Genetically determined cutaneous nevi and risk of cancer.

Numerous epidemiologic studies have reported positive associations between higher nevus counts and internal cancers. Whether this association represents a true relationship or is due to bias or confounding by factors associated with both nevus counts and cancer remains unclear. We used germline genetic variants for nevus count to test whether this phenotypic trait is a risk-marker for cancer. We calculated polygenic risk scores (PRS) for nevus counts using individual-level data in the UK Biobank (n = 394 306) and QSkin cohort (n = 17 427). The association between the nevus PRS and each cancer site was assessed using logistic regression adjusted for the effects of age, sex and the first five principal components. In both cohorts, those in the highest nevus PRS quartile had higher risks of melanoma than those in the lowest quartile (UK Biobank odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.29-1.55; QSkin OR 1.58, 95% CI: 1.29-1.94). We also observed increases in risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) associated with higher nevus PRS quartiles (BCC UK Biobank OR 1.38, 95% CI: 1.33-1.44; QSkin OR 1.20, 95% CI: 1.05-1.38 and SCC UK Biobank OR 1.41, 95% CI: 1.28-1.55; QSkin OR 1.44, 95% CI: 1.19-1.77). We found no consistent evidence that nevus count PRS were associated with risks of developing internal cancers. We infer that associations between nevus counts and internal cancers reported in earlier observational studies arose because of unmeasured confounding or other biases.

Post Zygotic, Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer, Producing a Monolateral Palmar Epidermolytic Nevus.

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.

Differences in Risk Factors for Melanoma in Young and Middle-aged Higher-risk Patients.

BACKGROUND/AIM: Differences in risk factors for melanoma between young adults (18-39 years) and middle-aged (40-60 years) are not well documented. In this study, we aimed to determine differences in risk factors and characteristics of melanoma between these groups. PATIENTS AND METHODS: This retrospective study is a review on 330 patients, including 250 middle-aged and 80 young adults, during the period 2006-2016 in the Tampere university hospital, in Finland. RESULTS: Forty-one per cent of middle-aged and 47% of young adults were defined as higher-risk patients. High nevus count was the most common host risk factor in both groups. Young were more likely to have a family history of melanoma. Middle-aged had more often excessive intermittent sun exposure and a history of sunburn. Host risk characteristics were less commonly associated with thicker melanomas. CONCLUSION: A high number of patients have host risk factors for melanoma. Several differences exist in risk factors and characteristics of melanomas between young adults and middle-aged patients.

Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort.

Importance: Nevi are a risk factor for melanoma and other forms of skin cancer, and many of the same factors confer risk for both. Understanding childhood nevus development may provide clues to possible causes and prevention of melanoma. Objectives: To describe nevus acquisition from the ages of 3 to 16 years among white youths and evaluate variation by sex, Hispanic ethnicity, and body sites that are chronically vs intermittently exposed to the sun. Design, Setting, and Participants: This annual longitudinal observational cohort study of nevus development was conducted between June 1, 2001, and October 31, 2014, among 1085 Colorado youths. Data analysis was conducted between February 1, 2015, and August 31, 2017. Main Outcomes and Measures: Total nevus counts on all body sites and on sites chronically and intermittently exposed to the sun separately. Results: A total of 557 girls and 528 boys (150 [13.8%] Hispanic participants) born in 1998 were included in this study. Median total body nevus counts increased linearly among non-Hispanic white boys and girls between the age of 3 years (boys, 6.31; 95% CI, 5.66-7.03; and girls, 6.61; 95% CI, 5.96-7.33) and the age of 16 years (boys, 81.30; 95% CI, 75.95-87.03; and girls, 77.58; 95% CI, 72.68-82.81). Median total body nevus counts were lower among Hispanic white children (boys aged 16 years, 51.45; 95% CI, 44.01-60.15; and girls aged 16 years, 53.75; 95% CI, 45.40-63.62) compared with non-Hispanic white children, but they followed a largely linear trend that varied by sex. Nevus counts on body sites chronically exposed to the sun increased over time but leveled off by the age of 16 years. Nevus counts on sites intermittently exposed to the sun followed a strong linear pattern through the age of 16 years. Hispanic white boys and girls had similar nevus counts on sites intermittently exposed to the sun through the age of 10 years, but increases thereafter were steeper for girls, with nevus counts surpassing those of boys aged 11 to 16 years. Conclusions and Relevance: Youths are at risk for nevus development beginning in early childhood and continuing through midadolescence. Patterns of nevus acquisition differ between boys and girls, Hispanic and non-Hispanic white youths, and body sites that are chronically exposed to the sun and body sites that are intermittently exposed to the sun. Exposure to UV light during this period should be reduced, particularly on body sites intermittently exposed to the sun, where nevi accumulate through midadolescence in all children. Increased attention to sun protection appears to be merited for boys, in general, because they accumulated more nevi overall, and for girls, specifically, during the adolescent years.

Melanoma - role of the environment and genetics.

Melanoma rates have increased in populations that are mainly European. The main etiologic factor is ultraviolet radiation, from the sun as well as artificial tanning devices. Host factors such as skin color, number of nevi, hair and eye color and tanning ability are critical factors in modifying an individual's response to the sun. Genetic factors interact with host factors and environmental factors to increase risk. This review summarizes our current knowledge of environment and genetics on melanoma risk and on gene-environment interaction.

A 10-years retrospective study on Severe Cutaneous Adverse Reactions (SCARs) in a tertiary hospital in Penang, Malaysia.

INTRODUCTION: Severe cutaneous adverse drug reactions (SCARs) are not uncommon and potentially lifethreatening. Our objective is to study the patient characteristics, the pattern of implicated drugs and treatment outcome among patients with SCARs. METHODS: A 10-year retrospective analysis of SCARs cases in Penang General Hospital was carried out from January 2006 to December 2015. Data collection is based on the Malaysian Adverse Drug Reactions Advisory Committee registry and dermatology clinic records. RESULTS: A total of 189 cases of SCARs were encountered (F:M ratio; 1.2:1.0; mean age of 45 year). The commonest manifestation was Stevens-Johnson Syndrome [SJS] (55.0%), followed by toxic epidermal necrolysis [TEN] (23.8%), drug rash with eosinophilia and systemic symptoms [DRESS] (12.7%), acute generalised exanthematous pustulosis [AGEP] (4.8%), SJS/TEN overlap syndrome (2.6%) and generalised bullous fixed drug eruptions [GBFDE] (1.1%). Mean time to onset for TEN/SJS/Overlap syndrome was 10.5±13 days; AGEP, three days; GBFDE, 2.5±0.7 days, and DRESS, 29.4±5.7 days. The most common drugs implicated were antibiotics (33.3%), followed by allopurinol (18.9%) and anticonvulsant (18.4%). Out of 154 cases of SJS/TEN/overlap syndrome, allopurinol was the commonest causative agents (20.1%). In DRESS, allopurinol accounts for 45.8% of the cases. The mortality rate in SJS, TEN and DRESS were 1.9%, 13.3% and 12.5% respectively. No mortality was observed in AGEP and GBFDE. CONCLUSION: The commonest manifestations of SCARs in our setting were SJS, TEN and DRESS. Allopurinol was the most common culprit. Thus, judicious allopurinol use is advocated and pre-emptive genetic screening for HLAB *5801 should be considered.

A Multicenter Survey: How Do Transplant Dermatologists Monitor Organ Transplant Recipients With Nevi?

OBJECTIVES: The incidence and mortality of melanoma are increased in organ transplant recipients. Multiple acquired common and dysplastic nevi are risk factors for melanoma. A new or changing nevus may suggest melanoma. Strategies used by transplant dermatologists to monitor nevi are unknown. Herein, we aimed to assess the methods used by transplant dermatologists for monitoring multiple acquired common nevi, dysplastic nevi, and new or changing nevi. MATERIALS AND METHODS: A questionnaire was e-mailed to 63 members of the Skin Care in Organ Transplant Patients, Europe. RESULTS: Thirty-eight (92.7%) of 41 responders reported that they instruct their patients to perform regular self-skin examinations. Of 41 responders, 41.5% prescribed screening every 6 months, 36.6% prescribed it every 12 months, 12.2% prescribed it every 3 months, and 9.7% performed screening without regular intervals. Regarding type of examination, 80.5% performed full-body skin examinations with the naked eye, 70.7% performed dermoscopy of clinically suspicious nevi, 53.6% offered dermoscopic photography of dermoscopically suspicious nevi, 36.6% provided close-up photography of clinically suspicious nevi, 34.1% performed baseline total body photography, and 24.4% conducted dermoscopy of all nevi. We also found that 7.3%, 4.9%, and 4.9% performed only full-body skin examination with the naked eye, only dermoscopy of clinically suspicious nevi, and only dermoscopy of all nevi, respectively. CONCLUSIONS: Dedicated transplant dermatologists perform a wide variety of nevi screening procedures in organ transplant recipients. Transplant dermatologists should include sequential digital dermoscopic imaging in their armamentarium to follow organ transplant recipients with melanocytic lesions. A combination of techniques is advisable for detecting early posttransplant melanomas.

Distinct Patterns of Acral Melanoma Based on Site and Relative Sun Exposure.

Acral melanoma is distinct from melanoma of other cutaneous sites, yet there is considerable variation within this category. To better define this variation, we assessed melanomas occurring on dorsal (n = 21), volar (n = 9), and subungual/interdigital (n = 13) acral skin as well as acral nevi (n = 24) for clinical, histologic, and molecular features. Melanomas on dorsal acral surfaces demonstrated clear differences compared with volar and subungual/interdigital melanomas. The latter two groups exhibited significantly less frequent BRAF mutations (P = 0.01), were significantly less likely to have the superficial spreading histologic subtype (P = 0.01), occurred in older patients (P = 0.05), and had more frequent involvement in non-Caucasians (P = 0.01). These differences can be explained by differing levels of UV exposure. Subungual/interdigital melanomas had the most diverse group of oncogenic mutations including PIK3CA (2/13), STK11 (2/13), EGFR (1/13), FGFR3 (1/13), and PTPN11 (1/13). In addition, subungual/interdigital melanomas had a significantly higher frequency of copy number aberrations (67%) than other subgroups (P = 0.02), particularly in CDK4 and cyclin D1, and were less likely to have BRAF mutations or a superficial spreading histologic subtype (P = 0.05) compared with volar acral melanomas. Although based on a limited sample size, differences between volar and subungual/interdigital melanomas in our study may be the result of differing levels of UV exposure.

Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome.

BACKGROUND: The plantar cerebriform connective tissue nevus (CCTN) is the most common and problematic cutaneous manifestation of Proteus syndrome. OBJECTIVE: To gain insights into CCTN pathogenesis and natural history. METHODS: The size and location of plantar CCTN was measured on 152 images from 22 individuals with Proteus syndrome by 2 independent, blinded reviewers. Average measures of plantar CCTN were transformed into a linear mixed model to estimate proportionate change in size with age. RESULTS: Median patient age was 6.9 years at study onset. The intraclass correlation coefficient between 2 blinded reviewers was 0.946 for CCTN single measures. The CCTN relative area increased with age in children (n = 18, P < .0001) by 5.6% per year. Confluent papules and nodules extending beyond the boundaries of CCTNs were gradually replaced by typical CCTN over time. The location of CCTN in different individuals overlapped near the ball of the foot. A positive relationship between CCTN growth rate and AKT1 mutant allele frequency was observed (0.62, P = .10, n = 8). LIMITATIONS: This was a retrospective review using photographs. CONCLUSION: CCTN growth is affected by age and extent of the CCTN precursor lesion. Monitoring of CCTN size might prove useful for evaluating drug response in the treatment of Proteus syndrome.

A case of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome with lipoatrophy as an important clinical manifestation.

Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies and/or scoliosis syndrome is a PIK3CA-related overgrowth spectrum presenting with congenital, asymmetric, disproportionate overgrowth associated with dysregulated adipose tissue, enlarged bony structures, and mixed primarily truncal vascular malformations. We present this case to raise awareness that very thin body habitus (lipoatrophy) contrasting with areas of overgrowth can be an important clinical feature of this syndrome and, if not recognized, can lead to unnecessary investigations.

Clinical Characteristics of Connective Tissue Nevi in Tuberous Sclerosis Complex With Special Emphasis on Shagreen Patches.

Importance: Patients with tuberous sclerosis complex (TSC) frequently develop collagenous connective tissue nevi. The prototypical lesion is a large shagreen patch located on the lower back, but some patients only manifest small collagenomas or have lesions elsewhere on the body. The ability to recognize these variable presentations can be important for the diagnosis of TSC. Objective: To describe the clinical characteristics of connective tissue nevi on the trunk and extremities of patients with tuberous sclerosis complex. Design, Setting, and Participants: A retrospective analysis of patient medical records and skin photography was performed; 104 adult patients with TSC were enrolled in an observational cohort study that was enriched for those with pulmonary lymphangioleiomyomatosis, and was therefore composed mostly of women (99 women, 5 men). All patients included were examined at the National Institutes of Health (NIH) in Bethesda, Maryland, from 1998 to 2013. Connective tissue nevi were categorized per anatomic location and size. Lesions less than 1 cm in diameter were termed collagenomas. Shagreen patches were characterized as small (1 to <4 cm), medium (4 to <8 cm), and large (≥8 cm). Main Outcome and Measures: Frequency, anatomic location, size, and histological appearance of connective tissue nevi in patients with TSC. Results: Overall, 58 of 104 patients (median [range] age, 42 [19-70] years) with TSC (56%) had at least 1 connective tissue nevus on the trunk or thighs; of these, 28 of 58 patients (48%) had a solitary lesion, and 30 of 58 patients (52%) had 2 or more lesions. Overall, 120 lesions from 55 patients were classified by size; 46 lesions (38%) were collagenomas; 39 lesions (32%) were small shagreen patches; 21 lesions (18%), medium shagreen patches; and 14 lesions (12%), large shagreen patches. The distribution of lesions was 9% (n = 11), upper back; 29% (n = 35), middle back; 51% (n = 61), lower back; and 11% (n = 13), other locations. All 26 shagreen patches that were analyzed histopathologically had coarse collagen fibers and 24 of 26 stained with Miller elastic stain had decreased elastic fibers. On immunoblot analysis, fibroblasts grown from shagreen patches expressed higher levels of phosphorylated ribosomal protein S6 than paired fibroblasts from normal-appearing skin. Conclusions and Relevance: Tuberous sclerosis complex-related connective tissue nevi are not limited to the lower back, and occasionally present on the central or upper back, buttocks, or thighs. Elastic fibers are typically decreased. Recognition of these variable presentations can be important for TSC diagnosis.

Nevi, Ambient Ultraviolet Radiation, and Thyroid Cancer Risk: A French Prospective Study.

BACKGROUND: Incidence rates have increased considerably worldwide for both differentiated thyroid cancer and cutaneous melanoma, and two-way associations between these neoplasms have been described. Whether melanoma risk factors are associated with thyroid cancer risk remains unknown. METHODS: Using Cox regression modeling, we prospectively analyzed the relationship between self-reported pigmentary traits, baseline residential ultraviolet (UV) exposure, and thyroid cancer risk in 86,960 women from the E3N cohort, followed-up over 1990-2008 through biennial questionnaires. We assessed associations of pigmentary traits and UV exposure with personal history of benign thyroid diseases using logistic regression modeling. All statistical tests were two sided. RESULTS: In models adjusted for age and thyroid cancer risk factors, number of nevi was positively associated with thyroid cancer risk ("very many" vs. "none": hazards ratio [HR] = 1.7, 95% confidence interval [CI] = 1.0, 2.8; Ptrend = 0.01), independently of residential UV exposure or iodine intake. Risk was inversely associated with latitude and positively associated with mean daily UV level at baseline (HRs for the fourth vs. first quartile of latitude and spring/summer UVB level = 0.7, 95% CI = 0.5, 0.9; Ptrend = 0.03, and HR = 1.9, 95% CI = 1.4, 2.7; Ptrend = 0.02, respectively); associations were restricted to women with dietary iodine below the median intake. Number of nevi and UV level were also associated with personal histories of dysthyroidism and of goiter/nodules, although more weakly so. CONCLUSIONS: Our results suggest that number of nevi and residential UV exposure are associated with the risks of thyroid cancer and benign conditions. They point to novel pathways in thyroid cancer or melanoma etiologies and warrant replication.

Papillary transitional cell bladder carcinoma and systematized epidermal nevus syndrome.

Epidermal nevus syndrome (ENS), also known as Solomon syndrome, is a rare neurocutaneous disorder defined by mosaicism. Epidermal nevus syndrome may be associated with a variety of systemic findings, several of which have been described in the literature, including but not limited to central nervous system abnormalities and internal malignancies. There is a paucity of reports of patients with both epidermal nevi and papillary transitional cell bladder carcinoma in the literature. We present a rare case of systematized epidermal nevi associated with development of papillary transitional cell bladder carcinoma in a young woman. Patients diagnosed with generalized epidermal nevi should have workup for possible associated central nervous system, musculoskeletal, genitourinary abnormalities, and internal malignancies. The association of epidermal nevi and transitional cell bladder carcinoma may be linked to a mutation in the fibroblast growth factor receptor 3 gene, FGFR3, but a clear link has yet to be substantiated and additional molecular studies are needed.

Cutaneous features of myotonic dystrophy types 1 and 2: Implication of premature aging and vitamin D homeostasis.

Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in which way skin is a target of specific disease alterations in DM1 and DM2 has not been yet clarified. This study aims to explore cutaneous features of DM1 and DM2 patients. Skin examination was performed in 60 DM1, 15 DM2, and 103 control, unselected patients by means of dermoscopy. It revealed quantitative and qualitative abnormalities of nevi and typical signs of premature aging in both DM1 and DM2 patients, with a significantly higher frequency of dysplastic nevi, alopecia, xerosis and seborrheic dermatitis. Twenty-eight nevi were excised in DM patients and none showed histological features of melanoma, although 12 of them were diagnosed as dysplastic and the remaining 16 presented histological irregularity in melanin distribution. In DM1 patients, the number of nevi correlated with CTG expansion size, whereas the presence of dysplastic nevi and xerosis inversely correlated with vitamin D levels. DM1 and DM2 patients display a high frequency of skin abnormalities, the most common of which correlate with genotype severity and serum vitamin D levels. Skin examination is highly informative in these patients and reveals features suggestive of premature aging and impaired vitamin D homeostasis.