Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.

Mosaic NRAS Q61R mutation in a child with giant congenital melanocytic naevus, epidermal naevus syndrome and hypophosphataemic rickets.

The association of hypophosphataemic rickets with verrucous epidermal naevus (EN) and elevated fibroblast growth factor 23 levels is known as cutaneous-skeletal hypophosphataemia syndrome (CSHS), and can be caused by somatic activating mutations in RAS genes. We report a unique patient with CSHS associated with giant congenital melanocytic naevus (CMN), neurocutaneous melanosis and EN syndrome, manifesting as facial linear sebaceous naevus, developmental delay and ocular dermoids. An activating mutation Q61R in the NRAS gene was found in affected skin and ocular tissue but not blood, implying that the disparate manifestations are due to a multilineage activating mutation (mosaic RASopathy). We speculate on the apparently rare association of CSHS with CMN compared with EN. We also report the favourable outcome of this patient at the age of 8 years after extensive neonatal curettage of the giant CMN and use of vitamin D and phosphate supplementation.

Subthreshold transpupillary thermotherapy in management of foveal subretinal fluid in small pigmented choroidal lesions.

PURPOSE: To evaluate the effect of subthreshold transpupillary thermotherapy (sTTT) in foveal subretinal fluid of small pigmented choroidal lesions. METHODS: Retrospective, noncomparative, interventional case series. We reviewed patients with small pigmented choroidal lesions presenting foveal subretinal fluid and treated with sTTT to evaluate fluid regression. RESULTS: We treated 13 patients with small pigmented choroidal lesions with a mean height of 2.02 ± 0.54 mm (range, 1.4-2.9 mm) and a mean largest diameter of 7.60 ± 1.98 mm (range, 5-11 mm). In 11 cases, foveal subretinal fluid was completely resolved (84.6%), with a mean follow-up of 42.46 ± 26.29 months (range, 12-103 months). The mean number of sTTT sessions applied was 1.38 ± 0.77 (range, 1-3 sessions), at a mean spot size of 1,570.59 ± 795.1 µm (range, 500-3,000 µm), and overall exposure time of 2.32 ± 1.2 minutes (range, 1-6 minutes). Mean laser power applied was 370.63 ± 162.87 mW (range, 200 to 600 mW). Best-corrected visual acuity at the time of diagnosis was maintained or improved in 69.3% of patients after sTTT treatment. During follow-up, tumor progression was reported in 5 cases, regardless of the presence of subretinal fluid. These cases were treated promptly with brachytherapy. CONCLUSION: However, sTTT may be effective in solving foveal subretinal fluid in small pigmented choroidal lesions, attaining satisfactory visual acuity in most cases.

Complete regression of a melanocytic nevus under intense pulsed light therapy for axillary hair removal in a cosmetic center.

Intense pulsed light (IPL) therapy using noncoherent broad-spectrum light has been reported to be effective for hair removal, and also for treating superficial pigmented lesions like ephelides and solar lentigines. We report complete regression of a pigmented melanocytic nevus, histologically confirmed, after hair removal treatment with IPL. The use of lasers and IPL is a common procedure used by dermatologists and even other professions for the treatment of cosmetically troubling skin conditions. The main advantage of such treatment is a reduction of surgical scars, thus producing a favorable cosmetic outcome, but a major limitation is that histopathologic diagnosis is not usually obtained prior to treatment. Such devices should be carefully used in patients with potentially dangerous melanocytic lesions. We also review the recent literature regarding inadequate treatment of melanocytic lesions with lasers.

Effectiveness of skin cancer screening for individuals age 14 to 34 years.

BACKGROUND: Approximately 15 % of all cases of melanoma are diagnosed before age 35 years. In Germany, individuals ≥ 35 years are eligible for the national skin cancer screening program. The effectiveness of a population-based skin cancer screening in general and in particular for young adults is unclear. OBJECTIVES: Assessment of the effectiveness of a skin cancer screening program and of risk factors for detection of a melanoma/atypical nevus in the setting of a screening for the age group 14 to 34 years. METHODS: A total of 12,187 individuals age 14 to 34 years were screened in Saxony for skin cancer by a dermatologist in the program "Haut-Check 14-34 Jahre" of the AOK PLUS, a large German health insurance, between January and July 2009. Demographic, clinical and histopathological data and UV-exposure data were collected from each participant. Multivariate logistic regression models were used to assess risk factors for the detection of a (histopathologically confirmed) melanoma or atypical nevus. RESULTS: 2.8 % of the eligible individuals participated in the skin cancer screening program with women being more likely to do so. In 1 072 individuals (8.8 %) screening included at least one excision of a skin lesion leading to the diagnosis of melanoma in two participants, melanoma in situ in four persons, and atypical nevus in 641 persons. Use of tanning beds, higher age, number of nevi, and previous cutaneous excision were independent risk factors for the detection of a melanoma or atypical nevus. CONCLUSIONS: In 5.5 % of all cases skin cancer screening resulted in the excision of a malignant or atypical melanocytic lesion. It remains unclear what proportion of these cases would have been detected in routine care. The rate of excisions per newly diagnosed melanoma was 179 : 1. Further investigations are necessary to explore the reasons for this low diagnostic specificity. This study highlights the possibilities and limitations of routine data to evaluate screening programs and indicates the need to collect additional information on healthcare utilization behaviour.

Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center.

BACKGROUND: Histopathologic analysis remains the gold standard for the pathologic diagnosis of melanoma. Numerous histologic criteria are used to diagnose melanoma, but none alone are sufficient to establish this diagnosis. Therefore, differentiating between benign pigmented lesions and melanoma may be controversial. Although several studies have examined the interobserver variability in the pathological diagnosis of melanoma, the prevalence of discordant diagnoses of melanocytic neoplasms is unknown. OBJECTIVE: We sought to examine the discordance rate of melanoma diagnoses referred to our pigmented lesion clinic, a subset of the University of California, San Francisco (UCSF) Department of Dermatology and Comprehensive Cancer Center Melanoma Center during a 2-year period. METHODS: A total of 392 new patients given a diagnosis of thin melanoma (melanoma in situ, stage IA, stage IB) or benign nevus were referred in 2006 and 2007, with initial diagnoses rendered by an outside dermatopathologist or surgical pathologist. Subsequently, these specimens were re-evaluated by routine histopathologic examination at the UCSF Dermatopathology Service and a distinct diagnosis was rendered. The two available diagnoses were compared, and discordance was defined as the lack of agreement between two pathologists when rendering a benign versus malignant versus ambiguous diagnosis. RESULTS: The discordance rate of melanomas and nevi between the referring centers and UCSF was 14.3%. LIMITATIONS: This review was limited in that there were few patients with benign pigmented lesions referred to the pigmented lesion clinic at UCSF. CONCLUSION: The level of discordance in the routine histopathologic interpretation of melanocytic neoplasms can be high.

Diagnosis and treatment of pigmentary disorders in Asian skin.

Individuals of Asian heritage are predisposed to congenital and acquired pigmentary disorders. Cosmetic enhancement is frequently the primary treatment goal for these benign lesions. Accurate diagnosis of the nature of the pigmentary disorder is fundamental for administering safe and effective therapy. Before the advent of modern laser technology, such reported treatments as cryotherapy, dermabrasion, chemical peeling, and surgical excision resulted in unpredictable results. This article focuses on the diagnosis of disorders of pigmentation in Asian patients and reviews laser and light treatment modalities.

Estudio sobre la expresión de galanina en tumores melanocitarios / Expression of galanin in melanocytic tumors

Introducción. La galanina es un neuropéptido que controla numerosas funciones en el sistema nervioso y endocrino y que está presente en la piel. Diferentes tumores neurales, endocrinos y neuroendocrinos expresan galanina y, por otro lado, varios neuropéptidos, especialmente la &apha;-MSH, se han involucrado en la patogénesis del melanoma. Objetivo. Estudiar la expresión de galanina en melanomas y nevi melanocíticos cutáneos, comparándola con la de α-MSH, y relacionándola con variables clínicas e histológicas con valor pronóstico en el melanoma. Material y métodos. Estudio observacional, retrospectivo de la expresión de galanina y αMSH mediante inmunohistoquímica en una muestra significativa de secciones histológicas de los melanomas cutáneos diagnosticados en el hospital San Jorge de Huesca en los últimos 5 años, y un número similar de distintos tipos de nevi melanocíticos. Resultados. Se estudiaron un total de 130 lesiones pigmentadas: 38 melanomas cutáneos primarios, 6 metástasis cutáneas de melanoma y 86 nevi melanocíticos. El inmunomarcaje con galanina y α-MSH fue significativamente mayor en melanomas que en nevi (p < 0,001), aunque dentro de los nevi destacan la expresión de α-MSH en los azules y fusocelulares. Más del 50 % de los melanomas nodulares y del 90 % de los de extensión superficial fueron positivos para galanina y α-MSH, y además estos últimos fueron los que mostraron un mayor porcentaje de células positivas tanto para galanina (media = 35,09 ± 28,16 %) como para α-MSH (media = 67,64% ± 35,38 %), siendo la correlación entre ambos en melanomas del 71%. No se encontró asociación estadísticamente significativa entre la expresión de galanina y las variables edad, sexo, localización, índice de Breslow, nivel de Clark y proliferación celular. Conclusión. Nuestro estudio demuestra la presencia de galanina en secciones histológicas de melanoma cutáneo, y esta inmunorreactividad se relaciona significativamente con la de α-MSH

Introduction. Galanin is a neuropeptide with wide-ranging effects, especially within the endocrine and nervous systems. Galanin and its receptors are present in human skin. Galanin is expressed in different neural, endocrine and neuroendocrine tumors and, on the other hand, several neuropeptides, particularly α-MSH, seem to play a role in the pathogenesis of melanoma. Objective. To investigate the expression of galanin in cutaneous melanomas and melanocytic nevi and correlate it with α-MSH expression and several prognostic factors for melanoma. Material and methods. We performed an observational and retrospective study of the immunohistochemical expression of galanin and α-MSH in samples of cutaneous melanomas diagnosed in the last 5 years in the San Jorge Hospital, Huesca (Spain). Different types of melanocytic nevi were also analyzed. Results. A total of 130 pigmented lesions were studied: 38 primary cutaneous melanomas, 6 cutaneous melanoma metastases and 86 melanocytic nevi. Immunostaining with galanin and α-MSH was significantly higher in melanomas than in melanocytic nevi (p < 0.001), although spindle cell and blue nevi showed significant expression of α-MSH. More than 50 % of nodular melanomas and 90 % of superficial spreading melanomas were positive for galanin and α-MSH, and the latter also showed the highest percentage of positive cells for galanin (mean 35.09 ± 28.16) as well as for α-MSH (mean 67.64% ± 35.38). A positive correlation of 71 % was found for immunostaining of both neuropeptides in melanomas. No significant correlation was observed between galanin expression and age, gender, location of the lesions, Breslow index, Clark level and mitotic index. Conclusion. Our study shows the expression of galanin in cutaneous melanoma and its significant correlation with α-MSH immunostaining

Transpupillary thermotherapy for subfoveal choroidal neovascularization associated with choroidal nevus.

PURPOSE: To describe a patient with classic subfoveal choroidal neovascularization (CNV) associated with choroidal nevus, which was successfully treated using transpupillary thermotherapy. DESIGN: Interventional case report. METHODS: A 53-year-old woman underwent ophthalmologic evaluation, including fluorescein and indocyanine green angiography. Clinical and angiographic data were prospectively analyzed to evaluate visual acuity changes and angiographic evolution. RESULTS: Three months after transpupillary thermotherapy, visual acuity had improved from 20/100 to 20/40. Fluorescein and indocyanine green angiograms showed absence of leakage from CNV. Final visual acuity was 20/32 after a 15-month follow-up. CONCLUSIONS: Transpupillary thermotherapy may be a viable option for subfoveal CNV associated with CN, although further studies are needed to establish the correct setting.

Estudio clínicopatológico de nevus melanocíticos en distintos grupos de edad / Clinical-pathological study of melanocytic nevi in diferent age groups

Objetivo: Conocer la frecuencia de presentación, las características clínicas y la correlación clinicopatológica de los nevus melanocíticos en distintos grupos de edad. Material y Métodos: Realizamos el estudio en 2247 lesiones melanocíticas correspondientes a 461 pacientes. En 90 individuos pudimos realizar un protocolo clínico en el que se recogían los datos sobre tipo de piel, color de ojos y pelo, hábitos de exposición solar, localización, número y características de los nevus melanocíticos y antecedentes familiares. De las 2247 lesiones estudiadas clínicamente, 593 fueron extirpadas y estudiadas histopatológicamnete. Resultados: Estudiamos 461 pacientes (68,1 por ciento mujeres y 31,9 por ciento hombres), de edades comprendidas entre 4 y 97 años (Media= 33,02 años). El tipo medio de piel fue el III (48,1 por ciento). Respecto a los hábitos de exposición solar, el 62,4 por ciento había sufrido alguna vez quemaduras solares, y un 20 por ciento se quemaba a menudo. La localización de los nevus más frecuente fue el tronco (34,5 por ciento de los nevus), la cabeza y el cuello (16,3 por ciento). El número total de nevus fue de 2247 (media=21.1 nevus y SD=20,3 nevus). Encontramos una asociación significativa del número de nevus con el sexo masculino (p<0.003), (media=24,2 nevus) y entre el tipo de piel (fototipo claro) y el número de nevus melanocíticos (p<0,05). Según la clasificación ABCD para los nevus atípicos, el 23,8 por ciento de los individuos estudiados presentaban un nevus con alguna de estas características. El estudio anatomopatológico se realizó sobre 593 nevus: nevus intradérmicos (30,5 por ciento), compuestos (26,8 por ciento) y congénitos, tanto intradérmicos como compuestos (22,6 por ciento). La correlación con la edad fue: nevus de unión en edades inferiores a 15 años, nevus compuestos entre 15 y 24 años, nevus intradérmicos a partir de los 45 (p<0.001), los nevus congénitos se diagnosticaban preferentemente en hombres menores de 24 años. Desde el punto de vista microscópico, el 11 por ciento de las lesiones eran nevus displásicos, asociándose significativamente a hombres entre 15 y 24 años (p<0,001). La correlación clinicopatológica fue del 100 por ciento en aquellos nevus que reunían todas las características clínicas atípicas (ABCD) e histopatológicas del displásico. Conclusión: El fototipo cutáneo representa la sensibilidad a la radiación solar: los tipos I y II presentan mayor número de nevus melanocítico y y riesgo de padecer melanoma, lo cual debe condicionar el comportamiento frente a la exposición solar desde la infancia. Además, los programas de prevención deberían combinar una alta sensibilidad, para extirpar los melanomas en un estadio inicial y una especificidad elevada, para extirpar el menor número de nevus comunes (AU)

[A case of Cogan-Reese syndrome (iris nevus syndrome)]. / Przypadek zespolu Cogana-Reese'a ("znamienia" teczówki).

A case of 37 years old woman with a classic form of Cogan-Reese iris naevus syndrome is presented. Closure angle glaucoma, being a part of syndrome, with glaucomatous disc damage was initially treated with drugs (betaxolol, trusopt) without effective IOP decrease. A surgery was performed (goniotrepanatio by Fronimopoulos modified by Palmberg, but without iridectomy), 5 fluorouracil subconjunctival injections were given to the patient postoperatively for 5 days. We received a good IOP control on the level of 12 mm Hg. The visual acuity was 1.0 after surgical procedure. We wanted to present this case because of its rarity and a typical surgical procedure (without applying iridectomy).

[The radiophosphorus (32P)-test in precanceroses and malignant tumors of the skin]. / Radiophosphor (32P)-Test bei Präkanzerosen und malignen Tumoren der Haut

In 21 patients with a variety of skin tumors (squamous cell carcinomas, malignant melanomas, basal cell epitheliomas and mycosis fungoides) or pre-cancerous lesions (Bowen's disease, actinic keratosis, junctional nevus cell nevus) the radioactive phosphorus uptake test demonstrates a significantly increased concentration of P32 in those tumors. There were no false negative tests. The possibility of differentiation of malignant melanoma from benign nevus cell nevus and the early recognition of cutaneous metastases is described. Furthermore recurrence of previously irradiated or excised basal cell epitheliomas can be detected without a biopsy. No hematological side-effects were observed.