium:YAG laser has produced slight improvement. ⁶⁸⁴

Pachyonychia congenita is a rare genodermatosis in which symmetrical, hard thickening of the nails of the fingers and toes is the most striking and consistent feature.^{693.694. and 695.} Various other abnormalities of keratinization are usually present. ⁶⁹⁶ These include palmar and plantar keratoderma, follicular keratoses on the extensor surfaces of the knees and elbows, keratosis pilaris, blister formation on the feet and sometimes on the palms, callosities of the feet, leukokeratosis of the oral mucosa (often complicated by candidosis),^{697. and 698.} hair abnormalities, and hyperhidrosis of the palms and soles. Acro-osteolysis is an uncommon complication. ⁶⁹⁹ These clinical features typify the so-called ‘type I’ (Jadassohn–Lewandowsky – OMIM 167200) cases.^{696. and 700.} Patients with the type II variant (Jackson–Lawler type – OMIM 167210) have the addition of natal teeth (teeth erupted prior to birth) and multiple cutaneous cysts, either epidermal cysts or steatocystomas,701. ^{and 702.} but no oral leukokeratosis. ⁷⁰³ Woolly hair was present in one case. ⁷⁰⁴ In type III, the features of type I are accompanied by leukokeratosis of the cornea. Type IV combines the clinical features of the other types with laryngeal lesions, mental retardation, and alopecia. ⁷⁰⁵

There is some variability in the age of onset of the various manifestations, but nail changes are usually present at birth or soon afterwards and become progressively more disfiguring over the first year of life. Nail dystrophy of late onset (pachyonychia congenita tarda) has been reported.^{706.707.708. and 709.}

Pachyonychia congenita is usually inherited as an autosomal dominant trait with variable expression and high penetrance, although several cases with autosomal recessive inheritance have been reported. ⁶⁹³Type II pachyonychia congenita is due to an abnormality in the keratin 17 (KRT17) gene and in its expression partner keratin 6b (KRT6B), ⁷¹⁰ the former resulting from a gene mutation in the type I keratin cluster on chromosome 17q12–q21 and the latter from a mutation in KRT6B at 12q13. ⁷¹¹ Similar mutations in the KRT17 gene can cause steatocystoma multiplex with little or no nail dystrophy. ⁷¹²Type I pachyonychia congenita results from a mutation in the helix initiation peptide of the keratin 16 (KRT16) gene^{713. and 714.} or in the keratin 6a (KRT6A) gene located at 12q13.^{715.716. and 717.} Mutations of KRT6A are said to be more frequent than those of KRT16. ⁷¹⁸

The thickened nails and callosities have been treated with urea paste 40% with good results. ⁷¹⁹ As plantar sweating at high ambient temperatures increases the blistering of the plantar callosities, control of the sweating with injections of botulinum toxin has been carried out. ⁷²⁰ This relieves the pain associated with walking on these callosities. ⁷²⁰

Mention is made here for completeness of ectopic nails. They have been reported on the volar surface of fingers and toes and elsewhere. ⁷²¹ Ectopic plantar nails are smaller than normal ones. ⁷²² Ectopic nails are most frequently caused by traumatic inoculation of nail matrix. They may be associated with polydactyly. ⁷²³ Congenital malalignment of the great toenails is another malformation. It is heritable. ⁷²⁴ The yellow nail syndrome (OMIM 153300) and other diseases of nails will not be considered further.^{725.726.727.728.729.730. and 731.}

Porokeratosis is a genodermatosis with many different clinical expressions. ⁷⁵⁴ Lesions may be solitary or numerous, inconspicuous or prominent, small or large (giant),^{755.756.757.758. and 759.} atrophic or hyperkeratotic, ⁷⁶⁰ and asymptomatic or pruritic. ⁷⁶¹ The lip, ⁷⁶² mouth, ⁷⁶³ face,^{764.765.766. and 767.} scalp, ⁷⁶⁸ nail fold, ⁷⁶⁹ penis,^{770. and 771.} scrotum, ⁷⁷² genitocrural and perianal regions,^{773.774.775.776. and 777.} and natal cleft⁷⁷⁸ are sites that are rarely involved. Facial lesions may be destructive and disfiguring.^{779. and 780.} Linear facial lesions have also been seen. ⁷⁸¹ Involvement of a burn scar has been reported. ⁷⁸² Other rare clinical associations include Crohn’s disease, ⁷⁸³ trisomy 16, ⁷⁸⁴ chronic renal failure,^{785. and 786.} hepatitis C virus-related hepatocellular carcinoma, ⁷⁸⁷ cholangiocarcinoma, ⁷⁸⁸ previous renal transplant,^{789.790.791. and 792.} bone marrow transplantation, ⁷⁹³ myelodysplastic syndrome, ⁷⁹⁴ lymphedema, ⁷⁹⁵ herpes simplex infection, ⁷⁹⁶ systemic lupus erythematosus, ⁷⁹⁷ microsatellite instability in association with hereditary non-polyposis colorectal cancer, ⁷⁹⁸ lesions localized to the access region for hemodialysis, ⁷⁹⁹ and onset after electron beam radiation,^{800.801. and 802.} PUVA, ⁸⁰³ tanning salon use, ⁸⁰⁴ prolonged topical corticosteroid use, ⁸⁰⁵ and furosemide (frusemide). ⁸⁰⁶ The simultaneous development of DSAP and ovarian cancer in one patient may have been coincidental rather than a true paraneoplastic association. ⁸⁰⁷ Although it was originally regarded as a familial disease with autosomal dominant inheritance, ⁸⁰⁸ numerous non-familial cases have now been reported. Congenital cases are rare.^{781. and 809.}

The most important clinical forms are porokeratosis of Mibelli (OMIM 175800), characterized by one or more round, oval or gyrate plaques with an atrophic center and a thin, elevated, guttered, keratotic rim which may show peripheral expansion, and disseminated superficial actinic porokeratosis (DSAP – OMIM 175900) consisting of multiple, annular, keratotic lesions less than 1 cm in diameter, with a hyperkeratotic, thread-like border and occurring particularly on the sun-exposed extremities.^{810.811. and 812.} They usually develop during the third or fourth decade of life. DSAP appears to be heterogeneous with two forms identified – DSAP1 (OMIM 175900) tentatively linked to the 12q24.1 region, although nearby regions have also been suggested;^{813. and 814.} and DSAP2 (OMIM 607728) on chromosome 15q25.1–26.1.^{815.816. and 817.} Other candidate genes that have been suggested on chromosome 12 are slingshot 1 (SSH1) and ARPC3, both involved in the actin cytoskeleton pathway,^{817. and 818.} and the SART3 gene. ⁸¹⁹ A new locus has recently been discovered on 1p31.3–p31.1, for an autosomal dominant form of DSAP (DSAP3). ⁸²⁰

Rare clinical variants include a linear^{821.822.823.824.825.826.827.828.829. and 830.} or systematized^{831. and 832.} variant, a reticulate form, ⁸³³ a follicular variant, ⁸³⁴ an eruptive pruritic form, ⁸³⁵ porokeratosis plantaris discreta^{836. and 837.} (painful plantar lesions), porokeratotic palmoplantar keratoderma discreta, ⁸³⁸ punctate porokeratotic keratoderma, also known as punctate porokeratosis,^{839.840.841.842.843. and 844.} and porokeratosis punctata palmaris et plantaris – spiny keratoderma584.^{845. and 846.} (PPPP – OMIM 175860 (asymptomatic pits or plugs, usually on the palms, digits, or soles and not universally accepted as a variant of porokeratosis)). ⁸⁴⁷ Other variants include linear palmoplantar porokeratotic hamartoma (the cornoid lamellae are not related to eccrine ostia), ⁸⁴⁸ porokeratosis plantaris, palmaris et disseminata^{849.850.851.852.853.854.855. and 856.} (annular and serpiginous lesions on the palms and soles with later involvement of other areas (PPPD – OMIM 175850)), and the related superficial disseminated eruptive form.^{857. and 858.} PPPD may be due to the same gene as DSAP1. ⁸¹⁵ Another rare variant of porokeratosis is a hyperkeratotic verrucous type.^{859.860. and 861.} In yet another variant craniosynostosis, anal anomalies, and porokeratosis are associated (CAP syndrome – OMIM 603116). ⁸¹⁹ Closely related are the cases with cornoid lamellae in eccrine and hair follicle ostia, described as ‘porokeratotic eccrine ostial and dermal duct nevus’,^{862.863.864.865.866.867.868.869.870.871.872. and 873.} ‘porokeratotic eccrine duct and hair follicle nevus’,^{874. and 875.} and ‘reticular erythema with ostial porokeratosis’. ⁸⁷⁶ Porokeratotic eccrine ostial and dermal duct nevus is most commonly found on the palms and soles. It usually presents in early childhood with a linear distribution of asymptomatic papules. ⁸⁷³ The lesions may develop along Blaschko’s lines^{877. and 878.} or be systematized. ⁸⁷⁹

Porokeratoma is a recently described solitary, hyperkeratotic plaque or nodule, sometimes verrucous, with a predilection for the distal extremities of middle-aged to elderly males. ⁸⁸⁰ It is akin to warty dyskeratoma and epidermolytic acanthoma. Histological examination shows a well-defined lesion, characterized by acanthosis and verrucous hyperplasia with prominent multiple and confluent cornoid lamellae. ⁸⁸⁰

The disseminated superficial actinic variant coexists rarely with other types of porokeratosis, particularly the linear type.^{823.827.881.882.883.884. and 885.} The association of these two forms is an example of type 2 segmental involvement, occurring in an autosomal dominant skin disorder. ⁸⁸⁶ The coexistence of DSAP and porokeratosis of Mibelli has also been reported. ⁸⁸⁷ The various clinical types of porokeratosis are listed in Table 9.4.

DSAP may be exacerbated by exposure to ultraviolet light,^{888. and 889.} but it does not appear to be due to radiation hypersensitivity. ⁸⁹⁰ There appears to be an inherent defect in the terminal differentiation program.^{890. and 891.} Both DSAP and porokeratosis of Mibelli have developed in immunosuppressed patients.^{892.893.894.895.896.897.898. and 899.} Age-related immunosuppression has been used to explain the occurrence of disseminated porokeratosis in the elderly. ⁹⁰⁰

Reflectance confocal microscopy has been used to diagnose DSAP, and to distinguish lesions from actinic keratoses. The cornoid lamella is easily identified by this technique. ⁹⁰¹ Other dermoscopic methods can also be used.^{902. and 903.} Fake sun tan lotion will highlight lesions of DSAP serendipitously. ⁹⁰⁴ Povidone-iodine can also be used to highlight the cornoid lamella. ⁹⁰⁵

Porokeratotic lesions are usually persistent although clearance with subsequent recurrence has been reported. ⁹⁰⁶ The development of squamous cell carcinoma^{748.885.907.908.909.910. and 911.} or intraepidermal carcinoma^{912. and 913.} is a rare clinical complication of several of the variants of porokeratosis. The linear type is particularly prone to malignant change.^{914.915. and 916.} Fatal squamous cell carcinomas have developed in transplant-associated porokeratosis. ⁹¹⁷ The term ‘malignant disseminated porokeratosis’ has been applied to several cases in which the porokeratotic lesions had a significant potential to undergo malignant degeneration.^{918. and 919.} Allelic loss has been suggested as a possible pathogenetic mechanism for these tumors. ⁹¹⁴

Epidermolytic acanthoma is an uncommon lesion which presents clinically as a wart in patients of all ages.^{960. and 961.} A disseminated form has also been reported;^{962.963.964. and 965.} in one report of four cases, the lesions developed after sun exposure. ⁹⁶⁶ Trauma has also been incriminated. ⁹⁶⁵ Multiple scrotal epidermolytic acanthomas have been reported. They were thought to have resulted from the trauma of chronic scratching. ⁹⁶⁷

Although the term ‘focal acantholytic dyskeratosis’ is often used both for clinically inapparent incidental foci and for clinically apparent solitary lesions with the histological pattern of acantholytic dyskeratosis, ⁹⁹⁰ some authors restrict its use to its incidental finding in histological sections. This is not an uncommon event.^{991. and 992.} Ko and colleagues have recently coined the term ‘acantholytic dyskeratotic acanthoma’ for this lesion, apparently on the basis that it is more than an incidental finding, and it often presents clinically as a basal cell carcinoma of the trunk. ⁹⁹³ The author sees at least one case each week of this phenomenon, whether it be incidental or otherwise. The term ‘papular acantholytic dyskeratoma’ has been applied to the clinically apparent solitary lesions, ⁹⁹⁴ and ‘papular acantholytic dyskeratosis’ to the exceedingly rare cases in which multiple lesions have developed on the vulva,^{995.996.997.998.999.1000. and 1001.} perianal area,^{1002.1003. and 1004.} or penis¹⁰⁰⁵ (see below). A clinically apparent lesion has also been reported on the lip. ⁹⁹⁰ A case reported as ‘congenital acantholytic dyskeratotic dermatosis’ appears to be a variant of papular acantholytic dyskeratosis. There were multiple erosive papules and plaques located on the left thigh, left ankle, and right neck that were present at birth. ¹⁰⁰⁶ There was no family history of Darier’s disease and no genetic studies were performed. ¹⁰⁰⁶

Incidental focal acantholytic dyskeratosis is statistically increased in atypical melanocytic lesions. ¹⁰⁰⁷

Darier’s disease (OMIM 124200) is a rare, autosomal dominant genodermatosis in which greasy, yellow to brown, crusted papular lesions develop, mainly in the seborrheic areas of the head, neck, and trunk.^{1025.1026.1027. and 1028.} A rare acral variant exists;^{1029. and 1030.} lesions are sometimes hemorrhagic in this form. ¹⁰³¹ The coalescence of papules produces plaques, which may at times become papillomatous. The prevalence of Darier’s disease varies from 1 : 30 000 in parts of Scotland to 1 : 100 000 in Denmark.^{1032. and 1033.} It is much less common in Singapore. ¹⁰³⁴ Onset is usually in early adolescence and the disease runs a chronic course. Congenital onset is rare. ¹⁰³⁵ There is an equal sex incidence, but its clinical expression is usually milder in females. ¹⁰³³ Verrucous lesions resembling acrokeratosis verruciformis may be present on the dorsum of the hands and feet in approximately 70% of cases.^{1027. and 1036.}

Punctate keratoses are sometimes found on the palms and soles. ¹⁰³⁶ Longitudinal striations are usually present in the nails. ¹⁰³⁷ Rare clinical variants include a bullous,^{1038. and 1039.} a comedonal,^{1040.1041. and 1042.} and a hypertrophic (cornifying) form.^{1043. and 1044.} Comedomal Darier’s has clinical features similar to acne and histopathological features akin to warty dyskeratoma. It is exceedingly rare. ¹⁰⁴⁵ A ‘groversid’ variant with smooth papules has been reported. It was of late onset. ¹⁰⁴⁶ Cutaneous depigmentation (guttate leukoderma),^{1047.1048.1049.1050. and 1051.} secondary eczematization, ¹⁰⁵² cutis verticis gyrata, ¹⁰⁵³ mucosal lesions,^{1054. and 1055.} ocular disorders, ¹⁰⁵⁶ bone cysts, ¹⁰⁵⁷ gynecomastia, ¹⁰⁵⁸ and mental deficiency¹⁰⁵⁹ have also been recorded. Mucosal lesions usually involve the mouth but the esophagus has also been involved. ¹⁰⁶⁰ Darier’s disease has been exacerbated and initiated by lithium carbonate therapy¹⁰⁶¹ and by UVB radiation.^{1034.1062. and 1063.} A variant restricted to sun-exposed areas has been reported. ¹⁰⁶⁴ A paraneoplastic variant has also been reported. ¹⁰⁶⁵ Localized (segmental) disease has been precipitated by the administration of menotropin, ¹⁰⁶⁶ and it has been associated with Gardner’s syndrome in one case. ¹⁰⁶⁷ Patients with segmental, unilateral, or localized lesions are regarded as examples of mosaicism. They were discussed in the introduction to this section (see p. 266). The involved skin has the same genetic mutation that occurs in the generalized form of Darier’s disease. ⁹⁸⁵ In one case unilateral Darier’s disease involving the entire right side of the body was present. It was associated with unilateral guttate leukoderma. Lesions did not follow Blaschko’s lines as is usual in localized and segmental disease. ¹⁰⁶⁸ The case reported as unilateral Grover’s disease along Blaschko’s lines was probably linear Darier’s disease.^{1069. and 1070.}

There is a predisposition to bacterial, fungal, and viral infections, although no consistent and specific immunological abnormality has been demonstrated.^{1025.1034.1071. and 1072.} Infection with herpes simplex virus, vaccinia, ¹⁰⁷³ and even coxsackievirus A16¹⁰⁷⁴ may produce the features of Kaposi’s varicelliform eruption^{1075.1076.1077. and 1078.} (see Ch. 26, p. 616). Herpes zoster has occurred in linear Darier’s disease in a patient infected with HIV. ¹⁰⁷⁹ An HPV-related subungual squamous cell carcinoma has been reported. ¹⁰⁸⁰

The mechanism of acantholysis in Darier’s disease is still the subject of controversy. ¹⁰²⁵ It is usually ascribed to a defect in the synthesis, organization, or maturation of the tonofilament–desmosome complexes. ¹⁰⁸¹ Ca²⁺-ATPases play a key role in the assembly of desmosomes. ¹⁰⁸² It appears that the proteins of the desmosomal attachment plaque are primarily affected.^{1083. and 1084.} There is a loss of desmoplakin I and II and plakoglobin from the desmosomes. ¹⁰⁸³ This results from an abnormality in the sorting of desmoplakin. ¹⁰⁸² The pathogenetic significance of the finding that there is a delay in the expression of the suprabasal skin-specific keratins is uncertain. ¹⁰⁸⁵ Loss of desmosomal adhesion triggers anoikis, ¹⁰⁸⁶ a type of apoptosis characterized by cell detachment. This process contributes to the formation of dyskeratotic cells. ¹⁰⁸² The loss of Bcl-2 and Bcl-x in lesional skin of Darier’s disease reflects an imbalance in the apoptotic pathway in this disease.^{1087. and 1088.} The adherens junction is another site of abnormality. ¹⁰⁸⁹

The genetic defect in Darier’s disease has been mapped to chromosome 12q23–q24.1.^{1090.1091.1092. and 1093.} It is due to mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca²⁺-ATPase type 2 isoform (SERCA2), a keratinocyte Ca²⁺ pump.^{1094. and 1095.} Several isoforms of SERCA exist: SERCA2a, SERCA2b, and SERCA3. ¹⁰⁹⁶ Their differential expression may explain the localization of lesions. Variable clinical severity may occur in different members of the same family¹⁰⁹⁷ but no involvement of other organs in which SERCA2 plays a role has been found. ¹⁰⁹⁸ No particular mutational ‘hotspots’ have been found to explain the phenotypic variation that occurs in some pedigrees with Darier’s disease. ¹⁰⁹⁵ Numerous mutations have now been described in this gene.^{1099.1100. and 1101.} In one novel missense mutation, the disease was restricted to the extremities. ¹¹⁰²

Galli–Galli disease is an acantholytic variant of Dowling–Degos disease, an autosomal dominant disorder characterized by progressive pigmented lesions involving large body folds and flexural areas. ¹¹¹⁵ It is due to a mutation of the keratin 5 (KRT5) gene on chromosome 12q13. Mutations in this gene are also responsible for epidermolysis bullosa simplex with palmoplantar keratoderma. ¹¹¹⁶ The term ‘Galli–Galli’ is derived from the family name of the two brothers originally reported with this variant. ¹¹¹⁵

The eponymous designation Grover’s disease is the preferred title for several closely related dermatoses characterized by the sudden onset of small, discrete, sometimes crusted, erythematous papules and papulovesicles.^{1117.1118. and 1119.} They usually develop on the upper trunk of older men. A zosteriform variant has been reported. ¹¹²⁰ Lesions may be transient, lasting for weeks or several months¹¹¹⁷ (transient acantholytic dermatosis), or they may persist for several years¹¹²¹ (persistent acantholytic dermatosis^{1122.1123. and 1124.} or papular acantholytic dermatosis¹¹²⁵). Intense pruritus is often present. Oral involvement has been reported, ¹¹²⁶ as has the coexistence of other dermatoses such as asteatotic eczema,^{1127. and 1128.} allergic contact dermatitis, ¹¹²⁸ atopic eczema,^{1128. and 1129.} psoriasis, ¹¹²⁷ pemphigus foliaceus, ¹¹³⁰ a drug reaction, and a neutrophilic dermatosis in association with Waldenström’s macroglobulinemia. ¹¹³¹

Some cases of Grover’s disease have followed or been exacerbated by exposure to ultraviolet light.1123. ^{and 1125.} Cases associated with lentiginous sun-induced ‘freckling’ have been reported.^{1132. and 1133.} A few are associated with chronic renal failure.^{1134. and 1135.} One case involved a febrile postoperative patient. ¹¹³⁶ The role of heat, persistent fever, and sweating has been postulated in the etiology of this condition.^{1137.1138.1139. and 1140.} This theory has been challenged as a consequence of the study performed at the Ackerman Academy of Dermatopathology in New York. ¹¹⁴¹ Grover’s disease was present in 0.09% of biopsy specimens. It was diagnosed approximately four times more commonly in winter than in summer. It was suggested that Grover’s disease arises against a backdrop of a xerotic epidermis with decreased sweat production, rather than being caused by sweating and heat as previously postulated. ¹¹⁴¹ Both mechanisms are probably involved. The cytokine interleukin-4, the synthetic guanosine analogue ribavirin, ¹¹⁴² and d-penicillamine therapy¹¹⁴³ have all precipitated Grover’s disease. ¹¹⁴⁴ Other chemotherapeutic agents, often used in ‘cocktail’ form, have also resulted in Grover’s disease. ¹¹⁴⁵ Other drugs appear to precipitate this condition, and the author is currently supervising a study of over 300 cases of Grover’s disease to elucidate its clinical associations. In cases thought to have been drug-related, cessation of the drug has not necessarily led to the cure of the Grover’s disease.

Several mechanisms are theoretically possible as explanations for the occurrence of Grover’s disease in cancer patients.^{1146.1147. and 1148.} Several cases appear to have followed induction therapy, and one followed the use of 2-chlorodeoxyadenosine in the treatment of hairy cell leukemia. ¹¹⁴⁹ Other cases have been in patients who underwent high-dose chemotherapy followed by bone marrow transplantation or autologous stem cell infusion. ¹¹⁵⁰

Despite the histological similarity to Darier’s disease, Grover’s disease does not share an abnormality in the ATP2A2 gene. ¹¹⁵¹ Its pathogenesis is unknown. Loss of syndecan-1 expression occurs, but this is seen in other bullous diseases. Syndecan-1 is a heparan sulfate proteoglycan present on the keratinocyte membrane; it functions in intercellular adhesion. ¹¹⁵²

Hailey–Hailey disease (familial benign chronic pemphigus – OMIM 169600) is an uncommon genodermatosis with recurrent, erythematous, vesicular plaques, which progress to small flaccid bullae with subsequent rupture and crusting.^{1163. and 1164.} The plaques are well demarcated and spread peripherally, often with a circinate border. Rare clinical forms include papular, ¹¹⁶⁵ verrucous,^{1166. and 1167.} annular, and vesiculopustular variants. ¹¹⁶⁸ Targetoid lesions resembling erythema multiforme have been reported. ¹¹⁶⁹ Nikolsky’s sign may be positive. There is a predilection for the neck, axillae, and intertriginous areas such as the genitocrural, perianal, and inframammary region. Occasionally large areas of the skin are involved. ¹¹⁷⁰ There are rare reports of involvement of oral, ocular, esophageal, ¹¹⁷¹ and vaginal¹¹⁷² mucous membranes or of lesions limited to the vulva^{996.1173. and 1174.} or perianal¹¹⁷⁵ region. These latter cases are best included with the cases that are now classified as ‘acantholytic dermatosis of the genitocrural region’ (see p. 266).

Another condition with the histological features of Hailey–Hailey disease and unique clinical features is relapsing linear acantholytic dermatosis, in which there are lesions, following the lines of Blaschko, that wax and wane in a systematic pattern. ¹¹⁷⁶ Segmental Hailey–Hailey disease limited to the left inframammary area has been reported, an example of type I segmental disease. ¹¹⁷⁷

Hailey–Hailey disease is inherited as an autosomal dominant condition with incomplete gene penetrance. The responsible gene, ATP2C1, has been mapped to chromosome 3q21–q24. ¹¹⁷⁸ It encodes a novel Ca²⁺ pump protein hSPCA1, localized to the Golgi apparatus.^{1179. and 1180.} It has been shown that extracellular calcium homeostasis and functioning Ca²⁺ pumps play a critical role in regulating differentiation and cell-to-cell adhesion of keratinocytes. ¹¹⁸¹ Numerous different mutations have been described.^{1182.1183.1184.1185.1186. and 1187.} Phenotypic variations do not appear to correlate with specific mutations.^{1188. and 1189.} Nearly one-third of cases are sporadic. Onset is usually in the late teens and there is a tendency for the disease to improve in late adulthood. ¹¹⁹⁰

The chronic course is punctuated by periods of spontaneous remission with subsequent exacerbations. Premenstrual exacerbations have been reported. ¹¹⁹¹ Lesions may be induced in genetically predisposed tissues by trauma,^{1192. and 1193.} patch testing, ¹¹⁹⁴ heat, ultraviolet light, ¹¹⁹⁵ perspiration and infection with scabies, ¹¹⁹⁶ bacteria, ¹¹⁹⁷ herpes virus, ¹¹⁹⁸ or yeasts. HPV-6 was present in the verrucoid perineal lesions in one patient. ¹¹⁹⁹ HPV-5 was present in a similar case. ¹²⁰⁰ Lesions are often mildly pruritic or burning. They are also malodorous.

Rare associations have included psoriasis,^{1192.1201. and 1202.} Darier’s disease,^{1203. and 1204.} localized bullous pemphigoid, ¹²⁰⁵ syringomas of the vulva, ¹²⁰⁶ and squamous and basal cell carcinomas.^{1207.1208. and 1209.}

The actual mechanism of the acantholysis in Hailey–Hailey disease appears to be localized in the adherens junction region.^{1089. and 1210.} Initially, the defect was thought to be related to a deficiency in one of the intracellular desmosomal proteins, but recent work has shown that they are all biochemically intact. ¹²¹¹ They may be dysfunctional in other ways. However, there is dissociation of intra- and extracellular domains of desmosomal cadherin and E-cadherin (an adherens junction-associated protein). ¹⁰⁸⁹ This occurs in both Hailey–Hailey and Darier’s disease, but not in pemphigus. ¹⁰⁸⁹ There is normal expression of the gap junction proteins connexins 26 and 43 in non-lesional skin. ¹²¹² Haploinsufficiency is another mechanism used to explain the pathogenesis of this condition. ¹²¹³ Expression of ATP2C1 mRNA is experimentally suppressed following UVB irradiation. ¹²¹³ This may be relevant to the clinical presentation of this disease following sunlight exposure. ¹²¹³ During acantholysis there is internalization of gap junctions, but this appears to be a secondary process. ¹²¹² In contrast to Darier’s disease, in which abnormal cell adhesion is only demonstrable in clinically involved skin, Hailey–Hailey disease is characterized by a widespread subclinical abnormality in keratinocyte adhesion.^{1210. and 1214.} Cultured keratinocytes from patients with Hailey–Hailey disease and Darier’s disease show altered calcium metabolism. ¹²¹⁵

Warty dyskeratomas (follicular dyskeratomas) are rare, usually solitary, papules or nodules with an umbilicated or pore-like center.^{1227.1228. and 1229.} They have a predilection for the head and neck of middle-aged and elderly individuals.^{1230. and 1231.} A subungual and an oral lesion have also been reported.^{1232.1233. and 1234.} Warty dyskeratomas average 5 mm in diameter, although an unusually large example, 3 cm in diameter, has been described. ¹²³⁵ They occasionally bleed or intermittently discharge cheesy material. ¹²²⁸ There is no evidence of associated Darier’s or Grover’s disease. ¹²²⁹ PCR analysis for HPV-DNA is negative. ¹²²⁹

The lesions in comedonal Darier’s disease have the histological features of warty dyskeratoma.^{1040. and 1041.}

Hyperkeratosis lenticularis perstans (Flegel’s disease – OMIM 144150) ¹²⁴⁴ is a rare genodermatosis of late onset in which an abnormality in keratinization results in the development of multiple, discrete, 1–5 mm keratoses.^{1245.1246. and 1247.} An autosomal dominant inheritance is sometimes present.^{1248.1249. and 1250.} The lesions are most prominent on the dorsum of the feet and the anterior aspect of the lower legs, but they may also develop on the thighs, upper limbs, and pinnae.^{1246. and 1251.} The keratoses develop in mid to late adult life and persist. Removal of the spiny scale causes slight bleeding. ¹²⁵² A unilateral variant has been described. ¹²⁵³ This may be a manifestation of the postzygotic mosaicism seen in autosomal dominant skin disease.

Several reports, but not all,^{1251. and 1254.} have documented a decrease in or qualitative defects of the membrane-coating granules (lamellar or Odland bodies) in affected areas of epidermis.^{1255.1256.1257.1258. and 1259.} In one study these granules were normal in old lesions but not found in keratinocytes of early lesions. ¹²⁶⁰ It has been suggested that these abnormalities are the basis for the defect in keratinization. ¹²⁵⁶

No uniformly effective treatment is available. Emollients, topical 5-fluorouracil, retinoids, topical calcipotriol, and PUVA phototherapy have all been used. ¹²⁶¹

The eponymous designation Kyrle’s disease (OMIM 149500) is preferable to the original designation of hyperkeratosis follicularis et parafollicularis in cutem penetrans. ¹²⁶⁶ This controversial entity is regarded by some as a late-onset genodermatosis in which abnormal clones of epidermal cells lead to premature keratinization at the expense of epidermal thickness, with the subsequent introduction of keratinous material into the dermis.^{1267. and 1268.} Others regard it as a variant of perforating folliculitis, a view which is supported by the finding of perforating lesions in patients with chronic renal failure on dialysis, with clinical and histological overlap features between Kyrle’s disease, perforating folliculitis, and even reactive perforating collagenosis.^{1269.1270. and 1271.} It has also been suggested that Kyrle’s disease and Flegel’s disease (hyperkeratosis lenticularis perstans – see above) may be different manifestations of the same disease process.^{1272. and 1273.}

Kyrle’s disease, as traditionally described, consists of hyperkeratotic papules 2–8 mm in diameter, containing a central, cone-shaped plug.^{1266. and 1274.} The papules may be follicular or extrafollicular in location and they may coalesce to form a verrucous plaque. ¹²⁷⁵ There is a predilection for the lower limbs, but lesions may also occur on the upper limbs and less often on the head and neck.^{1274. and 1276.} Palmar and plantar surfaces are rarely involved.^{1277. and 1278.} Mucosal involvement is exceedingly rare. ¹²⁷⁸ A female preponderance has been noted in some series. ¹²⁶⁸ Onset is usually in the fourth decade. A family history has been present in a few cases.^{1268. and 1278.} Kyrle’s disease has been associated with chronic renal failure,^{1279.1280. and 1281.} and with diabetes mellitus, ¹²⁸⁰ and more rarely with hepatic dysfunction.^{1274. and 1282.}

Multiple minute digitate keratosis is a rare non-follicular disorder of keratinization, also known as disseminated spiked hyperkeratosis. It can occur in four different clinical settings: a familial type with autosomal dominant inheritance,^{1285.1286.1287.1288. and 1289.} a sporadic type,^{1289.1290. and 1291.} a paraneoplastic variant, ¹²⁹² and a postinflammatory type.^{1293. and 1294.} Hundreds of minute keratotic spikes develop, usually in early adult life. Cases localized to the palms and soles (spiny keratoderma, palmar filiform hyperkeratosis, ¹²⁹⁵ music box spine keratoderma) are probably best classified with the palmoplantar keratodermas.^{1296.1297. and 1298.} There is a predilection for the upper part of the trunk and for the proximal parts of the limbs.^{1299. and 1300.}

A closely related entity, minute aggregate keratoses, ¹³⁰¹ has dome-shaped papules and crateriform or annular lesions in addition to the spicular lesions seen in multiple minute digitate keratoses.

Minute keratotic spikes have been reported as an acquired phenomenon following X-irradiation, ¹³⁰² in Crohn’s disease, ¹³⁰³ and following the use of etretinate. ¹³⁰⁴ Follicular spicules have been reported in multiple myeloma. They may be composed of proteinaceus material. ¹³⁰⁵ Hair casts were present in another case. ¹³⁰⁶

A solitary spiked lesion, representing a vertically growing ectopic nail, may occur on a finger tip. ¹³⁰⁷

Waxy keratoses (kerinokeratosis papulosa¹³¹¹) are easily detachable, hyperkeratotic papules with a shiny yellowish ‘waxy’ appearance and an onset in childhood. ¹³¹² The distribution is predominantly truncal and the condition may be familial. ¹³¹² A segmental form, representing mosaicism, has been reported.^{1311. and 1313.} The associated presence of confluent hyperkeratosis at other sites is a variable feature.

Larger papules with a mosaic pattern and acral distribution have been reported under the title ‘mosaic acral keratosis’. ¹³¹⁴

Acrokeratosis verruciformis of Hopf (OMIM 101900) is an autosomal dominant genodermatosis in which multiple papules, resembling plane warts, develop on the dorsum of the hands and fingers and to a lesser extent on the feet, forearms, and legs.^{1315.1316.1317.1318. and 1319.} Sporadic cases also occur. Onset is usually before puberty, but late onset has been recorded.^{1315.1316.1317. and 1318.} It is more common in males. ¹³¹⁸ Other clinical features include punctate hyperkeratoses of the palms, and nail abnormalities. ¹³²⁰

Lesions identical to those of acrokeratosis verruciformis develop in a significant number of patients with Darier’s disease (see p. 268). Such lesions may precede, follow or develop concurrently with the onset of the more usual lesions of Darier’s disease. ¹³²¹ Acrokeratosis verruciformis has been reported in the relatives of individuals with Darier’s disease. ¹³²² There is considerable controversy as to the nature of the relationship of these two conditions and also about their relationship to the palmar and plantar keratoses which may accompany either disease. One view is that the acral lesions of Darier’s disease and acrokeratosis verruciformis are separate entities. ¹³¹⁸ This is based on the finding of small foci of acantholytic dyskeratosis in some acral keratotic lesions of Darier’s disease if multiple sections are examined. This is also supported by a recent finding that there is genetic heterogeneity in acrokeratosis verruciformis. In one Chinese study no evidence of any linkage to the ATP2A2 gene on chromosome 12q23–q24 was found. ¹³²⁰ The contrary view is that both diseases result from a single autosomal dominant genetic defect with variable expressivity of the gene.^{1321.1323. and 1324.} This latter theory was supported by the finding in 2003 of a mutation in the ATP2A2 gene in two patients from a British family with acrokeratosis verruciformis, indicating that it is allelic to Darier’s disease. ¹³²⁵ As already stated (see above), a Chinese study found no such link. ¹³²⁰

Xeroderma pigmentosum is a rare, autosomal recessive genodermatosis characterized by deficient DNA repair, photophobia, severe solar sensitivity, cutaneous pigmentary changes, xerosis, and the early development of mucocutaneous and ocular cancers, particularly in sun-exposed areas.1326.^{1327.1328.1329.1330.1331.1332.1333. and 1334.} Dermoscopy has been used to monitor skin lesions in this condition. ¹³³⁵ Neurological abnormalities are present in up to 20%¹³³⁶ and these are most severe in the De Sanctis–Cacchione syndrome (microcephaly, dwarfism, choreoathetosis, and mental deficiency – OMIM 278800),^{1326.1328. and 1337.} which in most cases is associated with the XP-A variant of xeroderma pigmentosum. The earliest changes in xeroderma pigmentosum usually develop before the age of 2 with a severe sunburn reaction and the development of multiple freckles with variable intensity of melanin pigmentation and interspersed hypopigmented macules. ¹³³⁸ Pigmentation often develops on the palms and soles and mucous membranes. Later there is dry, scaly skin (xerosis) with poikilodermatous features. Skin tumors, which include solar keratoses, cutaneous horns, keratoacanthomas, squamous and basal cell carcinomas, basosquamous carcinoma, atypical fibroxanthoma, ¹³³⁹ malignant melanomas, ¹³⁴⁰ and angiomas, may develop in late childhood; patients may ultimately die from the consequences of their tumors. ¹³³⁶ The development of the cutaneous lesions can be retarded by protection from the sun from birth.^{986. and 1341.} Immunological abnormalities have been present in some patients. ¹³⁴²

Xeroderma pigmentosum involves both sexes and all races with an incidence of 1 : 250 000 and a gene frequency of 1 : 200. ¹³²⁶ There is a high incidence of consanguinity.^{1343. and 1344.} Heterozygotes could not, until recently, be reliably demonstrated in the laboratory. ¹³⁴⁵ They are asymptomatic, although there is one report of an increased incidence of malignant skin tumors in these individuals. ¹³²⁶ Prenatal diagnosis of xeroderma pigmentosum can be made by an analysis of DNA repair in cells cultured from the amniotic fluid of women at risk. ¹³⁴⁶

There is genetic heterogeneity with at least nine different groups recognized by somatic cell fusion studies – so-called ‘complementation groups’.^{1326. and 1347.} Seven of these groups (labeled A to G) have deficient excision repair of ultraviolet radiation-induced DNA damage (particularly nucleotide excision repair), ¹³⁴⁸ while in one (the so-called ‘XP variant’) there is defective ability to convert newly synthesized DNA from low to high molecular weight after UV irradiation (postreplication repair).^{1326.1349.1350. and 1351.} These different complementation groups have different clinical correlations, including differing susceptibility to the various cutaneous tumors. ¹³⁵² For example, XP-A is the most severe form and some of this group have the De Sanctis–Cacchione syndrome (see above). The severity of the neurological abnormalities in Japanese patients in this group correlates with the sites of nonsense mutations in the XP-A gene. ¹³⁵³ XP-E is the mildest form, with late onset and a higher residual capacity to repair UV-induced DNA damage in in-vitro studies.^{1354. and 1355.} XP-F,^{1356.1357. and 1358.} XP-G, ¹³⁵⁹ and XP-B are extremely rare; the latter group has in some cases been associated with the Cockayne syndrome (short stature, photosensitivity, deafness, mental deficiency, large ears and nose, and sunken eyes).^{1326.1329.1360.1361.1362.1363.1364.1365. and 1366.} The gene responsible for the severe type 2 Cockayne syndrome (OMIM 133540) is the excision repair cross-complementing group 6 (ERCC6) gene, located on chromosome 10q11, but the classic type 1 Cockayne syndrome (OMIM 216400) is due to mutations in ERCC8 on chromosome 5q12. XP-C is the most prevalent form of xeroderma pigmentosum among North Americans and Europeans. ¹³⁶⁷ Squamous cell carcinomas are commonly found in group A, basal cell carcinomas in groups C and E and in the variant form, and malignant melanomas in groups C and D and also in the variant form.^{1326.1368.1369. and 1370.} A new disorder with defective DNA repair distinct from xeroderma pigmentosum or Cockayne syndrome, and associated with UV-induced skin cancers, has been reported. ¹³⁷¹

In one study, a skin fibroblast cell strain from a patient with xeroderma pigmentosum was reported to have shown spontaneous morphological transformation to an anchorage-independent form after serial passage. ¹³⁷² This presumably has some significance in the development of tumors in vivo; the finding of reduced natural killer cell activity may have a similar significance. ¹³⁷³

It is now well established that cultured fibroblasts from patients with xeroderma pigmentosum show defective DNA repair following ultraviolet radiation. This abnormality is also present in keratinocytes and melanocytes cultured from affected patients. ¹³⁷⁴ Cultured keratinocytes from patients with xeroderma pigmentosum are more sensitive than normal cells to UVB-induced apoptosis. ¹³⁴⁸ The DNA nucleotide excision repair pathway involves at least 28 genes, 11 of which have been associated with clinical diseases. ¹³⁷⁵ The defect in xeroderma pigmentosum involves an initial phase in the process of excision repair. ¹³⁷⁶

All the genes for xeroderma pigmentosa have now been cloned. The gene responsible for xeroderma pigmentosum group A (XP-A) has been cloned and designated the XPA gene. At least 20 mutations of this gene exist, resulting in a different clinical severity for each mutation group.^{1345.1377.1378. and 1379.} The various genes involved in each of the types of xeroderma pigmentosum are listed in Table 9.5.

Absolute sun protection is the key to the management of this condition.

The ectodermal dysplasias are an expanding but nevertheless rare group of genodermatoses characterized by a diffuse, non-progressive disorder of the epidermis and at least one of its appendages.^{1383. and 1384.} The epidermal component may involve keratinocytes, melanocytes¹³⁸⁵ or Langerhans cells or any combination thereof; the ‘appendageal’ component may affect the hair, sebaceous or eccrine glands, the nails or the teeth. ¹³⁸⁶ The ectodermal dysplasias comprise approximately 200 clinically distinct syndromes and the limits of this entity are not clearly defined.^{1387. and 1388.} Their incidence in the United States is approximately 1 : 100 000 births. ¹³⁸⁹ Abnormalities of non-ectodermal structures may also be present.

The traditional classification of the ectodermal dysplasias into hidrotic and anhidrotic types is not appropriate for the broad range of abnormalities that may occur in this group. They are now classified on the basis of the presence or absence of trichodysplasia, ¹³⁹⁰ dental abnormalities, onychodysplasia, and dyshidrosis. Sometimes more than one such abnormality is present such as the odonto-onycho-dermal dysplasia syndrome (OMIM 257980) which also includes dystrophic nails, hyperhidrosis, palmoplantar keratoderma, and atrophic patches on the malar area. ¹³⁹¹ Other examples are cranioectodermal dysplasia (OMIM 218330) with craniofacial and skeletal anomalies including dental anomalies, ¹³⁹² and Ellis–van Creveld syndrome (OMIM 225500) due to mutations in the EVC gene on chromosome 4p16.^{390. and 1393.} It combines chondrodystrophy with central nervous system and urinary anomalies. There may also be dystrophic nails, partial adontia, and multiple frenulae. ¹³⁹³ The Naegeli–Franceschetti–Jadassohn syndrome (OMIM 161000) affects sweat glands, nails, teeth, and skin. It includes reticulate pigmentation of the skin as an important component and is therefore discussed with other disorders of pigmentation (see p. 297). The gene maps to chromosome 17q21 in the region of the type 1 keratin gene cluster. ¹³⁹⁴ Another ectodermal dysplasia, this time with pure hair and nail disturbances (OMIM 602032), is due to a defect in the keratin basic hair protein 5 (KRTHB5) gene on 12q13. ¹³⁹⁵ A novel locus has also been described on chromosome 17p12–q21.2. ¹³⁹⁶ The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (OMIM 240300) is due to mutations in the autoimmune regulator (AIRE) gene. ¹³⁹⁷ Alopecia areata and vitiligo may also be present. Most of the syndromes are extremely rare and of little dermatopathological importance. ¹³⁹⁸ Six of them merit further discussion.

There has been a report describing a father and son with brownish papules with central keratotic plugs. ¹⁴⁷¹ Single cell keratinization (dyskeratosis) was present in the epidermis, as well as in the epithelium of the mouth and the conjunctiva. ¹⁴⁷¹ A similar condition has been called hereditary benign intraepithelial dyskeratosis. There were prominent oral lesions. ¹⁴⁷² In another case, numerous dyskeratotic cells were present in epithelium of the lips, palate, and gums and on the labial surfaces of the genitalia, as an acquired phenomenon: this condition was referred to as acquired dyskeratotic leukoplakia. ¹⁴⁷³ Dyskeratotic cells were also a feature of the cases reported as hereditary mucoepithelial dysplasia (HMD). ¹⁴⁷⁴ HMD is characterized by the triad of non-scarring alopecia, well-demarcated erythema of oral mucosa, and psoriasiform perineal rash. ¹⁴⁷⁵ No genetic mutations have been found but many have been excluded. ¹⁴⁷⁵

The rare condition nevoid hyperkeratosis of the nipple and areola is manifest by hyperpigmentation of the areola with accompanying verrucous thickening. ¹⁴⁷⁶ Over 50 cases have now been reported. It may be unilateral or bilateral.^{1477.1478. and 1479.} Similar, but usually milder, changes may be seen in Darier’s disease, pregnancy and, rarely, in men receiving estrogen therapy for prostatic adenocarcinoma. ¹⁴⁸⁰ Its association with acanthosis nigricans is well documented.^{1481. and 1482.} Cases unrelated to estrogen therapy have been reported in males.^{1483. and 1484.} It has also been reported in a patient with incomplete androgen insensitivity syndrome (46XY karyotype) on estrogen replacement therapy. ¹⁴⁸⁵

There are no trials on the treatment of this condition. All reports are anecdotal. Cryotherapy and topical keratolytics have been used but agents such as 40% urea, 12% lactic acid lotion, and topical retinoids have given mixed or poor results. ¹⁴⁸⁶ Several cases have responded well to calcipotriol.^{1481. and 1487.}

The peeling skin syndrome (OMIM 270300) is a rare autosomal recessive disorder characterized by spontaneous, continual peeling of the skin.^{1491. and 1492.} Variants in which the peeling has been localized to the palm, ¹⁴⁹³ face, ¹⁴⁹⁴ or acral regions^{1495. and 1496.} have been reported. The acral variant (OMIM 609796) is caused by a homozygous mutation in the transglutaminase-5 (TGM5) gene. ¹⁴⁹⁷ Azathioprine has been associated with a clinical simulant. Aminoaciduria was present in another case. ¹⁴⁹⁸

Erythrokeratolysis hiemalis (keratolytic winter erythema, Oudtshoorn disease – OMIM 148370), a rare autosomal dominant genodermatosis with seasonal variation, is common in South Africa and related to an abnormality in chromosome 8p22–p23. It is also characterized by foci of erythema and skin peeling. ²³⁹ Spontaneous mutations appear to occur. ¹⁴⁹⁹

Granular parakeratosis is an acquired abnormality of keratinization first described in 1991 as axillary granular parakeratosis.^{1503.1504.1505. and 1506.} It has since been described in other intertriginous areas such as the inguinal region, ¹⁵⁰⁷ inter- and submammary region, ¹⁵⁰⁸ the vulva and perianal region.^{1504. and 1508.} Multiple intertriginous areas may be involved simultaneously. ¹⁵⁰⁹ Rare cases involving the abdomen and the knee have been seen, indicating that the adjectives ‘axillary’ and ‘intertriginous’ are both inappropriate in the title. Most cases occur in adults but children may also be involved.^{1510.1511.1512. and 1513.} There is a female predominance. ¹⁵¹⁴ The lesions are scaly red to hyperpigmented plaques that are often pruritic. ¹⁵¹⁵ Sometimes the lesions appear macerated. ¹⁵¹⁶ Rarely they are papillomatous. ¹⁵¹⁴ Axillary lesions can resemble acanthosis nigricans. A case of granular parakeratosis of eccrine ostia presented with small pruritic papules on the face and neck. ¹⁵¹⁷

Granular parakeratosis has been observed as an incidental finding overlying molluscum contagiosum, ¹⁵¹⁸ and in association with dermatomyositis, ¹⁵¹⁹ dermatophyte infection, ¹⁵²⁰ and cutaneous carcinomas. ¹⁵²¹ It has also developed in a woman with ovarian carcinoma treated with liposomal doxorubicin. ¹⁵²² The lesions spontaneously regressed after 4 weeks.

The cases reported by Resnik and colleagues as granular parakeratotic acanthoma were regarded as akin to epidermolytic acanthoma and acantholytic dyskeratotic acanthoma. ¹⁵²³ If this analogy is accepted then the cases reported are worthy of acceptance and not dismissible as seborrheic keratoses as suggested by Wang et al. ¹⁵¹⁷

There appears to be a defect in the processing of profilaggrin to filaggrin that results in a failure to degrade keratohyaline granules. ¹⁵⁰⁴ The etiology is unknown. Suggestions that the condition may result from excess use of topical antiperspirants seem difficult to sustain in cases occurring outside the axilla. ¹⁵²⁴ Mechanical irritation may also play a role in inducing these skin changes.^{1525. and 1526.} In several childhood cases, the mothers all reported the habit of frequent washing followed by application of many topical products. ¹⁵¹² Diaper wearing or the treatment of diaper rashes appears to play an important role in the genesis of infantile cases.^{1513. and 1527.}

Granular parakeratosis usually clears spontaneously after months to one year. ¹⁵²⁷ It has cleared rapidly following the topical use of tretinoin. ¹⁵²⁸ Other treatments used include 40% urea cream, ¹⁵¹⁴ topical calcipotriene and ammonium lactate, ¹⁵²⁹ and a combination of 1% hydrocortisone cream and 1% clotrimazole cream. ¹⁵⁰⁹

Originally described in 2002 as circumscribed palmar or plantar hypokeratosis by Pérez and colleagues, ¹⁵³¹ the word ‘acral’ was suggested by Berk et al in 2007 as a shortened title. ¹⁵³² It has merit. This entity has a predilection for the thenar and hypothenar aspects of the palm and, much less commonly, the medial side of the sole.^{1531. and 1533.} Lesions present as circumscribed round to oval erythematous areas of depressed skin.^{1534. and 1535.} In most cases lesions are solitary, but more than one lesion is uncommonly present. ¹⁵³⁶ There is a predilection for middle-aged and elderly females.

The etiology is unknown. Chronic repetitive trauma may, in some cases, induce the lesions. ¹⁵³⁷ HPV-4 has been isolated from one case, ¹⁵³⁸ and HPV-6 in another, but this latter patient had previously been treated for warts in the same location. HPV has been specifically excluded in other reports.^{1539. and 1540.} It more likely represents a localized defect in keratinization on acral sites, morphologically expressed in the granular and horny layers.^{1540. and 1541.}

As the lesions are asymptomatic no treatment is necessary. ¹⁵⁴² Cryotherapy, ¹⁵⁴³ photodynamic therapy, ¹⁵⁴⁴ and prolonged treatment with topical calcipotriol¹⁵⁴¹ have been successfully used.

Parenthetically, a case seen by the author 35 years ago was regarded by the late Dr Hermann Pinkus, to whom the lesion was sent in consultation, as a ‘minus nevus’, a term with some merit.

Although white sponge nevus (OMIM 193900) predominantly affects non-cornified stratified squamous epithelia, most often the buccal mucosa, it is considered here because pathogenic mutations in two of the keratin genes, KRT4 and KRT13, have been found in this condition. ¹⁵⁴⁶KRT4 maps to 12q13 and KRT13 to 17q21–q22. These two keratins are normally found in the suprabasal keratinocytes of buccal, nasal, and esophageal mucosa, and anogenital epithelia. ¹⁵⁴⁶

It is an autosomal dominant disorder characterized by thickened spongy mucosa with a white opalescent tint. It involves predominantly the buccal mucosa. It usually presents in early childhood.