Keratinocytic epidermal nevi are associated with mosaic RAS mutations

Background: Activating RAS mutations in the germline cause rare developmental disorders such as Costello syndrome. Somatic RAS mutations are found in approximately 30% of human cancers. Keratinocytic epidermal nevi (KEN) represent benign congenital skin lesions arranged along Blaschko's lines. A subgroup of KEN is caused by hotspot oncogenic FGFR3 and PIK3CA mutations in mosaicism, but the majority lack these mutations. Methods: This study screened 72 KEN for activating mutations in RAS genes and other oncogenes. Results: Activating RAS mutations were identified in 28/72 (39%) of KEN. HRAS was the most commonly affected oncogene (86%), with the HRAS p.G13R substitution representing a new hotspot mutation. Conclusion: These results indicate that activating RAS somatic mutations leading to mosaicism result in benign KEN of the skin. Given the prevalence of KEN, mosaic HRAS mutations appear to be more common in patients than germline ones. These findings identify KEN as a mosaic RASopathy and lend further support to the notion that genetic mosaicism is an important contributor to disease

Patterns of incidental perineural invasion and prognosis in cutaneous squamous cell carcinoma: A multicenter, retrospective cohort study

To the Editor: Perineural invasion (PNI) is rare and usually incidental in cutaneous squamous cell carcinoma (SCC), with an incidence of 2.5% to 14%.1 Incidental PNI is associated with poor prognosis in cutaneous SCC,2 and some evidence suggests its outcome differs, depending on the PNI pattern. We evaluated patterns of incidental PNI, using a multicenter retrospective cohort of 140 cutaneous SCCs with incidental PNI to determine the influence of nerve involvement on cutaneous SCC prognosis.Dr Canueto is partially supported ~ by grants PI18/000587 (Instituto de Salud Carlos III, cofinanced by Fondo Europeo de Desarrollo Regional) and GRS 1835/A/18 (Gerencia Regional de Salud de Castilla y Leon)

Evaluation of urinary porphyrin excretion in neonates born to mothers exposed to airborne hexachlorobenzene.

The existence of a link between hexachlorobenzene (HCB) and porphyria cutanea tarda has been known for a long time. However, the epidemiologic data on effects on health caused by prenatal exposure have not provided convincing evidence that HCB alters porphyrin metabolism. Our objectives were to analyze urinary porphyrin excretion and HCB in maternal serum and fetal cord blood in neonates born in a village (Flix) near a chlorinated solvent factory, to detect possible adverse effects in urinary porphyrin excretion caused by prenatal exposure, and to assess their relationship with HCB blood levels. We conducted a cross-sectional study in the Porphyria Unit at a tertiary care facility in Barcelona, Spain, and the Pediatric Unit of the Móra d'Ebre Hospital, the reference hospital of the study area. We included in the study all neonates (n = 68) born in Móra d'Ebre Hospital 1997-1999 and their mothers. We obtained 68 urine specimens of singleton neonates on the third day after birth to test for urinary porphyrin excretion. We obtained 52 fetal cord blood and 56 maternal serum samples for HCB analysis. Total urinary porphyrins were quantified using spectrofluorometry. Porphyrin profile was determined by HPLC. Serum HCB was analyzed by gas chromatography coupled with electron capture detection. In total population, median HCB levels were 1.08 ng/mL in cord blood and 3.31 ng/mL in maternal serum. Total urinary porphyrin concentration was 37.87 micromol/mol creatinine. Coproporphyrin I and coproporphyrin III were the major porphyrins excreted. We found no positive relationship between urinary porphyrin excretion and HCB levels. However, we observed an association between maternal smoking and coproporphyrin excretion. Although high environmental levels of HCB are reported in the town of Flix, we found no alteration in urinary porphyrin excretion

Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis

TREX2 is a 3'-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response

Skin manifestations in COVID-19: prevalence and relationship with disease severity

Background: Data on the clinical patterns and histopathology of SARS-CoV-2 related skin lesions, as well as on their relationship with the severity of COVID-19 are limited. Methods and Materials: Retrospective analysis of a prospectively collected cohort of patients with SARS-CoV-2 infection in a teaching hospital in Barcelona, Spain, from 1 April to 1 May 2020. Clinical, microbiological and therapeutic characteristics, clinicopathological patterns of skin lesions, and direct immunofluorescence and immunohistochemical findings in skin biopsies were analyzed. Results: Fifty-eight out of the 2761 patients (2.1%) either consulting to the emergency room or admitted to the hospital for COVID-19 suspicion during the study period presented COVID-19 related skin lesions. Cutaneous lesions could be categorized into six patterns represented by the acronym "GROUCH": Generalized maculo-papular (20.7%), Grover's disease and other papulo-vesicular eruptions (13.8%), livedo Reticularis (6.9%), Other eruptions (22.4%), Urticarial (6.9%), and CHilblain-like (29.3%). Skin biopsies were performed in 72.4%, including direct immunofluorescence in 71.4% and immunohistochemistry in 28.6%. Patients with chilblain-like lesions exhibited a characteristic histology and were significantly younger and presented lower rates of systemic symptoms, radiological lung infiltrates and analytical abnormalities, and hospital and ICU admission compared to the rest of patients. Conclusion: Cutaneous lesions in patients with COVID-19 appear to be relatively rare and varied. Patients with chilblain-like lesions have a characteristic clinicopathological pattern and a less severe presentation of COVID-19

Estudi de les mutacions dels exons 2 i 4 del gen HFE en pacients amb porfiria cutània tarda esporàdica

[cat] La Porfíria Cutània Tarda (PCT) és una malaltia metabòlica que afecta a la pell i al fetge i que és desencadenada per la interacció de múltiples factors que inclouen l´herència, l´alcohol, el VHC, els estrògens i alguns agents tòxics, entre d´altres encara en estudi. La sobrecàrrega fèrrica, de forma primària o secundària a d´altres factors de risc (com la infecció pel VHC), és un factor desencadenant de la PCT. En aquest contexte, considerem la hipòtesi de que la sobrecàrrega fèrrica observada en alguns pacients amb PCT pot estar associada amb les mutacions descrites en el gen de l´hemocromatosi (C282Y i H63D). Considerem d´interès també conèixer la interrelació entre la freqüència d'aquestes mutacions i els altres factors de risc, especialment el VHC, en el desencadenament de la malaltia en el nostre àmbit geogràfic.OBJECTIUS:1. Establir les prevalences de les mutacions C282Y i H63D del gen HFE en pacients amb PCT esporádica en el nostre ambient.2. Determinar la relació entre les mutacions del gen HFE en pacients amb PCT esporádica i la sobrecàrrega de ferro hepàtic. 3. Establir la relació entre la prevalença d'aquestes mutacions i la infecció pel VHC.MATERIAL I MÈTODES:S´han seleccionat de forma retrospectiva 99 pacients amb PCT i 126 controls (76 sans sense infecció per VHC i 50 individus amb infecció crònica per VHC). En els pacients amb PCT s´han recollit les següents variables: gènere, ingesta d´alcohol, presa d´anticonceptius, serologies per VHC, VHC i VIH. Els paràmetres se sobrecàrrega de ferro determinats en els pacients amb PCT han estat els següents: quantificació del ferro hepàtic (en 41 pacients) i la ferritina (en 71 pacients). S´ha estudiat la presència de les mutacions C282Y i H63D dels exons 4 i 2 respectivament del gen de l´hemocromatosi (HFE) mitjançant les següents tècniques:1-Extracció de l´ADN a partir de sang total i precipitació de l´ADN, 2-amplificació dels exons 2 i 4 i 3-digestió de l´ADN amb endonucleasses de restricció mitjançant tècnica de restriction fragment length polymorphism (RFLP). RESULTATS:Hem observat un augment de la prevalença de la mutació C282Y en els pacients amb PCT en el nostre àmbit geogràfic. Aquest augment és independent de la infecció pel VHC. A més, la mutació C282 s´associa amb un augment del ferro hepàtic i de la ferritina. Per altra banda, no hem observat un augment de la mutació H63D en els pacients amb PCT, excepte en el genotipus en homozigosi. Sí hem observat una associació significativa amb la PCT quan es comparen els pacients infectats per VHC i els controls amb aquesta infecció. Per tant, la mutació H63D pot actuar de forma sinèrgica amb la infecció per VHC en la inducció de PCT. No hem observat tampoc una associació entre la mutació H63D i la sobrecàrrega de ferro. Les mutacions del gen HFE, en especial la mutació C282Y, poden estar relacionades amb la sobrecàrrega de ferro i per tant en el possible desenvolupament d´hepatopatia crònica i de carcinoma hepatocelular. Per altra banda, el tractament amb flebotomies pot ser l´idoni en els pacients amb sobrecàrrega de ferro. Per tant, l´anàlisi de les mutacions del gen HFE s´ha d´incloure de forma sistemàtica en els protocols d´estudi dels pacients amb PCT.[eng] Title: STUDY ON EXONS 2 AND 4 HFE GENE MUTATIONS IN PATIENTS WITH SPORADIC PORPHYRIA CUTANEA TARDAHYPOTHESIS: the iron overload frequently observed in patients with Porphyria Cutanea Tarda (PCT) may be associated with the mutations that are usually found in the HFE gene in patients with hemochromatosis (C282Y and H63D mutations). These mutations may be independent of other risk factors of PCT, such as VHC infection and alcohol intake OBJECTIVES:1-To establish the prevalences of mutations C282Y and H63D of HFE gene in patients with sporadic PCT in our environment.2-To establish the relationship between the mutations in HFE gene in patients with sporadic PCT and iron overload.3-To establish the relationship between these mutations and VHC infectionDESIGN: Retrospective case-control study.SETTING: A large clinical and research institute for the study and treatment of cutaneous diseases in Barcelona, Spain.PATIENTS: Ninety-nine patients with PCT and one hundred and twenty six control patients (76 healthy subjects and 50 patients chronically infected with HCV), were included in the study. MAIN OUTCOME MEASURES: The frequency of the C282Y and H63D mutations in patients with PCT vs controls and the relationship of these mutations with HCV infection, and iron status, as judged by serum iron, liver iron and ferritin levels. RESULTS: C282Y mutation was significantly increased in PCT patients. This mutation was more frequent among non HCV-infected patients. Increased ferritin levels and hepatic iron overload were also observed in PCT patients with heterozygous C282Y state. H63D mutation was only significantly increased among PCT patients with chronic hepatitis C infection. No significant iron overload was observed in patients with H63D mutation.CONCLUSIONS: This study confirms the high frequency of C282Y mutation in patients with PCT and its relationship with iron overload. The C282Y mutation has a relevant role in Spanish patients with PCT non-associated with HCV chronic infection. On the other hand, the prevalence of the H63D mutation seems not to be increased in patients with PCT. The possibility of an association between HCV infection and H63D mutation in inducing PCT can be hypothesized

Erythematous papules on the penis as first manifestation of metastatic prostate adenocarcinoma

We report a 70-year-old man with asymptomatic reddish papules on the glans penis that histologically showed metastases of prostate adenocarcinoma. He had a medical history of a stage IV undifferentiated prostate adenocarcinoma that was currently being treated with chemotherapy. The medical history of advanced stage prostate adenocarcinoma associated with the clinical and pathological findings confirmed the diagnosis of penile metastatic prostate adenocarcinoma. This is an example of the relevance of a thorough history combined with histopathological and immunohistochemical correlation which allowed the diagnosis of a penile lesion that may be the first manifestation of prostate metastatic progression and should therefore be included among the differential diagnoses of penile tumors

Erythematous papules on the penis as first manifestation of metastatic prostate adenocarcinoma

We report a 70-year-old man with asymptomatic reddish papules on the glans penis that histologically showed metastases of prostate adenocarcinoma. He had a medical history of a stage IV undifferentiated prostate adenocarcinoma that was currently being treated with chemotherapy. The medical history of advanced stage prostate adenocarcinoma associated with the clinical and pathological findings confirmed the diagnosis of penile metastatic prostate adenocarcinoma. This is an example of the relevance of a thorough history combined with histopathological and immunohistochemical correlation which allowed the diagnosis of a penile lesion that may be the first manifestation of prostate metastatic progression and should therefore be included among the differential diagnoses of penile tumors

Cutaneous Venous Malformations in Familial Cerebral Cavernomatosis Caused by KRIT1 Gene Mutations

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. Although often asymptomatic, seizures, cerebral haemorrhages and focal neurological deficits are well-documented complications. Mutations in the CCM1 (7q21-22), CCM2 (7p13-15) and CCM3 (3q25.2-27) genes have been identified in familial CCM. In rare instances, the association of congenital hyperkeratotic cutaneous capillary-venous malformations (HCCVMs) with CCM1 has been reported. OBSERVATIONS: We studied 6 members of a family with CCMs. Four members of the family developed late-onset multiple, tiny, bluish, soft, cutaneous papules, mainly located on the face, arm and abdominal area, corresponding histologically to venous malformations. A splice donor site mutation in intron 4 (c. 1146 + 1 G-->A) in the CCM1 gene was identified. CONCLUSIONS: Our findings suggest that mutations in the KRIT1 gene may cause phenotypically heterogeneous cutaneous vascular lesions other than those previously described as HCCVMs

Heinz-Lippmann disease as an underrecognized cause of chronic venous insufficiency-associated cutaneous ulcers: Clinical and imaging findings

Venous insufficiency is a frequent cause of consultation in primary care settings. Heterotopic ossification, consisting of an abnormal formation of true bone in extraskeletal soft tissues, is an underrecognized complication of chronic venous insufficiency that may cause torpid ulcers. We report a case of 78-year-old woman, with a long-standing history of venous insufficiency and tibial fracture, showing a non-healing ulcer associated with subcutaneous calcifications of the left lower extremity. Gold standard of imaging diagnosis are both plain radiographs and computed tomography but also magnetic resonance imaging could be useful for assessing the characteristics of the pathology. We describe a case of Heinz-Lippmann disease, diagnosed by using both computed tomography and magnetic resonance imaging