Ichthyosis vulgaris

INTRODUCTION — Ichthyosis vulgaris (IV; MIM #146700) is the most common of the ichthyoses, a heterogeneous group of inherited disorders of keratinization characterized by generalized scaling of the skin of varying severity (picture 1A). IV is generally considered mildest in comparison with other ichthyosis types [1]. IV is caused by pathogenic variants in the filaggrin gene (FLG), encoding profilaggrin, which is a major component of the keratohyalin granules in the granular layer of the epidermis [2].

This topic will review the pathogenesis, clinical features, diagnosis, and management of IV. An overview of syndromic and nonsyndromic ichthyoses is presented separately (table 1 and table 2). Other types of inherited ichthyoses are also discussed separately.

●(See "Overview and classification of the inherited ichthyoses".)

●(See "Autosomal recessive congenital ichthyoses".)

●(See "X-linked ichthyosis".)

●(See "Keratinopathic ichthyoses".)

EPIDEMIOLOGY — Ichthyosis vulgaris (IV) is relatively common. Its exact prevalence is unknown, but the best available estimates in British populations suggest a prevalence between 1 in 80 to 1 in 250 individuals [3,4]. The prevalence of identified FLG null variants in Europe varies from 2.7 to 14.2 percent, with a median of 7.7 percent and 83 to 96 percent penetrance [5-9]. Prevalence in other populations may be lower, ranging from 1 to 6.5 percent in Chinese and Japanese populations to 0.5 to 1.3 percent in African Americans [6].

PATHOGENESIS

Genetics — Ichthyosis vulgaris (IV) is caused by loss-of-function variants in the filaggrin gene (FLG) on chromosome 1q21.3, encoding the protein profilaggrin, which is a major component of the keratohyalin granules in the granular layer of the epidermis [2]. FLG variants result in impaired epidermal barrier function and reduced formation of the natural moisturizing factor.

The IV inheritance pattern is semidominant, with individuals inheriting a single mutated allele being much less severely affected than those with homozygous or compound heterozygous variants [2]. Although early studies supported the role of FLG variants in the pathogenesis of IV, the highly repetitive sequence of human FLG repeats with varying numbers of repeats (10 to 12) and limited heterogeneity between repeats thwarted initial efforts to sequence the gene [10-12]. Studies of large kindreds with the clinical and histologic phenotype of IV finally led to identification of loss-of-function variants in the first (amino-terminal) full FLG monomer and demonstrated the semidominant inheritance of IV [2]. FLG null variants show incomplete penetrance and variable expressivity within families [2]. These findings led to a sequencing strategy that allows sequencing of the entire third profilaggrin exon and recognition that both common and uncommon loss-of-function mutations exist [5].

In the Northern European population, approximately 80 percent of the loss-of-function variants are seen in the two alleles initially identified (R501X, arginine to stop codon; and 2282 del 4, deletion of a 4-bp segment in position 2282 of the FLG coding sequence). Both variants lead to premature stop codons in the first FLG repeat and lack of profilaggrin expression in the epidermis of affected individuals. However, many less common variants have been shown. Over 60 loss-of-function variants, with more described as studies continue, have been demonstrated, with many specific to other regions and populations [6,13]. Regardless of which of the 10 to 12 FLG repeats is affected, loss-of-function variants in FLG lead to almost total loss of keratohyalin granules and FLG expression and are associated with additional abnormalities in keratinization [14].

Impairment of the skin barrier — Barrier function of the epidermis is established through an elaborate series of pathways as epidermal cells (keratinocytes) differentiate and are ultimately desquamated [15-17]. A critical anatomic area in this process is the junction of the granular and cornified cell layers, where keratohyalin granules disappear; lamellar bodies secrete their contents into the intercellular space; nuclei and cytoplasmic contents are degraded; keratin intermediate filaments aggregate; and the keratinocyte plasma membrane is replaced by a chemically resistant, cornified envelope in which lipids, desmosomal proteins, and other peptides are covalently crosslinked. As cells in the cornified layer flatten, keratin filaments condense and are covalently crosslinked within the cornified envelope to form squamous cells.

Filaggrin (FLG) is named for its participation in keratin filament aggregation and plays an important role in the formation of the epidermal barrier [16,18]. FLG is synthesized in the granular layer as a large, approximately 400 kb precursor profilaggrin that is highly phosphorylated post-translationally, which may account for its precipitation into intracellular granules; profilaggrin makes up most of the content of keratohyalin granules in human interfollicular skin. Profilaggrin is a member of the S-100-fused, calcium-binding proteins [19]. Genes coding for several of the S-100 proteins are located on chromosome 1 in the epidermal differentiation complex, along with those that code for other precursors of the cornified envelope and other proteins involved in epidermal differentiation [20].

FLG contains three exons; the third exon codes for most of an amino-terminal segment, a partial FLG repeat, 10 to 12 FLG repeat monomers of identical 972 base pair length, a second partial FLG repeat, and a short carboxy-terminal segment. FLG repeats are connected by short linker peptides, much like beads on a string [21,22]. Profilaggrin does not participate in aggregation of keratin filaments. At the granular-stratum corneum interface, profilaggrin is rapidly dephosphorylated and proteolyzed to FLG monomers, which are thought to aggregate and condense keratin filaments [23]. Aggregated keratin filaments are covalently crosslinked and serve as a scaffold for formation of the cornified envelope.

Portions of FLG remain covalently bound to the cornified envelope, but most of the protein is proteolyzed to component residues that contribute to hydration of the upper layers of the cornified layer and, possibly, pH control, ultraviolet (UV) protection, and immune function [24]. Postulated roles for the amino- and carboxy-terminal segments are beyond the scope of this topic; however the carboxy-terminal segment appears to be necessary for the processing of profilaggrin to monomers [5]. This may explain the almost complete loss of FLG expression in loss-of-function mutations, regardless of which of the 10 to 12 repeats is affected.

CLINICAL MANIFESTATIONS

Cutaneous findings — Ichthyosis vulgaris (IV) presents in infancy or early childhood as diffuse, scaly skin with centrally attached, fine, white or light-gray scale (picture 1D). Extensor extremities and the trunk are commonly affected, with sparing of intertriginous (eg, axillary, antecubital, popliteal) skin (picture 1A-C). Involvement of the sides of the neck is uncommon. The severity of scaling is variable. Individuals with one mutated allele (heterozygotes) have a mild phenotype that can be confused with simple dry skin, whereas those with mutations in both alleles (homozygous or compound heterozygotes) have more apparent disease. There is a marked seasonal variation in severity, with improvement in warm and sunny weather with high degree of ambient humidity and worsening in dry and cold environment.

Increased major and minor lines (hyperlinearity) of the palms are commonly seen (picture 2A), along with keratosis pilaris (picture 3A-B). (See "Keratosis pilaris".)

Hyperlinearity of the thenar eminence is thought to be more specific to IV (picture 2B) [25]. Although both of these findings are not restricted to IV, palmar hyperlinearity is reported in 34 to 71 percent of those with common null variants (positive predictive value), while 85.5 to 90 percent of those without palmar hyperlinearity do not carry identified variants (negative predictive value). For keratosis pilaris, the positive and negative predictive value are 32 to 53 percent and 79 to 90 percent, respectively [3,26].

Other physical findings — Corneal biomechanical properties (eg, corneal resistance factor, central corneal thickness, and intraocular pressure) are lower in IV, which could result in false negatives when screening for glaucoma and should be considered in patients with IV undergoing refractive surgery [27]. Heat intolerance is reported by some affected individuals, although whether this is related to IV or associated atopic eczema is unclear [8].

ASSOCIATED CONDITIONS

Atopic dermatitis and other atopic diseases — A strong association of atopic dermatitis with ichthyosis vulgaris (IV) was noted soon after null variants of the filaggrin gene (FLG) were identified in patients with atopic eczema [7]. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Over 20 studies have confirmed this association, which is one of the most robust gene associations thus far identified in complex trait genetics [28-31]. FLG variants are associated with early-onset, moderate to severe, persistent eczema; asthma in the setting of eczema; and allergic rhinitis [32-34]. However, penetrance is not complete, with only 37 to 70 percent of individuals with the clinical diagnosis of IV having atopic conditions or a peanut allergy [4,25,35,36].

Other skin disease — Mutations in FLG have been associated with a more severe phenotype of X-linked ichthyosis and possibly with pachyonychia congenita, and chondrodysplasia punctata type II [37-41]. (See "X-linked ichthyosis" and "Pachyonychia congenita" and "Skeletal dysplasias: Specific disorders", section on 'Chondrodysplasia punctata'.)

No association has been reported with other more common skin disorders, such as acne or psoriasis, or other inflammatory diseases, such as inflammatory bowel disease or sarcoidosis [42-45].

PATHOLOGY — In homozygotes and compound heterozygotes for filaggrin gene (FLG) variants, histology shows orthohyperkeratosis, with a granular layer severely diminished or absent (picture 4). This is accompanied by virtual absence of immunoreactivity to antibodies to FLG (picture 5) [2]. Absent or "crumbly" keratohyalin granules are seen on electron microscopy (picture 6) [2,46,47]. Histologic findings in heterozygotes are variable.

DIAGNOSIS

Clinical — The clinical diagnosis of ichthyosis vulgaris (IV) is based on the combination of clinical findings on physical examination and the patient's personal and family history. Although the clinical diagnosis may be relatively easy in patients carrying homozygous or compound heterozygous variants of the filaggrin gene (FLG) who have a more severe phenotype, it may be elusive in heterozygotes, who typically have a very mild phenotype.

Clinical findings that suggest the diagnosis of IV include:

●Scale – Fine, white or gray, central attachment; involvement of extensor surface of extremities and trunk; sparing of folds (picture 1A-D).

●Palmar hyperlinearity – Accentuated major fissures, increased minor fissures; accentuated lines on thenar eminence (picture 2A-B).

●Keratosis pilaris (picture 3A-B).

Elements of personal and family history that support the diagnosis of IV include:

●Onset after birth, often in early childhood

●Improvement with warm weather and emollients

●Possible improvement with age

●Association with atopic eczema or other atopic diseases

●Familial occurrence

Biopsy — A skin biopsy is usually not necessary for the diagnosis. If performed, hematoxylin and eosin staining showing marked reduction or absence of the granular layer in the epidermis (picture 4) confirms the diagnosis of IV (see 'Pathology' above). The extensor aspect of the arm or shin are ideal sites for biopsy. Electron microscopy, although rarely used for routine skin diagnosis, may confirm keratohyalin granule abnormalities.

Genetic testing — Genetic testing demonstrating pathogenic variants in the FLG gene provides the definitive diagnosis of IV, although this is not routinely done in clinical practice. The difficulty in sequencing the gene and heterogeneity among populations makes the molecular diagnosis difficult and, undoubtedly, results in underestimation of both variant prevalence and disorders associated with FLG variants. Adding to the difficulty in clinical diagnosis is the very mild phenotype seen in heterozygotes.

Common population associations may be useful for screening, although variants vary among populations, and identification of "private" variants is difficult and may be missed, unless Sanger sequencing or an equivalently comprehensive analysis of the entire gene is conducted.

In the United States, Clinical Laboratory Improvement Amendments (CLIA)-certified genetic testing is available from multiple commercial laboratories. Information on CLIA-certified and research-based laboratories performing disease-specific genetic testing worldwide is available through the Genetic Testing Registry.

DIFFERENTIAL DIAGNOSIS

●Recessive X-linked ichthyosis – Recessive X-linked ichthyosis (XLI, MIM #308100) is the second most common ichthyosis after ichthyosis vulgaris (IV); it is caused by deletions or mutations in the STS gene encoding the steroid sulfatase enzyme [48]. It presents in the first few weeks of life with mild, diffuse scaling (picture 7). Over time, large, polygonal scales may become apparent, especially on the anterior aspect of the lower legs (picture 8). During childhood, the scalp, preauricular areas, and neck may be involved. Palmar hyperlinearity is generally absent in XLI. The diagnosis of recessive XLI can be supported by fluorescence in situ hybridization studies, as approximately 90 percent of affected individuals have detectable abnormalities. The diagnosis can be confirmed by demonstrating reduced steroid sulfatase activity in cultured fibroblasts from a skin biopsy, by reduced serum levels of steroid sulfatase, or by genetic testing. (See "X-linked ichthyosis".)

●Dry skin – Dry skin and desquamation is a common feature of atopic dermatitis. It is generally less severe than IV. Palmar hyperlinearity is less common, as is keratosis pilaris. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

●Acquired ichthyosis – Acquired ichthyosis is clinically and histologically similar to IV (picture 9). In contrast with the inherited IV, it develops later in life and is usually associated with malignancy, most frequently Hodgkin lymphoma and other lymphoproliferative disorders, or systemic diseases [49]. (See "Cutaneous manifestations of internal malignancy", section on 'Acquired ichthyosis'.)

TREATMENT — The treatment of ichthyosis vulgaris (IV) is directed at removing scales, reducing skin dryness, and improving skin appearance. It involves regular bathing and use of moisturizers and keratolytics. An overview of the management of the inherited ichthyoses is provided separately. (See "Inherited ichthyosis: Overview of management".)

Bathing — Individuals with dry skin, including those with IV, are often encouraged to take long baths to facilitate scale removal. This advice makes common sense and has withstood the test of time, although limited studies support it [50]. The benefit of bath additives, including oils and sodium bicarbonate, is controversial [51]. Bathing with or without the use of soaps or synthetic detergents should be followed by the application of moisturizers.

Emollients and moisturizers — Frequent and liberal use of emollients and moisturizers is the mainstay of treatment for IV [52]. Moisturizers hydrate and smooth the skin. Components include humectants, such as glycerin; occlusives, such as petrolatum; emollients, such as cetyl alcohol; keratolytics, such as urea and alpha-hydroxy acids; and other components. Humectants draw and hold water in the epidermis; occlusives prevent water loss; emollients, which are water insoluble but of lower molecular weight than occlusives, smooth the skin; and keratolytics aid in removing scale [53].

The choice of moisturizers for the treatment of IV is generally based on patient preference and personal experience. Studies comparing different moisturizers for IV are limited and generally of low quality [54].

A few studies suggest that keratolytics, such as urea, alpha-hydroxy acids, and salicylic acid, are superior to simple emollients [55-57]. In a systematic review of 48 randomized trials and uncontrolled studies including 3262 patients with atopic eczema or IV, moisturizers (and especially those containing urea or glycerin) were generally beneficial in improving the clinical symptoms of atopic dermatitis and IV [54]. Studies comparing the efficacy of different moisturizers for IV are lacking. A meta-analysis of 77 randomized trials assessing the efficacy of different moisturizers for atopic dermatitis, while demonstrating a beneficial effect for most moisturizers, did not find evidence that one moisturizer is superior to another [58].

Topical retinoids, topical corticosteroids, calcipotriene, and systemic retinoids are not indicated in the treatment of IV. The treatment of associated atopic dermatitis is discussed elsewhere [50,51]. (See "Treatment of atopic dermatitis (eczema)".)

PROGNOSIS AND FOLLOW-UP — Individuals with ichthyosis vulgaris (IV) live normal lives with no known compromise to longevity but must deal with daily treatment of scaling skin disease, often in the context of moderate to severe atopic eczema. Quality-of-life studies in the ichthyoses focus on the more severe disorders [59]; none has addressed IV.

Most individuals with ichthyosis desire information about their disorder and how to treat it most effectively. Once they have this information, they usually have better insight into what works for their skin and rarely seek care unless problems are encountered. This applies more so to IV, where the most issues with treatment and complications are associated with eczema.

SUPPORT GROUPS — The Foundation for Ichthyosis and Related Skin Types (FIRST) is a lay organization that supports affected individuals, their family members, and professionals. Information about the ichthyoses and associated support groups, research studies, and therapeutic help is available online at FIRST.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ichthyosis".)

SUMMARY AND RECOMMENDATIONS

●Pathogenesis – Ichthyosis vulgaris (IV) is the most common of the inherited ichthyoses, a heterogeneous group of disorders of keratinization characterized by generalized scaling of the skin of varying severity and impairment of the skin barrier function. IV is caused by loss-of-function variants in the FLG gene, encoding the protein profilaggrin, a major component of the keratohyalin granules in the granular layer of the epidermis. (See 'Pathogenesis' above.)

●Clinical presentation – IV presents in infancy or early childhood as diffuse, scaly skin with centrally attached, fine, white or light-gray scale (picture 1D). Extensor extremities and the trunk are commonly affected, with sparing of intertriginous (eg, axillary, antecubital, popliteal) skin (picture 1A-C). Palmar hyperlinearity is characteristic (picture 2A). Atopic dermatitis is frequently associated in affected individuals. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of IV is suspected in individuals presenting with diffuse scaling of the skin since childhood, palmar hyperlinearity, and a positive family history of the disease. A skin biopsy for hematoxylin and eosin staining showing severe reduction or absence of the granular layer (picture 4) may be helpful to confirm the diagnosis. Genetic testing demonstrating pathogenic variants in the FLG gene provides the definitive diagnosis, although this is not routinely done in clinical practice. (See 'Diagnosis' above.)

●Treatment – The treatment of IV is directed at removing scales, reducing skin dryness, and improving skin appearance. It involves regular bathing and frequent and liberal use of moisturizers and keratolytics. (See 'Treatment' above and "Inherited ichthyosis: Overview of management".)

●Support groups – Information about the ichthyoses and associated support groups, research studies, and therapeutic help is available at the Foundation for Ichthyosis and Related Skin Types (FIRST), a lay organization that supports affected individuals, their family members, and professionals. (See 'Support groups' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Philip Fleckman, MD (deceased), who contributed to earlier versions of this topic review.