Treatment of hereditary palmoplantar keratoderma: a review by analysis of the literature.

BACKGROUND: No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments. OBJECTIVES: To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK. METHODS: We undertook a comprehensive review of the literature data published since 2008. RESULTS: Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future. CONCLUSIONS: More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases.

Loss of the laminin subunit alpha-3 induces cell invasion and macrophage infiltration in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a common cancer that invades the dermis through the basement membrane. The role of the basement membrane in poorly differentiated cSCC is not well understood. OBJECTIVES: To study the effect that loss of the laminin subunit alpha-3 (α3) chain from the tumour microenvironment has on tumour invasion and inflammatory cell recruitment. METHODS: We examined the role of the basement membrane proteins laminin subunits α3, ß3 and γ2 in SCC invasion and inflammatory cell recruitment using immunohistochemistry, short hairpin RNA knockdown, RNA-Seq, mouse xenograft models and patient tumour samples. RESULTS: Analysis of SCC tumours and cell lines using antibodies specific to laminin chains α3, ß3 and γ2 identified a link between poorly differentiated SCC and reduced expression of laminin α3 but not the other laminin subunits investigated. Knockdown of laminin α3 increased tumour invasion both in vitro and in vivo. Western blot and immunohistochemical staining identified increased phosphorylated myosin light chain with loss of laminin α3. Inhibition of ROCK (rho-associated protein kinase) but not Rac1 significantly reduced the invasive potential of laminin α3 knockdown cells. Knockdown of laminin subunits α3 and γ2 increased monocyte recruitment to the tumour microenvironment. However, only the loss of laminin α3 correlated with increased tumour-associated macrophages both in xenografted tumours and in patient tumour samples. CONCLUSIONS: These data provide evidence that loss of the laminin α3 chain in cSCC has an effect on both the epithelial and immune components of cSCC, resulting in an aggressive tumour microenvironment.

Distinctive clinical and histological characteristics of atrophic and hypertrophic facial photoageing.

BACKGROUND: Photoageing describes complex cutaneous changes which occur following chronic exposure to solar ultraviolet radiation (UVR). Amongst White Northern Europeans, facial photoageing appears as distinct clinical phenotypes: 'hypertrophic' photoageing (HP) and 'atrophic' photoageing (AP). Deep, coarse wrinkles predominate in individuals with HP, whereas those with AP have relatively smooth, unwrinkled skin with pronounced telangiectasia. AP individuals have an increased propensity for developing keratinocyte cancers. OBJECTIVES: To investigate whether histological differences underlie these distinct phenotypes of facial photoageing. METHODS: Facial skin biopsies were obtained from participants with AP (10 M, 10 F; mean age: 78.7 years) or HP (10 M, 10 F; mean age: 74.5 years) and were assessed histologically and by immunohistochemistry. RESULTS: Demographic characterization revealed 95% of AP subjects, as compared to 35% with HP, were Fitzpatrick skin type I/II; of these, 50% had a history of one or more keratinocyte cancers. There was no history of keratinocyte cancers in the HP cohort. Analysis of UVR-induced mitochondrial DNA damage confirmed that all volunteers had received similar lifetime cumulative doses of sun exposure. Histologically, male AP had a significantly thicker epidermis than did AP females or those of either sex with HP. HP facial skin exhibited severe solar elastosis, whereas in AP facial skin, solar elastosis was apparent only in females. Loss of papillary dermal fibrillin-rich microfibrils occurred in all HP and AP female subjects, but not in AP males. Furthermore, male AP had a significant reduction in collagen VII at the dermal-epidermal junction than did AP females or those of either sex with HP. CONCLUSIONS: This study provides further evidence that AP and HP represent distinct clinical and histological entities. Knowledge of these two phenotypes is clinically relevant due to the increased prevalence of keratinocyte cancers in those - particularly males - with the AP phenotype.

Tape strips in dermatology research.

Tape strips have been used widely in dermatology research as a minimally invasive method to sample the epidermis, avoiding the need for skin biopsies. Most research has focused on epidermal pathology, such as atopic eczema, but there is increasing research into the use of tape strips in other dermatoses, such as skin cancer, and the microbiome. This review summarizes the technique of tape stripping, and discusses which dermatoses have been studied by tape stripping and alternative minimally invasive sampling methods. We review the number of tape strips needed from each patient and the components of the epidermis that can be obtained by tape stripping. With a focus on protein and RNA extraction, we address the techniques used to process tape strips. There is no optimal protocol to extract protein, as this depends on the abundance of the protein studied, its level of expression in the epidermis and its solubility. Many variables can alter the amount of protein obtained from tape strips, which must be standardized to ensure consistency between samples. No study has compared different RNA extraction techniques, but our own experience is that RNA yield is optimized by using 20 tape strips and the use of a cell scraper.

Severe skin reactions associated with cladribine in people with multiple sclerosis.

OBJECTIVE: To report three cases of severe skin reactions in patients treated with cladribine for multiple sclerosis. METHODS: Case study. RESULTS: Patients developed severe rash 3-192 days after receiving cladribine. All were effectively treated with steroids and antihistamines. Additional doses of cladribine were administered after pretreatment with steroids and anti-histamines. One patient developed mild recurrence following re-exposure, which resolved within three days, whilst another patient tolerated re-exposure without further adverse reaction. CONCLUSION: Severe skin reactions, well described in patients receiving cladribine for treatment of haematological conditions, may occur in patients treated with this compound for multiple sclerosis. Neurologists need to be aware of this rare, but significant adverse reaction. Re-exposure may be safe with standard pre-treatment against allergic reactions.

Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype.

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is an inherited, frequently underdiagnosed disorder, which can predispose individuals to sudden cardiac death. Rare, recessive forms of AC can be associated with woolly hair and palmoplantar keratoderma, but most autosomal dominant AC forms have been reported to be cardiac specific. Causative mutations frequently occur in desmosomal genes including desmoplakin (DSP). OBJECTIVES: In this study, we systematically investigated the presence of a skin and hair phenotype in heterozygous DSP mutation carriers with AC. METHODS: Six AC pedigrees with 38 carriers of a dominant loss-of-function (nonsense or frameshift) mutation in DSP were evaluated by detailed clinical examination (cardiac, hair and skin) and molecular phenotyping. RESULTS: All carriers with mutations affecting both major DSP isoforms (DSPI and II) were observed to have curly or wavy hair in the pedigrees examined, except for members of Family 6, where the position of the mutation only affected the cardiac-specific isoform DSPI. A mild palmoplantar keratoderma was also present in many carriers. Sanger sequencing of cDNA from nonlesional carrier skin suggested degradation of the mutant allele. Immunohistochemistry of patient skin demonstrated mislocalization of DSP and other junctional proteins (plakoglobin, connexin 43) in the basal epidermis. However, in Family 6, DSP localization was comparable with control skin. CONCLUSIONS: This study identifies a highly recognizable cutaneous phenotype associated with dominant loss-of-function DSPI/II mutations underlying AC. Increased awareness of this phenotype among healthcare workers could facilitate a timely diagnosis of AC in the absence of overt cardiac features.

Acral peeling skin syndrome associated with a novel CSTA gene mutation.

Acral peeling skin syndrome (APSS) is a rare autosomal recessive condition, characterized by asymptomatic peeling of the skin of the hands and feet, often linked to mutations in the gene TGM5. However, more recently recessive loss of function mutations in CSTA, encoding cystatin A, have been linked with APSS and exfoliative ichthyosis. We describe the clinical features in two sisters with APSS, associated with a novel large homozygous deletion encompassing exon 1 of CSTA.

Suppression of TGFß and Angiogenesis by Type VII Collagen in Cutaneous SCC.

BACKGROUND: Individuals with severe generalized recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering disorder caused by mutations in the COL7A1 gene, develop unexplained aggressive squamous cell carcinomas (SCC). Here we report that loss of type VII collagen (Col7) in SCC results in increased TGFß signaling and angiogenesis in vitro and in vivo. METHODS: Stable knockdown (KD) of Col7 was established using shRNA, and cells were used in a mouse xenograft model. Angiogenesis was assessed by immunohistochemistry, endothelial tube-forming assays, and proteome arrays. Mouse and zebrafish models were used to examine the effect of recombinant Col7 on angiogenesis. Findings were confirmed in anonymized, archival human tissue: RDEB SCC tumors, non-EB SCC tumors, RDEB skin, normal skin; and two human RDEB SCC cell lines. The TGFß pathway was examined using immunoblotting, immunohistochemistry, biochemical inhibition, and siRNA. All statistical tests were two-sided. RESULTS: Increased numbers of cross-cut blood vessels were observed in Col7 KD compared with control xenografts (n = 4 to 7 per group) and in RDEB tumors (n = 21) compared with sporadic SCC (n = 24, P < .001). Recombinant human Col7 reversed the increased SCC angiogenesis in Col7 KD xenografts in vivo (n = 7 per group, P = .04). Blocking the interaction between α2ß1 integrin and Col7 increased TGFB1 mRNA expression 1.8-fold and p-Smad2 levels two-fold. Increased TGFß signaling and VEGF expression were observed in Col7 KD xenografts (n = 4) compared with control (n = 4) and RDEB tumors (TGFß markers, n = 6; VEGF, n = 17) compared with sporadic SCC (TGFß markers, n = 6; VEGF, n = 21). Inhibition of TGFß receptor signaling using siRNA resulted in decreased endothelial cell tube formation (n = 9 per group, mean tubes per well siC = 63.6, SD = 17.1; mean tubes per well siTßRII = 29.7, SD = 6.1, P = .02). CONCLUSIONS: Type VII collagen suppresses TGFß signaling and angiogenesis in cutaneous SCC. Patients with RDEB SCC may benefit from anti-angiogenic therapy.

The molecular genetic analysis of the expanding pachyonychia congenita case collection.

BACKGROUND: Pachyonychia congenita (PC) is a rare autosomal dominant keratinizing disorder characterized by severe, painful, palmoplantar keratoderma and nail dystrophy, often accompanied by oral leucokeratosis, cysts and follicular keratosis. It is caused by mutations in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16 or KRT17. OBJECTIVES: To identify mutations in 84 new families with a clinical diagnosis of PC, recruited by the International Pachyonychia Congenita Research Registry during the last few years. METHODS: Genomic DNA isolated from saliva or peripheral blood leucocytes was amplified using primers specific for the PC-associated keratin genes and polymerase chain reaction products were directly sequenced. RESULTS: Mutations were identified in 84 families in the PC-associated keratin genes, comprising 46 distinct keratin mutations. Fourteen were previously unreported mutations, bringing the total number of different keratin mutations associated with PC to 105. CONCLUSIONS: By identifying mutations in KRT6A, KRT6B, KRT6C, KRT16 or KRT17, this study has confirmed, at the molecular level, the clinical diagnosis of PC in these families.

Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation.

Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer metastasis.

The receptor tyrosine kinase Axl regulates cell-cell adhesion and stemness in cutaneous squamous cell carcinoma.

Axl is a receptor tyrosine kinase (RTK) upregulated in various tumors including cutaneous squamous cell carcinoma (SCC). Axl expression correlates with poor prognosis and induction of epithelial-mesenchymal transition (EMT), hence we hypothesized that Axl is involved in the disruption of cell-cell adhesion to allow invasion and chemotherapy resistance of the cancer stem cell population. Cutaneous SCC cell lines with stable knockdown of Axl were generated using retroviral vectors. Axl depletion altered expression of intercellular junction molecules increasing cell-cell adhesion with downregulation of Wnt and TGFßR signaling. Furthermore, Axl expression correlated with the expression of putative cancer stem cell markers, CD44 and ALDH1, increased resistance to chemotherapy drugs, enhanced sphere formation ability and expression of EMT features by cancer stem cells. Axl depletion resulted in loss of tumor formation in an in vivo zebrafish xenograft model. In conclusion, these data suggest that abrogation of Axl results in loss of cancer stem cell properties indicating a role for Axl as a therapeutic target in chemotherapy-resistant cancer.

An unusual case of vulval papulonecrotic tuberculid.

The tuberculids are a group of rare cutaneous hypersensitivity reactions that occur in response to a distant focus of mycobacterial infection. Typically, Mantoux testing is strongly reactive, and clinical response to antituberculous treatment is rapid. The papulonecrotic subtype is one such clinical variant, consisting of multiple symmetrical papules, often with central necrosis, distributed preferentially over the trunk and limbs. Localized forms are rare, and mainly involve the genitalia in men. We describe a 26-year-old Indian woman with lymphatic and pulmonary tuberculosis (TB) in association with localized papulonecrotic tuberculid of the vulva, which resolved promptly on treating the underlying TB.