U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma.

BACKGROUND: Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB-IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments. OBJECTIVES: To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect. METHODS: Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature. RESULTS: The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting. CONCLUSION: Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose.

Malignant melanoma arising in a nevus spilus.

Malignant melanoma arising within a nevus spilus is rare. Nevus spilus is characterized by darkly pigmented macules and papules with background hyperpigmention. We report a 65-year-old woman who presented with a melanoma arising in a nevus spilus that had been present since birth.

Primary biliary cirrhosis associated pustular vasculitis.

The association between primary biliary cirrhosis (PBC) and cutaneous vasculitides is well recognized. Pustular skin lesions though, have been described in association with hepatobiliary diseases other than PBC. Once the more common infective pustular rashes have been excluded, the differential diagnoses for a pustular skin rash are acute generalized exanthematous pustulosis (AGEP), Sweet's Syndrome (SS), pyoderma gangrenosum (PG) and pustular vasculitis(PV). We present a case of pustular vasculitis associated with PBC.

Photosensitive Smith-Lemli-Opitz syndrome is not caused by a single gene mutation: analysis of the gene encoding 7-dehydrocholesterol reductase in five U.K. families.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive malformation syndrome characterized by a disorder in cholesterol metabolism. SLOS is caused by mutations in the DHCR7 gene which encodes 7-dehydrocholesterol reductase, an enzyme that catalyses the final step in cholesterol biosynthesis. We have previously established the clinical and photobiological features of the photosensitivity that is frequently a feature of SLOS. OBJECTIVES: In this study, we have performed mutational analysis of the DHCR7 gene in individuals from five families with SLOS. In each family, one member was affected by severe photosensitivity as a manifestation of SLOS. METHODS: Fifteen samples (including family controls) were screened using polymerase chain reaction amplification and direct automated sequencing. RESULTS: Six different DHCR7 mutations were identified of which five were single point mutations that caused missense amino acid substitutions (P51H, T93M, L99P, E448K and R450L). The other was a splice site mutation (G-->C in splice acceptor site) affecting the intron 8-exon 9 splice junction (IVS8-1 G-->C). This splice site mutation and four of the five missense mutations have been previously published as causal in SLOS but the P51H is a novel mutation which has not previously been reported. CONCLUSIONS: This is the first study in which DHCR7 gene mutational analysis has been performed on SLOS subjects with severe photosensitivity and indicates that no single mutation is responsible for the photosensitivity which characterizes this disorder.

Squamous cell carcinoma arising in a psoriatic nail bed: case report with discussion of diagnostic difficulties and therapeutic options.

We describe a squamous cell carcinoma arising from a psoriatic nail bed. The tumour had a verrucous surface and was very well differentiated, raising the possibility of early verrucous carcinoma. Occurrence of any type of squamous carcinoma in this site and background is extremely rare. Particular diagnostic and therapeutic questions arise in this unusual setting. We discuss the aetiology and diagnostic differentiation from other nail bed squamoproliferative lesions, particularly so-called subungual keratoacanthoma. We also discuss therapeutic options, including Moh's surgery and retinoids.

Cholesterol supplementation objectively reduces photosensitivity in the Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz (SLO) affected children have multiple congenital physical and mental abnormalities; photosensitivity to ultraviolet A (UVA) has recently become a recognized feature. We present a patient with SLO and prominent photosensitivity in whom detailed phototesting has been performed at baseline and following 6 months of cholesterol supplementation. There was significant improvement in the symptoms of photosensitivity, confirmed objectively by phototesting and accompanied by partial correction of the biochemical abnormalities seen in SLO. This case report is the first to show that cholesterol supplementation in SLO can lead to an objective improvement in the associated photosensitivity.

Reduction in 8-methoxypsoralen immersion time alters the erythemal response to bath PUVA.

Topical psoralen plus ultraviolet A (PUVA) using 8-methoxypsoralen (8-MOP) bath solution is a well established and effective treatment in dermatology. The standard immersion time in the UK is 15 min, but a shorter bathing period could potentially increase treatment convenience. In order to examine the effect of reduction in immersion time on skin phototoxicity, we compared the erythemal response to UVA following 5 min and 15 min psoralen baths. The study was performed on the forearm skin of 7 healthy volunteers using an 8-MOP psoralen concentration of 2.6 mg/l. One forearm of each volunteer was soaked for 15 min and the other for 5 min, followed by immediate irradiation with a series of 10 doses of broadband UVA ranging from 0.1 J/cm2 to 6.9 J/cm2. At 72 h, the minimal phototoxic doses (MPDs) were noted and erythema readings (erythema index) were taken in triplicate with a reflectance instrument. The median MPD following 5 min immersion was 1.7 (range 0.7-2.7) J/cm2 compared with 1.0 (range 0.4-1.7) J/cm2 after 15 min treatment, with no significant difference. However, the mean slope of erythema dose-response on the 15-min treated side was significantly steeper than on the 5-min treated side, 0.036 and 0.021 respectively, P < 0.05. Hence, this preliminary work shows that reducing 8-MOP immersion time to 5 min reduces the erythemal response to UVA. It will clearly be necessary to examine the effect of a shortened immersion period on disease clearance before considering such a change to the topical PUVA regime.

Sunscreen application technique in photosensitive patients: a quantitative assessment of the effect of education.

Photosensitive patients are known to apply insufficient sunscreen and to neglect several prominently exposed skin sites. The aim of this study was to use fluorescence spectroscopy to assess the effect of education on sunscreen application technique in the short and longer term. Six patients with longstanding photosensitivity conditions were asked to apply an intrinsically fluorescent sunscreen to exposed skin, as they normally would on a sunny day. Detailed fluorescence measurements were taken from 70 sites on the head, neck and arms. Using the previously established dose-response relationship for cream fluorescence, measurements were converted to equivalent thicknesses of cream. Patients were told the results of their sunscreen application assessment and deficiencies in technique were highlighted. Following education, application technique was reassessed twice, after intervals of 2 weeks and 6 months. Before education, sunscreen application was poor with inadequate amounts applied, and prominently exposed sites including ears, temples and neck often missed. At 2 weeks following education, improved application was seen at all sites, and the improvement was sustained at 6 months. Overall, education improved sunscreen application from a baseline median sunscreen thickness of 0.11 mg/cm2 to 0.82 mg/cm2 at 2 weeks and 1.13 mg/cm2 at 6 months (P<0.0001). Notably, median sunscreen thickness on the face improved from a baseline of 0.33 mg/cm2 to 1.51 mg/cm2 at 6 months. These findings demonstrate the importance of careful instruction to patients concerning sunscreen application technique; failure to do this may result in overconfidence in the ability of a sunscreen to protect. The next step is to assess a larger number of photosensitive patients with different diagnoses and to see whether improved technique correlates with improvement in clinical features.

Chronic lymphoedema and angiosarcoma.

Angiosarcoma has frequently been described arising within chronic lymphoedema of the upper limb following mastectomy and radiotherapy for carcinoma of the breast. We report a case of angiosarcoma arising in a lymphoedematous leg that had been subjected to radiotherapy 20 years previously for Hodgkin's disease. The diagnosis was expedited once the patient noticed the development of bleeding nodules. Prognosis of angiosarcoma is poor with treatment options being wide-excision surgery, palliative radiotherapy or chemotherapy. Unusual bruised areas or bleeding nodules developing within chronic lymphoedematous limbs should be biopsied to exclude the diagnosis.