P.J. Hampton

Laugier-Hunziker syndrome: an important differential diagnosis for Peutz-Jeghers syndrome

Laugier-Hunziker syndrome (LHS) is a rare sporadic disorder, which shares some dermatological features with Peutz-Jeghers syndrome (PJS). However, whereas PJS is associated with hamartomatous gastrointestinal polyposis and carries a high risk of malignancy justifying intensive screening protocols,1 LHS is known to be an entirely benign disease with no systemic manifestations, which requires patient reassurance as the only intervention.2 To highlight the importance of this differential diagnosis, we present the case of a 52 year old white man who was referred to our genetics department for advice in view of his diagnosis of PJS. His dentist had first noted the appearance of perioral and intraoral pigmentation in him at the age of 45 and he was normotensive and systemically well with no history of intermittent vomiting, abdominal pain, anaemia, or rectal bleeding. On the basis of the clinical features supported by a biopsy of one of the lesions seven years earlier a dermatological diagnosis of PJS had been made and he had been referred for gastrointestinal screening and surveillance. Over the past six years he had undergone regular oesophagogastroduodenoscopies and two yearly colonoscopies which had disclosed a hiatus hernia and mild diverticulosis but no polyps. Unfortunately, one of his colonoscopies had resulted in a colonic perforation. Nothing abnormal was detected on a barium follow through and blood tests including kidney, liver, and thyroid function tests, full blood count, and measurement of α-fetoprotein and carcinoembryonic antigen were also normal. The patient was referred to the genetics department with the aim of molecular confirmation of diagnosis. When his family history was ascertained the patient reported that his 79 year old mother had an isolated freckle on her lower lip which had remained unchanged since birth. She was otherwise well with no history of gastrointestinal problems. His father had died from bronchial …

Increased nuclear β-catenin in suprabasal involved psoriatic epidermis

Background  Psoriasis is a common inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation, increased angiogenesis and inflammation. There is evidence that some keratinocyte differentiation events are controlled by changes in cell–cell adhesion. β‐catenin is a 94‐kDa protein which has a dual function as a component of intercellular adherens junctions and also as a transcription factor as part of the Wnt signalling pathway. β‐catenin is not required for keratinocyte proliferation but has been shown to regulate keratinocyte stem cells and hair follicle morphogenesis.

Implication for photosensitive patients of ultraviolet A exposure in vehicles

Background  Photosensitive patients sometimes report disease flares during journeys by car. Window glass blocks all UVB but not all UVA. All car windscreens are made from laminated glass. Side and rear windows are usually made of nonlaminated glass.

A case of Schöpf-Schulz-Passarge syndrome

Schöpf–Schulz–Passarge syndrome (SSPS) is a rare ectodermal dysplasia characterized by hypodontia, hypotrichosis, nail dystrophy, palmoplantar keratoderma, and periocular and eyelid margin apocrine hidrocystomas. Several other skin tumours have been described in association with this syndrome, in particular, multiple palmoplantar eccrine syringofibroadenoma (ESFA). We report a case of SSPS with diffuse palmoplantar hyperkeratosis, which was shown by histology and immunocytochemistry to be due to ESFA.

Lithium regulates keratinocyte proliferation via glycogen synthase kinase 3 and NFAT2 (nuclear factor of activated T cells 2).

Certain environmental factors including drugs exacerbate or precipitate psoriasis. Lithium is the commonest cause of drug‐induced psoriasis but underlying mechanisms are currently unknown. Lithium inhibits glycogen synthase kinase 3 (GSK‐3). As lithium does not exacerbate other T‐cell‐mediated chronic inflammatory diseases, we investigated whether lithium may be acting directly on epidermal keratinocytes by inhibiting GSK‐3. We report that lithium‐induced keratinocyte proliferation at therapeutically relevant doses (1–2 mM) and increased the proportion of cells in S phase of the cell cycle. Inhibition of GSK‐3 in keratinocytes by retroviral transduction of GSK‐binding protein (an endogenous inhibitory protein) or through a highly selective pharmacological inhibitor also resulted in increased keratinocyte proliferation. Nuclear factor of activated T cells (NFAT) is an important substrate for GSK‐3 and for cyclosporin, an effective treatment for psoriasis that inhibits NFAT activation in keratinocytes as well as in lymphocytes. Both lithium and genetic/pharmacological inhibition of GSK‐3 resulted in increased nuclear localization of NFAT2 (NFATc1) and increased NFAT transcriptional activation. Finally, retroviral transduction of NFAT2 increased keratinocyte proliferation whereas siRNA‐mediated knockdown of NFAT2 reduced keratinocyte proliferation and decreased epidermal thickness in an organotypic skin equivalent model. Taken together, these data identify GSK‐3 and NFAT2 as key regulators of keratinocyte proliferation and as potential molecular targets relevant to lithium‐provoked psoriasis. J. Cell. Physiol. 227: 1529–1537, 2012.

Bullous pemphigoid triggered by swine flu vaccination: case report and review of vaccine triggered pemphigoid.

BACKGROUND Bullous pemphigoid (BP) is an acquired autoimmune blistering disease mainly affecting the elderly. Recent reports have shown an association with pre-existing neurodegenerative diseases. Triggers including diseases, medications and vaccination have been reported although in most patients no clear trigger is identified. MAIN OBSERVATIONS We report a case of atypical bullous pemphigoid which was strongly suspected to have been triggered by the swine flu vaccination. This is the first reported case of pemphigoid triggered by this vaccine. CONCLUSIONS The use of the swine flu vaccine is likely to increase in the future and it is important that clinicians are aware of the potential adverse effect of swine flu vaccination induced bullous pemphigoid.

Investigation of cutaneous photoadaptation to narrowband ultraviolet B

Photoadaptation describes the skins ability to withstand an increased dose of ultraviolet (UV) radiation with repeated exposure, and this is the reason for exposure doses being increased during a course of phototherapy. However, directly measured data on photoadaptation are available only for broadband (BB) and not narrowband (NB)‐UVB.

Calcineurin inhibitors for the treatment of skin disease: how do they work?

Calcineurin inhibitors have been used for the treatment of skin disease for over 20 years following the observation in 1979 that psoriasis severity improved in patients receiving cyclosporin [1]. Formal randomized trials confirmed this observation [2] and cyclosporin is widely used in psoriasis management today although duration of therapy is often limited by side-effects. Calcineurin antagonists which include cyclosporin, tacrolimus and ascomycins (e.g. pimecrolimus) act by inhibiting the activation of the nuclear factor for activated T cells (NFAT). The NFATs are a family of five transcription factors (NFAT1–5). NFAT 1–4 show sequence homology; NFAT5 is included in the family because of homology of the DNA binding domain but is not regulated by calcineurin and in many ways is quite distinctive. In contrast, NFATs 1–4 are regulated by calcium and the calcium/calmodulin dependent phosphatase calcineurin. Elevation of intracellular calcium activates calcineurin which dephosphorylates NFAT, revealing a nuclear import region, with resulting nuclear translocation. In the nucleus NFAT binds with other transcription factors, for example activated protein-1 or GATA, to induce gene transcription. The NFAT signalling pathway has been extensively characterized in T cells and the known target genes in T cells include IL-2, IL-3, IL-4, IL-10, IFN-g and granulocyte macrophage-colony stimulating factor [3]. Calcineurin inhibitors work by first binding to a cytoplasmic immunophilin protein; for example, cyclophilin for cyclosporin and FK506 binding protein 12 (FKBP12) for tacrolimus and ascomycin, respectively. The drug, immunophilin, calcineurin complex then inhibits calcineurin from activating NFAT [4]. The therapeutic effects of calcineurin inhibitors in skin disease were initially assumed to be acting via inhibition of T cell activation and proliferation. However, there is now firm evidence that the NFAT/calcineurin pathway is also active in other cells found in the skin and that calcineurin inhibitors exert therapeutic effects on a variety of non-immune cells. NFAT isoforms are present in keratinocytes and calcineurin has been shown to be functionally active in keratinocytes [5, 6]. Induction of NFAT1 nuclear translocation in keratinocytes is blocked by treatment with either cyclosporin or tacrolimus [6]. Psoriasis is now generally thought of as a disease characterized by abnormal sustained T cell activation that results in increased keratinocyte proliferation although the development of a psoriasis-like phenotype in mice transgenic for constitutively active stat3, suggests that the interplay between keratinocytes and T cells may be more complex [7]. Cyclosporin remains one of the most effective therapies for psoriasis and this may be in part because of a combined effect on NFAT signalling in both T cells and keratinocytes. Hailey–Hailey disease (familial benign pemphigus) is an autosomal dominant disorder characterized by faulty keratinocyte adhesion leading to recurrent vesicles and erosions affecting mainly but not exclusively flexural sites. The mutated gene is ATP2C1 which encodes a P-type Catransport adenosine triphosphatase [8]. Several case reports and case series have described improvement of Hailey–Hailey disease in response to both oral cyclosporin and topical tacrolimus [9, 10]. Although randomized controlled trial data are lacking, in part because of the rarity of this disorder, these reports suggest that cyclosporin and tacrolimus may be exerting a therapeutic effect on human epidermis, as T cells are not thought to be involved in pathogenesis of Hailey– Hailey disease. The importance of NFAT signalling in histamine release in basophils and mast cells has been established. For example, cross-linkage of the high-affinity receptor (FceRIa) for IgE results in nuclear translocation of NFAT in the rat basophilic leukamia (RBL-2H3) mast cell line and rat bone marrowderived mast cells [11]. Furthermore, calcineurin antagonists inhibit anti-IgE-induced histamine release from human basophils [12] and cyclosporin has been demonstrated by Grattan et al. [13] to be an effective treatment for chronic idiopathic urticaria. Chronic urticaria describes the occurrence of weals occurring at least twice a week for greater than 6 weeks. In approximately 40% of these patients circulating histaminereleasing auto-antibodies can be identified [14] and this subset of patients may also be identified by the autologous serum skin test which shows a reasonable degree of sensitivity and specificity. These auto-antibodies have been shown to be directed against the a-subunit of the high-affinity IgE receptor (FceRIa) found on basophils and mast cells and to a lesser extent IgE [15]. Binding of complement C5a to FceRIa can also induce histamine release [16]. The paper by Marsland et al. [17] published in this issue of Clinical & Experimental Allergy investigates further the mechanism of action of calcineurin inhibitors in patients with chronic autoimmune urticaria. Patients selected for study had chronic autoimmune urticaria as assessed by the ability of their serum to induce histamine release from human basophils. They demonstrated that therapeutically relevant concentrations of cyclosporin inhibited histamine release from basophils induced by patient’s serum. The authors went on to dissect the effect of cyclosporin on histamine release induced by IgG and C5A and showed that the predominant effect is on histamine release induced by IgG with no inhibition of histamine release induced by C5A. Similar effects were observed with ascomycin but no effects were seen with antihistamines or methotrexate. Clin Exp Allergy 2005; 35:549–550 doi:10.1111/j.1365-2222.2005.02255.x

A Case Of Strawberry Gingivitis

A 67-year-old man presented with a 3-month history of painful and swollen gums. No other symptoms were reported, and the patient was medically fit and well apart from hypertension and gastro-oesophageal reflux. On physical examination of the oral cavity, granular atypical lesions were seen, involving multiple gingival sites (Fig. 1). Routine blood tests were all normal, but anti-neutrophil cytoplasmic antibody (cANCA) was positive, at a titre of 80 U ⁄ mL. Computed tomography of the maxillary and sinonasal regions did not reveal any abnormalities. An incisional biopsy of the gingival tissues on the lower left quadrant was taken.

Treatment of mucous membrane pemphigoid with the combination of mycophenolate mofetil, dapsone, and prednisolone: a case series

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disorder characterized by inflammation, blistering, and scarring and predominantly occurring at mucous membranes. Successful treatment can be challenging, and uncontrolled disease may result in significant morbidity with scarring of the conjunctiva and oropharynx leading to blindness and dysphagia, respectively. We report safe successful treatment of 6 patients with significant MMP-related oral inflammation with the use of a previously unreported combination of mycophenolate mofetil, dapsone, and prednisolone given at relatively low doses. We propose that this combination of treatments should be investigated further.