Traditional genetics has also been extended by the introduction of several new non-Mendelian concepts of importance in dermatology.

1. Mosaicism. A mosaic is a single individual made up of two or more genetically distinct cell lines. The concept is important in several skin disorders including incontinentia pigmenti (p. 348) and segmental neurofibromatosis (p. 345). The mutation of a single cell in a fetus (a post-zygotic mutation) may form a clone of abnormal cells. In the epidermis these often adopt a bizarre pattern of lines and whorls – Blaschko’s lines, named after the dermatologist who recorded them in linear epidermal naevi in 1901.
   
2. Contiguous gene deletions. Complex phenotypes occur when several adjacent genes are lost. In this way, for example, X-linked ichthyosis may associate with hypogonadism or anosmia.
   
3. Genomic imprinting means that genes may differ in their effect depending on the parent from which they are inherited. Genes from the father seem especially important in psoriasis, and from the mother in atopy (p. 88).
   
4. Uniparental disomy occurs when both of a pair of genes are derived from the same parent so that an individual lacks either a maternal or a paternal copy. In this way a disorder usually inherited as a recessive trait can arise even though only one parent is a carrier.
   
5. Mitochondrial mutations can cause genodermatoses (e.g. one type of palmoplantar keratoderma). The condition is passed from the mother to both male and female offspring, but affected males do not pass it on to their offspring.

Gene expression may be altered even when the genetic code (DNA sequence) remains unchanged; rarely, these changes may be inherited from one generation to the next. The study of these phenomena is termed epigenetics. There are three broad epigenetic mechanisms: (i) DNA hypermethylation tending to supress gene transcription; (ii) modification of histone proteins (proteins tightly associated with DNA to form chromatin), with acetylation being the most studied usually resulting in activation of genes; (iii) the presence of microRNA genes which themselves do not code for a protein but affect the transcription of other genes. Epigenetic changes are thought to have a role in the pathogenesis of multiple inflammatory and malignant skin conditions.

Two other important genetic concepts are clinical heterogeneity (when clinically distinct phenotypes are produced by different mutations within the same gene, such as red hair variants caused by different polymorphisms of the MC1R gene) and genetic heterogeneity (when the same clinical picture can be produced by mutations in different genes, as in tuberous sclerosis).

Inheritance is important in many of the conditions discussed in other chapters and this has been highlighted in the sections on aetiology. This chapter includes some genetic disorders not covered elsewhere.

Red hair is not, of course, a disease but it is the first normal variation in human appearance for which a causative genetic polymorphism was found. The melanocortin-1 receptor (MC1R) gene is found at 16q24.3. While at least 30 genetic variants have been described, three in particular are associated with an increased phaeo- (red) to eu- (black) melanin ratio. Individuals homozygous or heterozygous for one or two of these ‘red hair alleles’ are likely to have pale skin, red hair and poor tanning ability.

These relatively common disorders affect about 1 in 3500 people and are inherited as an autosomal dominant trait. There are two main types: von Recklinghausen’s neurofibromatosis (NF1; which accounts for 85% of all cases) and bilateral acoustic neurofibromatosis (NF2); these are phenotypically and genetically distinct.