Mark J. Eliason

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

First-in-human Mutation-targeted siRNA Phase Ib Trial of an Inherited Skin Disorder

The rare skin disorder pachyonychia congenita (PC) is an autosomal dominant syndrome that includes a disabling plantar keratoderma for which no satisfactory treatment is currently available. We have completed a phase Ib clinical trial for treatment of PC utilizing the first short-interfering RNA (siRNA)-based therapeutic for skin. This siRNA, called TD101, specifically and potently targets the keratin 6a (K6a) N171K mutant mRNA without affecting wild-type K6a mRNA. The safety and efficacy of TD101 was tested in a single-patient 17-week, prospective, double-blind, split-body, vehicle-controlled, dose-escalation trial. Randomly assigned solutions of TD101 or vehicle control were injected in symmetric plantar calluses on opposite feet. No adverse events occurred during the trial or in the 3-month washout period. Subjective patient assessment and physician clinical efficacy measures revealed regression of callus on the siRNA-treated, but not on the vehicle-treated foot. This trial represents the first time that siRNA has been used in a clinical setting to target a mutant gene or a genetic disorder, and the first use of siRNA in human skin. The callus regression seen on the patients siRNA-treated foot appears sufficiently promising to warrant additional studies of siRNA in this and other dominant-negative skin diseases.

The Phenotypic and Molecular Genetic Features of Pachyonychia Congenita

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis caused by heterozygous mutations in any one of the genes encoding the differentiation-specific keratins K6a, K6b, K16, or K17. The main clinical features of the condition include painful and highly debilitating plantar keratoderma, hypertrophic nail dystrophy, oral leukokeratosis, and a variety of epidermal cysts. Although the condition has previously been subdivided into PC-1 and PC-2 subtypes, the phenotypic characterization of 1,000 mutation-verified PC patients enrolled in the International PC Research Registry, coordinated by the patient advocacy group PC Project, shows that there is considerable overlap between these subtypes. Thus, a new genotypic nomenclature is proposed, in which PC-6a represents a patient carrying a mutation in the K6a gene, etc. Although a rare disorder, PC represents a good model for therapy development, and international efforts are ongoing to develop and deliver siRNA, gene, correction, small molecule, and other strategies to treat this painful, disabling skin condition. The special relationship between PC Project and the PC research community has greatly accelerated the development pathway from gene identification to clinical trials in only a few years and represents a paradigm of hope for other orphan diseases.

A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita

BACKGROUND Pachyonychia congenita (PC) is a group of autosomal dominant keratinizing disorders caused by a mutation in one of 4 keratin genes. Previous classification schemes have relied on data from case series and case reports. Most patients in these reports were not genetically tested for PC. OBJECTIVE We sought to clarify the prevalence of clinical features associated with PC. METHODS We surveyed 254 individuals with confirmed keratin mutations regarding their experience with clinical findings associated with PC. Statistical comparison of the groups by keratin mutation was performed using logistic regression analysis. RESULTS Although the onset of clinical symptoms varied considerably among our patients, a diagnostic triad of toenail thickening, plantar keratoderma, and plantar pain was reported by 97% of patients with PC by age 10 years. Plantar pain had the most profound impact on quality of life. Other clinical findings reported by our patients included fingernail dystrophy, oral leukokeratosis, palmar keratoderma, follicular hyperkeratosis, hyperhidrosis, cysts, hoarseness, and natal teeth. We observed a higher likelihood of oral leukokeratosis in individuals harboring KRT6A mutations, and a strong association of natal teeth and cysts in carriers of a KRT17 mutation. Most keratin subgroups expressed a mixed constellation of findings historically reported as PC-1 and PC-2. LIMITATIONS Data were obtained through questionnaires, not by direct examination. Patients were self- or physician-referred. CONCLUSIONS We propose a new classification for PC based on the specific keratin gene affected to help clinicians improve their diagnostic and prognostic accuracy, correct spurious associations, and improve therapeutic development.

Treatment of refractory chronic urticaria with tumor necrosis factor–alfa inhibitors

To the Editor: Chronic urticaria is a physically and emotionally debilitating condition that often fails to respond adequately to antihistamines. Systemic therapy with glucocorticoids, sulfasalazine, colchicine, intravenous immunoglobulin, dapsone, or other immunosuppressants including cyclosporine, cyclophosphamide, and methotrexate are used in many patients with the associated risks of renal and hepatic toxicity and anemia. Unfortunately, some patients have disease recalcitrant to these treatments. The pathogenic mechanisms of chronic urticaria are not well understood, but the primary effector cell is likely the mast cell. Activated mast cells release mediators, including tumor necrosis factorealfa (TNF-a), that recruit other immune cells and play a role in perpetuating an urticarial response. TNF-a is known to exist preformed in mast cells and to be newly synthesized upon mast cell activation. Several preclinical investigations have shown an upregulation of TNF-a in patients with chronic urticaria. Magerl et al described a patient with severe psoriasis and delayed pressure urticaria who became free of urticarial lesions after 4 days of treatment with etanercept. Based on these preclinical investigations and the case report, we treated six of our most refractory chronic urticaria patients with TNF-a inhibitors. The choice of TNF-awas primarily based on the patient’s insurance and our experience using the medications. When possible, we used doses tested for other systemic inflammatory conditions, such as psoriasis. A brief summary of each patient’s background and treatment course is provided in Table I. The theoretical basis for the use of TNF-ae targeting therapy to treat urticaria is supported by studies that have shown the upregulation of TNF-a in chronic urticaria. In a study of 19 chronic urticaria patients and 15 healthy controls, cytokine and chemokine production after autologous serum skin testing was analyzed and TNF-a, interleukin (IL)-10, RANTES, and macrophage inflammatory protein1a were upregulated in chronic urticaria patients but not controls. In another study that compared levels of TNF-a in lesional and nonlesional skin of chronic urticaria patients, TNF-a was found to be expressed throughout the epidermis in lesional and nonlesional chronic urticaria skin but not in control skin. Furthermore, a study by Piconi et al revealed similar immunologic profiles in patients with chronic urticaria and with rheumatoid arthritis, psoriasis, and psoriatic arthritis, with increased expression of TNF-a and IL-10, and decreased expression of IL-2 and interferon gamma. Interestingly, these diseases, along with chronic urticaria, tend to worsen with infection. Perhaps a common linkmay be an aberrant response of innate immunity mediated through TNF-a expression. In our series of six patients who were recalcitrant to all other immunosuppressive therapies, we observed dramatic improvement with TNF-a inhibitors. In most cases, the improvement was durable, lasting for several years, and in three cases the patients were subsequently tapered off all systemic treatment and their urticaria remains in remission. These results suggest that targeted TNF-a therapy may be useful for disease refractory to conventional or immunosuppressive therapy. Larger, controlled studies with longer followeup periods are needed to further confirm the efficacy and safety of TNF-a inhibitors in the management of patients with chronic urticaria.

Dermatological medication effects on male fertility

Many drugs have been reported to impair semen parameters, leading to temporary or persistent infertility. Therefore, potential fathers may be concerned about the effect of medications on fertility. We searched the MEDLINE database of articles in English combining key terms including “male infertility,” “spermatogenesis,” “fertility,” “drug effects,” and “dermatology.” Administration of methotrexate and finasteride has resulted in severe oligospermia and reversible infertility. Ketoconazole has had negative effects on sperm motility and testosterone production. Few individual case reports and a limited number of studies have demonstrated negative effects of tetracyclines, erythromycin, chloroquine, glucocorticoids, spironolactone, and antihistamines on fertility. It is important to counsel male patients when appropriate about the reversible negative effect on fertility when taking methotrexate and finasteride, and the adverse effect of ketoconazole. Patients may be reassured that taking oral retinoids, cyclosporine, azathioprine, and tumor necrosis factor alpha inhibitors should not affect their fertility.

Patient Preferences During Skin Cancer Screening Examination

Discussion | This study provides a framework that facilitates meaningful clinical interpretation of the numerical mMASI score. The ranges for mMASI provided herein correspond to global levels of severity using the MSS. Such categorization in MSS levels can assist clinicians in interpreting clinical trial data, severity of disease, and response to treatment. The mMASI is a simple, reliable validated tool that is a modification of the most commonly used outcome measure for melasma. This user-friendly tool can now be correlated with the newly proposed clinical ranges of severity presented in the Figure, which can be used to assist researchers in determining entry criteria for clinical trains for melasma and improvement of melasma with treatment.

Paternal Germ Cell Mosaicism in Autosomal Dominant Pachyonychia Congenita

BACKGROUND Pachyonychia congenita (PC) is a genodermatosis caused by mutations in 1 of 4 known keratin genes, including KRT6A, KRT6B, KRT16, or KRT17. The most common mode of inheritance is autosomal dominant. Families with an affected parent are routinely counseled about the 50% transmission risk to each offspring. In some cases, families with a rare disorder like PC can initially present with an affected child while both parents are unaffected. This is usually the result of a spontaneous in utero mutation, and the risk of subsequent offspring being affected with the same condition is negligible (but may be increased above the general populations risk, although the exact risk is not currently known for PC). OBSERVATIONS We discuss a case of 2 affected children born to unaffected parents. We performed mutational analyses of all 4 individuals in the family on DNA extracted from lymphocytes. Owing to the unusual presentation of 2 affected siblings, we also extracted DNA from the fathers sperm cells for keratin gene mutational analysis. We describe the first case, to our knowledge, of germ cell mosaicism in PC. CONCLUSION Counseling of unaffected parents with a first child diagnosed as having PC should entail a discussion of the possibility of germ cell mosaicism contributing to an increased risk of having subsequent affected children.