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Antecedents: La neurofibromatosi tipus 2 (NF2) es una malaltia genètica que es caracteritza per l'aparició de múltiples tumors benignes en el sistema nerviós, el que condiciona una gran morbiditat associada. Es por això que és molt important poder realitzar un diagnòstic precoç, especialment en els casos més greus. Un diagnòstic a les primeres fases de la vida facilita una gestió més adequada del pacient i millora la supervivència. Les lesions cutànies en la NF2 son freqüents i poden aportar una gran informació en el diagnòstic i el pronòstic de la mateixa; no obstant, a dia d'avui no han rebut l'atenció que mereixen i no s'ha aprofundit en el seu estudi. El principal objectiu d'aquesta tesi és caracteritzar amb detall les lesions cutànies en la NF2, tant des del punt de vista clínic com microscòpic. Els objectius secundaris d'aquest estudi son investigar si aquestes lesions cutànies tenen un valor pronòstic i si a més poden resultar útils en el diagnòstic genètic de la malaltia. Mètode: s'ha estudiat la clínica i la microscòpia de les lesions cutànies de 49 pacients amb NF2. Per analitzar si les lesions cutànies s'associaven a un pitjo pronòstic vam correlacionar la seva presència amb escales de gravetat clínica i genètica. Vam recollir dades sobre la presència o absència de les mateixes, la seva localització, l'edat al diagnòstic de la malaltia, l'edat d'aparició de les lesions cutànies, dades clíniques i microscòpiques d'aquestes lesions, el grau d'afectació sistèmica del pacient i el tipus de mutació genètica responsable de la malaltia. A més, vam realitzar l'anàlisi genètic del material obtingut de 7 lesions cutànies buscant la mutació constitucional responsable de la malaltia. Resultats: Es van analitzar 49 pacients (31 dones [63.3%] i 18 homes [36.7%]), dels quals 33 (67.3%) van presentar lesions cutànies suggestives en la clínica de schwannomes cutanis. En base al seu aspecte clínic, aquests schwannomes es van distribuir de la següent manera: 24 pacients (48%) tenien tumors profunds, 21 (42%) schwannomes en forma de placa i 3 (6%) tumors superficials. En l'estudi histològic de 27 mostres obtingudes de 23 pacients es van observar dos patrons, un en forma de schwannoma clàssic o de tumor híbrid schwannoma-neurofibroma i un altre de schwannoma plexiforme. El primer patró es va observar en 8 tumors profunds, mentre que el patró de schwannoma plexiforme va ser present en 17 lesions tipus placa i en 2 tumors superficials. El 100% de pacients amb lesions tipus placa o tumors superficials identificaven la seva aparició en les primeres 2 dècades de la vida. En la nostra cohort el 100% dels pacients amb lesions tipus placa i amb tumors superficials es trobaven dins els grups de major gravetat fenotípica i el 82.6% d'ells estaven en els 3 grups de major gravetat genètica. A més, en l'anàlisi genètic dels cultius de cèl·lules de Schwann obtinguts de 7 schwannomes en forma de plaques cutànies (100%) es va aconseguir identificar la mutació constitucional responsable de la malaltia en tots ells. Conclusió: Les lesions cutànies, en especial els schwannomes plexiformes, son freqüents en els pacients amb NF2, apareixen en els primers anys de vida i la seva existència s'associa a un pitjor pronòstic. A més, aquestes lesions poden ser útils en el diagnòstic genètic de la malaltia. Antecedentes: La neurofibromatosis tipo 2 (NF2) es una enfermedad genética que se caracteriza por la aparición de múltiples tumores benignos en el sistema nervioso, lo que condiciona una gran morbilidad asociada. Es por ello que es muy importante poder realizar un diagnóstico precoz, especialmente en los casos más graves. Un diagnóstico a edades tempranas facilita una gestión más adecuada del paciente y mejora la supervivencia. Las lesiones cutáneas en la NF2 son frecuentes y pueden aportar una gran información en el diagnóstico y el pronóstico de la misma; no obstante, a día de hoy no han recibido la atención que merecen y, por ende, no se ha profundizado en su estudio. El principal objetivo de esta tesis es caracterizar con detalle las lesiones cutáneas en la NF2, tanto desde el punto de vista clínico como microscópico. Los objetivos secundarios de este estudio son investigar si estas lesiones cutáneas tienen un valor pronóstico y si además pueden resultar útiles en el diagnóstico genético de la enfermedad. Método: Para ello se ha estudiado la clínica y la microscopia de las lesiones cutáneas de 49 pacientes con NF2. Para analizar si las lesiones cutáneas se asociaban a un peor pronóstico correlacionamos su presencia con escalas de gravedad clínica y genética. Recogimos datos sobre la presencia o ausencia de las mismas, la localización, la edad al diagnóstico de la enfermedad, edad de aparición de las lesiones cutáneas, datos clínicos y microscópicos de estas lesiones, el grado de afectación sistémica del paciente y el tipo de mutación genética responsable de la enfermedad. Además, realizamos el análisis genético del material obtenido de 7 lesiones cutáneas buscando la mutación constitucional responsable de la enfermedad. Resultados: Se analizaron 49 pacientes (31 mujeres [63.3%] y 18 hombres [36.7%]), de los cuales 33 (67.3%) presentaron lesiones cutáneas sugestivas en la clínica de schwannomas cutáneos. En base a su aspecto clínico, estos schwannomas se distribuyeron de la siguiente forma: 24 pacientes (48%) tenían tumores profundos, 21 (42%) schwannomas en forma de placa y 3 (6%) tumores superficiales. En el estudio histológico de 27 muestras obtenidas de 23 pacientes se observaron dos patrones, uno en forma de schwannoma clásico o de tumor híbrido schwannoma-neurofibroma y otro de schwannoma plexiforme. El primer patrón se observó en 8 tumores profundos, mientras que el patrón de schwannoma plexiforme estuvo presente en 17 lesiones tipo placa y en 2 tumores superficiales. El 100% de pacientes con lesiones tipo placa o tumores superficiales identificaban su aparición en las primeras 2 décadas de la vida. En nuestra cohorte el 100% de los pacientes con lesiones tipo placa y con tumores superficiales se encontraban dentro de los grupos de mayor gravedad fenotípica y el 82.6% de ellos estaban en los 3 grupos de mayor gravedad genética. Además, en el análisis genético de los cultivos de células de Schwann obtenidos de 7 schwannomas en forma de placas cutáneas (100%) se consiguió identificar la mutación constitucional responsable de la enfermedad en todas ellas. Conclusión: La presencia de lesiones cutáneas, en especial los schwannomas plexiformes, son frecuentes en los pacientes con NF2, aparecen en los primeros años de vida y su existencia se asocia a un peor pronóstico. Además, estas lesiones pueden ser útiles en el diagnóstico genético de la enfermedad. Background: Neurofibromatosis type 2 (NF2) is a genetic disease characterized by the appearance of multiple benign tumors in the nervous system. NF2 is associated with high morbidity. It is very important to diagnose the disease early in life, specially, in the most serious cases because an early diagnosis favors a better management and improves survival. Cutaneous lesions are common and may provide useful diagnostic and prognostic information, but they have not been widely studied. The main objective in our study is to characterize cutaneous lesions both clinically and histologically, in a cohort of patients with NF2. Secondary objectives of this study are to investigate whether these skin lesions have prognostic value and whether they can be useful in the genetic diagnosis of the disease. Method: We studied the clinical and histologic characteristics of cutaneous lesions in 49 patients with NF2 and analyzed correlations with phenotype- and genotype-based severity scores. We collected information on the presence/absence of cutaneous lesions, location, age at onset and age at diagnosis, type of lesion, and histologic features. We also studied level of systemic involvement and genetic mutations involved. Besides we genetically analyzed material obtained from skin lesions from 7 patients with NF2 searching a constitutional and a somatic mutation NF2 mutation. Results: Forty-nine patients (31 women [63.3%] and 18 men [36.7%]) were analyzed, and 33 (67.3%) had cutaneous lesions presumed to be schwannomas. According to their clinical form they were distributed as follow: 24 patients (48%) had deep schwannomas, 21 (42%) had plaque-like lesions, and 3 patients (6%) had superficial tumors. Histologic examination from 27 lesions analyzed out 23 patients showed classic schwannoma or hybrid schwannoma-neurofibroma features in the 8 deep tumors biopsied and plexiform schwannoma features in the 17 plaque-like lesions and the 2 superficial tumors analyzed. Early onset (first 2 decades of life) was reported by all patients with plaques and superficial tumors. In our cohort, 100% of the patients with plaque-like lesions and superficial tumors with microscopic features of plexiform schwannoma were in the 2 groups with the most severe clinical phenotypes, and 82.6% of them were in the 3 most severe genotype-based classes. Besides, genetic analysis of primary Schwann cell cultures derived from 7 skin plaques (100%) allowed the identification of a constitutional mutation in all of them. Conclusions: Cutaneous lesions, especially plexiform schwannomas, are common in NF2, they usually appear at an early age and their presence is associated with a worst prognosis. Besides, these lesions can be used to genetically diagnose the disease.

Altres ajuts: acords transformatius de la UAB Linear Cowden nevus, also known as linear PTEN nevus, is a type of epidermal nevus, first described in 2007, which is seen in patients with PTEN hamartoma tumor syndrome. It is considered to be a type 2 form of segmental mosaicism, and we suggest that it has certain clinical features that distinguish it from epidermal nevi seen in similar conditions, such as Proteus syndrome. We present a case of linear Cowden nevus in a 4-year-old boy and review the literature.

Background Neurofibromatosis type 2 (NF2) is a genetic disease characterized by the appearance of multiple tumours in the nervous system. Cutaneous lesions are common and may provide useful diagnostic and prognostic information, but they have not been widely studied. Objectives To characterize cutaneous lesions in a Spanish cohort of patients with NF2 and investigate associations with clinical and genetic severity. Methods We studied the clinical and histologic characteristics of cutaneous lesions in 49 patients with NF2 and analysed correlations with phenotype- and genotype-based severity scores. We collected information on the presence/absence of cutaneous lesions, location, age at onset, type of lesion, and histologic features. We also studied level of systemic involvement and genetic mutations involved. Results Forty-nine patients (31 women [63.3%] and 18 men [36.7%]) were analysed, and 33 (67.3%) had cutaneous lesions presumed to be schwannomas. According to their clinical form, they were distributed as follows: 24 patients (48%) had deep tumours, 21 (42%) had plaque-like lesions, and 3 (6%) had superficial tumours. Histologic examination from 27 lesions analysed out 23 patients showed classic schwannoma or hybrid schwannoma-neurofibroma features in the 8 deep tumours biopsied and plexiform schwannoma features in the 17 plaque-like lesions and the 2 superficial tumours analysed. Early onset (first 2 decades of life) was reported by all patients with plaques and superficial tumours. In our cohort, 100% of the patients with plaque-like lesions and superficial tumours with microscopic features of plexiform schwannoma were in the 2 groups with the most severe clinical phenotypes, and 82.6% of them were in the 3 most severe genotype-based classes. Conclusions and Relevance Cutaneous lesions, specially plexiform schwannomas, are common in NF2, and they usually appear at an early age providing useful diagnostic and prognostic information. These tumours are part of the spectrum of cutaneous manifestations in this disease. Although its diagnostic and prognostic value has been pointed out, there are few studies focussed on their analysis.

Altres ajuts: acords transformatius de la UAB Background: Neurofibromatosis type 2 (NF2) is a genetic disease characterized by the appearance of multiple tumours in the nervous system. Cutaneous lesions are common and may provide useful diagnostic and prognostic information, but they have not been widely studied. Objectives: To characterize cutaneous lesions in a Spanish cohort of patients with NF2 and investigate associations with clinical and genetic severity. Methods: We studied the clinical and histologic characteristics of cutaneous lesions in 49 patients with NF2 and analysed correlations with phenotype- and genotype-based severity scores. We collected information on the presence/absence of cutaneous lesions, location, age at onset, type of lesion, and histologic features. We also studied level of systemic involvement and genetic mutations involved. Results: Forty-nine patients (31 women [63.3%] and 18 men [36.7%]) were analysed, and 33 (67.3%) had cutaneous lesions presumed to be schwannomas. According to their clinical form, they were distributed as follows: 24 patients (48%) had deep tumours, 21 (42%) had plaque-like lesions, and 3 (6%) had superficial tumours. Histologic examination from 27 lesions analysed out 23 patients showed classic schwannoma or hybrid schwannoma-neurofibroma features in the 8 deep tumours biopsied and plexiform schwannoma features in the 17 plaque-like lesions and the 2 superficial tumours analysed. Early onset (first 2 decades of life) was reported by all patients with plaques and superficial tumours. In our cohort, 100% of the patients with plaque-like lesions and superficial tumours with microscopic features of plexiform schwannoma were in the 2 groups with the most severe clinical phenotypes, and 82.6% of them were in the 3 most severe genotype-based classes. Conclusions and Relevance: Cutaneous lesions, specially plexiform schwannomas, are common in NF2, and they usually appear at an early age providing useful diagnostic and prognostic information. These tumours are part of the spectrum of cutaneous manifestations in this disease. Although its diagnostic and prognostic value has been pointed out, there are few studies focussed on their analysis.

The widespread use of anti-programmed cell death receptor-1 (PD-1) agents has shed light to unusual immune-related adverse effects, especially affecting the skin. We report a case of bullous pemphigoid secondary to nivolumab therapy for metastatic renal carcinoma with a previously unreported complete response to clobetasol ointment alone. The autoimmune blistering disease was successfully treated without oral corticosteroids, and the anti-PD-1 agent could be maintained without recurrence of the skin lesions. Topical therapy remains a good option in selected, mild-to-moderate cases of induced bullous pemphigoid.

Protein S deficiency is rare in systemic lupus erythematosus (SLE) and is generally associated with the presence of antiphospholipid (APL) antibodies. Lack of protein S can cause skin necrosis, but when it does it is generally in response to warfarin exposure. In this article, we describe the case of a patient who had not received warfarin and without APL antibodies who developed extensive skin necrosis due to protein S deficiency. It is important to investigate protein S deficiency in patients with lupus and extensive skin ulcers as it is a sign of arterial thrombosis and venous thromboembolism.

Protein S deficiency is rare in systemic lupus erythematosus (SLE) and is generally associated with the presence of antiphospholipid (APL) antibodies. Lack of protein S can cause skin necrosis, but when it does it is generally in response to warfarin exposure. In this article, we describe the case of a patient who had not received warfarin and without APL antibodies who developed extensive skin necrosis due to protein S deficiency. It is important to investigate protein S deficiency in patients with lupus and extensive skin ulcers as it is a sign of arterial thrombosis and venous thromboembolism.

Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients, mostly due to the effect of immunosuppressive treatment.Even so, before asserting that said complication is indeed secondary to drugs, it is very important to establish a differential diagnosis with other mouth ulcer causes, such as systemic diseases or viral infections, which are also common in these patients. Resumen: Las úlceras orales son una de las complicaciones cutáneas que pueden afectar con frecuencia a los pacientes trasplantados renales, debido muchas veces al efecto del tratamiento inmunosupresor.Aun así, es importante, antes de asegurar que dicha complicación es secundaria a los fármacos, establecer el diagnóstico diferencial con otras causas de úlceras orales como pueden ser enfermedades sistémicas o infecciones virales, también frecuentes en este tipo de pacientes. Keywords: Kidney transplant, Mycophenolate mofetil, Mouth ulcers, Cytomegalovirus, Palabras clave: Trasplante renal, Micofenolato mofetilo, Úlceras orales, Citomegalovirus