The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant condition attributed to pathogenic variants in fumarate hydratase (FH) and presents with cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs) and renal cell cancer (RCC). The objective of this study was to characterize the spectrum of clinical and genetic findings in HLRCC at a large academic tertiary care referral center with a focus on dermatologic manifestations. Fifty-seven patients, 41 female and 16 male, with 27 unique pathogenic or likely-pathogenic FH variants were identified from 38 families. Mean age of HLRCC diagnosis was 44.4 years (range 8-82). CLMs were the primary reason for referral in 49.1% (n=28). CLMs were present in 43/56 patients who underwent full skin examination. Three of these 56 patients were diagnosed with cutaneous leiomyosarcoma. Incidence of ULMs was 37/41 female patients; no uterine leiomyosarcomas were observed. RCC was observed in 6/57 patients (mean age of diagnosis: 47.3 years (range 28-79)). CLMs predated RCC in the 3 patients diagnosed with both. Dermatologists have an opportunity to recognize cutaneous manifestations of HLRCC, including cutaneous leiomyomas and rarely cutaneous leiomyosarcomas, and refer for genetic evaluation to provide definitive diagnosis. Identification of HLRCC can promote family cascade testing and screening for RCC.

A Germline Mutation in the C2 Domain of PLCγ2 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases.

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2-knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to control-transfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects.

Laboratory Monitoring During Isotretinoin Therapy for Acne: A Systematic Review and Meta-analysis.

IMPORTANCE: Oral isotretinoin has been associated with several adverse effects, but evidence-based estimates of laboratory changes during isotretinoin therapy in large patient samples are limited. OBJECTIVE: To develop estimates of the laboratory changes that occur during isotretinoin therapy for acne using extant data and meta-analytic methods. DATA SOURCES: A comprehensive search strategy using Ovid/MEDLINE, EMBASE, and gray literature was conducted (1960-August 1, 2013) to identify all relevant studies of isotretinoin use in acne vulgaris. Terms related to acne treatment, isotretinoin, and diagnostic procedures were searched with all available synonyms. STUDY SELECTION: Inclusion criteria consisted of clinical trials using oral isotretinoin, doses of 40 mg/d or more, duration of at least 4 weeks, patients aged 9 to 35 years with acne vulgaris, and 10 or more participants. Studies from all countries published in any language were included. Exclusion criteria were use of modified isotretinoin products, isotretinoin therapy for conditions other than acne vulgaris, and concomitant acne therapy. The initial search yielded 342 records; 116 of these were screened for full-text examination. DATA EXTRACTION AND SYNTHESIS: Two authors independently reviewed the publications to determine eligibility, and disagreements were resolved by a third author. Generated weighted means and 99% CIs were calculated using the reported means (SDs or SEs). A random effects model was created, and statistical heterogeneity was quantified. Data were analyzed from August 25, 2014, to December 4, 2015. MAIN OUTCOMES AND MEASURES: Laboratory values for lipid levels, hepatic function, and complete blood cell count were evaluated. RESULTS: Data from 61 of the 116 studies were evaluated; 26 studies (1574 patients) were included in the meta-analysis. The mean (99% CI) values during treatment (nonbaseline) for triglycerides was 119.98 mg/dL (98.58-141.39 mg/dL); for total cholesterol, 184.74 mg/dL (178.17-191.31 mg/dL); for low-density lipoprotein cholesterol, 109.23 mg/dL (103.68-114.79 mg/dL); for high-density lipoprotein cholesterol, 42.80 mg/dL (39.84-45.76 mg/dL); for aspartate aminotransferase, 22.67 U/L (19.94-25.41 U/L); for alanine aminotransferase, 21.77 U/L (18.96-24.59 U/L); for alkaline phosphatase, 88.35 U/L (58.94-117.76 U/L); and for white blood cell count, 6890/µL (5700/µL-8030/µL). This meta-analysis showed that (1) isotretinoin is associated with a statistically significant change in the mean value of several laboratory tests (white blood cell count and hepatic and lipid panels), yet (2) the mean changes across a patient group did not meet a priori criteria for high-risk and (3) the proportion of patients with laboratory abnormalities was low. CONCLUSIONS AND RELEVANCE: The evidence from this study does not support monthly laboratory testing for use of standard doses of oral isotretinoin for the standard patient with acne.

Actinic Keratosis Clinical Practice Guidelines: An Appraisal of Quality.

Actinic keratosis (AK) is a common precancerous skin lesion and many AK management guidelines exist, but there has been limited investigation into the quality of these documents. The objective of this study was to assess the strengths and weaknesses of guidelines that address AK management. A systematic search for guidelines with recommendations for AK was performed. The Appraisal of Guidelines for Research and Evaluation (AGREE II) was used to appraise the quality of guidelines. Multiple raters independently reviewed each of the guidelines and applied the AGREE II tool and scores were calculated. Overall, 2,307 citations were identified and 7 fulfilled the study criteria. The Cancer Council of Australia/Australian Cancer Network guideline had the highest mean scores and was the only guideline to include a systematic review, include an evidence rating for recommendations, and report conflicts of interest and funding sources. High-quality, effective guidelines are evidence-based with recommendations that are concise and organized, so practical application is facilitated. Features such as concise tables, pictorial diagrams, and explicit links to evidence are helpful. However, the rigor and validity of some guidelines were weak. So, it is important for providers to be aware of the features that contribute to a high-quality, practical document.