RESUMO
SIGNIFICANCE: Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon type of epidermal nevus and is refractory to therapy. We report the effectiveness of photodynamic therapy (PDT) for treating ILVEN with claudication in a young girl. ADDITIONAL CONTRIBUTIONS: We thank the patient for granting permission to publish this information. APPROACH: Aminolaevulinic Acid Hydrochloride (ALA) photodynamic therapy (PDT) was applied six times in 1-month interval. RESULTS: Most lesions and pruritus have subsided markedly, with mild scarring and a marked reduction in claudication. CONCLUSIONS: ALA PDT might be an effective and promising treatment for ILVEN in the future.
Assuntos
Nevo Sebáceo de Jadassohn , Nevo , Fotoquimioterapia , Feminino , Humanos , Nevo Sebáceo de Jadassohn/patologia , Virilha/patologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Nevo/patologiaRESUMO
The fibroblast growth factor receptors comprise a family of related but individually distinct tyrosine kinase receptors. Within this family, FGFR2 is a key regulator in many biological processes, e.g., cell proliferation, tumorigenesis, metastasis, and angiogenesis. Heterozygous activating non-mosaic germline variants in FGFR2 have been linked to numerous autosomal dominantly inherited disorders including several craniosynostoses and skeletal dysplasia syndromes. We report on a girl with cutaneous nevi, ocular malformations, macrocephaly, mild developmental delay, and the initial clinical diagnosis of Schimmelpenning-Feuerstein-Mims syndrome, a very rare mosaic neurocutaneous disorder caused by postzygotic missense variants in HRAS, KRAS, and NRAS. Exome sequencing of blood and affected skin tissue identified the mosaic variant c.1647=/T > G p.(Asn549=/Lys) in FGFR2, upstream of the RAS signaling pathway. The variant is located in the tyrosine kinase domain of FGFR2 in a region that regulates the activity of the receptor and structural mapping and functional characterization revealed that it results in constitutive receptor activation. Overall, our findings indicate FGFR2-associated neurocutaneous syndrome as the accurate clinical-molecular diagnosis for the reported individual, and thereby expand the complex genotypic and phenotypic spectrum of FGFR-associated disorders. We conclude that molecular analysis of FGFR2 should be considered in the genetic workup of individuals with the clinical suspicion of a mosaic neurocutaneous condition, as the knowledge of the molecular cause might have relevant implications for genetic counseling, prognosis, tumor surveillance and potential treatment options.
Assuntos
Craniossinostoses , Síndromes Neurocutâneas , Nevo Sebáceo de Jadassohn , Feminino , Humanos , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Genótipo , Mutação de Sentido Incorreto , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Craniossinostoses/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Schimmelpenning-Feuerstein-Mims syndrome (SFMS), an epidermal nevus disease, features skin lesions including craniofacial nevus sebaceous and extracutaneous anomalies (e.g. brain, eye, and bone). Recent genetic studies implicate HRAS, KRAS, and NRAS genes in somatic mutations. Our case, a 48-year-old man, presented with nevus sebaceous on the scalp; pigmented skin lesions on the right side of his neck, back, and chest along the Blaschko lines; a history of epilepsy; and mild intellectual disability. Accordingly, SFMS was suspected. DNA analysis of nevus sebaceous skin and peripheral blood leukocytes showed a pathogenic HRAS variant NM_005343.4:c.34G > A p.(Gly12Ser) in biopsy specimens from different skin layers but not blood, indicating somatic mosaic mutation. Until now, the HRAS p.(Gly12Ser) mutation has been reported in somatic RASopathies but not SFMS. The authors report this mutation in a case of SFMS, review another 15 cases of SFMS, and discuss HRAS c.34G > A p.(Gly12Ser) somatic mutations. RAS mutations of somatic RASopathies share activating hotspot mutations found in cancers, and produce different phenotypes depending on the developmental stage at which the somatic mutations occur.
Assuntos
Nevo Pigmentado , Nevo Sebáceo de Jadassohn , Nevo , Neoplasias Cutâneas , Humanos , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Nevo/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
Linear nevus sebaceous syndrome (LNSS) is a neurocutaneous disorder caused by somatic gain-of-function mutations in KRAS or HRAS. LNSS brains have neurodevelopmental defects, including cerebral defects and epilepsy; however, its pathological mechanism and potentials for treatment are largely unclear. We show that introduction of KRASG12V in the developing mouse cortex results in subcortical nodular heterotopia and enhanced excitability, recapitulating major pathological manifestations of LNSS. Moreover, we show that decreased firing frequency of inhibitory neurons without KRASG12V expression leads to disrupted excitation and inhibition balance. Transcriptional profiling after destabilization domain-mediated clearance of KRASG12V in human neural progenitors and differentiating neurons identifies reversible functional networks underlying LNSS. Neurons expressing KRASG12V show molecular changes associated with delayed neuronal maturation, most of which are restored by KRASG12V clearance. These findings provide insights into the molecular networks underlying the reversibility of some of the neuropathologies observed in LNSS caused by dysregulation of the RAS pathway.
Assuntos
Epilepsia , Nevo Sebáceo de Jadassohn , Camundongos , Animais , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Neuropatologia , Mutação/genéticaAssuntos
Carcinoma Basocelular , Ceratoacantoma , Neoplasia de Células Basais , Nevo Sebáceo de Jadassohn , Nevo , Neoplasias Cutâneas , Humanos , Nevo Sebáceo de Jadassohn/diagnóstico , Nevo Sebáceo de Jadassohn/patologia , Ceratoacantoma/diagnóstico , Epiderme/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Nevo/patologiaAssuntos
Carcinoma , Nevo Sebáceo de Jadassohn , Neoplasias das Glândulas Sudoríparas , Glândulas Apócrinas , Carcinoma/patologia , Humanos , Mutação , Nevo , Nevo Sebáceo de Jadassohn/diagnóstico , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologiaRESUMO
Schimmelpenning-Feuerstein-Mims (SFM) syndrome is a neurocutaneous disorder that can affect many body systems. The principal and most characteristic anomalies are craniofacial naevus sebaceous in association with neurological, ocular and skeletal findings. The presence of vascular malformations in this condition is unusual; nevertheless, vascular malformations have been suggested by many authors to be part of the spectrum of the same disease. Few cases have been published on the association of SFM with lymphatic malformations. This syndrome is categorized as a mosaic RASopathy due to postzygotic mutations in the HRAS, KRAS or NRAS genes. These genes are involved in the RAF-MEK-ERK signalling pathway, which is activated by mutant cells, increasing cellular proliferation. These mutations have been found only in naevus sebaceous cells, and may be also the explanation for many of the associated pathologies. We report a case of an 18-year-old boy diagnosed with SFM syndrome associated with lymphatic malformation in the legs and agenesia of the inguinal lymph nodes. The lymphatic alterations were diagnosed by gammography of the legs. The genetic diagnosis was confirmed by the presence of a KRAS postzygotic mutation in naevus sebaceous cells of a skin specimen. Genetically confirmed cases of mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular targeted therapy.
Assuntos
Linfonodos/anormalidades , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Virilha , Humanos , Perna (Membro) , Imageamento por Ressonância Magnética , Masculino , Mutação , Nevo Sebáceo de Jadassohn/diagnóstico por imagemAssuntos
Displasia Ectodérmica/diagnóstico , Herpes Simples/diagnóstico , Nevo Sebáceo de Jadassohn , Complicações Infecciosas na Gravidez/diagnóstico , Neoplasias Cutâneas , Diagnóstico Diferencial , Progressão da Doença , Dermatoses Faciais/diagnóstico , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Masculino , Nevo Sebáceo de Jadassohn/diagnóstico , Nevo Sebáceo de Jadassohn/patologia , Nevo Sebáceo de Jadassohn/cirurgia , Nevo Sebáceo de Jadassohn/terapia , Prognóstico , Procedimentos Cirúrgicos Profiláticos/métodos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controleRESUMO
Linear Sebaceous Nevus Syndrome is a rare disorder that presents with nevus sebaceus in association with corneal dermoids, colobomas, choroidal osteomas, and arachnoid cysts. It is thought to represent a mosaic RASopathy. These are disorders characterized by postzygotic somatic mutation in genes involved in RAS/MAPK signaling pathway. In this report we describe two patients with linear sebaceous nevus syndrome found to have mutations in codon 146 of KRAS with evidence of mosaicism. This specific mutation has previously been reported in Oculoectodermal Syndrome and Encephalocraniocutaneous Lipomatosis, two other mosaic RASopathies with predominantly cerebrooculocutaneous manifestations. These findings suggest that, while initially classified as different syndromes, these disorders should be evaluated and managed as a spectrum of related disorders.
Assuntos
Predisposição Genética para Doença , Nevo Sebáceo de Jadassohn/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pré-Escolar , Códon/genética , Humanos , Lactente , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mosaicismo , Mutação/genética , Nevo Sebáceo de Jadassohn/diagnóstico , Nevo Sebáceo de Jadassohn/patologiaRESUMO
Adult-onset inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon cutaneous disease compared to childhood-onset ILVEN. The typical histopathologic features are alternating parakeratosis and orthokeratosis with an absent granular layer underneath parakeratosis, in contrast to a thickened granular layer below the foci of orthokeratosis in psoriasiform epidermal hyperplasia. Herein, we present a 49-year-old woman with typical clinical and histopathologic characteristics of adult-onset ILVEN, including linear arrangement of thick scaly papules and plaques localized on the medial side of her right leg, ankle, and foot. Immunohistochemical studies included involucrin, Ki-67, and keratin-10. Compared to the staining pattern in psoriasis, the expression of involucrin in this case was of lower intensity and localized to upper epidermal layers with relatively less extensive staining beneath regions of parakeratosis as compared to orthokeratosis; Ki-67 showed lower basal layer proliferative activity; and keratin-10 showed a greater intensity of staining within suprabasal epidermis.
Assuntos
Nevo Sebáceo de Jadassohn/patologia , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Linear nevus sebaceous syndrome (LNSS) is a rare genetic disease characterized by large linear sebaceous nevus typically on the face, scalp, or neck. LNSS could be accompanied by multisystem disorders including the central nervous system. Herein, we report gene mutational profile via whole exome sequencing of both lesional and non-lesional skin samples in a LNSS patient. CASE PRESENTATION: A 17-year-old girl presented with multisystem abnormalities, including large skin lesions, ocular disorders, abnormal bone development and neurological symptoms. A diagnosis of LNSS was established based on clinical manifestations, histopathological and imaging findings. The skin lesions were resected and no recurrence was noted at the time of drafting this report. Whole exome sequencing of genomic DNA revealed the following 3 mutations in the lesions of the index patient: KRAS (c.35G > A, p.G12D), PRKRIR (c.A1674T, p.R558S), and RRP7A (c. C670T, p.R224W), but no mutation was found in the healthy skin and peripheral blood sample of the index patient, or in the blood samples of her parents and sibling. PCR-mediated Sanger sequencing of DNA derived from lesional skin sample of the index patient verified KRAS mutation, but not PRKRIR (c.A1674T, p.R558S) and RRP7A (c. C670T, p.R224W). None of the 3 mutations was found in Sanger sequencing in skin lesions of 60 other cases of nevus sebaceous patients. CONCLUSIONS: Our findings show the relevance of KRAS mutation to LNSS, providing new clues in understanding related genetic heterogeneity which could aid genetic counselling for LNSS patients.
Assuntos
Anormalidades Múltiplas/genética , Genes ras/genética , Nevo Sebáceo de Jadassohn/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Exotropia/etiologia , Feminino , Heterogeneidade Genética , Neoplasias de Cabeça e Pescoço/congênito , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Anormalidades Maxilomandibulares/genética , Aparelho Lacrimal/anormalidades , Nevo Sebáceo de Jadassohn/congênito , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/patologia , Neoplasias Torácicas/congênito , Neoplasias Torácicas/genética , Neoplasias Torácicas/patologia , Sequenciamento do ExomaAssuntos
Melanoma/diagnóstico , Pescoço/patologia , Nevo Sebáceo de Jadassohn/diagnóstico , Verrugas/patologia , Adulto , Biópsia , Dermoscopia/métodos , Erros de Diagnóstico , Humanos , Ceratose/patologia , Melanócitos/patologia , Melanoma/patologia , Nevo Sebáceo de Jadassohn/patologia , Papiloma/patologia , Transtornos da Pigmentação/patologia , Neoplasias Cutâneas/patologia , Pigmentação da PeleRESUMO
Overgrowth syndromes are a large group of rare disorders characterized by generalized or segmental excessive growth. Segmental overgrowth syndromes are mainly due to genetic anomalies appearing during the embryogenesis and leading to mosaicism. The numbers of patients with segmental overgrowth with an identified molecular defect has dramatically increased following the recent advances in molecular genetic using next-generation sequencing approaches. This review discusses various syndromes and pathways involved in segmental overgrowth syndromes and presents actual and future therapeutic strategies.
TITLE: Les syndromes de surcroissance segmentaire et les stratégies thérapeutiques. ABSTRACT: Les syndromes de surcroissance sont un groupe de pathologies caractérisées par une croissance excessive généralisée ou segmentaire. Les syndromes de surcroissance segmentaires sont principalement dus à des anomalies génétiques apparaissant durant l'embryogenèse et aboutissant à un mosaïcisme. Le nombre de patients atteints d'un syndrome de surcroissance avec une mutation identifiée a fortement augmenté grâce à des avancées récentes en génétique moléculaire, en utilisant le séquençage de nouvelle génération (NGS). Cette revue détaille les différents syndromes de surcroissance segmentaire ainsi que les voies moléculaires impliquées et les options thérapeutiques envisageables.
Assuntos
Transtornos do Crescimento/genética , Transtornos do Crescimento/terapia , Mosaicismo , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Síndrome de Beckwith-Wiedemann/terapia , Oftalmopatias/genética , Oftalmopatias/patologia , Oftalmopatias/terapia , Testes Genéticos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lipomatose/genética , Lipomatose/patologia , Lipomatose/terapia , Mosaicismo/embriologia , Mutação , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/patologia , Síndromes Neurocutâneas/terapia , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/patologia , Nevo Sebáceo de Jadassohn/terapia , Fosfatidilinositol 3-Quinases/genética , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patologia , Síndrome de Sturge-Weber/terapia , SíndromeRESUMO
Nevus sebaceus is a benign skin hamartoma of congenital onset that grows during puberty, and in adulthood can develop secondary benign and malignant neoplasms. The most common benign neoplasms occurring in nevus sebaceus are believed to be syringocystadenoma papilliferum, trichilemmoma, and trichoblastoma. A patient with nevus sebaceus developed not only syringocystadenoma papilliferum but also prurigo nodularis within her hamartomatous lesion; multiple biopsies were necessary to establish the diagnoses. Excision of the residual nevus sebaceus also revealed an apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma. Also, it is important to select the appropriate biopsy site and size when evaluating a patient for secondary neoplasms within their nevus sebaceous. Indeed, more than one biopsy may be required if additional diagnoses are suspected.
Assuntos
Segunda Neoplasia Primária/patologia , Nevo Sebáceo de Jadassohn/patologia , Prurigo/patologia , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias Cutâneas/patologia , Adenomas Tubulares de Glândulas Sudoríparas/patologia , Idoso , Biópsia/métodos , Feminino , HumanosRESUMO
Linear verrucous epidermal nevi (LVEN) are characterized by verrucous papules often coalescing into well-demarcated skin-colored or brown plaques following the lines of Blaschko. We present two new cases of LVEN with oral mucosa involvement and briefly discuss this very rare finding. In both cases, oral biopsies showed hyperkeratosis, acanthosis, and papillomatosis. Although several treatment modalities have been reported for the cutaneous lesions, there is no consensus for the management of oral lesions so far.
Assuntos
Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Nevo Sebáceo de Jadassohn/patologia , Neoplasias Cutâneas/patologia , Biópsia , Criança , Feminino , Humanos , MasculinoRESUMO
El nevus epidérmico verrucoso inflamatorio lineal (NEVIL) es un tipo de nevus epidérmico queratinocítico, poco frecuente, de aparición predominante en la infancia, con preponderancia sobre el sexo femenino. Se caracteriza por la presencia de pápulas eritematosas descamativas de aspecto psoriasiforme, intensamente pruriginosas, que tienden a coalescer para formar placas que se distribuyen siguiendo las líneas de Blaschko. Suele presentarse de forma unilateral en extremidades inferiores y tiene pobre respuesta al tratamiento.
Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare type of keratinocytic epidermal nevus that predominantly appears in childhood and female sex. It is characterized by the presence of psoriasiform, scaly, intensely itchy erythematous papules that tend to coalesce to form plaques that are distributed along Blaschko's lines. It usually affects the lower extremities unilaterally, and responds poorly to treatment.