Asunción Vicente

Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast‐flow vascular anomalies are caused by RASA1 mutations

Capillary malformation‐arteriovenous malformation (CM‐AVM) is a newly recognized autosomal dominant disorder, caused by mutations in the RASA1 gene in six families. Here we report 42 novel RASA1 mutations and the associated phenotype in 44 families. The penetrance and de novo occurrence were high. All affected individuals presented multifocal capillary malformations (CMs), which represent the hallmark of the disorder. Importantly, one‐third had fast‐flow vascular lesions. Among them, we observed severe intracranial AVMs, including vein of Galen aneurysmal malformation, which were symptomatic at birth or during infancy, extracranial AVM of the face and extremities, and Parkes Weber syndrome (PKWS), previously considered sporadic and nongenetic. These fast‐flow lesions can be differed from the other two genetic AVMs seen in hereditary hemorrhagic telangiectasia (HHT) and in phosphatase and tensin homolog (PTEN) hamartomatous tumor syndrome. Finally, some CM‐AVM patients had neural tumors reminiscent of neurofibromatosis type 1 or 2. This is the first extensive study on the phenotypes associated with RASA1 mutations, and unravels their wide heterogeneity. Hum Mutat 29(7), 959–965, 2008.

RASA1 mutations and associated phenotypes in 68 families with capillary malformation-arteriovenous malformation

Capillary malformation–arteriovenous malformation (CM–AVM) is an autosomal‐dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast‐flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM–AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM–AVM (n = 100), common CM(s) (port‐wine stain; n = 100), Sturge–Weber syndrome (n = 37), or isolated AVM(s) (n = 24). Fifty‐eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM–AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the “second‐hit” hypothesis as a pathophysiological mechanism for CM–AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild‐type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM–AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast‐flow lesions warrants careful clinical and radiologic examination, and regular follow‐up.

Prevalence study of nevi in children from Barcelona. Dermoscopy, constitutional and environmental factors.

Background: Malignant melanoma is becoming an increasingly important problem in public health as incidence rates have been increasing continuously in Caucasian populations. Childhood and adolscence is an important time of life for the formation and evolution of nevi, and the presence of a higher number of nevi in early life could predict a major risk of developing melanoma. Objectives: (1) To determine the number of nevi and the dermoscopic pattern predominance in children of our population. (2) To relate it to constitutional and environmental factors. Methods: Clinical and dermoscopic examinations were performed in 180 children aged 1–15 years. A questionnaire including topics such as past history of sunburns, tanning ability, tendency to sunburn, history of sunlight exposure, use of sunscreens, tendency to freckle and family history of cancer was completed in a face-to-face interview with the parents. On clinical examination, we evaluated hair color, eye color, number of nevi and the presence of nevi in specific locations. All melanocytic lesions were examined dermoscopically, and all patterns were registered as present or absent. We also registered the predominant dermoscopic pattern of the child, defined as being present in more than 40% of all of the individual’s nevi. Results: The mean number of moles was 17.5. Male gender, past history of sunburns, facial freckling and family history of breast cancer were independent risk factors for having a higher number of nevi. We found that 61.1% of children had nevi on the face and neck, 17.2% on the buttocks, 11.7% on the scalp, 19.4% had acral nevi and 31.7% had congenital nevi. We found the presence of nevi in some of these locations to be a risk factor for having a higher number of nevi. The most frequent dominant dermoscopic pattern found in our population was the globular type. Interestingly, we found that the homogeneous pattern predominates in the youngest children, the reticular pattern predominates in adolescents and the dominant globular pattern is constant among all ages evaluated. Conclusion: This is the first study clinically and dermoscopically characterizing nevi in children from our population, and evaluating constitutional and environmental risk factors.

Prevalence of autosomal recessive congenital ichthyosis: A population-based study using the capture-recapture method in Spain

BACKGROUNDnPrevious reports on the prevalence of autosomal recessive congenital ichthyosis (ARCI) were based on single source data, such as lists of members in a patient association. These sources are likely to be incomplete.nnnOBJECTIVESnWe sought to describe the prevalence of ARCI.nnnMETHODSnWe obtained data from 3 incomplete sources (dermatology departments, a genetic testing laboratory, and the Spanish ichthyosis association) and combined them using the capture-recapture method.nnnRESULTSnWe identified 144 living patients with ARCI. Of these, 62.5% had classic lamellar ichthyosis and 30.6% had congenital ichthyosiform erythroderma. The age distribution included fewer elderly patients than expected. The prevalence of ARCI in patients younger than 10 years, the best estimate as less subject to bias, was 16.2 cases per million inhabitants (95% confidence interval 13.3-23.0). According to the capture-recapture model, 71% of the patients were not being followed up in reference units, 92% did not have a genetic diagnosis, and 78% were not members of the ichthyosis association.nnnLIMITATIONSnThe prevalence of ARCI in Spain and findings related to the Spanish health care system might not be generalizable to other countries.nnnCONCLUSIONSnThe prevalence of ARCI is higher than previously reported. Many patients are not being followed up in reference units, do not have a genetic diagnosis, and are not members of a patient association, indicating room for improvement in their care. Data suggesting a reduced number of older patients might imply a shorter life expectancy and this requires further study.

Germline loss-of-function mutations in EPHB4 cause a second form of capillary malformation-arteriovenous malformation (CM-AVM2) deregulating RAS-MAPK signaling

Background: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. Results: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.

Trichophyton violaceum: un patógeno emergente

Los cambios poblacionales (viajes a zonas endemicas, inmigracion o adopciones internacionales) han contribuido al resurgimiento de ciertos patogenos en nuestra area geografica, como ha ocurrido con Trichophyton violaceum. Se ha hecho una revision retrospectiva de todas las micosis superficiales por T. violaceum durante los anos 2000-2006, que representaron un 18,5% de los 275 dermatofitos aislados en el citado periodo. El 96% de estos pacientes eran extranjeros con diagnostico de tinea capitis. Concluimos que el aumento de tinea capitis por T. violaceum en pacientes pediatricos esta directamente relacionado con la inmigracion.

Prevalence of Dystrophic Epidermolysis Bullosa in Spain: A Population-Based Study Using the 3-Source Capture–Recapture Method. Evidence of a Need for Improvement in Care

BACKGROUNDnDystrophic epidermolysis bullosa (DEB) is a rare disease that represents a heavy burden for both the patient and the health care system. There are currently no data on the prevalence of DEB in Spain.nnnOBJECTIVEnTo determine the prevalence of DEB in Spain.nnnMETHODSnWe used data from 3 incomplete population-based sources (hospital dermatology departments, diagnostic laboratories performing antigenic mapping, genetic testing or both, and the Spanish Association of Epidermolysis Bullosa Patients [DEBRA]) and combined them using the 3-source capture-recapture methodology.nnnRESULTSnWe identified 152 living DEB patients. The estimated prevalence of DEB was 6.0 cases per million (95% CI, 4.2-11.8) in adults and 15.3 (95% CI, 10.4-40.8) in children under 18 years of age. The data indicated that 77% of the patients were not being followed up in specialized centers of reference; 65% had not had a genetic diagnosis, and 76% were not members of DEBRA.nnnCONCLUSIONSnThe prevalence of DEB in Spain is 6.0 patients per million (95% CI, 4.2-11.8), a figure higher than previous estimates in many areas, but similar to those found in other southern Europe countries. The north-south difference may represent real geographic differences in prevalence, but it might be due to the fact that most of the data come from registries with a lower than expected catchment. Many patients are not being followed up in centers of reference, do not have genetic diagnosis, and are not members of patients associations, suggesting that there is room for considerable improvement in their care.

Reference centers for epidermolysis bullosa and ichthyosis: an urgent need in spain

a Departamento de Dermatologia, Hospital Infantil del Nino Jesus, Madrid, Spain b Departamento de Dermatologia, Hospital La Paz, Madrid, Spain c Departamento de Dermatologia, Hospital Sant Joan de Deu, Barcelona, Spain d Departamento de Dermatologia, Hospital Santa Creu y Sant Pau, Barcelona, Spain e Director of DeBRA, Spain f Enfermera del Centro de Referencia Estatal de Atencion a personas con Enfermedades Raras y sus familias, Burgos, Spain g Instituto de Investigacion de Enfermedades Raras. Instituto de Salud Carlos III, Madrid, Spain loaded from http://www.actasdermo.org, day 10/05/2016. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

Langerhans cell histiocytosis presenting as fingernail changes

Langerhans cell histiocytosis (LCH) identifies a spectrum of disorders that are classified according to the organs involved (single- or multi-organ disease) and the presence or absence of organ failure. Patients younger than 2xa0years with a multisystem disease have a significantly higher mortality rate than older children.1 n nNail involvement in LCH is extremely uncommon and rarely reported. To our knowledge, 18 cases have been documented in the literature to date. According to most cases reported, it is thought to indicate a poor prognosis.2, 3, 4, 5, 6 We report the case of a child with nail lesions, which led to a diagnosis of LCH.

Agminated cellular blue naevi of the penis: dermoscopic, confocal and histopathological correlation of two cases.

Blue naevi may present rarely as multiple lesions grouped in a circumscribed area, described as agminated blue naevi. This clinical presentation may mimic metastatic malignant melanoma. We present two cases of agminated cellular blue naevi of the penis, with dermoscopy, reflectance confocal microscopy and histopathological correlation. Dermoscopy of the area showed multiple grouped lesions of homogeneous dark‐brown to blue colour. Using reflectance confocal microscopy, focusing on the bluish areas, predominantly bright dendritic cells were visible at the dermoepidermal junction and papillary dermis, while in the brownish areas the presence of dendritic and bright cells predominated in the basal layer. Our patients are of special interest as they are the first cases, to our knowledge, reported of agminated blue naevi on the penis, studied by both dermoscopy and confocal microscopy, confirming the diagnosis with histopathological correlation. Moreover, one case represented a divided or ‘kissing’ blue naevus of the penis.