Ichthyosis Vulgaris

A number sign (#) is used with this entry because of evidence that ichthyosis vulgaris is caused by heterozygous mutation in the filaggrin gene (FLG; 135940) on chromosome 1q21. Patients with homozygous or compound heterozygous mutations in this gene have a more severe phenotype.

Clinical Features

Ichthyosis is one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren (Wells and Kerr, 1966). The phenotypic characteristics of ichthyosis vulgaris include palmar hyperlinearity, keratosis pilaris, and a fine scale that is most prominent over the lower abdomen, arms, and legs.

Wells and Kerr (1965) suggested that dominant ichthyosis vulgaris is distinguishable clinically from the X-linked variety (308100). In the dominant form, the first skin involvement is usually noted after the first 3 months of life and less of the body surface is affected. Lesions are rarely observed in the axillae or antecubital and popliteal fossae but the palms and soles often show increased markings. There are some histologic differences also. A considerable proportion of patients with dominant ichthyosis have asthma, eczema, or hay fever. For a useful classification and discussion of the various forms of ichthyosis, see Schnyder (1970).

Mevorah et al. (1978) described ichthyosis in a mother and 6 of her sons. A seventh son and 2 daughters were normal. The disorder in the mother was clinically and histologically of the dominant type, whereas the affected sons showed features of both the autosomal dominant and X-linked recessive forms. The authors concluded that the mother was heterozygous for both forms.

Biochemical Features

Anton-Lamprecht (1978) pointed out that electron microscopy is particularly revealing in dominant disorders in which structural abnormality of a protein is likely to be found, whereas biochemistry is more likely to be revealing in recessive disorders. The examples he used from dermatology to illustrate electron microscopic abnormalities were structural defects of tonofibrils in hystrix-like ichthyoses, of the anchoring fibrils in dominant dystrophic epidermolysis bullosa of Pasini, and of keratohyalin in autosomal dominant ichthyosis vulgaris.

In skin fibroblasts from patients with autosomal dominant ichthyosis vulgaris, Meyer et al. (1982) found elevation of arylsulfatase C activity using 4-methylumbelliferylsulfate. This may correspond to the f isoform (ARSC2; 301780) (see Chang et al. (1986, 1990)). However, Meyer et al. (1982) found that steroid sulfatase (STS; 300747) activity using 3-dehydroepiandrosteronsulfate was normal. In leukocytes, both activities were the same in patients and controls.

Ichthyosis vulgaris is characterized histologically by absent or reduced keratohyalin granules in the epidermis and mild hyperkeratosis. Keratohyalin contains a histidine-rich protein which is the precursor form (profilaggrin) of filaggrin (FLG; 135940), a keratin filament-aggregating protein. Using an antiserum, Sybert et al. (1985) demonstrated that profilaggrin and filaggrin were reduced or absent in 5 patients from 2 kindreds with ichthyosis vulgaris. The biochemical abnormality correlated with the morphologic reduction in amount of keratohyalin.

Nirunsuksiri et al. (1998) presented evidence that profilaggrin mRNA in keratinocytes cultured from subjects with ichthyosis vulgaris is intrinsically unstable and has a shorter half-life compared with that in normal cells. When ichthyosis vulgaris-affected keratinocytes were treated with the protein synthesis inhibitor cycloheximide, the steady-state level of profilaggrin mRNA was increased due to stabilization of the transcript. The number of filaggrin repeats (10 to 12) in individuals with ichthyosis vulgaris did not differ from that of unaffected subjects. Expression of the gene was biallelic and coequal in both control and affected individuals. The results of Nirunsuksiri et al. (1998) suggested a model in which a labile ribonuclease and a stabilizing factor may modulate the profilaggrin mRNA steady-state level in normal cells, whereas the stabilizing factor may be absent or functionally inactive in ichthyosis vulgaris-affected keratinocytes.

Mapping

By linkage analysis, Zhong et al. (2003) identified a locus for ichthyosis vulgaris on chromosome 1q22 with a maximum 2-point lod score of 2.47 at marker D1S1653 with a recombination fraction of 0.00. The epidermal differentiation complex (EDC; see 152445) comprises 3 gene families that are functionally related and mapped to 1q21. Zhong et al. (2003) stated that there was no overlap between the EDC region and the ichthyosis vulgaris locus on 1q22. However, only 4 Mb of genomic DNA separated EDC from D1S1653.

In an American family, Compton et al. (2002) showed linkage between ichthyosis vulgaris associated with a histologically absent granular layer and markers in the EDC on 1q21. The EDC is a dense cluster of genes encoding scores of epidermal structural proteins including filaggrin, loricrin (LOR; 152445), involucrin (IVL; 147360), trichohyalin (THH; 190370), and others.

Molecular Genetics

Smith et al. (2006) analyzed the filaggrin gene in 7 unrelated ichthyosis vulgaris patients and 8 sporadic cases, based on linkage and histologic evidence presented by Compton et al. (2002) and Zhong et al. (2003). In 1 family they identified a homozygous mutation, R501X (135940.0001), near the start of repeat 1 in exon 3 of the FLG gene. Further studies showed this mutation in the other 14 ichthyosis vulgaris kindreds studied. The mutation created a new restriction enzyme site which could be used to confirm the mutation and screen populations. By this means, they found the mutation to be present in relatively high allele frequencies in Irish, Scottish, and European American populations (combined frequency, 0.027).

In 3 families, Smith et al. (2006) found that ichthyosis vulgaris patients with a very pronounced phenotype were homozygous for R501X. In other families, they found individuals with the marked ichthyosis vulgaris phenotype to be heterozygous for R501X. Further sequencing in these cases showed the existence of a second mutation, 2282del4 (135940.0002), in exon 3 of the FLG gene. The 2282del4 mutation leads to a premature termination codon 107 bp downstream and, like R501X, stops protein translation within the first filaggrin repeat. This mutation also created a restriction enzyme site which could be used to screen ichthyosis vulgaris families and populations. The 2282del4 mutation segregated in 10 of the ichthyosis vulgaris families. Of the 8 'sporadic' cases of clinically significant ichthyosis vulgaris in which family history was not available, 4 were homozygous for R501X and the remaining 4 were R501X/2282del4 compound heterozygotes. Restudy of the family reported by Compton et al. (2002) showed that severely affected individuals were compound heterozygotes for these 2 mutations.

The association of ichthyosis vulgaris with atopic diathesis is well established; 37 to 50% of people with ichthyosis vulgaris have atopic diseases, and roughly 8% of patients with atopic dermatitis (603165) have classic features of ichthyosis vulgaris.

Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese patients with ichthyosis vulgaris from 4 unrelated families who were negative for the R501X and 2282del4 mutations, and identified heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA (135940.0004), respectively. The older sister of 1 proband, who had a more severe presentation of the disease, was found to be homozygous for the S2554X mutation. Noting that the R501X and 2282del4 mutations were absent from a total of 253 Japanese individuals, including their patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations in Japan are different from those found in European-origin populations.

Inheritance

In 1 family studied by Smith et al. (2006), the semidominant mode of inheritance of ichthyosis vulgaris was exemplified by multiple examples of patients with very mild presentation as well as by R501X homozygotes and R501X/2282del4 compound heterozygotes with the full ichthyosis vulgaris phenotype. In their series of families studied by Smith et al. (2006), there were only 2 individuals who were heterozygous for a null mutation, namely R501X, and had no obvious phenotype. On the basis of these small numbers, Smith et al. (2006) calculated the penetrance in heterozygotes to be about 90%.

Animal Model

Presland et al. (2000) demonstrated that 'flaky tail' (ft) mice express an abnormal profilaggrin (135940) polypeptide that does not form normal keratohyalin F-granules and is not proteolytically processed to filaggrin. This autosomal recessive trait maps to the central region of mouse chromosome 3, in the vicinity of the epidermal differentiation complex. Affected homozygous ft/ft mice exhibit large, disorganized scales on tail and paw skin, marked attenuation of the epidermal granular layer, mild acanthosis, and orthokeratotic hyperkeratosis. Cultured ft/ft keratinocytes synthesized reduced amounts of profilaggrin mRNA and protein, demonstrating that the defect in profilaggrin expression is intrinsic to epidermal cells. Presland et al. (2000) proposed that the absence of filaggrin, and in particular the hygroscopic, filaggrin-derived amino acids that are thought to function in epidermal hydration, underlies the dry, scaly skin characteristic of ft/ft mice.