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 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.
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 ... 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.