Retinosquisis ligada al X en homocigosis: A propósito de un caso / X-linked retinoschisis: About a case

La retinosquisis ligada al cromosoma X (RLX) es una causa de degeneración retiniana que afecta a varones en edades tempranas. Los desórdenes ligados al cromosoma X clásicamente afectan sólo a varones. Presentamos el caso de una mujer de 10 años de edad, con el espectro completo de la patología. MAVC 0.7 AO. En la tomografía de coherencia óptica (TCO) presentaba alteración foveal bilateral de aspecto quístico. En el estudio genético se identifica la variante c.644A>T (p.Glu215Gly) en el gen RS1 en homocigosis, asociada a retinosquisis con modo de herencia recesiva ligada al X. La RXL es una condición que tiene una gran variedad en la severidad de la enfermedad y no existe correlación entre esta última y la progresión de la patología. La enfermedad ha sido descrita en un limitado número de mujeres principalmente en familias con alto grado de consanguinidad (AU)

X-linked retinoschisis (XLR) is a cause of retinal degeneration that affects males at an early age. X-linked disorders classically affect only males. We present the case of a 10-year-old female with the full spectrum of the pathology. BCVA 0.7 OU. Optical coherence tomography (OCT) showed bilateral foveal alteration with cystic appearance. The genetic study identified the variant c.644A>T (p.Glu215Gly) in the RS1 gene in homozygosis, associated with retinoschisis with X-linked recessive mode of inheritance. XLR is a condition that has a great variety in the severity of the disease and there is no correlation between the latter and the progression of the pathology. The disease has been described in a limited number of females mainly in families with high degree of consanguinity (AU)

Whole-exome sequencing identified a homozygous novel RAG1 mutation in a child with omenn syndrome

Introduction and objectives Omenn syndrome (OS) is a very rare type of severe combined immunodeficiencies manifested with erythroderma, eosinophilia, hepatosplenomegaly, lymph-adenopathy, and elevated level of serum IgE. OS is inherited with an autosomal recessive mode of inheritance. Germline mutations in the human RAG1 gene cause OS. Materials and methods In this study, we investigated a 2-month-old boy with cough, mild anaemia, pneumonia, immunodeficiency, repeated infection, feeding difficulties, hepatomegaly, growth retardation, and heart failure. Parents of the proband were phenotypically normal. Results Karyotype analysis and chromosomal microarray analysis found no chromosomal structural abnormalities (46, XY) and no pathogenic copy number variations (CNVs) in the proband. Whole-exome sequencing identified a novel homozygous single nucleotide deletion (c.2662delC) in exon 2 of the RAG1 gene in the proband. Sanger sequencing confirmed that both the proband parents were carrying this variant in a heterozygous state. This variant was not identified in two elder sisters and one elder brother of the proband and in the 100 ethnically matched normal healthy individuals. This novel homozygous deletion (c.2662delC) leads to the frameshift, which finally results in the formation of the truncated protein (p.Leu888Phefs*3) V(D)J recombination-activating protein 1 with 890 amino acids compared with the wildtype V(D)J recombination-activating protein 1 of 1043 amino acids. Hence, it is a loss-of-function variant. Conclusion Our present study expands the mutational spectrum of the RAG1 gene associated with OS. We also strongly suggested the importance of whole-exome sequencing for the genetic screening of patients with OS (AU)

Mesotelioma pleural / Pleural mesothelioma

El diagnóstico de mesotelioma pleural difuso requiere en la mayoría de los casos una biopsia pleural, realizada bajo control de imagen (ecografía o tomografía computarizada) o mediante toracoscopia. La pérdida de expresión de BAP1 o de MTAP (inmunohistoquímica) y la deleción homocigota de CDKN2A (hibridación fluorescente in situ) constituyen los marcadores moleculares básicos para el diagnóstico de mesotelioma. El tipo histológico y el estado funcional del paciente son los factores pronósticos más importantes. El control del derrame pleural se puede realizar a través de la inserción de catéteres pleurales tunelizados, bien como medida aislada (p. ej. pacientes no susceptibles de terapia multimodal que se han diagnosticado por citología del líquido pleural o biopsia guiada por imagen) o combinada con la administración de talco aerosolizado durante una toracoscopia diagnóstica. La inmunoterapia constituye una de las primeras líneas de tratamiento en pacientes inoperables, particularmente en las variedades histológicas bifásicas o sarcomatosas. (AU)

The diagnosis of diffuse pleural mesothelioma requires in most cases a pleural biopsy, performed either under imaging guidance (ultrasound or computed tomography) or thoracoscopy. Loss of BAP1 or MTAP expression (immunohistochemistry) and homozygous deletion of CDKN2A (fluorescence in situ hybridization) are the basic molecular markers for the diagnosis of mesothelioma. The histologic type and patient's performance status are the most important prognostic factors. Pleural effusion can be managed by the insertion of tunneled pleural catheters, either as a stand-alone measure (e.g., patients not amenable to multimodality therapy who have been diagnosed by pleural fluid cytology or image-guided biopsy) or combined with the administration of aerosolized talc during a diagnostic thoracoscopy. Immunotherapy is one of the front-line approaches in inoperable patients, particularly in biphasic or sarcomatous histologic varieties. (AU)

A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations

Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1. Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation. Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID. Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder (AU)

A familial Mediterranean fever patient with double homozygous mutations treated with anakinra after kidney transplantation / Un paciente con poliserositis familiar recurrente con mutaciones homocigóticas dobles tratado con anakinra tras un trasplante renal

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Características radiológicas de la artropatía microcristalina asociada a hemocromatosis hereditaria con mutación homocigota C282Y / Radiological features of crystal-induced arthropathy associated with hereditary hemochromatosis with homozygous C282Y mutation

Se expone el caso clínico de un paciente varón de 64 años con hemocromatosis (homocigoto C282Y) y artropatía microcristalina mostrando las características radiológicas más comunes que se encuentran en este trastorno metabólico y las diferencias que pueden existir al compararla con otros procesos degenerativos primarios u otras patologías inflamatorias

I present a clinical case of a 64-year-old male patient with hemochromatosis (homozygous C282Y) and crystal induced arthropathy showing the most common radiological features found in this metabolic disorder and the differences that may exist when compared to other primary degenerative processes or other inflammatory pathologies

Amiloidosis cardiaca por transtiretina causada por la mutación Val122Ile en homocigosis en varón de raza blanca / Transthyretin cardiac amyloidosis due to homozygous Val122Ile mutation in a caucasian man

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Exome sequencing revealed C1Q homozygous mutation in Pediatric Systemic Lupus Erythematosus

INTRODUCTION AND OBJECTIVES: Pediatric Systemic Lupus Erythematosus (pSLE) is an autoimmune disorder of children. Early disease onset raises the probability of genetic etiology and it is more severe than adult SLE. PATIENTS AND METHODS: Herein an eight-year-old girl with pSLE from consanguineous parents is reported. RESULTS: Although she was diagnosed as pSLE since the age of two years, Whole Exome Sequencing (WES) revealed a rare stop-gained C>T mutation in C1QA gene. The variant was validated and segregated in patient and the family. Furthermore, serum levels of the C1q protein were measured and found to be much lower than normal ranges. CONCLUSIONS: This study indicated that C1Q deficiency should be considered as a differential diagnosis of pSLE. Therefore, measurement of C1q should be recommended in all cases with pSLE

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A novel homozygous mutation with different clinical presentations in 2 IRAK-4-deficient siblings: first case with recurrent salmonellosis and non-hodgkin lymphoma

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Diagnóstico prenatal de síndrome de Bruck en una paciente con tres gestaciones consecutivas afectas / Prenatal diagnosis of Bruck syndrome in a patient with three consecutive pregnancies affected

La osteogénesis imperfecta es una enfermedad genética autosómica dominante, en la que existe un defecto en la formación de colágeno. Esto se traduce en distintos grados de debilidad y fragilidad ósea. Existen una serie de síndromes que durante años fueron clasificados como tipos de osteogénesis imperfecta, pero que más tarde se ha comprobado que a pesar de causar un fenotipo similar, no son causados por mutaciones en los genes del procolágeno tipo I. El síndrome de Bruck es un trastorno recesivo con contracturas congénitas y fragilidad ósea que fenotípicamente se parece a la osteogénesis imperfecta pero que el defecto se encuentra en ciertas regiones del cromosoma 3 y 17. Presentamos el caso de una paciente que realizó 3 interrupciones voluntarias del embarazo por fetos afectos de un síndrome caracterizado por fracturas patológicas intraútero. La necropsia del feto del tercer embarazo y los estudios genéticos realizados en tejido fetal y sangre de los padres, condujeron al diagnóstico de un síndrome de Bruck, lo que permitirá a la pareja la posibilidad de una futura gestación libre de enfermedad (AU)

Imperfect osteogenesis is a dominant autosomal genetic disease, which produce a defect in collagen formation, that results in degrees of weakness and bone fragility. For years, a number of syndromes were classified as types of imperfect osteogenesis, but it was found that despite it had a similar phenotype, they are caused by mutations in the genes of procollagen type I. Bruck syndrome is a recessive disorder with congenital contractures and bone fragility that phenotypically resembles imperfect osteogenesis, but that defect is found in certain regions of chromosome 3 and 17. We report a case of a patient who performed three abortions for fetuses suffering from a syndrome characterized by pathological fractures in utero. The autopsy of the fetus from the third pregnancy and genetic studies performed in fetal tissue and blood of parents, led to the diagnosis of Bruck syndrome, which allow the couple the possibility of future free disease gestation (AU)

Deficiencia de mevalonato quinasa (síndrome de hiper-IgD) y solapamiento con mutación de fiebre mediterránea familiar / Mevalonate kinase deficiency (hyper-IgD syndrome) overlap mutation familial Mediterranean fever

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Síndrome de descamación de la piel acral: presentación de un caso y revisión bibliográfica / Acral peeling skin syndrome: a case report and literature review

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Proven: The causative role of homozygous H63D mutation in hereditary haemochromatosis / Se demuestra el papel causal de la mutación H63D en homocigosis en la hemocromatosis hereditaria

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Methylenetetrahydrofolate Reductase gene polymorphism in children with allergic rhinitis

BACKGROUND: Methylenetetrahydrofolate Reductase (MTHFR) polymorphisms by impairing folate metabolism may influence the development of allergic diseases. The results of studies evaluating the relationship between MTHFR polymorphisms and atopic disease are controversial. The aim of this study was to investigate the association between the polymorphisms of C677T and A1298C for MTHFR gene and allergic rhinitis (AR) in children. METHODS: Ninety patients followed up with diagnosis of allergic rhinitis in our clinic and 30 children with no allergic diseases were included in the study. All participants were genotyped for the MTHFR (C677T) and (A1298C) polymorphisms. Vitamin b12, folate and homocysteine levels were measured. RESULTS: The mean age of patients was 9.2 ± 2.9 years; 66.7% of the patients were male. There was no significant difference between patient and control groups regarding gender, age and atopy history of the family (p > 0.05). The frequency of homozygotes for MTHFR C677T polymorphism in the patient and control groups was 3.3% and 10%, respectively. The frequency of homozygotes for MTHFR A1298C polymorphism among groups was 26.7% and 16.7%, respectively. The association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene was not statistically significant in patients compared with controls (p > 0.05). There were no statistically significant differences between the patients and the control group in terms of serum vitamin b12, folate and homocysteine levels (p > 0.05). CONCLUSION: We found no evidence for an association between allergic rhinitis and polymorphisms of C677T and A1298C for MTHFR gene in children. Further studies investigating the relationship between MTHFR polymorphism and AR are required

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Hipercolesterolemia familiar homocigota: adaptación a España del documento de posición del grupo de consenso sobre hipercolesterolemia familiar de la Sociedad Europea de Arteriosclerosis. Documento de Consenso de la Sociedad Española de Arteriosclerosis (SEA) y la Fundación Hipercolesterolemia Familiar (FHF) / Homozygous familial hypercholesterolaemia: Spanish adaptation of the position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Consensus document of the Spanish Society of Arteriosclerosis (SEA) and Familial Hypercholesterolaemia Foundation (FHF)

La hipercolesterolemia familiar homocigota (HFHo) es una enfermedad rara y potencialmente mortal que se caracteriza por la presencia en sangre de niveles muy elevados de colesterol en las lipoproteínas de baja densidad (cLDL) y por la aparición prematura y acelerada de enfermedad cardiovascular arteriosclerótica (ECVA). El Grupo de Consenso sobre hipercolesterolemia familiar de la Sociedad Europea de Arteriosclerosis (EAS) ha publicado recientemente una guía clínica para el diagnóstico y manejo clínico de la HFHo (Eur Heart J. 2014;35:2146-57). Tanto la Sociedad Española de Arteriosclerosis (SEA) como la Fundación Hipercolesterolemia Familiar (FHF) consideran este documento de consenso europeo de gran valor y utilidad. Sin embargo, existen particularidades propias de nuestro país que aconsejan realizar una adaptación española del documento europeo de HFHo, con el objeto de aproximar esta útil guía de práctica clínica a nuestro entorno más próximo. En España, el tratamiento crónico con estatinas, ezetimiba y resinas (colesevelam) tiene aportación reducida en el Sistema Nacional de Salud y es uno de los pocos países europeos donde la aféresis de LDL está incluida en la Cartera Básica de Servicios. El documento incluye, además, experiencias clínicas en el manejo de estos pacientes en nuestro país. Este comité de redacción enfatiza la necesidad de un diagnóstico precoz de los pacientes con HFHo, su remisión inmediata a una unidad especializada y el inicio temprano del tratamiento apropiado. Se espera que estas recomendaciones constituyan una guía para el abordaje del paciente con HFHo en España

Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening disease characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). The Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) has recently published a clinical guide to diagnose and manage HoFH (Eur Heart J. 2014;35:2146-57). Both the Spanish Society of Atherosclerosis (SEA) and Familial Hypercholesterolaemia Foundation (FHF) consider this European Consensus document of great value and utility. However, there are particularities in our country which advise to have a Spanish adaptation of the European HoFH document in order to approximate this clinical guide to our environment. In Spain, chronic treatment with statins, ezetimibe and resins (colesevelam) has a reduced contribution in the National Health System (NHS) and is one of the few European countries where LDL apheresis is included in the Basic Service Portfolio coverage. This Spanish document also includes clinical experience in the management of these patients in our country. The Drafting Committee emphasizes the need for early identification of HoFH patients, prompt referral to specialized units, and an early and appropriate treatment. These recommendations will provide a guidance for HoFH patient management in Spain

Tromboembolia pulmonar en un paciente con trombofilia familiar de origen genético debida a homocigosis en mutación 20209C>T / Pulmonary embolism in a patient with familial thrombophilia due to homozygotic genetic mutation in 20209C>T

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Síndrome de Sjögren-Larsson: tomografía de coherencia óptica y una nueva mutación / Sjögren-Larsson syndrome: Optical coherence tomography and a novel mutation

CASO CLÍNICO: Varón de 30 años con ictiosis, retraso intelectual, epilepsia y espasticidad. La exploración oftalmológica presenta agudeza visual corregida de 0,5 y maculopatía cristalina bilateral. La tomografía de coherencia óptica (OCT) muestra depósitos hiperrefringentes y pequeños quistes intrarretinianos foveales. Se diagnostica de síndrome de Sjögren-Larsson (SSL) y se confirma con el análisis genético. DISCUSIÓN: El SSL ocurre por mutaciones en el gen ALDH3A2. Se identifica una nueva mutación, la c.681-14T>G, no descrita previamente. La OCT permite analizar la mácula y detectar cambios, incluso no visibles oftalmoscópicamente. Su empleo es importante, porque ofrece imágenes específicas del SSL y ayuda al diagnóstico de esta rara enfermedad sistémica

CASE REPORT: A case is presented of a thirty year-old male with ichthyosis, mental retardation, epilepsy and spasticity. Ocular examination showed a best-corrected visual acuity of 0.5 and bilateral crystalline maculopathy. Optical coherence tomography (OCT) revealed focal hyperreflective spots and intrafoveal microcystoid spaces. The diagnosis of Sjögren-Larsson syndrome (SLS) was made, and confirmed by genetic analysis. DISCUSSION: SLS is caused by mutations in the ALDH3A2 gene. A previously unreported novel mutation was identified, c.681-14T>G. Macular OCT makes it possible to find even funduscopy invisible changes. Its use is important because the OCT features of SLS are specific and, therefore, it can help to diagnose this rare systemic disease