Loss of NHEJ1 Protein Due to a Novel Splice Site Mutation in a Family Presenting with Combined Immunodeficiency, Microcephaly, and Growth Retardation and Literature Review.

INTRODUCTION: Non-homologous end joining gene 1 (NHEJ1) defect is a rare form of primary immune deficiency. Very few cases have been described from around the world. PURPOSE: We are reporting the first family from the Arabian Gulf with three siblings presenting with combined immunodeficiency (CID), microcephaly, and growth retardation due to a novel NHEJ1 splice site mutation, in addition to a review of the previously published literature on this subject. METHODS: Patients' clinical, immunological, and laboratory features were examined. Samples were subjected to targeted next-generation sequencing (NGS). The pathogenic change in NHEJ1 was confirmed by Sanger sequencing, then further assessed at the RNA and protein levels. RESULTS: Patients were found to have a homozygous splice site mutation immediately downstream of exon 3 in NHEJ1 (c.390 + 1G > C). This led to two distinct mRNA products, one of which demonstrated skipping of the last 69 basepairs (bp) of exon 3 while the other showed complete skipping of the entire exon. Although both deletions were in-frame, immunoblotting did not reveal any NHEJ1 protein products in patient cells, indicating a null phenotype. CONCLUSION: Patients presenting with CID, microcephaly, and growth retardation should be screened for NHEJ1 gene mutations. We discuss our data in the context of one of our patients who is still alive at the age of 30 years, without transplantation, and who is the longest known survivor of this disease.

Clinical, immunological, and molecular characterization of hyper-IgM syndrome due to CD40 deficiency in eleven patients.

PURPOSE: Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency with few reported cases. In this study, we further characterize the clinical, immunological, and molecular profiles of the disease in a cohort of 11 patients. METHODS: Molecular genetic analysis and a comprehensive clinical review of patients diagnosed with HIGM3 at our tertiary care center from 1994 to 2011 were undertaken. RESULTS: Eleven patients from seven families were enrolled. The patients had a median age of 9 years [ranging from 2 to 22 years old]. All 11 patients had recurrent chest infections at presentation. Pneumocystis jiroveci pneumonia was confirmed in three patients. Five patients had sclerosing cholangitis, and five patients had Cryptosporidium isolated from their stool. Six patients had nasal and sinus infections, and two of these patients had destructive nasal fungal infections. Eight patients had neutropenia. All of the patients had low IgG and normal or high IgM levels. IgA was undetectable in all but three patients. Two novel mutations were found: a splice site for intron 3 and a missense mutation located in the coding region of exon 3. Two patients underwent successful stem cell transplantation from a matched donor. Four patients are doing well on prophylaxis; two are very sick, one with protracted diarrhea and persistent Cryptosporidium and the other with neurological complications. Three patients died early in life as a result of severe sepsis. CONCLUSIONS: To our knowledge, this report provides the largest cohort of patients with this disease with a very long follow-up period. Our cohort showed variable disease severity

Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients.

PURPOSE: Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis. METHODS: Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations. RESULTS: Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes. CONCLUSION: Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.

[Managing complications in severe traumatic injury with VAC therapy with instillation]. / Manejo de complicaciones en herida traumática terapia de presión negativa VAC con instilación.

The complex fractures caused by high energy trauma, poses a major surgical challenge. Vessels, skin and subcutaneous tissues. The Vacuum Assisted Therapy (VAC) has become a very useful tool since the last century's 90 decade. Based in the application of negative pressure to the wound bed, promotes healing by granulation tissue formation, keeping the wound clean and avoiding bacterial colonization. Used as a primary method or in combination with others, VAC therapy allows more conservative options in the treatment of these wounds. We describe the application of the VAC therapy in a clinical case with complex injury, showing its efficacy, added the benefit of the instillation therapy.

[Treatment applied to post-perfusion phlebitis]. / Tratamientos aplicados a las flebitis posperfusión.

During the physio-pathological process which causes phlebitis, a vesicular constriction and an aggregation of platelets occurs. Therefore, the authors believe that the application of a vesicular dilator such as nitroglycerine would alleviate the symptoms of post-perfusion phlebitis and would be an alternate treatment to the commonly utilized heparinized cream, about whose effectiveness in treating this medical problem virtually no documentation exists.

Manejo de heridas complejas en fractura de cadera con terapia de presión negativa / Complex wound management after hip fracture with vacuum assisted therapy

Introducción: La Terapia con Presión Negativa (TPN) se considera un método avanzado para el manejo de las heridas, ya que promueve la curación de éstas mediante la aplicación de presión negativa, de manera que el uso de niveles controlados de presión subatmosférica y succión, acelera la resolución de las heridas favoreciendo la vascularización y el desbridamiento. Material y Métodos: Presentamos el caso de una fractura extracapsular de fémur en una paciente con obesidad mórbida, en el que con el uso de la TPN se consiguió un excelente resultado clínico. Resultados Tras 4 meses de uso continuado de TPN, se consiguió la curación completa de la herida con la resolución del caso. Conclusiones: Según la evidencia científica, el tratamiento con terapia de presión negativa, constituye un avance importante en el cuidado de las heridas, tiene un importante impacto en salud, y contribuye a reducir en gran medida las posibles complicaciones

Introduction: Negative pressure therapy is considered an advanced method for handling wounds because it promotes healing by applying negative pressure, so that the use of controlled levels of subatmospheric pressure and suction accelerates resolution of wounds by promoting vascularization and debridement. Material and methods: We present the case of extracapsular hip fracture in a patient with morbid obesity, in which case, with the use of negative pressure therapy, it was achieved an excellent clinical outcome. Results After four months of continuous use of negative pressure therapy, complete wound healing was achieved with the resolution of the case. Conclusions: According to scientific evidence, treatment with negative pressure therapy is a relevant progress in wound care, it has an important impact on health and helps to greatly reduce potential complications

Manejo de complicaciones en herida traumática. Terapia de presión negativa vac® con instilación / Managing complications in severe traumatic injury with vac® therapy with instillation

Las fracturas complejas de los miembros inferiores, ocasionadas por traumatismos de alta energía, suponen un reto terapéutico debido a la gravedad de las heridas. Desde la aparición en los años 90 de una nueva técnica, la Therapy Vacuum Assisted Closure (Terapia VAC®), que se basa en la aplicación de vacío o presión negativa sobre la herida, contamos con un recurso terapéutico que permite una pauta más conservadora de tratamiento de estas fracturas tan complejas, ayudando en la granulación de las heridas, y previniendo su colonización; en consecuencia, reduciendo los riesgos y la morbilidad, y minimizando las complicaciones. Se presenta un caso de fractura de miembro inferior compleja, muy demostrativo del excelente resultado clínico que se puede obtener mediante el empleo de la terapia con presión negativa con el Sistema VAC®, con la ventaja añadida de la terapia de instilación (AU)

The complex fractures caused by high energy trauma, poses a major surgical challenge. Vessels, skin and subcutaneous tissues. The Vacuum Assisted Therapy (VAC®) has become a very useful tool since the last century´s 90 decade. Based in the application of negative pressure to the wound bed, promotes healing by granulation tissue formation, keeping the wound clean and avoiding bacterial colonization. Used as a primary method or in combination with others, VAC® therapy allows more conservative options in the treatment of these wounds. We describe the application of the VAC® therapy in a clinical case with complex injury, showing its efficacy, added the benefit of the instillation therapy (AU)