23.3 Inherited skin disease 5602 Thiviyani Marutha

23.3 Inherited skin disease 5602 Thiviyani Maruthappu and David P. Kelsell

ESSENTIALS Considerable advances in our understanding of inherited skin diseases have been made over the last decade as a result of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. The genetic basis of a myriad of monogenic epidermal disorders and syndromes including blistering diseases, ichthyoses, palmoplantar keratodermas, and the ectodermal dysplasias have now been elucidated. However, most patients referred from primary care to the dermatology clinic will be seeking treatment for a few common skin disorders such as psor- iasis, eczema, and acne. The genetic basis of these disorders is rather more complex, but progress has been made through genome-​wide association studies, which, for example, have linked susceptibility variants in the gene for filaggrin (FLG) to atopic eczema, and IL23R and many other immune-​related genes to psoriasis. Several genes have also been identified that predispose to malignancies of the skin including p16 (CDKN2A) and CDK4 in melanoma. Not only have these breakthroughs allowed a greater understanding of the patho- logical basis of skin diseases, but they have also highlighted novel targets for therapeutic development. Structure of the epidermis To understand inherited skin disease, it is first necessary to understand the basic biology of the epidermis and associated basement membrane zone. The basic structure of the epidermis is illustrated in Fig. 23.3.1. The epidermis is a stratified squa- mous epithelium consisting predominantly of keratinocytes. The remaining small percentage of intraepidermal cells includes resi- dent melanocytes, Langerhans’ cells, and migratory leucocytes. The keratinocyte undergoes a process of terminal differentiation resulting in the stratum corneum, the critical component for the barrier function of the epidermis. The highly insoluble stratum corneum consists of a cornified envelope enclosing keratin microfibres separated by a highly lipid-​rich intercellular layer. This lamellated lipid is the predominant component of the bar- rier, and is secreted into the extracellular space from membrane-​ coating granules synthesized in the stratum granulosum. The epidermis is separated from the underlying dermis by a complex basement membrane zone. The basement membrane zone When studied ultrastructurally, the basement membrane zone of the epidermis contains four distinct layers: • the basal cell membrane of the basal keratinocyte, which contains electron-​dense adhesion plaques called hemidesmosomes • the electron-​lucent lamina lucida, which is traversed by anchoring fibrils • the electron-​dense lamina densa • within the sublamina densa region, the lamina fibroreticularis contains distinct anchoring structures called anchoring fibrils, which insert into the lamina densa and loop around bundles of connective tissue collagens The hemidesmosome Although the morphology of this organ ultrastructurally resembles that of the desmosome, there are clear differences in biochemical composition. Two major hemidesmosomal proteins were initially identified by the characterization of autoantibodies arising in bul- lous pemphigoid, an autoimmune mechanobullous disease of late adult life. The proteins are known as bullous pemphigoid antigen 1 (dystonin (DST); 230 kDa) and bullous pemphigoid antigen 2 (COL17A1; 180 kDa). Bullous pemphigoid antigen 2 has been iden- tified as a unique transmembrane collagen, type XVII, which has an extracellular domain containing the immunodominant epitope of bullous pemphigoid. Bullous pemphigoid antigen 1, like plectin, a further component of hemidesmosomes, is a member of the plakin family of proteins. Plakins have been thought to contribute to plaque structures within the hemidesmosome; other members of the plakin family include desmoplakin, envoplakin, and periplakin, and are found associated with the desmosome. Plectin and bullous pemphigoid antigen appear to interact with keratin intermediate filaments as they course towards the hemidesmosome, and bind them into the hemidesmosome structure, acting as a protein clamp. This appears to provide a stable link between the intermediate filament cytoskeleton and the basement membrane zone. Basal keratinocytes also express 23.3 Inherited skin disease Thiviyani Maruthappu and David P. Kelsell

23.3  Inherited skin disease 5603 several integrins, which are members of a superfamily of receptors for extracellular matrix proteins. The major hemidesmosomal in- tegrin is α6β4 integrin, although other aspects of the basal cell mem- brane express α6β1, α5β1, α3β1, ανδ, and α2β1 integrins. The lamina lucida appears to contain a complex of laminin mol- ecules, particularly laminins 5 and 6. It is thought that laminin 5 is the major component of the anchoring filament. The lamina densa is constructed of a meshwork of interacting type VII collagen, from which arises the anchoring fibrils of the basement membrane com- plex, which are made of aggregates of antiparallel dimers of type VII collagen. Keratins The cytoskeleton of all epithelial cells contains several filamentous systems, including actin, microfilaments, microtubules, and inter- mediate filaments. The protein family that is characteristic of the intermediate filaments of all epithelial cells are the keratins. Keratin polypeptides are segregated by two-​dimensional gel electrophor- esis into acidic and basic polypeptides. Fifty-​four keratin genes have been identified expressed in epithelial cells and/​or the hair follicle: 28 belong to the type I group and 26 to the type II group. The type II keratin gene family encodes the basic keratin polypeptides, and the type I family the acidic keratin polypeptides. Each keratin gene is expressed in a body-​site and cell-​type specific manner (e.g. KRT9 is only expressed in the suprabasal layer of the palmoplantar epidermis and KRT6, KRT16, and KRT17 are rapidly induced in response to injury in stratified epithelia). The keratin genes are clustered in two chromosomal regions of the human genome:  the type I  keratins mapping to 17q12-​q21, and the type II keratins to 12q11-​q13. A keratin intermediate filament consists of both type I and type II keratin. The fundamental building block of a keratin filament is a heterodimer of a type I and type II keratin comprising four hel- ical regions separated by non​helical linking regions, with non​helical head and tail domains. These heterodimers aggregate in a complex antiparallel fashion to form the intermediate filaments, which an- chor to both hemidesmosomes and desmosomes to provide stability to the cell and ensure its integrity. In addition to keratin mutations associated with human disease, in vitro and transgenic models of keratin genes harbouring mutations have shown that there are critical regions for filament assembly, particularly the helix initiation and termination motifs. The amino terminal head domain of type II keratins mediates interaction with desmosomes but the function of the tail domain remains unclear. Desmosomes Desmosomal proteins form a complex structure at the interface be- tween adjacent epithelial cells. The desmosomal plaques of electron-​ dense material run along the cytoplasm parallel to a junctional region in which three ultrastructural bands can be seen. The plaques contain plakoglobin (which is also found in adherens junctions and is thought to be important in cell signalling), desmoplakin, and plakophilin 1.  In addition, the desmosomal cores are en- riched with calcium-​binding glycoproteins called desmogleins and desmocollins. These are the adhesive proteins of the desmosome, and are similar to the classical cadherins in their general structure, with five extracellular repeats that contain Ca2+-​binding sites, a single transmembrane region, and a cytoplasmic domain. To date, seven human desmosomal cadherins have been iden- tified, clustered in the chromosomal region 18q11-​q12. The cyto- plasmic domain has binding sites for plakoglobin, plakophilin 1, and desmoplakin, linking them to the intermediate filaments. Desmoglein 1 has been identified as the dominant target antigen for the autoimmune bullous disease pemphigus foliaceus, and desmoglein 3 is the target antigen for pemphigus vulgaris. Gap junctions Gap junctions provide a mechanism for synchronized cellular re- sponses to a variety of intercellular signals by regulating the diffusion of small molecules (<1 kDa) such as metabolites and ions between the cytoplasm of adjacent cells. Connexins are the major proteins of gap junctions and are encoded by a large gene family. All connexins have four transmembrane domains and two extracellular loops, with the N-​ and C-​termini located in the cytoplasm. Connexins assemble into hexameric hemichannels (termed connexons) in the endo- plasmic reticulum, and are then transported into the lipid bilayer of the plasma membrane. A connexon then docks with a connexon of an adjacent cell to form a dodecameric aqueous channel, the gap junction. These cluster together in macromolecular complexes of several hundred channels. Connexons can form either homotypic or heterotypic channels, with various channel types having distinct molecular permeabilities. Most connexins have wide tissue distribu- tion. Those expressed in the skin include connexin 26, 31, and 43. Disease associations with the aforementioned structural proteins have provided a molecular classification of disease to complement the classical morphological description of hereditary blistering diseases and disorders of keratinization, some of which are described next. Epidermolysis bullosa Genetic analysis of the heterogeneous group of mechanobullous disorders has facilitated enormous progress in understanding the function of proteins involved in the basement membrane at the dermoepidermal junction, and the role of keratins in the cyto- skeleton (Table 23.3.1). The clinical phenotypes of epidermolysis bullosa correspond to different levels of skin separation within the basement membrane zone or basal keratinocyte, identified Keratin filaments Desmosome Gap junction Nucleus Hemidesmosome Lamina lucida Lamina densa Anchoring filaments Anchoring plaque Anchoring fibrils Cornified cell envelope e.g. loricrin Suprabasal keratinocytes e.g. desmoglein 1, desmoplakin, keratins (1, 6a, 6b, 9, 10, 16, 17) Basement membrane e.g. laminins (1,5,6), type IV collagen Dermis e.g. type VII collagen Basal keratinocytes e.g. keratins (5,14) plectin, α6 β4 integrin Fig. 23.3.1  A schematic representation of the epidermis indicating its organization, important structures, and site of expression of several skin disease-​associated proteins.

section 23  Disorders of the skin 5604 via electron microscopic examination. All cases of epidermolysis bullosa are atrophic skin disorders characterized by the blistering of mucocutaneous sites following minor trauma, and are classified according to a combination of laboratory and clinical criteria. Epidermolysis bullosa simplex In epidermolysis bullosa simplex, skin tissue separates at the level of the basal keratinocyte, with or without the aggregation of keratin intermediate filaments. This is the most common form of epi- dermolysis bullosa, and is usually inherited in an autosomal dom- inant fashion. Blister formation occurs in the basal keratinocytes, which may show aggregates of keratin filaments. Mutations in the genes encoding the basal cell-​specific keratins 5 (KRT5; OMIM 148040) and 14 (KRT14; OMIM 148066) plus in the gene encoding the ubiquitination-associated protein KLHL24 have been found to underlie epidermolysis bullosa simplex, probably leading to the cytoskeletal weakness that results in the tendency for cells to rupture on pressure. Three types of the disease are described next, and clin- ical pictures are shown in Fig. 23.3.2. Epidermolysis bullosa simplex Weber–​Cockayne The soles and palms are mainly affected, but other sites can also be involved, although rarely. The blistering occurs from infancy (with walking), and is exacerbated by heat and ameliorated by cold. The blisters heal without scarring. Epidermolysis bullosa simplex Koebner The blisters are widespread on the scalp, trunk, arms, and legs, in addition to the palmoplantar areas. These cases might represent autosomal recessive inheritance. Nail dystrophy, oral blisters, and dental caries are common. Epidermolysis bullosa simplex Dowling–​Meara (herpetiform epidermolysis bullosa simplex) The blistering can be very severe, and is potentially fatal in infancy. The blisters occur in groups on an erythematous bed, which heals without scarring, but hyperpigmentation and milia formation can occur. Patchy keratoderma develops in later life. Junctional epidermolysis bullosa In junctional epidermolysis bullosa, the epidermis separates from the dermis at the lamina lucida of the basement membrane zone. Most mutations lie within genes encoding the three polypeptide subunits of laminin 5 (LAMA3, OMIM 600805; LAMB3, OMIM 15010; LAMC2, OMIM 150292). Clinically, the disease has been subdivided into two main categories:  Herlitz (lethal) and non-​ Herlitz (non​lethal) forms. Herlitz junctional epidermolysis bullosa Blistering and erosions are present at birth, and become widespread as the skin is so fragile that it peels away on contact. The resulting lesions are slow to heal and tend to persist, becoming infected. The oropharyngeal mucosa is involved, often making feeding difficult. If the infant survives for a few months, typical crusted lesions will be seen on the nose, mouth, and jaw, and across the rest of the skin in patches. The teeth have abnormal enamel and are lost easily, as are the nails. Infants usually die from overwhelming infection. Non-​Herlitz junctional epidermolysis bullosa Patients show generalized skin fragility and blistering, but the mucosae are less severely affected. The lesions heal leaving atrophic scars (generalized atrophic benign epidermolysis bullosa). Poor hair and tooth development is seen, and the nails are dystrophic. Large hyperpigmented patches are also present. Dystrophic epidermolysis bullosa In both the recessive and dominant forms of dystrophic epiderm- olysis bullosa, skin separation occurs below the dermoepidermal region at the level of the anchoring fibrils, and a large number of mutations have been discovered in the type VII collagen gene (COL7A1; OMIM 120120) that encodes the constituent protein of the anchoring fibrils. Scarring and dystrophy are prominent features in addition to skin fragility and blistering. Severe generalized recessive dystrophic epidermolysis bullosa This is the most severe form of dystrophic epidermolysis bullosa, and is very disabling in view of the deformities produced by scar- ring. Blisters are present at birth and recur readily at sites of trauma, especially the hands, feet, neck, shoulders, and sacrum. They heal slowly, with scarring and milia formation producing a mitten-​like deformity of the hands, and clubbed feet. The severe oral lesions lead to microstomata, and the inability to protrude the tongue or open the mouth. Poor dentition leads to feeding problems. Scalp blistering and scarring brings permanent hair loss, eye involvement gives corneal erosions and opacities, and general physical develop- ment is retarded. Oesophageal and perianal strictures lead to dif- ficulty in swallowing, and constipation. Although children often survive into adult life, multiple squamous cell carcinomas can de- velop in the chronically scarred skin and progress rapidly. Dominant dystrophic epidermolysis bullosa The skin is less fragile than in recessive dystrophic epidermolysis bullosa, and blistering is much more difficult to provoke, so that it tends to be localized to bony prominences: knees, elbows, hands, and feet. Localized scarring with milia can replace the nails. Other areas, such as the oral and anal regions, are much less affected. Hemidesmosomal epidermolysis bullosa Rarer forms of epidermolysis bullosa result from inherited defects in three hemidesmosomal components: plectin mutations in epiderm- olysis bullosa simplex with muscular dystrophy (PLEC1; OMIM Table 23.3.1  Genetics of epidermolysis bullosa Type of epidermolysis bullosa: site of blistering Genetic defect Associated disorder Simplex: basal cells Keratin 5 Keratin 14 KLHL24 Hemidesmosomal: basal cells/​ lamina lucida Plectin Integrin α6 Integrin β4 Type XVII collagen Muscular dystrophy Pyloric atresia Junctional: lamina lucida Laminin α3 Laminin β3 Laminin γ2 Dystrophic: sublamina densa Type VII collagen

23.3  Inherited skin disease 5605 601282), type XVII collagen mutations in generalized atrophic be- nign epidermolysis bullosa (COL17A1; OMIM 113811), and α6β4 integrin mutations in epidermolysis bullosa with pyloric atresia (ITGB4; OMIM 147557). Diagnosis and management of blistering in childhood Early diagnosis is key to the management of the disease and the prognosis. The diagnosis of a baby born with blisters is often difficult on clinical grounds, so diagnosis will rest on electron microscopy of a shave skin biopsy. Immunohistochemistry is likely to be indi- cative in recessive cases of gene knockout, the diagnostic reagents being LH7.2 antibody to type VII collagen, and GB3 antibody to laminin 5. There is no specific treatment for any form of epiderm- olysis bullosa, so management centres on wound care, the avoidance of physical trauma, and general physical and psychological support. Specialist nurses can advise on nursing babies with silk-​covered dressing pads, and the use of Vaseline gauze dressings. Oral hygiene and dental care needs to be lifelong. A high-​calorie and high-​fibre diet is essential to improve growth. Gastrostomy feeding can also help maintain body weight in children unable to eat. Finger and hand contractures require splinting at night and regular surgical re- lease by an expert surgeon. Now that the genetic basis of epiderm- olysis bullosa has been identified, prenatal diagnosis by DNA-​based techniques, and gene therapy by ex vivo techniques are actively being explored. Active areas of research into treatments for recessive dystrophic epidermolysis bullosa include allogeneic haematopoi- etic cell transplantation and induced pluripotent stem cells (iPSCs) with the ability to deliver collagen VII locally into chronic wounds. Ultimately, gene-​correction using viral vectors to reintroduce wild-​ type collagen VII into recessive dystrophic epidermolysis bullosa cells could provide a long-​term therapeutic strategy. Hailey–​Hailey disease and Darier’s disease The genetic bases of these rare autosomal dominant intraepidermal blistering diseases are mutations in the genes for calcium pumps:  ATP2C1 (OMIM 604384)  in Hailey–​Hailey disease, and (a) (b) (e) (g) (h) (f) (c) (d) Fig. 23.3.2  Clinical photographs of the different forms of epidermolysis bullosa. (a) and (b) a patient with dystrophic epidermolysis bullosa; (c) the hand of an infant with Herlitz junctional epidermolysis bullosa; (d) blister on the foot of a patient with epidermolysis bullosa simplex; (e) baby with epidermolysis bullosa simplex Dowling–​Meara; (f) baby with Herlitz junctional epidermolysis bullosa; (g) baby with dystrophic epidermolysis bullosa; (h) intraepidermal blister from a Weber Cockayne epidermolysis bullosa simplex patient. Skin section stained with Richardson’s stain.

section 23  Disorders of the skin 5606 ATP2A2 (OMIM 108740) in Darier’s disease. Darier’s disease typ- ically presents in the mid teenage years, with small pink and brown papules with greasy scale, and might distribute in a seborrhoeic pat- tern. However, the pattern and severity of the disease can be highly variable. Histology shows characteristic clefts in the epidermis, and dyskeratotic cells. Peeling skin syndrome Peeling skin syndrome describes a group of autosomal recessive dis- orders that present with mild superficial peeling, which can either be generalized (PSS1) or restricted to acral (palms and soles) sites (PSS2-​4). Typically presenting in childhood, affected sites may ex- hibit erythema, inflammation, or more rarely, vesiculation. PSS1 can be caused by mutations in corneodesmosin gene (CDSN; OMIM 602593) or in the calpastatin gene (CAST; OMIM 616295) where it is associated with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads. The acral form of the disorder can be caused by mutations in TGM5 (OMIM 603805), CHST8 (OMIM 610190), and CSTA (OMIM 184600). The condition can be aggravated by heat, humidity, and exposure to water. Treatment includes regular appli- cation of emollients and avoiding the aforementioned triggers. Ichthyoses Ichthyoses manifest as dry, rough skin, with persistent scaling over most of the body, which can resemble fish scales (ichthys, Greek: fish). Congenital ichthyosis can be bullous, or associated with other abnormalities (ichthyosiform syndromes). Ichthyosis can be acquired in later life as a result of drugs such as hypocholesterolaemic agents, chronic hepatic disease, lymphoma, and other malignancies, thyroid disease, chronic renal or hepatic failure, and malabsorption. When an individual’s ichthyosis has improved in adult life and then worsened in late adult life, it is sometimes difficult to be absolutely sure whether a patient has a congenital or an acquired ichthyosis. Progress in the understanding of the molecular and cellular biology of the ichthyoses will aid in establishing their classification and po- tential treatment. Autosomal dominant ichthyosis vulgaris This, the most common form of ichthyosis, is associated with atopic eczema in up to 50% of individuals. The condition improves in teen- agers and young adults, and often worsens again with age. The clin- ical features present with dryness and scaling in the neonatal period, and become progressively more obvious in childhood. Scales are small, flaky, or brown, and are most pronounced on the extensor aspects of the arms and lower legs. Facial involvement is often min- imal, although patients might have dandruff and increased mark- ings on the palms and soles. Hyperlinearity of palm creases might be seen in addition to keratosis pilaris occurring in a symmetrical distribution on the upper arms, thighs, and buttocks. It is usually very well-​tolerated symptomatically, with only the dryness and roughness being a problem. Treatments have therefore been aimed at removing the keratotic-​retained stratum corneum with keratolytic agents such as salicylic acid or 1–​5% lactic acid, other hydroxy acids, or buffered urea creams. Histopathology shows hyperkeratosis, with a diminished or absent granular cell layer, but otherwise very little abnormality at both the light and ultrastructural levels. This disease appears to be inherited in an autosomal dominant manner; however, there is variable penetrance, and difficulties in as- certainment. Loss-​of-​function mutations in FLG, the gene-​encoding filaggrin (filament aggregating protein), underlie ichthyosis vulgaris (OMIM 135940). Filaggrin plays a role in the differentiation of the epidermis and the formation of the skin barrier. X-​linked recessive ichthyosis This disorder is much less common than the autosomal dominant form, and predominantly affects the male children of female car- riers. The scaling is usually absent for the first week of life, but pro- gressively increases; it tends to be prominent on the arms, thighs, and lower legs, and very large adherent brown scales may involve the flexures and the face. On ultrastructural examination the granular cell layer and keratohyalin granules appear normal. The molecular basis of this form of ichthyosis was determined from observations of low urinary oestriol secretion in the third trimester of pregnancy, and reduced steroid sulphatase activity. Subsequently, the steroid sulphatase gene was mapped to the X chromosome (STS; OMIM 300747), and disease-​associated mutations in this gene have been identified in the vast majority of patients. Steroid sulphatase mutations lead to the abnormal breakdown of cholesterol sulphate in the stratum corneum lipids, resulting in reduced epidermal bar- rier function and and increased stratum corneum thickening. A small proportion of patients will have the additional mani- festations of Kallman’s syndrome (KAL1; OMIM 308700), with hypogonatropic, hypogonadal, and neurological abnormalities. These result from contiguous gene defects, usually a large deletion on the short arm of the X chromosome encompassing the steroid sulphatase locus. Bullous ichthyosiform erythroderma
(epidermolytic hyperkeratosis) This is a rare autosomal dominant ichthyosis. There is mild erythroderma at birth, and blisters and peeling can occur at sites of minor trauma. Large areas of denuded skin are often apparent after a difficult birth. In infancy, a yellow-​brown hyperkeratosis develops, particularly at the sites of joint flexure, with cobblestone keratoses present on the hands, feet, and trunk. Ridged scale can accumu- late in skin creases, which are highly susceptible to bacterial and/​or fungal infection, leading to a pungent body odour. Histologically, there is lysis and clumping of the keratin fila- ments in the granular layer of the epidermis. Intercellular spaces are often apparent because of the rupture of suprabasal keratinocytes. Immunohistochemical studies have revealed the specific aggrega- tion of the suprabasal keratins of the epidermis, keratins 1 and 10. Subsequently, mutations in either KRT1 (OMIM 139350) or KRT10 (OMIM 149080) have been shown to underlie the disease in many patients. Mutations in KRT9 (OMIM 607606) have been shown to underlie a form of bullous ichthyosiform erythroderma limited to the palms and soles. Superficial epidermolytic ichthyosis This is a more rare form of bullous ichthyosis. Neonatal disease is much milder, with episodic superficial blistering occurring throughout childhood, sometimes into adulthood. The blisters occur mainly on the flexures, lower limbs, and abdomen. At these sites, a rippled grey hyperkeratosis can occur. Plate-​like scaling and

23.3  Inherited skin disease 5607 focal peeling (mauserung phenomenon) are usually found. There is an absence of palmoplantar keratoderma and erythroderma. Mutations in the gene encoding another suprabasal keratin, KRT2 (OMIM 600194), have been identified as the basis of this condition. This type II keratin is expressed in many of the higher suprabasal keratinocytes. Lamellar ichthyosis Lamellar ichthyosis is a severe form of autosomal recessive congenital ichthyosis characterized by severe hyperkeratosis and the formation of large, often brownish-​coloured plate-​like scales over the whole body surface, including the face, with some flexural accentuation. The scales are present at birth, and might appear as a carapace-​like sheet over the body of the newborn (collodion babies), which then sheds. Bathing suit ichthyosis is a rare variant of lamellar ichthyosis in South African black patients, where the scale is centrally distributed on the trunk, upper limbs, scalp, and neck. Mutations in the genes encoding transglutaminase 1 (TGM1; OMIM 190195), a lipid trans- porter (ABCA12; OMIM 607800), ichthyin (ICHYN; OMIM 609383), and arachidonate lipoxygenase 3 (ALOXE3; OMIM 607206) and 12 (ALOX12B; OMIM 603741) underlie both lamellar ichthyosis and non​bullous congenital ichthyosiform erythroderma (see next). Non​bullous congential ichthyosiform erythroderma Although these patients have a severe generalized autosomal re- cessive ichthyosis, and present as collodion babies, this condition differs from lamellar ichthyosis by the presence of generalized erythroderma, which contributes to the characteristic facies and ectropion. This also produces problems with temperature and fluid control. The scaling is often finer and more brawny than in lamellar ichthyosis, and inflammation and parakeratosis are additionally found on histopathology. Netherton’s syndrome Netherton’s syndrome is a severe autosomal recessive disorder which can result in infant mortality due to fluid/​protein loss and infection, and is characterized by ichthyosis with erythroderma and trichorrhexis invaginata (hair-​shaft abnormalities often termed ‘bamboo hair’). Scanning electron microscopy of patients’ hair often also reveals torsion nodules, pili torti, and trichorrhexis nodosa. Light microscopy can show invagination of the hair cuticle into the cortex. Mutations in the gene SPINK5 encoding LEKTI, a serine protease inhibitor, underlie Netherton’s syndrome. Sjögren–​Larsson syndrome Sjögren–​Larsson syndrome is inherited as an autosomal recessive trait, and is particularly prevalent in northwestern Sweden (1 in 10 000), occurring less frequently elsewhere. The syndrome char- acteristically includes ichthyosis, spastic diplegia, and mild-​to-​ moderate developmental delay. The skin disease presents as mild erythroderma at birth, with scaling developing in the first few months, which persists particularly on the face and limbs. In the flex- ures, neck, and periumbilical folds, an orange/​brown lichenification overlaid with hyperkeratosis is a characteristic feature. In early life, neurological defects including upper motor neurone defects of the limbs, learning difficulties, and often ocular abnormalities (spots on the retina) are observed. Histologically, the affected skin displays orthohyperkeratosis, acanthosis, and papillomatosis. The genetic defect has been shown to be in the fatty aldehyde dehydrogenase gene (FALDH; OMIM 609523), which affects essential fatty acid metabolism. Ichthyosis prematurity syndrome This recessive ichthyosis has a higher prevalence in Norway and Sweden (OMIM 608649). It manifests with complications at mid-​ trimester leading to premature birth. The babies are born with thick desquamating skin and atopic features. Mutations in the FATP4 gene underlie this condition and is associated with defective very long chain fatty acid metabolism. Harlequin ichthyosis Harlequin ichthyosis is the most severe and often lethal form of re- cessive congenital ichthyosis. Infants born with this condition have hard, thick skin covering most of their bodies. The skin forms large diamond-​shaped plates separated by deep fissures that restrict move- ment. These skin abnormalities also affect the shape of the eyelids, nose, lips, and ears. The severely compromised skin barrier func- tion in neonates leads to increased transepidermal water loss and impaired thermoregulation, and they are more susceptible to infec- tion. In addition, the tightened skin can cause breathing difficulties leading to respiratory failure. Supportive treatment and oral retinoid therapy can enable Harlequin infants to survive the neonatal period, surviving children and adults may display dry erythematous skin and sparse hair, resembling non​bullous congenital ichthyosiform erythroderma. Mutations in the ABCA12 gene encoding an ATP-​ binding cassette (ABC) transporter (OMIM 607800) are found in almost all Harlequin ichthyosis cases. Keratodermas The inherited keratodermas are characterized by the presence of thickened skin on the palms and soles. Palmoplantar skin is uniquely adapted to withstand weight bearing and friction, so the stratum corneum is much thicker (hyperkeratotic) than the rest of the epi- dermis. The keratodermas can be classified clinically according to the pattern of thickening on the palm and sole skin. Three distinct clinical patterns have been observed: • diffuse—​the hyperkeratotic thickening is evenly and symmet- rically distributed over the palm and sole, usually manifesting at birth • focal—​hyperkeratotic plaques develop particularly at sites of weight bearing and friction; these are usually plaque-​like callosites or linear thickening (striate keratoderma) • punctate—​multiple bead-​like keratoses that pepper the palmoplantar skin The keratodermas can have autosomal recessive or dominant in- heritance, and may occur in syndromes. They can be further subgrouped into: • simple—​palmoplantar involvement only • complex—​associated with lesions of non​volar skin, hair, teeth, nails, and sweat glands (including ectodermal dysplasias) • syndromic—​associated with abnormalities in other organs, inclu­ ding deafness, cancer, cardiomyopathy, and adrenal insufficiency

section 23  Disorders of the skin 5608 They can also be classified biologically by their underlying genetic defects (see Fig. 23.3.3 and Tables 23.3.2 and 23.3.3). This branch of the genodermatoses is genetically heterogeneous, with mutations in genes encoding keratins, desmosomal proteins, connexins, prote- ases, and a water-​channel protein. Diffuse facies (PPK) Simple—​diffuse epidermolytic palmoplantar keratoderma This condition is characterized by epidermolytic hyperkeratosis with keratin filament clumping in suprabasal keratins. This auto- somal dominant disease presents with symmetrical thickening giving a cracked, crocodile skin-​like surface resulting from the underlying epidermolysis, which starts in early infancy. Most epidermolytic PPK pedigrees are linked to the type I keratin cluster on chromosome 17q12-​q21, and disease is because of mutations in the palmoplantar-​specific keratin 9 (KRT9; OMIM 607606), the majority clustering in the helix initiation domain of the protein. However, epidermolytic palmoplantar keratodermas can also be associated with mutations in the type II keratin 1 (KRT1; OMIM 139350). Simple—​diffuse non​epidermolytic palmoplantar
keratoderma (NEPPK) Non​epidermolytic PPK is also inherited as an autosomal dominant trait, and is often difficult to distinguish from epidermolytic PPK because of the inconsistent finding of epidermolysis by electron mi- croscopy in epidermolytic palmoplantar keratodermas. There is a uniform waxy yellow thickening over the palms and soles, which can spread onto the dorsum of the hands and wrists, with a sharp cut-​off. It is commonly aggravated by secondary fungal infection, (a) (b) (d) (c) Fig. 23.3.3  Clinical photographs of: (a) bullous ichthyosiform erythroderma (BIE) and three types of keratoderma: (b) focal palmoplantar keratoderma (PPK) associated with a keratin 16 mutation; (c) striate palmoplantar keratoderma associated with a desmoglein 1 mutation; and (d) constriction around the digit from an individual with Vohwinkel’s syndrome associated with mutation in the gene-​encoding connexin 26 (GJB2; OMIM 121011).

23.3  Inherited skin disease 5609 which might require intermittent oral antifungal agents. These often improve the keratoderma. Some families have disease linked to 12q11-​q13. A single family has a mutation in the variable head do- main of keratin 1; however, in most non​epidermolyic palmoplantar keratodermas families, fine mapping of the 12q11-​q13 locus has ex- cluded abnormalities of the type II keratin genes. Complex—​erythrokeratoderma variabilis Erythrokeratoderma variabilis is a rare autosomal dominant skin dis- ease characterized by diffuse PPK and transient figurate red patches at various sites of varying severity. Germline mutations in connexin 31 (GJB3; OMIM 603324) and in the 3-ketodihydrosphingosine reductase (KDSR; OMIM 617526) have been identified in the af- fected members of some erythrokeratoderma variabilis families. Focal keratoderma Most focal palmoplantar keratodermas are characterized by the presence of discoid lesions, and the majority can be regarded as complex PPKs as they are often associated with abnormalities of hair, nails, teeth, and glands. Simple—​striate PPK This focal palmoplantar keratoderma is characterized by the pres- ence of distinctive linear streaks on the palms and soles, and over the ventral aspects of the fingers extending onto the palms. The le- sions are often more extreme on the feet. Variable nail and hair in- volvement with fragility or splitting is seen. Mutations in the genes for two desmosomal proteins: desmoglein 1 (DSG1; OMIM 125670; 18q11-​12) or desmoplakin 1(DSP; OMIM 125647; 6p21) have been described, which result in a hemizygous gene knockout leading to haploinsufficiency of the gene product. Keratin 1 mutations have also been reported. Complex—​pachyonychia congenita type 1/​focal PPK with
oral mucosal hyperkeratosis This clinical overlap syndrome presents in childhood with nail changes (pachyonychia). Typically, a subungual hyperkeratosis pro- duces a trumpet-​shaped nail, especially on the thumb, first finger, and toes. The sole lesions consist of painful callosities over weight-​ bearing areas; less prominent callosities occur on the palms. The gingival mucosa shows milky hyperkeratosis. Nutmeg-​grater-​like follicular keratoses also occur. Variable fragility and blistering can be associated with severe pain on walking. Milder nail involvement may present as splinter haemorrhages. The pathological finding of epidermolytic hyperkeratosis with keratin filament clumping sug- gests that keratin gene mutations underlie this disorder; this was confirmed by the identification of mutations in the genes encoding keratin 6A (KRT6A; OMIM 148041) and keratin 16 (KRT16; OMIM 148067) in affected individuals from multiple families. Complex—​pachyonychia congenita
type 2/​steatocystoma multiplex The palmoplantar keratoderma might be very limited, although pachyonychia nail changes present early. Multiple epidermal cysts and steatocysts are seen. Woolly scalp hair, fuzzy eyebrows, and natal teeth are also common features. The finding of keratin clumps in skin bearing keratin 17, particularly the hair follicle’s deep outer root sheath, suggested KRT17 (OMIM 148069)  as the candidate gene, and autosomal dominant mutations have been extensively de- scribed. Mutations in KRT6B (OMIM 148042) have also been iden- tified. The resulting pathology varies from keratin cysts, vellus hair cysts, and oil-​filled cysts. Complex—​Papillon–​Lefevre syndrome This focal palmoplantar keratoderma is inherited in an autosomal recessive manner, and is marked by associated severe periodon- titis and secondary ulceration, with opalescent oral mucosae. The inflammatory lesions often result in pocket formation seen patho- logically. Mutations in cathepsin C, a lysosomal protease, have been shown to underlie this disorder. It is postulated that cathepsin C may Table 23.3.2  Genetics of diffuse palmoplantar keratoderma (PPK) Type of diffuse PPK Associated disorder Genetic defect EPPK (epider-​molytic PPK) Keratin 9 NEPPK (non​epidermolytic PPK) Umbilical hyperkeratosis Keratin 1 NEPPK Diffuse Nagashima-​type NEPPK Aquaporin 5 Serpin B7 Syndromic NEPPK (Naxos disease) Woolly hair and cardiomyopathy Plakoglobin Desmoplakin Vohwinkel’s syndrome Sensorineural deafness Connexin 26 Ichthyosis Loricrin Erythrokeratoderma variablis Generalized erythroderma Connexin 31 KDSR Clouston’s syndrome Alopecia, nail dystrophy, sensorineural deafness Connexin 30 and connexin 30.3 Hypohidrotic ectodermal dysplasia Erythroderma, impaired sweating, hair and nail abnormalities Plakophilin 1 Mal de Meleda Olmsted syndrome Hyperhidrosis and perioral erythema Palmoplanter keratodema and perioroficial keratosis SLURP-​1 TRPV3 NEPPK, non​epidermolytic palmoplantar keratoderma. Table 23.3.3  Genetics of focal palmoplantar keratoderma (PPK) Type of focal PPK Associated disorder Genetic defect Focal NEPPK Follicular and orogenital hyperkeratosis Keratin 16 Focal NEPPK (tylosis) Oesophageal cancer, oral and follicular hyperkeratosis iRhom2 Pachyonychia congenita type 1 Nail dystrophy and oral lesions Keratin 6a Keratin 16 Pachyonychia congenita type 2 Epidermal cysts, nail dystrophy, and oral lesions Keratin 6b Keratin 17 Striate PPK Desmoglein 1 Desmoplakin Keratin 1 Papillon–​Lefevre Cathepsin C Oculocutaneous tyrosinaemia Photophobia, corneal ulceration, and mental retardation Tyrosine aminotransferase NEPPK, non​epidermolytic palmoplantar keratoderma.

section 23  Disorders of the skin 5610 be important in the processing of key structural proteins, such as keratins, in the epidermis. Simple—​punctate PPK This is inherited as an autosomal dominant trait and presents with a uniform bead-​like hyperkeratosis over the palms and soles with secondary broader areas of hyperkeratosis in weight-​bearing areas. They can appear clinically similar to acquired punctate keratoses, but are more uniform, appear earlier in life, and have a positive family history. Both acquired and inherited forms are associated with malignancies. Rarer porokeratotic forms exist. Mutations in the AAGAB gene (OMIM 614888) have been found to underlie this disease. Syndromic keratodermas (multiple phenotypic) PPK and deafness Several families with palmoplantar keratoderma and sensorineural deafness have been described. This might be due to a mutation in a single gene expressed in all affected tissues, or cosegregation of two distinct gene mutations. One such disorder is Vohwinkel’s syndrome; a mutating palmoplantar keratoderma with constric- tions developing around the fingers, leading to autoamputation. Autosomal dominant mutations in the genes encoding the gap junction protein connexin 26 (GJB2; OMIM 121011) have been described in families with Vohwinkel’s syndrome, and other forms of palmoplantar keratoderma and sensorineural deafness. There is a genotype–​phenotype correlation between the site of the GJB2 mutation and the severity of the keratoderma and ex- tent of the hearing impairment. Mutations in the gene for loricrin (LOR; OMIM 152445), a cornified cell-​envelope component of the stratum corneum, have also been identified in individuals affected with a variant form of Vohwinkel’s syndrome that is as- sociated with ichthyosis. In addition, palmoplantar keratoderma and deafness have also been associated with mutations in mitochondrial DNA. PPK and cancer Focal non​epidermolytic PPK and oesophageal cancer (Tylosis with oesophageal cancer –​TOC) Two large pedigrees from the United Kingdom and smaller pedigrees from the United States of America, Spain, Finland and Germany have been studied in which a focal non​epidermolytic palmoplantar keratoderma with oral hyperkeratosis segregates with a high lifetime risk of squamous cell carcinoma of the oesophagus (up to 95% by age 65 years). The cutaneous phenotype is completely penetrant by puberty. Gain-​of-​function mutations in the gene encoding the in- active rhomboid protease, iRhom2 (RHBDF2; OMIM 148500) have been determined as the underlying cause in all described cases. The autosomal dominantly inherited mutation is associated with dysregulated EGFR signalling, which has been postulated to con- tribute to carcinogenesis in these patients. Huriez disease (sclerotylosis) This is an autosomal dominant disease characterized by PPK, nail changes, and scleroatrophy of the distal extremities. Around 15% of individuals develop aggressive squamous cell carcinomas in their thirties and forties. It is proposed that the scarring resulting from skin fragility predisposes to the carcinomas. The Huriez disease gene has been mapped to chromosome 4q23. PPK, woolly hair, and cardiomyopathy Diffuse non​epidermolytic PPK with arrhythmogenic ventricular cardiomyopathy (which leads to heart failure and arrhythmias) can result from recessive or dominant mutations in the gene for either desmoplakin (DSP; OMIM 125647) or plakoglobin (JUP; OMIM 173325), two major proteins of the desmosome. It is now known that affected individuals may present with cardiac features, cutaneous features or both, and these studies have alerted dermatologists to the possible covert cardiac problems that may occur in patients with palmoplantar keratoderma and woolly hair. Triple A syndrome In triple A or Allgrove’s syndrome, individuals have ACTH-​resistant adrenal insufficiency, achalasia, and alacrima with palmoplantar keratoderma. This disease has been mapped to 12q13, and muta- tions in a novel gene, AAAS (OMIM 605378), have been identified. The predicted protein is a WD repeat-​containing protein that might play a role in signalling, and RNA processing and transcription. Ectodermal dysplasias There are a many ectodermal dysplasias, in which abnormal- ities of the skin, hair, teeth, nails, and/​or sweating are seen. The clinical classification is unsatisfactory, but might become more transparent when the genetic basis of a significant number of these complexes has been classified. Two major subgroups in- clude hidrotic and non​hidrotic ectodermal dysplasia. The con- cept of dysplasia in these diseases is developmental rather than premalignant. Hidrotic ectodermal dysplasia (Clouston’s syndrome) Hidrotic ectodermal dysplasia is characterized by nail dystrophy with thick, slow-​growing, discoloured, short nails. Diffuse palmoplantar keratoderma is variable, but may be severe and spread to knuckles and finger joints. Scalp hair is sparse, fine, pale, and brittle, with thin eyebrows and sparse body hair. The disease is inherited as an auto- somal dominant trait. Mutations in connexin 30 encoded by GJB6 (OMIM 604418) underlie this condition. Keratosis, ichthyosis, deafness syndrome In this condition, a severe extensive and progressive erythrokera­ toderma is associated with sensorineural hearing loss and vascular- izing keratitis. Fatal cases have been reported. Missense germline mutations in the genes encoding connexin 26 (GJB2; OMIM 121011) and 30 (GJB6; OMIM 604418) have been found. Ectodermal dysplasia/​skin fragility syndrome This very rare inherited disorder presents with erythema at birth and skin blistering resulting from fragility, and is associated with nail dystrophy, palmoplantar keratoderma, and hair loss. It was initially confused with epidermolysis bullosa. It was found to be histologically associated with increased intercellular spaces and desmosomal ab- normalities, which led to the discovery of plakophilin 1 mutations (PKP1; OMIM 601975) in sporadic cases.

23.3  Inherited skin disease 5611 Hypohidrotic ectodermal dysplasia This X-​linked recessively inherited disease is characterized by a loss of sweat glands, causing absent or reduced sweating (hypohidrosis), and total or partial loss of teeth. Patients may be very uncomfortable on exertion and are heat intolerant. The teeth are characteristically conical and the mouth dry. In severe forms the facial appearance is altered, with saddle nose, sunken cheeks, and sparse, dry, fine, short hair with absent eyebrows. The disease maps to Xq12-​13.1 and is caused by mutations in the gene for ectodysplasin anhidrotic protein (EDA; OMIM 300451). An autosomal recessive form results from mutations in the ectodysplasin receptor (EDAR; OMIM 604095). Recent advances and possible future developments Major advances in our understanding of the genetic basis of several rare diseases such as ichthyoses, keratodermas, and blistering dis- orders have occurred in the last decade. What has become clearer is that vast herterogeneity exists and that mutations in different pro- teins can cause similar clinical manifestations (e.g. Vohwinkel’s syn- drome can result from mutations in either connexin 26 or loricrin). The study of rare, monogenic disease has also improved our under- standing of the molecular basis of more common skin diseases. For example, loss-​of-​function mutations in ADAM17 and EGFR both result in severe skin inflammation as well as inflammatory bowel disease, highlighting the importance of these pathways in inflamma- tory responses, such findings also have important therapeutic impli- cations beyond the scope of skin disease. FURTHER READING Akiyama M (2006). Harlequin ichthyosis and other autosomal re- cessive congenital ichthyoses:  the underlying genetic defects and pathomechanisms. J Dermatol Sci, 42, 83–​9. Blaydon DC, et al. (2011). Inflammatory skin and bowel disease linked to ADAM17 deletion. N Eng J Med, 365, 1502–​8. Blaydon DC, et  al. (2013). Mutations in AQP5 encoding a water-​ channel protein cause autosomal dominant diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum Genet, 93, 330–​5. Brooke MA, Nitoiu D, Kelsell DP (2012). Cell-​cell connectivity: desmo- somes and disease. J Pathol, 226, 158–​71. Fine JD, et al. (2014). Inherited epidermolysis bullosa: updated recom- mendations on diagnosis and classification J Am Acad Dermatol, 70, 1103–​26. Has C. (2017). The “Kelch” surprise: KLHL24, a new player in the pathogenesis of skin fragility. J Invest Dermatol, 137, 1211–2. Hu Z, et al. (2000). Mutations in ATP2C1, encoding a calcium pump, cause Hailey–​Hailey disease. Nat Genet, 24, 61–​5. Kere J, et al. (1996). X-​linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet, 13, 409–​16. Knöbel M, O’Toole EA, Smith FJ (2015). Keratins and skin disease. Cell Tissue Res, 360, 583–​9. Laird DW (2006). Life cycle of connexins in health and disease. Biochem J, 394, 527–​43. Lefevre C, et al. (2003). Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet, 12, 2369–​78. Lefevre C, et al. (2004). Mutations in ichthyin a new gene on chromo- some 5q33 in a new form of autosomal recessive congenital ichthy- osis. Hum Mol Genet, 13, 2473–​82. Maruthappu T, Scott CA, Kelsell DP (2014). Discovery in genetic skin disease: the impact of high throughput genetic technologies. Genes, 5, 615–​34. McGrath JA, Mellerio JE (2006). Epidermolysis bullosa. Br J Hosp Med (Lonod), 67, 188–​91. Mikkola ML (2007). p63 in skin appendage development. Cell Cycle, 6, 285–​90. Oji V, Traupe H (2006). Ichthyoses:  differential diagnosis and mo- lecular genetics. Eur J Dermatol, 16, 349–​59. Oji V, et al. (2006). Bathing suit ichthyosis is caused by transglutaminase-​ 1 deficiency: evidence for a temperature-​sensitive phenotype. Hum Mol Genet, 15, 3083–​97. Rajpopat S, et al. (2011). Harlequin ichthyosis: a review of clinical and molecular findings in 45 patients. Arch Dermatol, 147, 681–​6. Sakuntabhai A, et al. (1999). Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet, 21, 271–​7. Comment in: Nat Genet, 21, 252–​3. Smith FJ, et  al. (2006). Loss-​of-​function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet, 38, 337–​42. Takeichi et al. (2017). Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. J Invest Dermatol, 137, 2344–53. Toomes C, et al. (1999). Loss-​of-​function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet, 23, 421–​4. Uitto J, Richard G (2004). Progress in epidermolysis bullosa: genetic classification and clinical implications. Am J Med Genet C Semin Med Genet, 131C, 61–​74. Webber BR, Tolar J (2015). From marrow to matrix: novel gene and cell therapies for epidermolysis bullosa. Mol Ther, 23, 987–​92.