Biallelic variants in genes previously associated with dominant inheritance: CACNA1A, RET and SLC20A2.

A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.

Generation, establishment and characterization of a pluripotent stem cell line (CVTTHi001-A) from primary fibroblasts isolated from a patient with activated PI3 kinase delta syndrome (APDS2).

APDS2 is caused by mutations in PIK3R1 gene resulting in constitutive PI3Kδ activation. PI3Kδ is predominantly expressed in leukocytes and plays critical roles in regulating immune responses. Here we first derived fibroblast primary cells from a skin biopsy of a patient carrying a heterozygous single T deletion in intron 11 of the PIK3R1 gene. We next present the derivation of an induced pluripotent stem cell (iPS) line using a non-integrative reprogramming technology. Pluripotent-related hallmarks are further shown, including: iPSCs self-renewal and expression of pluripotent and differentiation markers after in vitro differentiation towards embryonic germ layers, assessed by RT-PCR and immunofluorescence.

Evaluating the apparent diffusion coefficient in MRI studies as a means of determining paediatric brain tumour stages. / Evaluación de la utilidad del coeficiente de difusión aparente en resonancia magnética para la diferenciación del grado tumoral de los tumores cerebrales pediátricos.

BACKGROUND: The apparent diffusion coefficient (ADC) in MRI seems to be related to cellularity in brain tumours. Its utility as a tool for distinguishing between histological types and tumour stages remains controversial. PROCEDURES: We retrospectively evaluated children diagnosed with CNS tumours between January 2008 and December 2013. Data collected were age, sex, histological diagnosis, and location of the tumour. We evaluated the ADC and ADC ratio and correlated those values with histological diagnoses. RESULTS: The study included 55 patients with a median age of 6 years. Histological diagnoses were pilocytic astrocytoma (40%), anaplastic ependymoma (16.4%), ganglioglioma (10.9%), glioblastoma (7.3%), medulloblastoma (5.5%), and other (20%). Tumours could also be classified as low-grade (64%) or high-grade (36%). Mean ADC was 1.3 for low-grade tumours and 0.9 for high-grade tumours (p=.004). Mean ADC ratios were 1.5 and 1.2 for low and high-grade tumours respectively (p=.025). There were no significant differences in ADC/ADC ratio between different histological types. CONCLUSION: ADC and ADC ratio may be useful in imaging-study based differential diagnosis of low and high-grade tumours, but they are not a substitute for an anatomical pathology study.

Spectrum and management of complement immunodeficiencies (excluding hereditary angioedema) across Europe.

INTRODUCTION: Complement immunodeficiencies (excluding hereditary angioedema and mannose binding lectin deficiency) are rare. Published literature consists largely of case reports and small series. We collated data from 18 cities across Europe to provide an overview of primarily homozygous, rather than partial genotypes and their impact and management. METHODS: Patients were recruited through the ESID registry. Clinical and laboratory information was collected onto standardized forms and analyzed using SPSS software. RESULTS: Seventy-seven patients aged 1 to 68 years were identified. 44 % presented in their first decade of life. 29 % had C2 deficiency, defects in 11 other complement factors were found. 50 (65 %) had serious invasive infections. 61 % of Neisseria meningitidis infections occurred in patients with terminal pathway defects, while 74 % of Streptococcus pneumoniae infections occurred in patients with classical pathway defects (p < 0.001). Physicians in the UK were more likely to prescribe antibiotic prophylaxis than colleagues on the Continent for patients with classical pathway defects. After diagnosis, 16 % of patients suffered serious bacterial infections. Age of the patient and use of prophylactic antibiotics were not associated with subsequent infection risk. Inflammatory/autoimmune diseases were not seen in patients with terminal pathway, but in one third of patients classical and alternative pathway defects. CONCLUSION: The clinical phenotypes of specific complement immunodeficiencies vary considerably both in terms of the predominant bacterial pathogen, and the risk and type of auto-inflammatory disease. Appreciation of these phenotypic differences should help both immunologists and other specialists in their diagnosis and management of these rare and complex patients.

[International adoption from Ethiopia in a 5-year period]. / Adopción internacional de Etiopía en un período de 5 años.

INTRODUCTION: An increase in the number of internationally adopted children has been observed in the last few years. The country of origin that has experienced a greater increase is Ethiopia. The health of internationally adopted children from Ethiopia has not been extensively assessed to date. The main objective of the study is to determine the prevalence of infectious diseases in children adopted from Ethiopia, and to assess their nutritional status. METHOD: A prospective, observational cohort study was conducted using the medical records of 251 children adopted from Ethiopia to Spain in the period from Jan 1, 2006 and December 31, 2010. RESULTS: The mean age of the children was 7 months (range 1-120). Abnormalities were detected on physical examination in 56.6%. In 90% of cases the child was less than 5 years-old. Half of the sample had a weight below the third percentile, with some degree of malnutrition in 65% of the children. HIV exposure was not uncommon (4.8%). CONCLUSIONS: Low weight and acute gastroenteritis were the main findings in this cohort. Infectious diseases should be systematically assessed.

Hemophagocytic lymphohistiocytosis secondary to Epstein Barr virus and Leishmania co-infection in a toddler.

This is the report of an EBV+Leishmanial co-infection. The patient developed hemophagocytic syndrome (HLH) and was treated with the standard HLH-2004 protocol. However, PCR in bone marrow discovered this secondary cause for HLH. In endemic countries, visceral leishmaniasis should be considered in the differential diagnosis even in EBV-related HLH, as chemotherapy toxicity may be avoided.

[Respiratory syncitial virus in immunocompromised patients in a pediatric hospital: 5 years experience]. / Infección por virus respiratorio sincitial en los pacientes inmunodeprimidos en un hospital pediátrico: experiencia de 5 años.

INTRODUCTION: Respiratory syncytial virus (RSV) infection is associated with an increase in morbidity and mortality in immunocompromised hosts. METHODS: A description is presented of all cases of RSV infection in immunocompromised pediatric patients in Hematology and Oncology and Immunodeficiency Units between 2008 and 2012. RESULTS: Nineteen patients were diagnosed with RSV infection. Nine patients required in-patient care and 2 required Pediatric Intensive Care Unit. Five patients were treated with specific therapy (ribavirin ± palivizumab). No deaths occurred in the study period. CONCLUSION: RSV infection may be severe in immunocompromised pediatric patients.

Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.

Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.

[Prenatal diagnosis and novel mutation in X-linked chronic granulomatous disease]. / Diagnóstico prenatal y nueva mutación en enfermedad granulomatosa crónica ligada al cromosoma X.

BACKGROUND: Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency caused by the alteration of the enzyme complex NADPH oxidase, which affects the phagocytic function. CGD patients are susceptible to recurrent infections mainly caused by bacteria and/or fungi. METHODS: We studied a 6 year-old boy with suspicion of CGD. The diagnosis was confirmed based on the functional study of NADPH oxidase. Simultaneously, the second pregnancy of the mother was reported and genetic counselling was requested. RESULTS: We identified a new disease-causing mutation by direct sequencing of the CYBB gene (X-linked CGD). The prenatal study resulted in the identification of the same mutation in the foetus. COMMENTS: Molecular genetics characterisation of CGD is needed to obtain an accurate diagnosis of the disease and to offer prenatal diagnosis and genetic counselling in future pregnancies.