Genetic polymorphism in Methylenetetrahydrofolate Reductase chloride transport protein 6 (MTHFR CLCN6) gene is associated with keratinocyte skin cancer in a cohort of renal transplant recipients.

Background: Renal transplant recipients (RTRs) are at increased risk of keratinocyte cancer (KC), especially cutaneous squamous cell carcinoma (cSCC). Previous studies identified a genetic variant of the Methylenetetrahydrofolate Reductase (MTHFR) gene, C677T, which conferred a risk for diagnosis of cSCC in Irish RTRs. Objective: We sought to find further genetic variation in MTHFR and overlap genes that may be associated with a diagnosis of KC in RTRs. Methods: Genotyping of a combined RTR population (n = 821) from two centres, Ireland (n = 546) and the USA (n = 275), was performed. This included 290 RTRs with KC and 444 without. Eleven single nucleotide polymorphisms (SNPs) in the MTHFR gene and seven in the overlap gene MTHFR Chloride transport protein 6 (CLCN6) were evaluated and association explored by time to event analysis (from transplant to first KC) using Cox proportional hazards model. Results: Polymorphism at MTHFR CLCN6 (rs9651118) was significantly associated with KC in RTRs (HR 1.50, 95% CI 1.17-1.91, p < 0.00061) and cSCC (HR 1.63, 95% CI 1.14-2.34, p = 0.007). A separate SNP, MTHFR C677T, was also significantly associated with KC in the Irish population (HR 1.31, 95% CI 1.05-1.63, p = 0.016), but not American RTRs. Conclusions: We report the association of a SNP in the MTHFR overlap gene, CLCN6 and KC in a combined RTR population. While the exact function of CLCN6 is not known, it is proposed to be involved in folate availability. Future applications could include incorporation in a polygenic risk score for KC in RTRs to help identify those at increased risk beyond traditional risk factor assessment.

Atypical naevus spilus: detection by in vivo confocal microscopy.

Naevus spilus (NS) is a naevoid disorder characterized by hyperpigmented macules or papules scattered over a café-au-lait macule. Such café-au-lait macules are often present at birth, and the darker pigmented speckles of NS slowly increase in number and size over a period of several years. NS can therefore be difficult to evaluate clinically for the development of melanoma. In vivo confocal microscopy (IVCM) is a novel method that allows examination at cellular resolution of cutaneous lesions in vivo. IVCM has been shown to have twice the specificity of dermoscopy for the diagnosis of melanoma, with comparable sensitivity. It has been shown to be useful in the detection and grading of dysplastic naevi, which are recognized precursors of melanoma in some cases. In this report, we highlight that IVCM can also be used as a tool complementary to dermoscopy to identify areas of dynamic change in clinically and dermoscopically equivocal lesions. IVCM may thereby assist in the early detection of melanocytic atypia and melanoma arising in NS, in turn leading to excision of melanoma at an early stage, which is associated with a favourable outcome. We also outline some of the difficulties encountered in confocal microscopy and histology when differentiating melanoma from dysplastic naevi.

Aberrant DNA methylation associated with MTHFR C677T genetic polymorphism in cutaneous squamous cell carcinoma in renal transplant patients.

BACKGROUND: Changes in genomic DNA methylation associated with cancer include global DNA hypomethylation and gene-specific hyper- or hypomethylation. We have previously identified a genetic variant in the MTHFR gene involved in the methylation pathway which confers risk for the development of squamous cell carcinoma (SCC) in renal transplant patients. This genetic variant has also been discovered to confer SCC risk in nontransplant patients with low folate status. OBJECTIVES: To explore the methylation profile of SCC compared with adjacent non-neoplastic skin using pyrosequencing, and to elucidate whether the MTHFR polymorphism impacts upon the methylation patterns in SCC. METHODS: We used pyrosequencing to evaluate global (using long interspersed nuclear element 1) and gene-specific (p16 and MGMT) methylation status in 47 SCCs and 40 adjacent autologous non-neoplastic skin samples in those with (n = 16) and without (n = 17) the MTHFR polymorphism. RESULTS: Pyrosequencing methylation analysis revealed that SCC was hypomethylated compared with adjacent non-neoplastic skin (P < 0.04). Patients with the MTHFR polymorphism had higher levels of global methylation in tumours and non-neoplastic skin compared with those without the MTHFR polymorphism (P < 0.002). There was no association between levels of methylation in tumour and non-neoplastic skin for the genes MGMT and p16. CONCLUSIONS: Global hypomethylation appears to be a feature of SCC. Aberrant methylation of DNA appears related to polymorphisms of MTHFR. Such findings suggest that intervention in the form of demethylating agents or folate supplementation might be beneficial in the treatment or prevention of SCC.

Botulinum toxin for treatment of glandular hypersecretory disorders.

SUMMARY: The use of botulinum toxin to treat disorders of the salivary glands is increasing in popularity in recent years. Recent reports of the use of botulinum toxin in glandular hypersecretion suggest overall favourable results with minimal side-effects. However, few randomised clinical trials means that data are limited with respect to candidate suitability, treatment dosages, frequency and duration of treatment. We report a selection of such cases from our own department managed with botulinum toxin and review the current data on use of the toxin to treat salivary gland disorders such as Frey's syndrome, excessive salivation (sialorrhoea), focal and general hyperhidrosis, excessive lacrimation and chronic rhinitis.

Improved renal allograft survival with vitamin D receptor polymorphism.

BACKGROUND: Polymorphisms in genes, coding for proteins involved in immune response, or the pathogenesis of atherosclerosis may influence immunological and non-immunological mechanisms that lead to allograft loss. Vitamin D receptor (VDR) agonists reduce allograft rejection in animal models, and there are a number of functional polymorphisms in VDR. METHODS: In all, 379 renal transplant recipients were genotyped for VDR (FokI & ApaI) polymorphisms, and the association of each genotype with renal allograft survival and acute rejection was determined. RESULTS: There was significantly improved allograft survival for patients who were homozygous or heterozygous for the VDR FokI T allele (Hazard Ratio [HR] = 0.488, p < 0.001). CONCLUSION: The association of VDR FokI T allele with improved renal allograft survival is a unique observation. The finding is in keeping with data showing the prevention of chronic allograft rejection with the use of Vitamin D receptor agonists.

Anaphylactic reaction to intralesional corticosteroid injection.

We report the case of anaphylactic reaction to carboxymethylcellulose, a dispersant in corticosteroid preparation and contrast media. Skin prick testing in this patient revealed a positive response to carboxymethylcellulose at a dilution of 1/1000. Anaphylaxis secondary to carboxymethylcellulose has previously been reported. To avoid further problems, this patient was advised to alert medical staff for the presence of allergy to carboxymethylcellulose in the event of the need for further interventional procedures. Care should be taken when giving intradermal steroids to patients with a history of anaphylaxis after contrast media.

Malignant melanoma in transplant patients: review of five cases.

The characteristics of malignant melanoma arising in transplant patients are not clearly delineated. We describe clinical and histological features of malignant melanoma in five transplant patients. All transplant patients with melanoma arising post-transplantation had a previous history of skin cancer. Two had a history of internal organ malignancy. Three patients had thick malignant melanomas (Clark level III or higher, or >0.76 mm Breslow thickness). Lymph-node metastases occurred in one patient with cutaneous melanoma. Local cutaneous metastases occurred in one patient. Mean duration from transplantation to melanoma was 15.6 years. Two cases of aggressive metastatic melanoma responded well to cessation of immunosuppression. Three patients with nonmetastatic disease responded well to conventional complete excision and continuation of immunosuppression.

Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: I. Application of a new model for estimation of the risk of disease associated with the marker.

We have identified 2 sisters with probable dementia of the Alzheimer type who have an unusual 22-derived marker chromosome with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. A marker chromosome similar in appearance is uncommon in the general population. Eleven of 24 of their biological relatives were also found to have the marker. The known pedigree of this family encompasses 6 generations in 2 of which there is evidence of 10 cases of dementia of the Alzheimer type. The average age-at-onset of dementia is 65.8 +/- 5.5 years; the average age-at-death among those apparently affected is 74.9 +/- 8.3 years. A new model for the estimation of risk was applied to the family data. Persons in this family with the marker were found to be 4 times more likely to develop dementia than those without the marker, the 95% confidence interval for this risk being 1-50. The probability that the association of dementia and the marker is due to chance alone is .05 (1 in 20).