Chapter 49. The Ichthyoses

The ichthyoses are a heterogeneous group of skin diseases characterized by generalized scaling. Scaling reflects altered differentiation of the epidermis. In this chapter, the terms epidermal differentiation, keratinization, and cornification will be used synonymously. The name ichthyosis is derived from the Greek ichthys, meaning “fish,” and refers to the similarity in appearance of the skin to fish scale. Both inherited and acquired forms are found. Early reports of ichthyosis in the Indian and Chinese literature date back to several hundred years bc, and the condition was discussed by Willan in 1808.1

Ichthyosis can present at birth or develop later in life. It can occur as a disease limited to the skin or in association with abnormalities of other organ systems. A number of well-defined types of ichthyosis with characteristic features can be reliably diagnosed. However, because of the great clinical heterogeneity and the profound effect of the environment on scaling, a specific diagnosis can be challenging in certain patients and families.

Siemens introduced genetic concepts into the ichthyoses.2 Wells and Kerr classified the ichthyoses on a genetic basis3 and separated X-linked recessive ichthyosis from ichthyosis vulgaris (IV).4 Gassman developed the concept of retention versus hyperproliferation hyperkeratosis5. Van Scott, Frost, and Weinstein subsequently proposed a classification of the ichthyoses based on differences in rates of epidermal turnover, characterizing them as either disorders of epidermal hyperproliferation or disorders of prolonged retention of the stratum corneum.6 Subsequently, Williams and Elias proposed a classification that lists the disorders of cornification in which clinical, genetic, or biochemical data suggest a distinct disease.7 Traupe reviewed the ichthyoses and suggested classification on a clinical level.5

Genetic approaches to understanding the ichthyoses have revealed the gene defects underlying many of these genodermatoses.8 A new classification is evolving based on the underlying molecular and genetic bases of these disorders. Knowing which gene is mutated directs us to the underlying pathophysiologic process. Understanding and describing these disorders on the basis of common molecular processes leads to more rational approaches to understanding their pathophysiology and treatment. A listing of the more common and the better understood hereditary ichthyoses according to pattern of inheritance and clinical features is shown in Tables 49-1, 49-2, and 49-3. Grouping these disorders according to underlying gene defect (Table 49-4) facilitates understanding of the clinical phenotypes in terms of underlying mechanism. However, further work is necessary to clearly understand how the gene mutations and resultant protein disruptions result in clinical disease, and furthermore, how therapeutic interventions can be creatively developed.

Online Mendelian Inheritance in Man, OMIM,10 (trademark Johns Hopkins University), a catalog of human genes and genetic disorders, is a useful reference with links to additional resources.

A specific diagnosis in an individual or family with ichthyosis can help to predict prognosis, is important for genetic counseling, and may direct treatment. Several features are useful in distinguishing different forms of ichthyosis. These include the age of onset, presence of collodion membrane at birth, quality of scale, presence/absence of erythroderma, abnormalities in other parts of the skin (e.g., palms and soles, ectropion, eclabium) and adnexal structures (e.g., alopecia, hair follicle, or shaft abnormality), and involvement of other organ systems. In different types of ichthyosis, the appearance of the surface of the skin may vary. Visible scaling may be seen in some patients, with flakes of stratum corneum varying in size from fine to coarse. There may also be thickening of the skin with or without visible scale. The term hyperkeratosis has been used clinically to describe thickened skin, with or without scale, that reflects thickening of the stratum corneum. A family pedigree may clarify the pattern of inheritance. However, many autosomal dominant diseases [e.g., epidermolytic hyperkeratosis (EHK)] have a high frequency of spontaneous mutation, and the lack of a positive family history does not rule out autosomal dominant inheritance. Alternatively, the presence of parental consanguinity may suggest autosomal recessive inheritance. Light microscopic features are usually diagnostic in epidermolytic hyperkeratosis and can be helpful in selected ichthyoses (e.g., Refsum disease, neutral lipid storage disease, acquired ichthyosis of sarcoidosis and mycosis fungoides), but histopathologic examination may not be useful to distinguish other ichthyoses. In many cases, the clinical diagnosis may be clarified by genetic analysis, although mutations are not always demonstrable. The development of ichthyosis in adulthood may be a marker of systemic disease.

The fully differentiated end product of the epidermis is the stratum corneum, which is composed of terminally differentiated keratinocytes, corneocytes (“bricks”), surrounded by an intercellular matrix (“mortar”) (see Chapter 47). The corneocyte bricks are protein-enriched, and the intercellular mortar is composed of hydrophobic, lipid-enriched membrane bilayers.7 The keratin-laden corneocytes are thought to be primarily responsible for the resilience and water retention properties of the stratum corneum, while the matrix forms most of the permeability barrier to water loss. The normal stratum corneum undergoes desquamation in an organized and invisible manner, with individual corneocytes separating from each other and shedding as single cells. Ichthyotic skin has an abnormal quality and quantity of scale, the barrier function of the stratum corneum is compromised, and there may be alterations in the kinetics of epidermal cell proliferation (see Chapter 46). The stratum corneum can be viewed as a compartment, with thickening of the stratum corneum being the result of cells entering the compartment at an increased rate, or leaving (corneocyte desquamation) too slowly, or both.

The process of epidermal differentiation is complex and not completely understood. Defects in many different aspects and steps of this process can lead to a similar end result: abnormal stratum corneum and scale. In some of these disorders, the underlying gene defect has been identified. For example, mutations in the genes that encode the suprabasal epidermal keratins, keratins 1 and 10, cause epidermolytic hyperkeratosis.11 Mutations in the gene encoding transglutaminase-1, an enzyme that catalyzes the cross-linking of proteins and attachment of ceramides during the formation of corneocytes, are found in up to 55% of patients with autosomal recessive congenital ichthyosis.12–15 The observation that key components of this process cause ichthyosiform disorders highlights the importance and complexity of normal keratinocyte differentiation.

Steroid sulfatase controls the hydrolysis of cholesterol sulfate in corneocytes and is thought to be important in the regulation of corneocyte desquamation. Deficiency of steroid sulfatase causes X-linked recessive ichthyosis.16,17 The observation that several drugs that lower serum cholesterol (e.g., nicotinic acid, triparanol) can induce ichthyotic skin changes indicates the importance of lipid homeostasis in normal keratinization.7 Further evidence is the identification of mutations in the genes encoding cholesterol biosynthetic enzymes as a cause of X-linked dominant chondrodysplasia punctata and CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome, and genes encoding other aspects of lipid biosynthesis in the autosomal recessive congenital ichthyoses.18 The identification of mutations in SPINK5 (serine protease inhibitor, Kazal type 5), encoding a serine protease inhibitor, in Netherton syndrome confirms a role for proteolysis and protease inhibitors in normal epidermal differentiation.19 The discoveries of connexin abnormalities as causes for erythrokeratodermia variabilis, KID (keratitis, ichthyosis, and deafness) syndrome, and other disorders involving ectodermal tissues highlight the role of intercellular communication for properly functioning skin.20,21 Mutations in the FLG gene result in reduced or absent filaggrin and decreased moisture binding in the stratum corneum of patients with IV.22 Mutations in FLG may also result in more severe clinical phenotype in other skin disorders.23,24

These examples highlight the complexity of the process of forming a normally functioning stratum corneum and demonstrate that diverse abnormalities can result in similar clinical phenotypes of thickened stratum corneum and scaling. How do diverse processes result in similar phenotype? The answers are unclear, although studies suggest that defects in the barrier may result in inflammation and hyperproliferation.25 Furthermore, our evolving understanding of these mechanisms continues to clarify the multisystem, clinical phenotypes observed in several ichthyosiform disorders.

Ichthyosis vulgaris (OMIM #146700), the most common ichthyosis, is relatively mild. While infants usually have normal skin, the disease often manifests within the first year. The scale of IV is usually most prominent on the extensor surfaces of the extremities, with flexural sparing (Fig. 49-1). The diaper area tends to be spared. There may be fine, white scales over large areas. Particularly on the lower extremities, which are often the most severely involved area, the scales may be centrally attached, with “cracking” (superficial fissuring through the stratum corneum) at the edges. This turning up at the edges can lead to the skin feeling rough.

A number of other findings are commonly observed in association with IV.26 Hyperlinear palms are usually present, and some patients may have palmar/plantar thickening approaching a keratoderma. Keratosis pilaris is common, even in individuals with mild IV, and usually involves the outside of the arms, extensor thighs, and buttocks. Atopy is also frequently observed and can manifest as hay fever, eczema, or asthma. These findings can confound an accurate diagnosis, because hyperlinear palms and keratosis pilaris may be seen in atopic individuals who do not have IV. Rarely, individuals with IV may have hypohidrosis with heat intolerance. There is great variation in the severity of clinical manifestations between affected individuals in the same family. The condition usually worsens in climates that are dry and cold and improves in warm, humid environments where the disease may clear dramatically.

The disease was thought to be autosomal dominant and in a study of English school children was found to affect 1 in 250.4 Recently, mutations in the gene encoding profilaggrin have been found to cause IV. Profilaggrin is the precursor protein for multiple copies of filaggrin, which functions during cornification. The inheritance pattern has been clarified to be semidominant; individuals who carry one mutated allele have a mild phenotype, while those with mutations in both profilaggrin alleles (homozygotes or compound heterozygotes for the mutations) (Fig. 49-1) manifest a severe clinical phenotype. In the Anglo-European population, the prevalence of clinical disease is as high as 1 in 80.22,27,28

It is difficult to distinguish some patients with mild IV from simple dry skin (xerosis). Evolving understanding of this very common condition is beginning to clarify how a spectrum of underlying mutations can cause the diverse clinical severity of dry skin from xerosis to severe IV. In addition, on the basis of skin findings alone, males with severe IV may be difficult to differentiate from those affected with X-linked recessive ichthyosis.26,29 The histopathologic findings of IV (Fig. 49-2A) may, as the clinical severity, be more pronounced, with hyperkeratosis and absent granular layer in individuals with two abnormal alleles.

Filaggrin is an epidermal protein involved in the aggregation of keratin intermediate filaments30 and retention of moisture in the stratum corneum.31 Keratin filaments form a network, or cell matrix, that gives structural integrity to the epidermal keratinocytes. As keratinocytes mature into corneocytes, the keratin filaments collapse and are cross-linked to the cornified cell envelope. Filaggrin is synthesized as a high-molecular weight precursor, profilaggrin, that contains multiple filaggrin molecules and is localized to keratohyalin granules. Biochemical studies of epidermis from patients with IV have shown absence of or decrease in filaggrin and its precursor, profilaggrin.32,33 In the Anglo-European population, null mutations in the gene encoding profilaggrin (FLG) are very strong predisposing factors for atopic dermatitis. A strong association is also found with individuals who have sensitivity to common allergens, allergic rhinitis, early onset and persistent eczema, and asthma in the presence of atopic dermatitis.27,34

In the 1960s, X-linked recessive ichthyosis (OMIM #308100) was distinguished clinically from other ichthyoses.4 Shortly thereafter, the syndrome of placental steroid sulfatase deficiency was described in pregnancies with failure to initiate labor in association with low maternal urinary estrogens. Because the majority of maternal urinary estrogens are derived from the fetal adrenal and are metabolized by the placenta, low levels can reflect fetal abnormalities or death. However, in this condition low levels do not indicate severe fetal morbidity. The association between failure to initiate or progress labor and ichthyosis in the male offspring was not appreciated until 1978.16,17 Steroid sulfatase hydrolyzes sulfate esters, which include cholesterol sulfate and sulfated steroid hormones.35 Sulfated fetal adrenal hormones undergo desulfation to estrogens, which are excreted in maternal urine. The absence of steroid sulfatase enzyme in the fetal placenta leads to low maternal urinary estrogens, and in some pregnancies, to a failure of labor to initiate or to progress normally. In males with X-linked recessive ichthyosis, steroid sulfatase enzyme activity is decreased or absent in many tissues, including epidermis, stratum corneum, and leukocytes, and in cultured fibroblasts.36 In addition, cholesterol sulfate, an enzyme substrate, accumulates in serum and in scale. Carrier females have been found to have leukocyte steroid sulfatase levels intermediate between those observed in normal individuals and those in affected males.

X-linked recessive ichthyosis occurs in approximately 1 in 2,000 to 6,000 males.4,37 Scaling may begin in the newborn period and is usually most prominent on the extensor surfaces, although there is significant involvement of the flexural areas. While the extent and degree of scaling are variable, X-linked ichthyosis can usually be distinguished from IV on clinical criteria.4,38 The latter tends to be associated with hyperlinear palms and soles, keratosis pilaris, and a family history of atopy. X-linked ichthyosis tends to have more severe involvement with larger scale, and comma-shaped, corneal opacities may be present in half of adult patients39,40 (Fig. 49-3). Corneal opacities do not affect vision and may be present in female carriers.40 Affected males have an increased risk of cryptorchidism, and independently they are at increased risk for the development of testicular cancer.41 Histopathologic examination shows compact orthohyperkeratosis, acanthosis, and papillomatosis. The granular layer is usually thickened (Fig. 49-2).

Cholesterol sulfate levels are elevated in the serum, epidermis, and scale,42 and there is increased mobility of β-lipoproteins (low-density lipoproteins) on electrophoresis, a feature that can suggest the diagnosis. Steroid sulfatase is one of a group of arylsulfatases located on chromosome Xp22. More than 90% of the mutations in X-linked ichthyosis are deletions that can often be detected by fluorescence in situ hybridization (FISH), available in many clinical laboratories. Confirmation of the diagnosis can also be made by finding an elevation in serum cholesterol sulfate levels. Unfortunately, cholesterol sulfate determination in serum and scale may not be readily available for laboratory confirmation of the clinical diagnosis. In the rare case where deletions are not detected and a clinical diagnosis is necessary, arylsulfatase C (steroid sulfatase) enzyme activity can be measured in cultured fibroblasts. Deletions that include adjacent sulfatases explain the overlap syndromes involving chondrodysplasia punctata and X-linked ichthyosis.43 The X-linked form of Kallmann syndrome, in which hypogonadotropic hypogonadism and anosmia are found, often with renal abnormalities, obesity, synkinesis (mirror image movements of the extremities), cleft palate, and spastic paraplegia, can also be seen in association with X-linked recessive ichthyosis as part of a contiguous gene deletion syndrome.43 Because of this, and because of the association with testicular carcinoma, patients with X-linked recessive ichthyosis should be queried about anosmia and have periodic testicular examination.44

In the epidermis, steroid sulfatase catalyzes the hydrolysis of cholesterol sulfate. The identification of steroid sulfatase deficiency in X-linked ichthyosis supports the importance of cholesterol sulfate hydrolysis in normal desquamation. Topical application of cholesterol sulfate in mice can induce a scaling disorder, further supporting the role of cholesterol sulfate hydrolysis in corneocyte desquamation.

A family was described with an ichthyosis inherited in an X-linked pattern but with normal steroid sulfatase activity and the absence of corneal opacities.45 This demonstrates heterogeneity within X-linked ichthyosis. Because of its frequent occurrence, steroid sulfatase deficiency accounts for most cases of X-linked ichthyosis, but a normal steroid sulfatase level in a male with ichthyosis does not rule out an X-linked pattern of inheritance.

The term autosomal recessive congenital ichthyosis (ARCI) is useful to describe a heterogeneous group of disorders that present at birth with generalized involvement of the skin. Autosomal recessive ichthyosis is rare and has been estimated to occur in about 1 in 300,000 persons.4

In older literature, nonbullous congenital ichthyosiform erythroderma (NCIE) [lamellar ichthyosis (LI), with autosomal recessive inheritance] was distinguished from bullous congenital ichthyosiform erythroderma (BCIE) (EHK, with autosomal dominant inheritance) based on clinical appearance (bullae) and pattern of inheritance.6,46 That the term LI was used interchangeably with NCIE and included a spectrum of phenotypes has led to some confusion. Williams and Elias distinguished LI from NCIE [usually called congenital ichthyosiform erythroderma (CIE)], a milder erythrodermic form.47 Some patients with LI can be clearly distinguished from those with CIE on the basis of clinical features. In LI one sees large, dark, plate-like scales, and while infants may be red at birth, adults have little to no erythroderma (Fig. 49-4). In the more severe, classic presentation of LI, tautness of the facial skin leads to traction on the eyelids and lips, resulting in ectropion and eclabium. Scarring alopecia, most prominent at the periphery of the scalp, may be partly due to traction at the hairline. In contrast, CIE has generalized redness and fine, white scales (Fig. 49-5). Patients with classic CIE have little to no ectropion, eclabium, or alopecia. However, many patients do not fit neatly into these two clinical descriptions,48 in that they have features of both LI and CIE with a clinical phenotype intermediate between both disorders. Therefore, it can be useful to consider these two distinctive presentations as ends of a spectrum, between which lie a gradation of clinical phenotypes with variable degrees of erythema and coarseness of scale. Individual features such as collodion membrane (discussed below), ectropion, and alopecia can occur across the spectrum. While attempts to refine the categorization of these disorders by biochemical and ultrastructural observations have failed to yield a consistent and replicable classification scheme,5 identification of the spectrum of specific molecular defects underlying these conditions will undoubtedly help.49 Identification of mutations has, so far, found ARCI to be caused by six different genes (Table 49-5) which are important for the formation of the intercellular lipid layer or the cornified envelope of keratinocytes.

Most patients with LI or CIE inherit the disease in an autosomal recessive pattern. Rarely, families have been described with similar phenotypes, where the disease is inherited as an autosomal dominant trait.5 This is an important consideration for genetic counseling.

LI is apparent at birth, and the newborn usually presents encased in a collodion membrane. At this time the skin may be red. Over time, the skin develops large, plate-like scales, which appear to be arranged in a mosaic pattern (see Fig. 49-4). In some areas, the scales are centrally attached with raised borders. The scales tend to be largest over the lower extremities, where the large, plate-like scales separated by superficial fissuring can lead to an appearance similar to that of a dry riverbed. During childhood and into adulthood the degree of erythema may vary, but usually is minimal or absent in the severe presentation of classic LI. Involvement of the palms and soles in LI is variable and ranges from minimal hyperlinearity to severe keratoderma.

The lips and mucous membranes tend to be spared in LI, but the adnexal structures may be compromised by the adherent, firm scales. Thick stratum corneum on the scalp tends to encase hairs, and in conjunction with the tautness of the skin, may lead to a scarring alopecia, most marked at the periphery of the scalp. The hyperkeratosis can interfere with normal sweat gland function, resulting in hypohidrosis, but the degree of impairment varies between patients. Some patients have severe heat intolerance and must be vigilant to avoid overheating. Treatment with oral retinoids can improve or prevent some sequelae of LI. Patients frequently notice an increase in sweating, with improved heat tolerance. While retinoid therapy can cause blepharitis or even conjunctivitis, it is usually well tolerated by patients with LI. Moreover, the ability of systemic retinoid (and in some cases, topical retinoid) therapy to decrease thick periocular scale can decrease the tendency to develop ectropion. Nevertheless, patients with severe, classic LI usually require careful eye maintenance. Because of the ectropion (see Fig. 49-4), the lids may fail to close fully, particularly during sleep; hydration with liquid tears during the day and ophthalmic lubricants at night can prevent exposure keratitis.

Histopathologic examination typically shows orthokeratotic hyperkeratosis with mild to moderate acanthosis. Rates of epidermal proliferation are normal or only slightly elevated in patients with LI, in contrast to those with CIE, which has significantly greater labeling indices.50

Mutations in TGM1, the gene encoding transglutaminase 1, were found in several families with LI, solidifying the role for transglutaminase 1 in the formation of a normal stratum corneum and its role as a cause of LI.12,13 The lamellar phenotype is more commonly associated with mutations in TGM1.15,49 The transglutaminases catalyze calcium-dependent cross-linking of proteins through the formation of ϵ-(γ-glutamyl)lysine isodipeptide bonds. During the formation of the stratum corneum, transglutaminase catalyzes the cross-linking of cellular proteins, including involucrin, loricrin, small proline-rich proteins, and others. The resulting protein complex is deposited on the inner side of the plasma membrane to form the cornified envelope. Transglutaminase also attaches ceramides secreted into the intercellular space by lamellar bodies to cornified envelope proteins, notably involucrin, and thereby is important in the formation of both the protein and lipid components of the stratum corneum.14

Bathing suit ichthyosis is an unusual form of LI where affected individuals develop the scaling typical of LI, but limited to the bathing suit area.51 The distribution correlates with warmer areas of skin. Decreased transglutaminase is found in these areas, and unique, temperature-sensitive mutations in TGM1 have been identified in affected individuals.52

In a human skin/immunodeficient mouse xenograph model, transfer of a transglutaminase-1 gene into transglutaminase-1-deficient keratinocytes from LI patients resulted in normalization of transglutaminase expression and epidermal architecture in addition to restoration of cutaneous barrier function.53 Additional disease-causing loci have been found (see below).

As with LI, CIE is apparent at birth, and the newborn usually presents with a taut, shiny, collodion membrane. After shedding of the membrane, the skin of infants with CIE remains red, usually with a fine, white, generalized scale (see Fig. 49-5). On the lower legs, the scale may be larger and darker. In contrast to LI, the classic presentation of CIE may have little to no ectropion, eclabium, or alopecia. As in LI, there is a wide variation in the ability to sweat, and patients with CIE may have minimal sweating with severe heat intolerance. Mucous membranes are usually spared. Palm/sole involvement is variable. Nails may have ridging, but they are often spared. As with all the ichthyoses, dermatophyte infection of the skin and nails is common.

Histopathologic examination shows hyperkeratosis, acanthosis, and often parakeratosis (Fig 49-2C). Studies of epidermal proliferation have shown markedly increased epidermal cell turnover, in contrast to LI.50

A small subset of patients with CIE have been found to have mutations in TGM1, and two siblings with a collodion presentation, CIE, and palmoplantar keratoderma had an autosomal dominant mutation in the cornified envelope protein, loricrin.54 Further genetic heterogeneity within ARCI has been demonstrated, with exclusion of TGM1 as the disease-causing gene in families with phenotypes within the spectrum of classic LI and CIE and identification of mutations in other genes. To date, mutations have been identified in five additional genes in ARCI (Table 49-5). In addition, two other genetic loci (12p11.2-q13 and 19p13.1-13.2) have been found to be associated with ARCI; the responsible genes have not been identified. The enzymes coded for by these genes (Table 49-5) are hypothesized to function together to convert arachidonic acid to a specific hepoxilin in a newly described pathway thought to form a common link in ARCI.18,55 This hypothesis remains to be tested, and how the most common mutation in ARCI, that of TGM1, might relate to lipid abnormalities is unclear.

In 1902, Brocq described bullous ichthyotic erythroderma and distinguished the blistering type from the nonblistering type of congenital ichthyotic erythroderma.56 The original description included three unrelated patients whose clinical manifestations varied. However, this was probably the first description of epidermolytic hyperkeratosis (EHK; OMIM #113800). The disease is named for the distinctive histopathologic features of vacuolar degeneration of the epidermis (i.e., epidermal lysis) and associated hyperkeratosis. EHK is also known as BCIE, an earlier descriptive name signifying the blistering, neonatal presentation, scaling, and redness.

EHK is transmitted as an autosomal dominant trait with a prevalence of approximately 1 in 200,000 to 300,000 persons. However, there is a high frequency of spontaneous mutation, and as many as one-half of the cases have no family history46 and represent new mutational events. The disease usually presents at birth with blistering, redness, and peeling (Fig. 49-6). With time, generalized hyperkeratosis may develop, which may or may not be associated with erythroderma. EHK skin usually has a characteristic pungent odor, thought to be related to superinfection by mixed flora.

In contrast to most other ichthyoses, the histopathologic picture of EHK is almost always distinctive. A tremendously thickened stratum corneum and vacuolar degeneration of the upper epidermis are seen, leading to the histologic term EHK (see Fig. 49-2D). The vacuolar degeneration usually involves the upper epidermis and occasionally all of the suprabasilar keratinocytes. Granular cells exhibit dense, enlarged, irregularly shaped masses that appear to be keratohyalin granules.6 On electron-microscopic examination, clumping of filaments is observed to begin in the first suprabasal layer. These aggregated filaments are clumps of keratin intermediate filaments that contain the suprabasal keratins 1 and 10.57

There is striking clinical heterogeneity between EHK families. Six distinctive clinical phenotypes have been described.58 Several clinical features can be useful to distinguish between the different subtypes, including the presence versus absence of severe palmar/plantar hyperkeratosis and of erythroderma, quality of scale, extent of involvement, presence of digital contractures, and gait abnormality (Table 49-6). Three types without palm/sole hyperkeratosis are called NPS types. Patients with the NPS-1 clinical phenotype have generalized involvement with thick, brown verrucous hyperkeratosis, most prominent over joints. Palms and soles are spared. Cobblestone or hystrix (porcupine-like) spiny papules are characteristic; this severe clinical presentation is one of the more commonly recognized types of EHK (Fig. 49-7A). NPS-2 is similar, but much milder, without the hystrix spines and with relative sparing of the skin between joints (Fig. 49-7B). Generalized exfoliative erythroderma is found in NPS-3 (Fig. 49-7C). Three types with severe palm/sole hyperkeratosis are called PS types. Patients with the PS-1 type have a smooth palmar/plantar hyperkeratosis with a sharp border, often delineated by a red halo. Blisters may be present at the border. There may be limited involvement of the trunk, usually confined to areas over joints (Fig. 49-8A). The PS-2 type is characterized by generalized erythroderma and scaling. Volar involvement may be severe, with contractures of the digits and ainhum-like constricting digital bands (Fig. 49-8B). The PS-3 type has generalized skin involvement with a pebbly hyperkeratosis that is arrayed in a distinctive, cerebriform pattern on the palms and soles (Fig. 49-8C).

Sporadic EHK due to a postzygotic, spontaneous mutation during embryogenesis can present in a mosaic pattern of skin involvement. Areas of hyperkeratosis alternating with normal skin are often distributed in streaks along Blaschko lines (Fig. 49-9A). These may be limited to a few streaks, or there may be many, with widespread, patchy involvement. Unilateral localization can also occur. This clinical mosaic pattern correlates with underlying genetic mosaicism in that keratin mutations characteristic of EHK, which were found in lesional skin, were absent in normal skin.59 If the germ line is involved, individuals with mosaic EHK can transmit the mutation, which leads to generalized EHK in affected offspring (Fig. 49-9B).60

Within keratinocytes, keratin intermediate filaments form an elaborate network that confers structural stability to the cells. In the suprabasilar, differentiating keratinocytes of interfollicular epidermis, this network is formed by keratins 1 and 10. In EHK, failure of this network leads to keratinocyte fragility (particularly of the upper epidermis), easy blistering, altered barrier function,61 abnormal epidermal kinetics (hyperproliferation), and thickened stratum corneum (hyperkeratosis). Keratin 10 is the coexpressed partner of keratin 1, both of which are required to form keratin intermediate filaments in the cells of the suprabasal layers of the epidermis. Mutations in genes coding for either keratin 1 or 10 have been identified in a number of EHK families.57,62 In most cases, palmar/plantar involvement implies mutations in K1; this may reflect the “redundancy” of K9 (a keratin that occurs only in the suprabasal epidermis of palmar and plantar skin) and K10 in palmar/plantar epithelium. Mutations in keratin 9 have been found in families with the type of EHK limited exclusively to the palms and soles (Vörner)63 (see Chapter 50).

Ichthyosis Bullosa of Siemens

Ichthyosis bullosa of Siemens (OMIM #146800) is a rare autosomal dominant genodermatosis that is similar in clinical appearance to EHK. Patients are born with redness and blistering. The redness subsides over the subsequent weeks to months, while the skin develops dark gray hyperkeratosis, particularly over flexural areas. In some areas, there may be a lichenified appearance to the skin. As with EHK, the epidermis is fragile; however, the fragility is more superficial. This can result in loss of the uppermost epidermis (predominantly stratum corneum), yielding a characteristic, collarette-like depressed area that has been described as “mauserung” (molting). Histologically, the epidermis shows hyperkeratosis and vacuolization similar to EHK, but it may be confined to the granular layer. Mutations have been found in the gene encoding keratin 2,64 a differentiation keratin of the suprabasilar epidermis that is expressed in the more superficial epidermal layers.

Ichthyosis Hystrix of Curth and Macklin

Ichthyosis hystrix of Curth and Macklin (OMIM #146590) is a rare, autosomal dominant disorder that clinically resembles EHK. Clinical expression varies, even within families, from palmoplantar keratoderma to severe generalized involvement. There can be widespread patchy, thick, gray–brown hyperkeratosis, most marked on the extensor arms and legs. Patients with extensive involvement resemble those with severe EHK without palmar/plantar involvement, with verrucous or porcupine-like (hystrix) hyperkeratosis. However, in contrast to EHK, blistering does not occur. Histologic examination of the epidermis shows acanthosis, papillomatosis, and severe orthokeratotic hyperkeratosis, with frequent binucleate cells. Keratinocytes within the granular and upper spinous layers may have perinuclear vacuolization, and some have prominent perinuclear shells. On electron microscopy, there are concentric, unbroken shells of tonofilaments surrounding the nucleus. Study of a three-generation family with ichthyosis hystrix of Curth and Macklin identified a mutation in the variable tail domain (V2) of the keratin 1 gene. Structural analyses of the resulting abnormal keratin showed a failure of keratin intermediate filament bundling, retraction of the cytoskeleton from the nucleus, and failure of localization of loricrin to desmosomal plaques.65

Annular Epidermolytic Erythema

Annular epidermolytic erythema (cyclic ichthyosis with EHK; OMIM #607602) presents at birth or in the first few months afterward with severe, intermittent scaling and blistering that resolves during puberty.66 Residual, limited thickened plaques of verrucous scale in linear rows can be seen in flexural and intertriginous skin. In some cases, explosive bouts of widespread erythema with blisters and pustules are seen.67 Patients subsequently develop widespread, migratory, polycyclic, and annular scaling plaques. Light and electron microscopy reveals findings of EHK. Mutations in keratin 1068 and keratin 167 have been found.

A unifying designation of keratinopathic ichthyosis for all ichthyoses with underlying keratin mutations has been suggested recently.9

Collodion Baby

A collodion baby is born encased in a translucent, parchment-like membrane that is taut and may impair respiration and sucking. Involvement may vary from mild to severe, but this variation has not been well characterized. In addition, the birth is often premature, which adds to morbidity. During the first 2 weeks of life, the membrane breaks up and peels off, often leaving fissures, with impairment of the barrier to infection and water loss. This can lead to an increased risk of infection, difficulties in thermal regulation, and hypernatremic dehydration.69 Newborn care should include careful monitoring for infection and of temperature, hydration, and electrolytes, and measures to keep the peeling membrane soft and lubricated to facilitate flexibility and desquamation. Appropriate pain management and eye care should be employed, when indicated. These newborns usually benefit from a humidified incubator where the air is saturated with water; wet compresses followed by bland lubricants can be used to further hydrate the membrane and achieve maximum pliability.70 If during peeling, residual areas of the membrane are allowed to dry and harden in areas such as the extremities, the taut membrane can constrict and lead to distal swelling. Collodion presentation can develop into a wide spectrum of ichthyotic phenotypes as the child grows (Box 49-1). It is the usual presentation of ARCI (see Fig. 49-10) and is less commonly seen in several other forms of ichthyosis, and rarely Gaucher disease (Box 49-1). In addition, an autosomal recessive, self-healing collodion baby has been described, where the skin greatly clears within the first few weeks and transitions into mildly affected or normal skin.71 Eleven Swedish and four Danish patients with a self-improving ichthyosis resulting in xerosis, hyperlinear palms, red cheeks, and anhidrosis were found to have mutations in ALOX12B, ALOX3E, or TGM1.72

Epidermolytic Hyperkeratosis

The newborn affected with one of the more severe, generalized types of EHK usually has erythema, blistering, widespread erosions, and denuded skin (see Fig. 49-6). Because there is a high frequency of new mutations, the disease may be unexpected and the diagnosis may be unknown. Epidermolysis bullosa or staphylococcal scalded-skin syndrome may be suspected, and the infant treated with antibiotics. The newborn may require intensive care with fluid and electrolyte monitoring. Specialized skin care can minimize blistering and enhance healing of erosions and may include lubrication to decrease friction and mechanical trauma, protective padding, and specialized wound dressings. The newborn with extensive erosions is prone to bacterial infection and sepsis, and carefully chosen topical and systemic antibiotics can minimize the extent of infection.

Harlequin Ichthyosis

A dramatic, severe, and often fatal presentation of ichthyosis is that of harlequin ichthyosis (OMIM #242500) (Fig. 49-11). The child is often premature and born with massive, shiny plates of stratum corneum separated by deep, red fissures that tend to form geometric patterns, as seen in the patched costumes of the harlequin clowns from the Italian Commedia dell’Arte dating from the sixteenth and seventeenth centuries. There are poorly developed or absent ears and marked ectropion and eclabium. The first report is from the diary of Rev. Oliver Hart, of Charleston, South Carolina, who described these features in 1750.73 These children are at great risk during the neonatal period and often die shortly after birth. Abnormal water loss through the skin and poor temperature regulation lead to risk of fluid and electrolyte imbalance. The infants are also at risk for infection beginning in the skin, but at the same time (because of poor temperature regulation) do not show the usual signs of infection. Normal respiration may be restricted by the taut skin. Treatment with systemic retinoids during the newborn period can facilitate desquamation of the membrane.74,75 Advances in neonatal intensive care, together with facilitating desquamation by judicious use of systemic retinoid therapy have led to improvements in survival and to the use of the name “harlequin baby” rather than “harlequin fetus.” Some babies have suffered from failure to thrive and require tube feeding. The skin of those who survive the newborn period usually resembles the skin of those with a severe phenotype of CIE.74,75

In harlequin ichthyosis, normal lamellar granules are not found; instead, there are small vesicles that lack internal structure. There is also no evidence of the lipid lamellae that form between granular and cornified cells as a result of discharge of lamellar granule contents into the intercellular space.76 The disorder results from autosomal recessive inheritance of mutations in ABCA12, which codes for an adenosine triphosphate (ATP)-binding cassette (ABC) transporter involved in lamellar granule secretion and epidermal lipid transport. Premature termination mutations underlie harlequin ichthyosis,77–79 while missense mutations in ABCA12 have been identified in a subset of individuals with less severe ARCI80 (Table 49-5).

Netherton Syndrome

Netherton syndrome (OMIM #256500) is a rare, autosomal recessive disorder characterized by the concurrence of ichthyosis, a structural hair shaft abnormality, and atopy.81,82 The usual cutaneous manifestation is ichthyosis linearis circumflexa, a distinctive condition of generalized hyperkeratosis and polycyclic and serpiginous erythematous plaques with a characteristic, migratory, double-edged scale at the margins (Fig. 49-12A). At birth, affected children may present with generalized erythroderma. Infants and children may have feeding problems, with poor absorption and failure to thrive.83 With atopic dermatitis, there may be pruritus, and scratching can lead to lichenification at the flexures. In some patients, the ichthyosis resembles LI or CIE.5,81 Histopathologic examination is not specific and may show features of hyperkeratosis, psoriasis, and atopic dermatitis. Most patients have a specific hair shaft abnormality called trichorrhexis invaginata, in which the distal hair segment is telescoped into the proximal one, forming a ball-and-socket-like deformity on microscopic examination (Fig. 49-12B). This is also known as “bamboo hair” and is due to abnormal cornification of the internal root sheath. Hair from multiple areas should be examined, because only 20–50% of hair may be affected; the characteristic abnormality may be more commonly observed on eyebrow hair.84 Trichorrhexis nodosa and pili torti (see Chapter 88) may also occur. The hair defects may not be detectable at birth, and may disappear with age. Atopy in these patients may manifest as atopic dermatitis asthma, or severe food allergy (particularly to nuts), and marked elevations of serum immunoglobulin (Ig) E may occur. In some patients, generalized aminoaciduria, mild developmental delay, and impaired cellular immunity may also be present.85 Netherton syndrome has been found to be due to mutations in SPINK5, a gene encoding LEKTI (lympho-epithelial Kazal-type related inhibitor).19 LEKTI is a serine protease inhibitor that is predominantly expressed in epithelial and lymphoid tissues, and may be important in the downregulation of inflammatory pathways. This discovery highlights the importance of the regulation of proteolysis in the overlap between epithelial barrier function and the hypersensitivity of atopy. Subsequently, LEKTI polymorphisms were associated with common atopy and atopic dermatitis.86 Prenatal testing for Netherton syndrome using molecular data has been successfully accomplished.87 Tacrolimus ointment, a topical immunomodulator (see Chapter 221), is effective in common atopic dermatitis with minimal systemic absorption. However, Netherton syndrome is complicated by an abnormal skin barrier, allowing increased percutaneous absorption and associated risk for systemic toxic effects. This should be considered when using topical agents such as tacrolimus, where monitoring of serum levels may be necessary,88 and topical steroids, where iatrogenic Cushing syndrome has been reported.89

ARC

ARC (OMIM #208085) is a rare autosomal recessive, multisystem disorder characterized by arthrogryposis, renal tubular dysfunction, and cholstasis often with ichthyosis and other abnormalities. Mutations have been found in the VPS33B gene that encodes a protein involved in intracellular trafficking pathways.90

CEDNIK

Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome (OMIM #609528) is an autosomal recessive neurocutaneous syndrome characterized by severe psychomotor retardation, ichthyosis, and palmoplantar keratoderma thought to result from abnormal lamellar granule maturation and secretion.91 In CEDNIK syndrome, lamellar granules are retained within the cornified cell layer resulting in reduced secretion of lipids and proteases into the extracellular space. This results in impaired barrier formation and decreased corneocyte disadhesion.

Chanarin–Dorfman Syndrome

Chanarin–Dorfman syndrome (neutral lipid storage disease; OMIM #275630) is an autosomal recessive disorder characterized by accumulation of triglycerides in the cytoplasm of leukocytes, muscle, liver, fibroblasts, and other tissues. However, blood lipid levels are normal. To date, approximately 30 patients have been reported, mainly from the Mediterranean basin. The ichthyosis is a generalized fine scaling with variable erythema, resembling congenital ichthyosiform erythroderma. Presentation is often that of a collodion baby with ectropion and eclabium. Skin changes may evolve to orange–red with brown scale, and are associated with pruritus. Extracutaneous involvement, which is variable and may be mild, includes cataracts, decreased hearing, hepatosplenomegaly with abnormal liver enzymes and fatty liver, psychomotor delay, myopathy with elevations in serum muscle enzymes, and neurologic abnormalities.

Histopathology of an oil red O or Sudan III stain of frozen sections of the skin shows lipid droplets in dermal cells, in the basal layer (and, to a lesser extent, suprabasally), as well as in the acrosyringia of the eccrine ducts. Examination of peripheral blood smears shows lipid vacuoles within granulocytes, eosinophils, and monocytes, a feature that may also be present in carriers.92 Mutations in the CGI-58 gene have been identified.93 CGI-58 belongs to a large family of proteins, most of which are enzymes, and appears to activate adipose-triglyceride lipase in the initial step in lipolysis of triglycerides. In the absence of CGI-58, triglycerides accumulate.94

CHILD Syndrome

The CHILD syndrome (OMIM #308050) is a rare disorder consisting of congenital hemidysplasia, ichthyosiform erythroderma, and limb defects, which is found almost exclusively in females.95 The disorder is related to X-linked dominant chondrodysplasia punctata (CDPX2), which also has skin and skeletal abnormalities, but is distinguished by a sharp midline demarcation of the psoriasiform ichthyosis, with minimal linear or segmental contralateral involvement. Involvement of the right side occurs more frequently than the left. There may be bands of normal skin on the affected side. A case with bilateral involvement has been described. Limb defects occur ipsilateral to the ichthyosis and range from digital hypoplasia to agenesis of the extremity. There may be punctate calcification of cartilage. Unilateral hypoplasia can involve the central nervous system and cardiovascular, pulmonary, renal, endocrine, and genitourinary systems. The inheritance pattern is thought to be X-linked dominant, with the condition being lethal in males. Peroxisomal deficiency has been described, and mutations in either of two peroxisomal genes were found to cause CHILD syndrome. One patient was found to have a mutation in the gene encoding EBP (3β-hydroxysteroid-δ8-δ7-isomerase) (the gene underlying CDPX2)96 and six patients (including one boy) were found to have mutations in NSDHL [NAD(P)H steroid dehydrogenase-like protein] encoding a 3β-hydroxysteroid dehydrogenase.97 Each enzyme functions in the postsqualene cholesterol biosynthetic pathway, catalyzing intermediate steps in the conversion of lanosterol to cholesterol.98

Chondrodysplasia Punctata

Chondrodysplasia punctata is a clinically and genetically diverse group of rare diseases, first described by Conradi, that share the features of stippled calcification of the epiphyses and skeletal changes. They are characterized by abnormal deposition of calcium in the areas of enchondral bone formation during fetal development and early infancy. Several forms also include ichthyosiform changes. Clinical severity ranges from severe dwarfism and death during infancy to a self-limited radiographic abnormality in others. An autosomal recessive (rhizomelic) type and both X-linked dominant99 and recessive forms100 have been described. The validity of the originally described autosomal dominant Conradi–Hünermann type has been questioned, because some reported cases were later shown to belong to the X-linked dominant type, and occurrences previously considered sporadic have subsequently been recognized as resulting from warfarin (Coumadin) anticoagulant embryopathy.99,101

Rhizomelic Chondrodysplasia Punctata

Rhizomelic chondrodysplasia punctata (RCDP) (autosomal recessive; OMIM #215100) is also known as peroxisomal biogenesis disorder complementation group 11 (CG11). It is a rare, multisystem developmental disorder characterized by dwarfism due to symmetric shortening of the proximal long bones (i.e., rhizomelia), specific radiologic abnormalities (i.e., the presence of stippled calcifications of cartilage, vertebral body clefting), joint contractures, congenital cataracts, ichthyosis, and severe mental retardation. Skin changes are present in approximately 25% of patients. Patients have low levels of red cell plasmalogens and accumulation of phytanic acid, starting with normal levels at birth and increasing to more than 10 times normal by age 1 year. RCDP is a disorder of peroxisomes, membrane-bound multifunctional organelles found in all nucleated cells. Their functions vary with cell type and include a variety of pathways (e.g., hydrogen peroxide-based respiration, fatty acid β-oxidation, and lipid and cholesterol synthesis) involving the synthesis and degradation of various compounds. Hereditary human peroxisomal disorders are subdivided into disorders of peroxisome biogenesis, in which the organelle is not formed normally, and those involving a single peroxisomal enzyme. RCDP is one of the groups of peroxisome biogenesis disorders, which are characterized by loss of multiple peroxisomal metabolic functions and have been sorted into at least 12 different complementation groups. Many have been found to be due to defects in peroxins, factors required for the import of proteins into the organelle. RCDP is caused by mutations in PEX7, a gene that encodes peroxin 7, a receptor required for targeting a subset of enzymes to peroxisomes.102 Refsum disease, another peroxisome disorder, exhibits genetic heterogeneity. In Refsum disease due to mutations in PAHX, the gene for phytanoyl-CoA hydroxylase (PhyH), there is deficiency of the single peroxisomal enzyme PhyH. Refsum disease can also result from mutations in PEX7; fibroblasts from those patients show deficiency of several peroxisomal enzymes, similar to fibroblasts from patients with RCDP. It is remarkable that different mutations in the same gene can result in such a wide spectrum of clinical disease.

X-Linked Recessive Chondrodysplasia Punctata

X-linked recessive chondrodysplasia punctata (CDPX; OMIM #302950) can involve skin (linear or whorled atrophic or ichthyosiform hyperkeratosis, follicular atrophoderma; may begin as erythroderma) (Fig. 49-13), hair (coarse, lusterless, cicatricial alopecia), short stature and skeletal abnormalities, cataracts, and deafness. Curry et al studied a family who had atypical ichthyosis and elevated cholesterol sulfate in two affected males and identified an X chromosomal deletion (Xp22) that included the gene for steroid sulfatase.100 There is a cluster of arylsulfatase genes at this location. Mutations in ARSE, the gene encoding the enzyme arylsulfatase E, were found in five patients; however, it is possible that the disorder may also be caused by mutations in adjacent arylsulfatase genes.103 The similarity to warfarin embryopathy suggests that warfarin embryopathy may be due to drug-induced inhibition of the same enzyme.

X-Linked Dominant Chondrodysplasia Punctata

Happle and coworkers identified X-linked dominant chondrodysplasia punctata (CDPX2) (Conradi–Hünermann–Happle syndrome; OMIM #302960) as a distinct variant characterized by a mosaic pattern of skin involvement and occurrence almost exclusively in females, with loss of the gene function hypothesized to be lethal to males.99 Affected females have a normal life expectancy and there may be increased disease expression in successive generations (anticipation). Occurrence in a male has been observed in association with a 47,XYY karyotype. CDPX2 presents at birth as a congenital ichthyosiform erythroderma that clears over months and is replaced by linear hyperkeratosis, follicular atrophoderma, and pigmentary abnormalities. Happle hypothesized that the linear involvement is due to mosaic X-chromosome inactivation (lyonization). Hair shaft abnormalities and cicatricial alopecia can also occur. Stippled calcifications are seen in radiographs of areas of endochondral bone formation during childhood but may no longer be visible after puberty. Stature may be short, with asymmetric shortening of the legs. Cataracts occur, usually asymmetrically, in about two-thirds of patients. Histochemical staining for calcium may show calcifications within the epidermis, especially within hair follicles in young children, which may not be present in older children.104 Mutations in the gene encoding the emopamil-binding protein (EBP) cause the Conradi–Hünermann–Happle Syndrome. EBP was first identified as a binding target for the drug emopamil, a calcium-channel blocker. It was later found to be 3β-hydroxysteroid-δ8-δ7-isomerase that catalyses an intermediate step in the conversion of lanosterol to cholesterol.105 How this defect causes clinical manifestations is unclear.

Congenital Reticular Ichthyosiform Erythroderma

This rare disorder, also known as ichthyosis variegata or ichthyosis en confetti(s), presents as congenital ichthyosiform erythroderma. Small islands of normal appearing skin begin to appear late in childhood. Band-like parakeratosis, psoriasiform acanthosis and vacuolated, binuclear upper epidermal keratinocytes with a filamentous perinuclear shell by electron microscopy and dermal amyloid deposits are seen.106 Normal areas of skin have been shown to arise from loss of heterozygosity on chromosome 17q via mitotic recombination of disease-causing mutations in the gene encoding keratin 10 (KRT10).107

Erythrokeratodermias

The erythrokeratodermias are a clinically and genetically heterogeneous group of disorders characterized by hyperkeratosis and localized erythema. Within a broad spectrum of phenotypes, at least two disorders can be delineated: (1) erythrokeratodermia variabilis and (2) progressive symmetric erythrokeratodermia. There are overlapping clinical features and phenotypic variability within these two designations.108

Erythrokeratodermia Variabilis

Erythrokeratodermia variabilis (OMIM #133200), described by Mendes da Costa in 1925, is a rare disorder that usually presents at birth or during the first year of life. Both autosomal dominant and recessive inheritance have been described.109 At least two distinct clinical presentations can be distinguished. One type (Fig. 49-14) is characterized by generalized, persistent, red–brown hyperkeratotic plaques, and accentuated skin markings. A second, localized type has involvement that is limited in extent and characterized by sharply demarcated, hyperkeratotic plaques; these are symmetrically arrayed and remain relatively fixed for months to years. In the localized type, there may be considerable variability between affected family members, and the disorder may not be apparent until later in life. Both types are characterized by striking, sharply demarcated, migratory red patches, which vary in size from a few to many centimeters. These geographic, figurate red patches appear or regress over minutes to hours; some individuals complain of burning at these sites, while in others they are asymptomatic. The red patches develop independently of the hyperkeratosis. Systemic retinoid treatment clears the hyperkeratotic lesions and may also clear the figurate red patches. The hyperkeratotic skin lesions may be triggered by trauma to the skin and the red patches may be triggered by a change in temperature. Palmoplantar hyperkeratosis may be present in either type, but hair, nails, and mucous membranes are unaffected. Histopathologic features are nonspecific and include hyperkeratosis, acanthosis, papillomatosis, and capillary dilatation. Epidermis involved with severe papillomatosis and suprapapillary thinning may result in a “church spire” appearance.

Several variants have been described. Erythrokeratodermia en cocardes was described in a family in which the erythematous component was in a target-like configuration.110 In a possible clinical variant of erythrokeratodermia en cocardes, erythema gyratum repens-like erythema (see Chapter 153) was described in a large kindred.111 Another family with erythema annulare centrifugum-like lesions (see Chapter 43) has also been described.112 A child with atypical erythrokeratodermia with neurosensory deafness, bilateral talipes (clubfoot) deformity, and neuropathy was described in which erythematous component changed only slowly over the year.113 Erythrokeratodermia with ataxia (Giroux-Barbeau type) is an autosomal dominant disorder that presents during infancy with well-defined, symmetric hyperkeratotic plaques, and underlying erythema distributed over the extensor surface of the extremities.114 Skin lesions regress during adulthood while a progressive spinocerebellar ataxia develops.

Both the localized type of erythrokeratodermia variabilis and erythrokeratodermia with ataxia have been mapped to a common region (chromosome 1p34-35).115 Subsequently, mutations in GJB3, the gene encoding connexin 31, were identified in four families with erythrokeratodermia variabilis.116 Connexins are a family of proteins that aggregate to form gap junctions, which are important channels for intercellular communication. This intercellular signaling system is crucial for maintaining tissue homeostasis, growth control, development, and synchronized response of cells to stimuli. The identification of connexin mutations as the cause of erythrokeratodermia variabilis implicates this pathway in epidermal differentiation and in the mechanism of skin response to external factors. Different mutations in the same connexin 31 gene (GJB3) have been found in other patients with deafness and also in some with peripheral neuropathy. Mutations in the related connexin 30.3 (GJB4) have been found in other families with erythrokeratodermia variabilis117; in the variants with erythema gyratum repens-like erythema that have been studied, connexin 30.3 mutations appear to be found exclusively.109

Progressive Symmetric Erythrokeratodermia

Progressive symmetric erythrokeratodermia (OMIM #602036), first definitively described by Darier in 1911,118 is characterized by well-demarcated, erythematous, hyperkeratotic plaques that are symmetrically distributed over the extremities and buttocks, and often the face.119 The trunk tends to be spared, but palms and soles may be involved. The plaques appear shortly after birth, progress slowly during the first few years, and then stabilize in early childhood. The plaques usually remain stable in location and appearance but may undergo partial regression at puberty. The variable, migratory erythema that defines erythrokeratodermia variabilis is absent. The disorder is inherited in an autosomal dominant pattern but with incomplete penetrance and variable expressivity. A mutation in the cornified envelope protein loricrin was found in one family,120 although the diagnosis (and the distinction from erythrokeratodermia variabilis) has been disputed.121 Recently, a mutation in GJB4, which encodes connexin 30.3, was found in patients from the Netherlands with either progressive symmetric erythrokeratodermia or erythrokeratodermia variabilis, demonstrating that both clinical presentations can arise from the identical mutation.122

Ichthyosis Follicularis, Alopecia, and Photophobia Syndrome

Noninflammatory follicular hyperkeratosis, total nonscarring alopecia, photophobia, and characteristic facies are seen in the IFAP syndrome (OMIM #308205). Less constant features include recurrent respiratory infections, nail abnormalities, angular cheilitis, keratotic plaques on the extensor surface of the extremities, inguinal hernia, cryptorchidism, short stature, seizures, and psychomotor developmental delay.123,124 Inheritance is thought to be X-linked recessive, although an autosomal dominant form and a third type, with “psoriasiform plaques,” have been postulated.125 Mutations in the MBTPS2 gene result in impaired cholesterol homeostasis and ability to cope with endoplasmic reticulum stress.126

Ichthyosis Prematurity Syndrome

Polyhydramnion complicates the second trimester in the ichthyosis prematurity syndrome (OMIM #608649), resulting in premature delivery of infants with erythrodermic, edematous, caseous scaling skin resembling excessive vernix caseosa, respiratory distress, and transient peripheral eosinophilia.127 The respiratory signs, erythema and skin changes resolve, leaving signs of atopy and dry, scaly skin with follicular accentuation more pronounced than is seen in keratosis pilaris. Characteristic trilamellar membrane inclusions are seen in the stratum corneum by electron microscopy. Mutations in the fatty acid transport protein 4 gene, FATP4 (SLC27) have been identified in affected members of one family.128

Keratitis, Ichthyosis, and Deafness Syndrome

KID syndrome (OMIM #148210) is a rare disorder characterized by keratitis (with progressive corneal opacification), ichthyosis, and deafness (neurosensory). Involvement of multiple ectodermal tissues qualifies KID syndrome as an ectodermal dysplasia. Most cases are compatible with autosomal dominant inheritance. However, occurrence in an inbred sibship suggests the existence of an autosomal recessive form. The disease is characterized by discrete erythematous plaques, and there may be mild, generalized hyperkeratosis. The distinctive plaques may have a discrete border and a verrucous appearance with crusting and may be conspicuously figurate and symmetric on the face (Fig. 49-15). Furrowing about the mouth results in characteristic facies. There may be prominent follicular hyperkeratosis, which can result in a scarring alopecia of the scalp. “Leather-like” palmar/plantar keratoderma is almost always seen.129 Several authors have suggested that because the plaques do not scale, this disorder is more accurately designated an erythrokeratodermia rather than an ichthyosis.5,129 Descriptions of nail changes vary from absent, delayed appearance after birth, atrophic, or brittle to thickened, with loss of or “rough” cuticles, subungual hyperkeratosis, and leukonychia. The teeth may be small. Auditory evoked potential studies allow detection of the hearing deficit in infancy. Keratitis may develop. Affected individuals can have an increased susceptibility to bacterial, fungal, or viral infections. Squamous cell carcinoma of the skin and tongue has also been reported. In contrast to many other ichthyotic conditions, treatment of these patients with oral retinoids has been reported to be of little benefit and possibly to exacerbate the corneal neovascularization.

Dominant mutations in GJB2, the gene encoding connexin 26, have been detected in sporadic cases and one family with KID syndrome. Functional studies of cells expressing mutated connexin 26 demonstrated failure of a fluorescent tracer to pass through gap junction channels to neighboring cells, consistent with disruption of intercellular communication.21 Different mutations in the same gene (GJB2) encoding connexin 26 have also been found in a family with a mutilating palmoplantar keratoderma (Vohwinkle's disease) and deafness (without ichthyosis)130 (discussed in Chapter 50), and a mutation in GJB6, the gene for connexin 30, has been demonstrated in one child with KID syndrome.131 The identification of mutations in the genes encoding a variety of connexin proteins has highlighted the role of connexin-mediated intercellular communication through gap junctions in the development and maintenance of ectodermal tissues. Connexins 26, 30, and 31 are expressed in the stratified epithelia of the cochlea and epidermis, and abnormalities in these proteins can cause sensorineural hearing impairment and/or skin disorders.20

Keratosis Linearis with Ichthyosis Congenita and Sclerosis Keratoderma

Keratosis linearis with ichthyosis congenital and sclerosing keratoderma (KLICK) syndrome (OMIM #601952) is a rare ichthyosis with palmoplantar keratoderma, constricting bands and flexural deformities of the fingers, and linear keratotic papules at the flexures. Mutations in the proteasome maturation protein gene (POMP) suggest a role for the proteasome in the process of cornification.132

MEDNIK

Mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK) syndrome is an autosomal recessive disorder described in a Quebec population with a founder mutation in the AP1S1 gene that encodes a protein involved in protein trafficking by intracellular vesicles.133

Multiple Sulfatase Deficiency

Multiple sulfatase deficiency (OMIM #272200) is a rare autosomal recessive disorder that is characterized by a deficiency of several sulfatases, which results in the accumulation of sulfatides, glycosaminoglycans, sphingolipids, and steroid sulfates in tissues and body fluids.134 The activity of both lysosomal (arylsulfatases A and B) and microsomal (arylsulfatase C/steroid sulfatase of X-linked ichthyosis) arylsulfatases is impaired. The disorder is a composite of the clinical features of both metachromatic leukodystrophy and of a mucopolysaccharidosis. Clinical features include neurologic deterioration, skeletal abnormalities, facial dysmorphism, and ichthyosis resembling that seen in X-linked steroid sulfatase deficiency. This disorder has been proposed to be due to a defect, common to all sulfatases, in posttranslational protein modification that is required for generating a catalytically active enzyme.135 The gene coding for sulfatase modifying factor 1 (SUMF1), which generates a unique amino acid derivative, Cα-formylglycine, necessary for catalytic activity of all sulfatases, is mutated in individuals with multiple sulfatase deficiency.136,137

Neonatal Ichthyosis with Sclerosing Cholangitis

Neonatal cholestatic jaundice and mild ichthyosis with fine, white scales are the presenting signs in the NISCH syndrome (OMIM #607626). Hypotrichosis with scarring alopecia affecting the scalp and eyebrows, enamel dysplasia and intracytoplasmic vacuoles within keratinocytes that do not stain with oil red O are also seen.138 In addition to different staining properties, the syndrome differs from Chanarin–Dorfman syndrome in the absence of ocular or muscle findings and of fatty liver. Mutations in CLDN1 the gene coding for claudin-1 have been identified.139

Peeling Skin Syndrome

The peeling skin syndrome (OMIM #270300) is an autosomal recessive disorder characterized by lifelong peeling of the stratum corneum. It may be associated with pruritus, short stature, and easily removed anagen hairs. Low plasma tryptophan levels and aminoaciduria have also been reported.140 Traupe suggested that there are two types of peeling skin syndrome.5 Type A, which is noninflammatory and asymptomatic, is characterized by generalized peeling in thin superficial flakes of differing size and shape. On electron microscopy, the intracellular separation occurs in the stratum corneum, within the corneocytes and not between adjacent cells. Intercellular electron-dense globular deposits representing abnormal lipids have been observed localized to the stratum corneum.141 An acral variant (OMIM #609796), in which peeling was limited to over the hands and feet, has been described.142,143 Abnormal keratohyalin granules were seen by electron microscopy. Mutations in the gene coding for transglutaminase 5, a ubiquitously expressed transglutaminase with widespread expression in skin, have been identified in two families with the acral form.143 In contrast, type B presents with congenital ichthyotic erythroderma and evolves into erythematous, scaling, migratory patches. This type is pruritic and may be associated with elevated levels of IgE, aminoaciduria, and short stature. The stratum corneum is easily separated mechanically from the lower epidermis, and histologically the split, which occurs intercellularly, is seen between the stratum corneum and the granular layer. On electron microscopy, electron-dense, irregularly vacuolated bodies have been observed in the granular layer, but observations have been variable.144 Although the type B is clinically similar to Netherton syndrome, mutations in SPINK5 have not been identified and the protein product of SPINK5 is overexpressed. Human tissue kallikreins and elevated stratum corneum protease activity have been demonstrated; this is thought to result in excessive desquamation and loss of barrier function.145 A variant, clinically similar to the inflammatory type B but with associated hair shaft abnormalities, has been described.144

Refsum Disease

Refsum disease (heredopathia atactica polyneuritiformis; OMIM #266500) is a rare, progressive, degenerative disorder of lipid metabolism resulting from the failure to break down dietary phytanic acid and its subsequent accumulation in tissues. This autosomal recessive condition affects mostly the Scandinavians and populations originating from Northern Europe. Clinical manifestations include retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, cranial nerve dysfunction (neural deafness, anosmia), miosis, electrocardiographic abnormalities, cardiomyopathy, renal tubular dysfunction, and skeletal abnormalities (epiphyseal dysplasia). Ichthyosis, which is variable, generally develops in adulthood after the neurologic and ophthalmologic manifestations. Often there are small white scales over the trunk and extremities resembling IV. Routine hematoxylin and eosin histologic examination shows variably sized vacuoles in the epidermal basal and suprabasal cells, which correspond to lipid accumulation seen with lipid stains of frozen sections.146

Phytanic acid (a 20-carbon, branched-chain fatty acid) is derived from a variety of dietary sources including dairy products, ruminant fats, and chlorophyll-containing foods, although chlorophyll-bound phytol cannot be absorbed in man. Phytanic acid and other chlorophyll metabolites bind the retinoid X receptor (RXR), as does its natural ligand, 9-cis-retinoic acid, and they may be physiologically active in coordinating cellular metabolism through RXR-dependent signaling pathways147; however, the role of RXR in the pathogenesis of Refsum disease is unclear. The disease is caused by a deficiency of PhyH, a peroxisomal protein that catalyzes the α-oxidation of phytanic acid. This is the first step in the breakdown of phytanic acid, and PhyH deficiency leads to the accumulation of phytanic acid in the serum and tissues, where it substitutes for the fatty acids normally present. While mutations in PAHX, the gene encoding PhyH are responsible for most cases of Refsum disease,148 there is genetic heterogeneity.149 Some affected patients have mutations in the PEX7 gene, which is the same gene mutated in RCDP (see above). Refsum disease is distinguished from infantile Refsum disease, a fulminant generalized peroxisomal biogenesis disorder in which young children present with severe neurologic abnormalities, mental retardation, hepatomegaly, and dysmorphic features in addition to the other signs of adult Refsum disease.150

The diagnosis can be made by detection of elevated levels of plasma phytanic acid. In children who do not have elevated plasma levels of phytanic acid, the diagnosis may be made by measuring PhyH activity in cultured fibroblasts.147 Treatment includes dietary restriction of foods containing phytanic acid and its precursors, and can include plasmapheresis or lipapheresis. In the clinical setting of a delayed onset of ichthyosis in association with neurologic impairment, this disease should be considered since therapy can arrest progression.

Rud Syndrome

Rud syndrome (OMIM #308200) is a poorly characterized disorder, probably of recessive inheritance, that includes epilepsy, mental retardation, infantilism, congenital ichthyosis, and retinitis pigmentosa. Steroid sulfatase deficiency has been reported in some patients. Traupe critically reviewed the literature and suggested that the clinical constellation usually labeled Rud syndrome is associated with steroid sulfatase deficiency (X-linked recessive ichthyosis) and likely reflects a heterogeneous group of disorders; because both the neurologic involvement and the ichthyosis are ill defined, the term Rud syndrome should be abandoned.5

Sjögren–Larsson Syndrome

In 1957, Sjögren and Larsson reported on 13 families from north Sweden with a syndrome of congenital ichthyosis, spastic paralysis, and mental retardation. Sjögren–Larsson syndrome (SLS; OMIM #270200) is a rare, autosomal recessive disorder that presents at birth with an ichthyosis that may range from fine scaling to generalized hyperkeratosis. Erythema may be present at birth but tends to gradually clear by 1 year of age. Collodion-like membranes are rarely seen. The ichthyosis manifests as fine scale, large scale, or a thickening of the stratum corneum without scale and may be pruritic. Thickened areas may be yellow to brown in color and have a lichenified appearance with accentuated skin markings. The most involved areas are the sides and back of the neck, lower abdomen, and flexures. Hair, nails, and the ability to sweat are generally normal.151 During the first 2 to 3 years, neurologic manifestations of spastic diplegia or tetraplegia and mental retardation develop and can be accompanied by speech defects and seizures. A characteristic ophthalmologic finding is the presence of glistening white dots in the macula of the retina; these occur after 1 year of age and may not be present in all patients. Histologic findings of hyperkeratosis, papillomatosis, acanthosis, and a mildly thickened granular layer are nonspecific. Electron-microscopic examination of the skin shows lamellar membranous inclusions in the granular and cornified cells.

Rizzo et al linked SLS to fatty alcohol:NAD oxidoreductase (FAO) deficiency. FAO is a complex enzyme with two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and subsequently to fatty acid. Further work identified the fatty aldehyde dehydrogenase (FALDH) activity in cultured fibroblasts from patients with SLS component as the affected component of FAO in SLS. FALDH is a microsomal enzyme that catalyzes the oxidation of medium- and long-chain aliphatic aldehydes derived from metabolism of fatty alcohol, phytanic acid, ether glycerolipids, and leukotriene B4.152 Mutations found in the FALDH gene (FALDH, ALDH10, recently renamed ALDH3A2) confirmed the role for this enzyme in the etiology of this disorder and the importance of this pathway for normal desquamation.153 Most mutations are specific to families, although several common mutations suggest founder effect or favored sites for mutation.154 The identification of decreased fibroblast FAO activity in a family with atypical cutaneous findings (lack of ichthyosis or discrete plaques rather than generalized ichthyosis) has expanded the spectrum of clinical phenotypes associated with abnormal FAO activity.155

Trichothiodystrophy

Trichothiodystrophy (TTD) (OMIM #601675) is an autosomal recessive disorder that includes a broad spectrum of clinical phenotypes linked by the characteristic features of sulfur deficient, brittle hair that exhibits tiger tail banding when viewed under polarizing microscopy (Fig. 49-16).156 Hair shaft abnormalities include trichoschisis, trichorrhexis nodosa-like defects and ribboning157,158 (see also Chapter 139). Patients may have photosensitivity, ichthyosis, intellectual impairment, short stature, microcephaly, characteristic facial features (protruding ears, micrognathia) recurrent infections, cataracts, dystrophic nails, and other features.159 The spectrum of clinical involvement is broad, ranging from only hair to severe multisystem abnormalities. A survey of 112 cases reported in the literature found ichthyosis (65%) as the most common skin finding, followed by photosensitivity (42%). The photosensitivity can range from subtle to severe. Of the patients with ichthyosis, about one-third presented with a collodion membrane at birth. Collodion newborns may have an erythroderma which decreases over weeks with evolution into a generalized ichthyosis, usually without erythema, which varies from fine, translucent scaling to large, dark yellow–brown hyperkeratosis (Fig. 49-17B).160,161 Some largely resolve and are left with mild ichthyosis. There may be flexural sparing and palmoplantar keratoderma. Nail findings are found in over half of the patients and include dystrophic nails (ridging, splitting) (Fig. 49-17A), hypoplasia, brittle nails, and koilonychia.159 Ectropion usually does not occur.

A series of mnemonics have been used to describe the constellation of findings as BIDS (brittle hair, intellectual impairment, decreased fertility, and short stature); patients who also have ichthyosis have been called IBIDS, and with the addition of photosensitivity, PIBI(D)S has been used.162 However, these terms do not account for the other multisystem findings commonly present.

The majority of TTD patients have a defect in XPD (ERCC2). A few have mutations in XPB (ERCC3) or TTDA (GTF2H5), genes which are components of the transcription factor IIH (TFIIH) that regulates both DNA repair and transcription. Some TTD patients have mutations in TTDN1.163 Although many TTD patients have photosensitivity, in contrast to xeroderma pigmentosum, these photosensitive patients have not been observed to be at high risk for the development of skin cancer. Nucleotide excision repair is one normal cellular mechanism by which structural DNA damage (e.g., ultraviolet-induced cyclobutane pyrimidine dimers) is removed and repaired (see Chapters 110 and 139). TFIIH is involved in the initiation of transcription and also in nucleotide excision repair, and consists of a complex of proteins including the XPD and XPB proteins. In the vicinity of the damage, these two helicase subunits of TFIIH unwind the DNA in opposite directions.

The development of ichthyosis in adulthood can be a manifestation of systemic disease, and has been described in association with malignancies, drugs, endocrine and metabolic disease, malnutrition, HIV and other infections, and autoimmune conditions.164,165 The granular layer is often attenuated in this disorder and the scale often resembles to that seen in mild IV. While Hodgkin disease is the most common malignancy reported with acquired ichthyosis, non-Hodgkin lymphomas and a variety of other malignancies have also been observed.166 Histology may be diagnostic in acquired ichthyosis associated with mycosis fungoides.167 Skin involvement may follow the course of malignancy and clear with effective cancer treatment. Acquired ichthyosis is commonly seen in association with AIDS; ichthyotic or xerotic skin has been observed in up to 30% of AIDS patients.168 A study of HIV-1-positive intravenous drug users found acquired ichthyosis occurred only after profound helper T cell depletion, more frequently with coinfection with human T cell leukemia/lymphoma virus type II (HTLV-II), and suggested that it may be a marker for concomitant infection with both viruses.169

In acquired ichthyosis occurring in association with sarcoidosis, skin biopsy can be diagnostic, showing noncaseating granulomas in the dermis.170 Acquired ichthyosis may be a marker of autoimmune disease, occurring with systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease, and eosinophilic fasciitis.171,172 It has been described in bone marrow transplant recipients, where it may be related to graft-versus-host disease.173

While occurrence in association with cholesterol-lowering agents (nicotinic acid, triparanol) highlights the relationship between cholesterol metabolism and normal desquamation, acquired ichthyosis has been observed with a variety of drugs, including cimetidine, clofazimine, hydroxyurea, cholesterol-lowering agents, and others.174–178 Kava is a psychoactive beverage made from the root of a pepper plant and used for thousands of years by Pacific Islanders. Heavy kava drinkers can acquire a reversible ichthyosiform eruption called kava dermopathy. In Western nations, kava is sold in health food stores as a relaxant.179

Pityriasis Rotunda

Sharply demarcated, round or oval scaly patches with hypo- or hyperpigmentation are seen in pityriasis rotunda. Although this uncommon disorder is usually acquired, occasional familial cases have been described.180

Reticulated Papillomatosis of Gougerot and Carteaud

Confluent and reticulated papillomatosis of Gougerot and Carteaud is an uncommon but distinctive acquired ichthyosiform dermatosis seen in young adults and characterized by persistent brown, scaly macules, papules, patches, and plaques. Lesions tend to be localized predominantly on the neck, upper trunk (intermammary and interscapular regions), and axillae where they tend to be confluent and become reticulated towards the periphery (Fig. 49-18). The lesions bear a clinical resemblance to tinea versicolor, a skin infection with Pityrosporum species. A variety of treatment approaches have been reported, including topical (keratolytics, derivatives of vitamin A and D, antimicrobials) and systemic (antibiotics, retinoids) agents. Minocycline has been suggested as a first-line treatment; successful retreatment of recurrences supports the concept that this condition is an abnormal response to an infection or inflammation.181,182

Current therapies for the inherited ichthyoses are symptomatic and focus on hydration, lubrication, and keratolysis.183,184 Ichthyotic skin, even if thickened, has a decreased barrier function and increased transepidermal water loss. Because pliability of the stratum corneum is a function of its water content, hydration can soften the surface of the skin. In moist, humid climates, most ichthyoses improve, and mild ichthyoses (e.g., IV) may undergo extensive clearing. Moistening the skin with, for example, long baths can hydrate it. Well-hydrated areas of hyperkeratosis can more easily be thinned with mild abrasives (sponges, buff puffs, pumice stones, etc.). Addition of bath oils or application of lubricants before drying can prolong the hydration and softening. Depending on the ichthyosis and environmental conditions, individual patients may prefer specific lubricating agents, which can take the form of lotions, creams, oils, ointments, or petrolatum. In dry climates and winter months, humidifiers can be used to create a more hospitable environment.

Keratolytic agents are used to enhance corneocyte desquamation and thereby remove scale and thin hyperkeratotic stratum corneum. There are many commercially available keratolytic creams and lotions containing urea, salicylic acid, or α-hydroxy acids (e.g., lactic acid, glycolic acid). Urea may function by its capacity to bind water. Propylene glycol (40–60% in water), with or without occlusion, can also be effective in scale removal. Occlusion can effectively increase skin hydration and facilitate desquamation; it can also enhance the effect of keratolytic agents. Special care should be taken when using extensive areas of occlusion with keratolytic agents and in individuals who may be heat intolerant. Topical retinoid or vitamin D preparations may also be effective but can be irritating in some patients. The markedly impaired barrier function in ichthyosis should be considered when using topical preparations over large areas of body surface. For example, widespread use of topical salicylic acid preparations can lead to significant absorption, intoxication (e.g., nausea, tinnitus, dyspnea, hallucinations), and even death.185 Children are at greater risk because they have a greater body surface area per unit weight than adults, a situation that effectively heightens the possibility of developing systemic toxicity from topicals. Although the use of topical retinoids in most of the ichthyoses appears to be safe,186 the abnormal skin barrier should be considered when treating concomitant dermatoses in ichthyosis patients. Topical 0.1% tacrolimus ointment or 1% pimecrolimus cream is effective in atopic dermatitis with minimal systemic absorption. However, the atopic dermatitis of Netherton syndrome is complicated by a defective ichthyotic skin barrier. The defective barrier is associated with increased percutaneous absorption and risk for systemic toxic effects. This should be considered when using topical agents such as tacrolimus, pimecrolimus, or topical steroids, where increased systemic absorption has been observed and monitoring of serum levels may be necessary.88,89

Another risk to children is that in several types of ichthyosis nutritional requirements may be high, and inadequate nutrition can lead to failure to thrive. This was thought to be related to the large turnover of scale; however, recent studies suggest energy loss from impaired barrier function is the cause.187 Some patients with ichthyosis (particularly LI and CIE) have decreased sweating with heat intolerance. It is important for the parents of a newborn with ichthyosis to be aware of the possibility of decreased sweating and to be attentive for signs of heat intolerance, such as flushing and lethargy, particularly during hot weather and, as the child grows, during exercise. Avoiding hot environments, carrying spray bottles with water to moisten the skin and cool it through evaporation, and cooling vests can minimize heat stress.

Systemic retinoid therapy with isotretinoin or acitretin (see Chapter 228) can induce dramatic improvement in many ichthyoses and is particularly useful in LI, CIE, and erythrokeratodermia variabilis. The decision to initiate systemic retinoid therapy should be weighed carefully, because once the drug is started, continued benefit usually requires chronic therapy. Treatment of the harlequin newborn with systemic retinoid therapy during the newborn period can be lifesaving due to enhanced desquamation of a constricting membrane. Retinoic acid metabolism blocking agents, which increase endogenous retinoid levels, offer a possible alternative.188

Fungal infections are common, both of skin and nails, and are often undiagnosed because of the generalized scaling. A high index of suspicion can help diagnose tinea corporis, capitis, or versicolor where the only symptom may be localized pruritus and the only sign a difference in the character of scale or a localized area of alopecia.

The management of EHK varies with the clinical type. Areas of thick, hard hyperkeratosis, which are not pliable and have a hard rough surface, are prone to mechanical trauma. In patients with the hystrix type of porcupine-like hyperkeratosis, the rough surface causes high traction with objects moving across the skin surface, which tend to catch on the hyperkeratotic horn and peel it off. Topical agents such as lubricants and keratolytics can reduce the thickened, rough areas and help to minimize blistering and erosion. In contrast, patients with erythroderma and peeling, who do not have the thick areas of hyperkeratotic spines, have less need for keratolytics but still need lubricants. Acute exacerbations may occur from skin infections. Bacterial infection of the skin is common, often leads to enhanced blistering, and may require frequent therapy with topical and oral antibiotics. In patients with extensive involvement, systemic retinoid therapy can be dramatically effective in decreasing the hyperkeratosis and the frequency of infections. Because these drugs can enhance blistering in EHK patients, they should be administered carefully and started at low doses.

Molecular diagnosis is preferred when possible. Alternative methods, including fetoscopy and fetal skin biopsy, are limited to later times in pregnancy, harbor a risk of fetal mortality, and are rarely performed.189 When it is possible to do prenatal diagnosis by molecular analysis of a fetal sample, it is optimally performed early in pregnancy. This can be done with chorionic villous sampling in the first trimester (10–12 weeks after last menstrual period) or by amniocentesis in the second trimester190 in disorders where the underlying genetic defect is known and the specific mutation in the family has been identified. Prenatal diagnosis by mutational analysis has been accomplished in a number of the ichthyoses. If a specific mutation has not been identified, in some circumstances where there is an appropriate family structure, prenatal diagnosis can be done using linkage analysis. Prenatal diagnosis of X-linked recessive ichthyosis by FISH analysis191 and of TTD by defective DNA repair capacity192 has been reported. In SLS, the diagnosis can be made by assay of enzyme activity in cultured amniocytes, even if the mutation in the ALDH10 gene is undefined. Preimplantation genetic diagnosis is a reasonable alternative, and has been accomplished for many inherited disorders, including LI and EHK (S. Bale, personal communication). The procedure requires that the couple undergo in vitro fertilization to obtain embryos. The embryos are then screened by molecular methods to detect the mutation that is segregating in the family. Only those embryos that screen negative for the mutation are selected and then can be used for implantation in the uterus to achieve pregnancy. Noninvasive methods of molecular diagnosis (evaluation of fetal DNA circulating in the mother's blood) offer the potential for the future.188 For autosomal recessive disorders where the mutation is known (e.g., LI and SLS), carrier detection may be performed for at-risk relatives.

The Foundation for Ichthyosis and Related Skin Types provides support and information for affected individuals, family members, friends, and health care providers. (FIRST, Tel: 800-545-3286; http://www.firstskinfoundation.org/; e-mail: info@firstskinfoundation.org.)

GeneTests (http://www.genetests.org/) provides disease reviews, genetic testing resources, and educational materials.

Online Mendelian Inheritance in Man, OMIM, (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM) (trademark Johns Hopkins University), a catalog of human genes and genetic disorders, is a useful reference with links to additional resources.

The National Registry for Ichthyosis and Related Disorders is a resource for investigators to improve diagnosis and treatment of these disorders (University of Washington, Dermatology, Box 356524, 1959 NE Pacific St., Seattle, WA 98195-6524 Tel: 1-800-595-1265; http://www.skinregistry.org/; e-mail: info@skinregistry.org).