Melanoma and non-melanoma (basal and squamous cell carcinoma) skin cancer (NMSC) are now the most common types of cancer in the white populations and the incidence of skin cancer has reached epidemic proportions According to recent population-based studies from Australia the incidence rate is over 2% for basal cell carcinoma in males and 1% for squamous cell carcinoma, and there are over 50 new cases of melanoma per 100 000

The epidemiology of skin cancer.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and 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. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

https://www.jidonline.org/article/S0022-202X(15)35676-1/pdf

One remarkable molecule: Filaggrin

Lamellar ichthyosis type 2 (LI2) is a rare autosomal recessive skin disorder for which a gene has been localized on chromosome 2q33–35. We report the identification of five missense mutations in the ABCA12 gene in nine families from Africa affected by LI2. The mutations were homozygous in eight consanguineous families and heterozygous in one non-consanguineous family. Four of these mutations are localized in the first ATP-binding domain (nucleotide-binding fold), which is highly conserved in all ABC proteins. The ABCA12 protein belongs to a superfamily of membrane proteins that translocate a variety of substrates across extra- and intracellular membranes. ABCA transporters have been implicated in several autosomal recessive disorders, notably of lipid metabolism. By analogy with ABCA3, a lamellar body membrane protein in lung alveolar type II cells, ABCA12 could function in cellular lipid trafficking in keratinocytes.

/pdf/mutations-in-the-transporter-abca12-are-associated-with-3qpzx1hj8d.pdf

Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2

Among the diagnostic problems of skin biopsy, lymphocytic and histiocytic proliferations may prove the most bewildering1. This difficulty stems from the fact that chronic inflammatory infiltrates are commonplace in the skin and can be so prolific and histologically bizarre that an erroneous impression of lymphoid neoplasia can be created. On the other hand, in the early stages of mycosis fungoides (a T-cell lymphocytic neoplasm) the changes may be so minor that appearances vary little from inflammatory dermatoses. There are also conditions like histiocytosis X, neither certainly neoplastic nor certainly reactive, which affect the skin and may cause diagnostic difficulty. Unfortunately, no general rules apply to assist histological diagnosis in this field (save the golden rule of caution), but there are some features of lymphoid infiltrates which should raise a suspicion of a neoplastic process (Table 17.1). Nodular lymphomas or leukaemic infiltrates tend to occupy the reticular rather than the papillary dermis and tend to extend into subcutaneous fat.

Arthur Knight

Papers

Lymphocytic, Mast-cell and Atypical Histiocytic Skin Tumours and Dermal Leukaemia