Disease-associated mutations have now been demonstrated in genes encoding ten different desmosomal proteins: these comprise PKP1 and 2; DSP; PG; DSG1, 2 and 4; DSC2 and 3; and CDSN (Fig. 4.2) [4]. Mutations in PKP1, DSP, PG, DSG1, DSG4, DSC2, DSC3 and CDSN may all result in inherited skin and/or hair abnormalities; skin/hair cases with mutations in DSP, PG or DSC2 may also be associated with heart muscle pathology depending on the inheritance pattern and nature of the mutation(s). Mutations in DSP, PG, PKP2, DSG2 and DSC2 may all cause cardiomyopathy in the absence of any changes in the skin or hair [5]. The precise clinical consequences associated with a particular desmosome gene mutation relate to its tissue and differentiation-specific expression pattern. One of the key clinical challenges in assessing patients with an inherited disorder of desmosomes is to determine whether or not there is cardiac involvement because of the risk of arrhythmias and sudden death [5]. Skin fragility, and thus a possible relationship to other forms of EB, has been associated with mutations in PKP1, DSP, PG, DSG1 and DSC3. In the other inherited disorders of desmosomes that affect the skin, the functional consequences do not lead to blisters or erosions but rather to changes in differentiation and proliferation, for example, manifesting as keratoderma [4].

PKP1 contributes to desmosome assembly and stabilisation of desmosomes, especially in the spinous and granular cell layers [6, 8]. PKP1 was the first desmosomal protein to be linked to an inherited skin disease in 1997 [9]. Autosomal recessive mutations leading to ablation of PKP1 were identified in an infant with features of skin fragility and ectodermal abnormalities affecting the skin, hair and nails. The combination of skin fragility, complete alopecia, palmoplantar keratoderma and nail dystrophy was termed “ectodermal dysplasia-skin fragility” syndrome. The skin fragility in this and more than a dozen other cases of ectodermal dysplasia-skin fragility syndrome typically includes perioral cracking and painful acral fissures rather than discrete blisters “in the latest classification of EB published in 2014 [10], this disorder is now termed “plakophilin 1-deficiency” or “EB simplex-plakophilin1”.

Desmoplakin (DSP) is the most abundantly expressed component of the desmosome [11]. It is composed of a central coiled-coil rod domain flanked by two globular heads, a carboxyl domain (C-terminus) and an amino domain (N-terminus) [12]. Autosomal dominant and autosomal recessive mutations in the DSP gene may underlie a spectrum of cutaneous, cardio-cutaneous and cardiac disorders, most of which do not cause skin blistering [5]. In 2005, DSP gene mutations were found to cause severe skin and mucosal fragility at birth, total alopecia, possible cardiomyopathy and stillbirth or early neonatal lethality [13]. The clinicopathological syndrome in this and a small number of similar cases was referred to as lethal acantholytic EB (sometimes also termed EB-lethal acantholytic) [13]. In the current classification of EB [10], the preferred diagnostic terminology is “desmoplakin-deficiency”, “EB simplex-desmoplakin”, “acantholytic EB simplex” or “skin fragility-woolly hair” depending on the particular phenotype.

Plakoglobin (PG) is an intracellular armadillo protein component of the desmosome [14], and the encoding gene is referred to as JUP. The central domain interacts with DSP, which tethers intermediate filaments to the desmosomal plaque [15]. The first human mutation in the JUP gene was reported in 2000 in individuals with cardiomyopathy, palmoplantar keratoderma and woolly hair (Naxos disease) [16]. There is no skin fragility in Naxos disease, but in 2011 a new severe phenotype caused by a homozygous nonsense JUP mutation, leading to complete loss of PG, was reported [17]. The clinical features, which led to neonatal lethality, comprised generalised epidermolysis, total alopecia and onycholysis. The authors labelled the disorder “lethal congenital epidermolysis bullosa” [17]. In the latest classification of EB [10], the new diagnostic terminology is “plakoglobin-deficiency”, “EB simplex-plakoglobin” or “skin fragility-plakoglobin”.

Desmogleins are part of the desmosomal cadherin family encoded by a gene cluster on chromosome 18q12. The first human cadherin gene mutation was reported in the DSG1 gene in 1999 [18]. The clinical features in the Dutch family reported were those of striate palmoplantar keratoderma. Further mutations (approximately 35 to date) affecting the extracellular part of DSG1 have subsequently been identified [19]. Most individuals had striate palmoplantar keratoderma (occasionally focal), but no hair or nail abnormalities, and non-palmoplantar skin was characteristically unaffected. Although blistering was not typically a feature, a novel heterozygous mutation was found in a Scottish man with striate keratoderma, mild hyperkeratosis of the knees and hyperhidrosis, who also experienced intermittent blistering [20].

DSC3 is a component of the transmembrane core of desmosomes that engages in homophilic as well as heterophilic adhesive interactions in the intercellular space [21]. Dsc3 null mutations in mice are embryonic lethal [22], but a conditional Dsc3 null mutation in stratified epithelia led to skin erosions with acantholysis in the lower layers of the epidermis [23]. Thus far, only one human case with DSC3 gene mutations has been reported [24]. Four individuals in a pedigree from Afghanistan had hereditary hypotrichosis as well as recurrent skin vesicles. There was sparse and fragile hair on the scalp, as well as absent eyebrows and eyelashes. Vesicles that were filled with thin, watery fluid were observed on the affected individuals’ scalps and several other body sites [24]. The histology presented, however, showed no vesicles, and several of the skin features only illustrated keratosis pilaris.

In the consensus classifications of EB reported in 1991 and 2000, desmosomal forms of EB did not feature, although acantholysis was a recognised histological finding in some cases of EB simplex with underlying mutations in keratin 5 or 14 [25–27]. In a subsequent classification of EB published in 2008, however, the concept of intraepidermal forms of EB was introduced with the addition of two desmosomal skin fragility disorders: ectodermal dysplasia-skin fragility (PKP1 gene mutations) and lethal acantholytic EB (DSP gene mutations) [28]. In the 2014 re-classification of EB [10], however, mutations in plakoglobin were also included, alongside name changes for the other established desmosomal forms of EB (see sections 4.3 and 4.4 above, as well as section 4.5 on plakoglobin). Not included in the latest classification, however, is hypotrichosis with scalp vesicles (DSC3 gene mutations) because of the current lack of clinical or histological evidence for the presence of skin blisters, as well as striate palmoplantar keratoderma with blistering (DSG1 mutations) since most other cases lack any skin fragility.