Inherited desmosomal diseases are characterised by skin and/or cardiac features. Dermatological features might be a clue in the determination of the underlying life-threatening cardiac disease. This article aims to propose a dermatological algorithm for the diagnosis of desmosomal diseases after a systematic review of published articles. Palmoplantar keratoderma (PPK), hair shaft anomalies and skin fragility are the major features in the 458 patients analysed. Isolated PPK or isolated hair shaft anomalies are associated with a desmosomal disease limited to skin. The combination of PPK and hair shaft anomalies was recorded in 161 patients, and this association is at high risk of cardiac disease (129/161, 80.1%). Skin features had led to cardiac monitoring in only 2.3% of those patients. We delineated three major phenotypes: the PPK–hair shaft anomalies–non-fragile skin subtype (77%), always associated with cardiac involvement; the PPK–hair shaft anomalies–skin fragility–normal cardiac function subtype (19.9%), frequently associated with PKP1 mutations; the PPK–hair shaft anomalies–skin fragility–cardiac involvement subtype (3.1%), always due to DSP mutations. Three mutation hotspots in DSP and JUP account for 90.8% of the patients with cardiac involvement. The combination of PPK and hair shaft anomalies justifies long-term cardiac monitoring.
- Palmoplantar Keratoderma
- Hair Shaft anomalies
- Arrhythmogenic cardiomyopathy/dysplasia
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- Palmoplantar Keratoderma
- Hair Shaft anomalies
- Arrhythmogenic cardiomyopathy/dysplasia
Desmosomes are intercellular junctions providing strong adhesion between cells by anchoring intermediate filaments to the plasma membrane. They are abundant in the heart and epidermis. Desmosomes play an important role in maintaining the integrity of these tissues and in signal transduction pathways.1 ,2 The desmosomal complex scaffolding includes armadillo proteins plakoglobin (PG) and plakophilins (PKP, isoforms 1 and 2), cadherins desmocollin (DSC, isoforms 1–3) and desmoglein (DSG, isoforms 1–4), and plakins desmoplakin (DSP).3 Corneodesmosin (CDSN), a component of corneodesmosome, is involved in the cohesion of corneocytes. All these proteins are present in the epidermis while five participate in the cardiomyocyte desmosomes: PKP2, DSP, PG, DSC2 and DSG2.
Since the first identification of PKP1 mutation, several cases of desmosomal genodermatoses have been reported.4 Autosomal dominant or recessive mutations in one of the genes encoding for a desmosomal protein may cause dermatological and/or cardiac abnormalities.5 ,6
Disease severity is related to cardiac involvement corresponding to an arrhythmogenic cardiomyopathy. Arrhythmogenic cardiomyopathy is a progressive genetic cardiomyopathy characterised by myocyte degeneration followed by a fatty and fibrous replacement of the ventricular myocardium. Depending on the more involved ventricle, three arrhythmogenic cardiomyopathy subtypes are described: classic right dominant, left dominant and biventricular. The first clinical presentation of each of these subtypes is an episode of arrhythmia.7
Dermatological features are a clue for the clinical and molecular diagnosis of desmosomal diseases. They justify cardiac investigations and follow-up. Palmoplantar keratoderma (PPK) is easily recognisable while skin fragility, and hair and nail anomalies might be hardly perceptible.8
We conducted a systematic review of the published data in order to propose a clinical and molecular algorithm for the diagnosis of desmosomal diseases with dermatological features.
Materials and methods
A systematic MEDLINE search, using Medical Subject Heading terms, covered 1995 through March 2015. The following terms were used in association with ‘mutations’: ‘plakoglobin’; ‘Naxos disease’, ‘plakophilin’, ‘desmoplakin’; ‘desmoglein’; ‘desmocollin’; ‘corneodesmosin’. Full text articles were systematically read. References quoted in the articles were checked. Articles were retained based on the following criteria: (1) at least one identified mutation in the following genes: JUP (junctional plakoglobin), PKP1, PKP2, DSP, DSG1 to 4, DSC1–3 and CDSN; (2) description of the cutaneous phenotype. Articles focusing on extracutaneous manifestations and/or cardiac involvement only were excluded. Redundant articles were excluded (figure 1). Data were extracted from each article and recorded in standardised form focusing on gender, age, dermatological, cardiac and other manifestations. Family history, mutation(s), mode of inheritance, ethnic background, epidemiological and clinical data were recorded. All the available pictures were carefully analysed in order to improve the description of dermatological manifestations. Sequence variations were checked and actualised using ENSEMBL software.
A total of 78 articles were retained. They reported 458 patients carrying at least one mutation in one of the epidermal desmosomal genes. For one family, the total of affected members was not specified.9 Among the 458 patients, 161 had the combination of PPK and hair shaft anomalies (ie, woolly and/or sparse and/or short hair or congenital atrichia). Among those 161, 129 had cardiac involvement, including 63 patients (48.8%) who experienced clinical manifestations, that is, syncope, stroke, heart failure, arrhythmias or sudden death, before cardiac disease diagnosis. For three patients only (2.3%), the initial detection of dermatological features had led to cardiac explorations. For the 63 remaining patients, the information was not available. Results were gathered according to the disease-causing gene (see online supplementary tables S1–S6).
Within the 305 ‘plakoglobin mutations’ and 92 ‘Naxos disease’ references, eight were retained (see online supplementary table S1). They correspond to 82 patients, all carrying a recessive JUP mutation. Male-to-female ratio was 1.07 for the 68.3% of patients for whom the information was available. Among them, 74 patients carry the Naxos homozygous deletion (c.2157del2, exon 14).10–14 The Naxos phenotype is characterised by diffuse PPK, woolly hair and classic right dominant arrhythmogenic cardiomyopathy in all reported patients. Two Turkish related patients carried a homozygous missense mutation (c.794G>A, exon 4).15 Their phenotype was close to Naxos syndrome and characterised by the association of cardiomyopathy (classic right dominant arrhythmogenic cardiomyopathy), alopecia (atrichia) and PPK (CAPK syndrome). In patients with Naxos and CAPK syndromes, symptomatic cardiac involvement started during the second decade (13–43 years).12–15
Five patients, aged 6 months to 14 years, presented with the association of skin fragility, woolly hair, diffuse PPK and normal cardiac function. For them, the repeated cardiac monitoring (echocardiography and 12-lead ECG) was reported as normal at the time of publication. Two different homozygous mutations were found: c.71C>A (exon 2) and c.468G>A (exon 3).16 In patients with JUP mutation, the woolly hair appears from birth, whereas PPK develops later after the first year of life.
The last female patient presented with lethal congenital generalised epidermolysis bullosa and complete absence of scalp hair at birth. She died at 12 days of life, and carried a homozygous nonsense mutation (c.1615C>T; exon 9).17
Among the 311 ‘desmoplakin mutations’ references, 27 were retained (see online supplementary table S2). A total of 93 patients carrying either an autosomal dominant or recessive mutation in DSP were found. Male-to-female ratio was 0.96 for the 96.8% of patients for whom the information was available.
Two autosomal dominant (39 cases) and four autosomal recessive (54 cases) cutaneous syndromes were described. Two large families with a striate PPK, characterised by linear and focal hyperkeratosis of the palms and soles, were reported. The three patients of the first family carried a heterozygous splice site mutation (c.939+1G>A, intron 7), while the 27 patients of the second family carried the heterozygous nonsense mutation (p.Q331X, exon 8).18 ,19
The first autosomal recessive syndrome related to DSP mutations is known as Carvajal syndrome. Thirty-seven patients carrying either a homozygous or a compound heterozygous mutation in DSP were identified. All the mutations were located in exon 23 or 24, except for one compound heterozygous patient who carried mutations in exons 9 and 16.20–29 The Carvajal phenotype is similar to Naxos disease: striate or focal PPK, woolly ± sparse hair and arrhythmogenic cardiomyopathy involving more frequently the left ventricle (left dominant arrhythmogenic cardiomyopathy).7 The median age of the first cardiac manifestation was 8 years (3–35). One 6-year-old boy had normal cardiac ultrasound at the time of publication.29
Nine patients presented with PPK, woolly and/or sparse hair, left dominant arrhythmogenic cardiomyopathy associated with oligodontia for eight and leukonychia or nail dystrophy in four of them. All of them carried a heterozygous DSP mutation in exon 13 (one mutation) or 14 (three mutations). The median age of the first cardiac symptom was 12 years (7–14).30–33
Three additional autosomal recessive syndromes, related to DSP mutations sharing the skin fragility feature, were reported in a total of 17 patients: (1) five patients carrying heterozygous compound mutations, with at least one of the mutation located in exon 23 or 24, presented with the combination of Carvajal syndrome, skin fragility ± ectodermal dysplasia features. Four of the five patients presented with nail dystrophy. The first cardiac symptom occurred early at the median age of 35 months (1–14 years). Blisters or erosions occurred spontaneously or after very mild trauma.34–38 (2) Eight patients presented with skin fragility associated with woolly hair. All the patients had nail dystrophy. Cardiac function was normal. At the time of publication, one 4½-year-old boy had normal cardiac monitoring, including ECG and echocardiography.39 One 14-year-old female patient with her four relatives, aged 3–16 years, had normal clinical cardiac examination at the time of publication, but three of them refused cardiac monitoring.40 For the two other patients, age and type of cardiac exploration were not specified.41 In patients with DSP mutation, the woolly hair appears from birth, whereas PPK develops after the first year of life. (3) The four last compound heterozygous patients died during their first month of life. They presented with lethal acantholytic epidermolysis bullosa, associated with alopecia and anonychia. Ultrasound showed cardiac hypocontractility in one patient only. For these three autosomal recessive syndromes, skin fragility was noticed at birth, or soon after, except for one patient for whom skin fragility started at 2 years.42–44
Among the 159 ‘plakophilin mutations’ references, 12 were retained (see online supplementary table S3). Nineteen patients carrying a homozygous or a heterozygous compound mutation were published. Male-to-female ratio was 1.83 for the 88.9% of patients for whom the information was available.
The corresponding McGrath syndrome, or ectodermal dysplasia/skin fragility syndrome, is characterised by the association of skin fragility, sparse and short hair, PPK and nail dystrophy. Cheilitis and/or perioral fissuring or redness, reported in at least 11 patients, are considered as a discriminative clinical feature. Cardiac function is normal. Five patients (26.3%) presented with reduced sweating and six with normal sweating. Information was not available for the last eight patients. Skin fragility started at birth or soon after, except for one patient for whom it started at 18 years.4 ,35 ,45–54
DSG1 and DSG4 mutations
Among the 201 ‘desmoglein mutations’ references, 21 were retained. Eleven articles correspond to DSG1 and 10 to DSG4 mutation (see online supplementary table S4).
Ninety-three patients had a heterozygous or homozygous mutation in DSG1. Male-to-female ratio was 0.96 for 94.6% of the patients for whom the information was available. DSG1 mutations are associated with autosomal dominant striate PPK and with autosomal recessive skin dermatitis, multiple allergies and metabolic wasting syndrome, or SAM syndrome. Eighty-six patients presented with isolated PPK; among them, 69 had striate PPK, and four had diffuse PPK. Information was not available for the 13 remaining patients. Seventeen different heterozygous mutations were reported.55–63 Seven patients belonging to three unrelated families carry three different homozygous DSG1 mutations. They presented with the association of congenital erythroderma, hypotrichosis or curly hair, striate PPK (for at least three of them), severe food allergy, high level of IgE and recurrent infections with severe metabolic wasting (for six of them). One patient presented with ventricular septal defect. The six remaining patients had no cardiac manifestation.64 ,65
Sixty-six patients had a recessive mutation in DSG4. Male-to-female ratio was 1.03 for 98.5% of the patients for whom the information was available. Two phenotypes are associated with recessive DSG4 mutations: localised autosomal recessive hypotrichosis (LAH)66–70 and monilethrix.71–75 In LAH, hypotrichosis affects the hair of the scalp, trunk and extremities, and spares facial, pubic and axillary regions. An in-frame intragenic homozygous deletion (Ex5_8del) was reported in 34 of the 41 patients with LAH. Two other homozygous mutations were identified (c.GG384–385TT and c.87delG). Monilethrix, reported in 25 patients, is characterised by periodic beaded hair shafts and pronounced hair fragility leading to hair loss. In these two diseases, manifestations started at birth or during the first month of life.
DSC2 and DSC3 mutations
Among the 102 ‘desmocollin mutations’, two articles, corresponding to six patients, were retained (see online supplementary table S5). While recessive mutations in DSC2 are known to cause isolated arrhythmogenic cardiomyopathy, two related patients presented with the combination of left cardiac involvement, woolly hair and mild PPK. Both carry a DSC2 homozygous mutation (c.1841delG, exon 12).76 Hypotrichosis, the only phenotype related to DSC3 mutations, is reported in four patients of the same Afghan family. They carry a homozygous mutation (c.2129T>G, exon 14). They presented with sparse and fragile whole body hair.77
Within the 31 ‘corneodesmosin mutations’ references, nine were retained (see online supplementary table S6). Mutations in CDSN are associated with hypotrichosis simplex of the scalp (HSS) and peeling skin syndrome type B (PSS). At least, 99 patients carried a mutation in CDSN. The total of affected relatives was not specified for one Danish family with HSS.9 Male-to-female ratio was 1.28 for 97% of the patients for which the information was available.
HSS is characterised by diffuse progressive scalp hair loss from childhood to adulthood. So far, more than 88 patients belonging to five HSS families have been reported. Four different heterozygous mutations in the exon 2 were identified.9 ,78 ,79 PSS is characterised by an inflammatory lifelong peeling of the stratum corneum on the whole body. Eleven patients with PSS were reported. The inflammatory exfoliation started at birth or during the first week of life (nine patients) or at 3 years (one patient). Information was not available for the last patient. To date, food allergies and a high level of IgE are reported. Six different homozygous mutations in exon 2 of CDSN were identified.80–85
Skin fragility, hair shaft anomalies and PPK are the main dermatological features of cutaneous desmosomal diseases. We propose a flow chart to detect the patient at risk of sudden death due to cardiac involvement and a strategy of gene sequencing (figure 2).
While isolated PPK or isolated hair shaft anomalies are associated with a desmosomal disease limited to skin, their combination is associated with classic right dominant (JUP mutations) or left dominant (DSP and DSC2 mutations) arrhythmogenic cardiomyopathy in 80.1% (129) of the 161 reported patients with such association (PPK–hair shaft anomalies). In all the 129 reported patients, dermatological features occurred before cardiac manifestations, that is, hair shaft anomalies since birth and PPK after 1 year. For the earliest case, cardiac involvement is reported during the first year of life. Interestingly, the detection of skin features led to cardiac disease diagnosis by systematic monitoring in only 2.3% of the patients with PPK–hair shaft anomalies.33 ,37 Therefore, regular cardiac monitoring is mandatory in all patients presenting with PPK–hair shaft anomalies, even in the absence of clinical cardiac manifestations. Importantly, 11.8% (19) of the remaining patients with PPK–hair shaft anomalies carried mutations in PKP1, which is not expressed in the cardiac desmosome. Finally, only 8.1% (13) patients with PPK–hair shaft anomalies, due to a recessive mutation in JUP (5) or DSP (8), were reported with normal cardiac function. Considering their median age at the time of publication (4 years (6 months to 17 years)), late cardiac involvement is not excluded.16 ,39–41
The clinical diagnosis of the third dermatological feature, known as ‘skin fragility’, might be challenging. The skin fragility spectrum ranges from easy recognisable blisters to superficial linear erosions accompanying scratching. Taking skin fragility into account, three major clinical subtypes might be individualised:
The PPK–hair shaft anomalies–non-fragile skin subtype, reported in 77% (124/161) of the patients, was always associated with arrhythmogenic cardiomyopathy. Recessive mutations of JUP, DSP and DSC2 were found in all but nine patients (7.3%) who carried a heterozygous mutation of DSP.
The PPK–hair shaft anomalies–skin fragility–cardiac involvement subtype is reported in 3.1% (5/161) of the patients or 13.5% (5/37) of the patients with skin fragility. For them, homozygous or compound heterozygous mutations of DSP were always identified.
The PPK–hair shaft anomalies–skin fragility–normal cardiac function subtype, reported in 19.9% (32/161) of the patients, might be divided into patients carrying recessive PKP1 mutations and patients carrying recessive JUP or DSP mutations. For the former, considering PKP1 tissue expression, cardiac follow-up is not required. For the latter, additional data are mandatory in order to exclude late cardiac involvement during adulthood.
Two additional severe diseases are associated with desmosomal gene mutations. Lethal epidermolysis bullosa, reported in five patients, associates epidermal detachment to ectodermal dysplasia features. The major concerns are early medical care requiring neonatal intensive care unit and positive diagnosis. Erythroderma seems to be constant in the seven patients with SAM syndrome.
Dominant or recessive mutations of JUP or DSP were identified in 87% (140) of the 161 patients with PPK–hair shaft anomalies. The ratio reached 98.4% (127/129) in case of cardiac involvement. In this group, the Naxos deletion (c.2157del2, exon 14) accounts for 97.4% (74/76) of the patients with JUP. Mutations in the long exons 23 and/or 24 accounted for 83.5% of the patients with DSP with PPK–hair shaft anomalies. These three mutation hotspots, accounting for 90.8%, of PPK–hair shaft anomalies with cardiac involvement cases might be sequenced first in this situation. Cardiac involvement occurring during the first 5 years of life suggested recessive DSP mutations. In case of normal cardiac function, identification of a recessive PKP1 mutation leads to stoppage of cardiac monitoring. Identification of a recessive mutation of JUP or DSP justifies cardiac monitoring throughout life.
Oligodontia and onychodystrophy were reported in at least 24.8% (40/161) of patients with PPK–hair shaft anomalies. With hair shaft anomalies, they represented the major features of ectodermal dysplasias. Unfortunately, nail, tooth and sweating anomalies were not detailed. Additional data might help to refine the phenotype-to-genotype correlation and to classify desmosomal skin disorders in the group of ectodermal dysplasias.
Finally, considering this extensive review of publications on desmosomal diseases, the combination of PPK and hair shaft anomalies justify long-term cardiac monitoring. This monitoring might be stopped in the situation of the identification of PKP1 gene mutation only.
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- Data supplement 1 - Online tables
Contributors SH-R designed the work. LP collected the data. SH-R and LP analysed the data and wrote the manuscript. CB participated in the critical revision of the manuscript for important intellectual content. All the authors agreed with the integrity of any part of the work.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
Data sharing statement All the data we collected were reported in the original article or in the online supplementary data section. We are available to answer any question.