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

Pseudoxanthoma elasticum is a disorder of elastic fibres and is inherited as both an autosomal recessive and occasionally an autosomal dominant trait. A variety of clinical syndromes with different inheritances exist. The tissue distribution of the abnormality is patchy. Abnormal elastic fibres may be found generally in the walls of arteries or in the skin, where the abnormality is most frequently located in the middle and lower thirds of the dermis. Appearing as groups of soft, yellow papules or macules, the skin lesions are normally first observed in the second or third decade of life. The macules slowly progress in extent and are usually found at the sides of the neck and in the groin. The involvement of elastic tissue in the arteries is most easily seen in the angioid streaks of the retina, and this alteration may progress to cause impairment of vision.

Miscellaneous Disorders of Connective Tissue

Acne is an inflammatory disorder of hair bearing skin, characterized initially by hyperkeratosis of follicular canals and an increased rate of sebum secretion and subsequently by the development of inflamed papules and abscesses (‘cysts’). It affects the majority of individuals mildly during adolescence, but can give rise to serious disease in a relatively small proportion of individuals. The lesions observed clinically are comedones (blackheads) which are really casts of the follicular canal and arise on the face, chest and upper back, papules and pustules, which are inflammatory lesions arising from obstructed follicles, and cysts, which are in reality cold abscesses, the result of colliquative necrosis around several follicles. The more inflamed and destructive lesions cause unsightly scarring.

Acne, Rosacea, Perioral Dermatitis and Related Disorders

This recently described condition1, also known as Sweet’s disease after its discoverer, consists of tender papules and plaques up to 2 cm in diameter. The papules are erythematous and are associated with the development of leukocytosis and fever. The face, neck and upper limbs are involved most. There may be an accompanying arthralgia or arthritis. The disorder rapidly responds to systemic corticosteroids but may relapse. Nothing is known of the aetiology or pathogenesis of Sweet’s disease although it may be related to erythema multiforme.

Other Inflammatory Diseases

The sequence of changes that occur in the skin after injury are similar regardless of whether the injury is caused by a knife, by a burn or by a disease process (Figure 2.1). Immediately after injury the extravasated blood clots, due to activation of the clotting cascade, and vasoconstriction occurs. Polymorphonuclear leukocytes accumulate at the site of injury and separate viable from damaged, non-viable tissue components. After some 12 to 24 hours the process of re-epithelialization begins1. In the initial stages, epidermal cells actively move over the wounded area. The migrating epidermal cells adopt a spindle- or ribbon-shaped profile, resembling fibroblasts (Figure 2.2). Ultrastructurally they lose their desmosomal apparatus and cell-to-cell contact reverts to primitive interdigitating microvilli. Some 48 hours after wounding, mitotic activity begins at a point behind the leading edge of the sheet of migrating epidermal cells, and on the third and fourth days maturation of the new epidermal cover begins. During the early stages of re-epithelialization the epidermal cells need no specialized dermo-epidermal apparatus, but burrow through the damaged tissue planes, isolating the viable deeper tissues from the superficial necrotic crust, which is eventually sloughed off. Later on, the new epidermis secretes its own junctional apparatus, restoring continuity with the dermis beneath2.

Reactions to Trauma and Vascular Injury

The dermatological manifestations of porphyria are the result of damage caused by photosensitivity to long-wave ultraviolet light absorbed by porphyrins in the skin1. The histological changes in the skin are similar in the various forms of porphyria, but they tend to vary in degrees of severity.

Arthur Knight

Papers

Miscellaneous Disorders of Connective Tissue

Acne, Rosacea, Perioral Dermatitis and Related Disorders

Other Inflammatory Diseases

Reactions to Trauma and Vascular Injury

Cutaneous Deposits in Metabolic Disorders