The IL-2RG R328X nonsense mutation allows partial STAT-5 phosphorylation and defines a critical region involved in the leaky-SCID phenotype.

In addition to their detection in typical X-linked severe combined immunodeficiency, hypomorphic mutations in the interleukin (IL)-2 receptor common gamma chain gene (IL2RG) have been described in patients with atypical clinical and immunological phenotypes. In this leaky clinical phenotype the diagnosis is often delayed, limiting prompt therapy in these patients. Here, we report the biochemical and functional characterization of a nonsense mutation in exon 8 (p.R328X) of IL2RG in two siblings: a 4-year-old boy with lethal Epstein-Barr virus-related lymphoma and his asymptomatic 8-month-old brother with a Tlow B+ natural killer (NK)+ immunophenotype, dysgammaglobulinemia, abnormal lymphocyte proliferation and reduced levels of T cell receptor excision circles. After confirming normal IL-2RG expression (CD132) on T lymphocytes, signal transducer and activator of transcription-1 (STAT-5) phosphorylation was examined to evaluate the functionality of the common gamma chain (γc ), which showed partially preserved function. Co-immunoprecipitation experiments were performed to assess the interaction capacity of the R328X mutant with Janus kinase (JAK)3, concluding that R328X impairs JAK3 binding to γc . Here, we describe how the R328X mutation in IL-2RG may allow partial phosphorylation of STAT-5 through a JAK3-independent pathway. We identified a region of three amino acids in the γc intracellular domain that may be critical for receptor stabilization and allow this alternative signaling. Identification of the functional consequences of pathogenic IL2RG variants at the cellular level is important to enable clearer understanding of partial defects leading to leaky phenotypes.

[Appendicular actinomycosis as a cause of ileocecal mass in children: Case report]. / Actinomicosis apendicular como causa de masa ileocecal en la edad pediátrica: Caso clínico.

INTRODUCTION: Appendicular actinomycosis is a rare disease produced by cecal appendix invasion by Actinomyces gender bacteria after a predisposing cause that disrupts mucosal barrier, such as acute appendicitis. The highest frequency appears in adults; however, there are cases in paediatric age described in literature. The aim of this article is to introduce a case of appendicular actinomycosis in a child with atypical presentation and to review the literature. CLINICAL CASE: 10-year-old boy transferred to our hospital due to intraoperative finding at a different centre of a right flank tumor, without identification of cecal appendix. After completing the study with image tests, the patient was re-intervened with the diagnosis of complicated acute appendicitis. Intraoperatively, an organized plastron lacking of acute inflammatory signs was found. Post-surgical evolution was positive with conventional antibiotic treatment. Histological study of the specimen revealed an appendicular actinomycosis, so antibiotic treatment was widened in an outpatient basis and predisposing diseases were ruled out. COMMENTS: Appendicular actinomycosis is an infrequent cause of appendicitis that can simulate an intra-abdominal tumor in children and adults. It is necessary to rule out predisposing diseases and to administer an adequate antibiotic treatment.

INTRODUCCION: La actinomicosis apendicular es una patología rara producida por la invasión del apéndice cecal por bacterias del género Actinomyces al alterarse la barrera mucosa después de una causa predisponente, como podría ser una apendicitis aguda. Se presenta con mayor frecuencia en adultos, aunque en la literatura se han descrito algunos casos en edad pediátrica. En este artículo se presenta un nuevo caso pediátrico de actinomicosis apendicular de presentación atípica y se revisa la literatura al respecto. CASO CLINICO: Paciente varón de 10 años de edad derivado a nuestro hospital por el hallazgo intraoperatorio en otro centro de una tumoración en flanco derecho, sin identificación del apéndice cecal. Tras completar el estudio con pruebas de imagen, el paciente fue reintervenido bajo la orientación diagnóstica de apendicitis aguda complicada. Intraoperatoriamente, se identifica un plastrón organizado y con escasos signos inflamatorios agudos. La evolución postquirúrgica fue favorable con tratamiento antibiótico convencional. El estudio anatomopatológico de la pieza reveló una actinomicosis apendicular, por lo que se amplió el tratamiento antibiótico de forma ambulatoria y se descartó patología predisponente. COMENTARIOS: La actinomicosis apendicular es una causa infrecuente de apendicitis que puede simular una tumoración intraabdominal en niños y adultos. Es necesario descartar patología predisponente y realizar un tratamiento antibiótico adecuado.

[Is familial screening useful in selective immunoglobulin A deficiency?]. / ¿Es útil el cribado familiar en el déficit selectivo de inmunoglobulina A?

INTRODUCTION: Selective immunoglobulin A deficiency (SIgAD), the most common primary immunodeficiency, is often asymptomatic. High rates of familial clustering have been described in SIgAD, but the causative genetic defect and mechanism of inheritance are unknown. OBJECTIVES: To determine whether familial SIgAD cases show more severe clinical and immunological characteristics than sporadic ones; to investigate the utility of screening first-degree relatives (FDRs) of these patients, and to determine whether symptoms in affected family members are important enough to justify screening. PATIENTS AND METHODS: Descriptive, cross-sectional study (October 2010-September 2011) of all patients with SIgAD and followed up in our center. Demographic, clinical, and analytical data were reviewed. A familial case was defined as an SIgAD patient with at least one affected FDR. RESULTS: Of the 130 participants, 42 were SIgAD patients and 88 FDR. There were 13 (31%) familial cases and and 14 (16%) affected FDRs. Six family members had to be analyzed in order to detect one affected one. There were no clinical differences between familial and sporadic SIgAD cases. The percentages of intestinal disease (p=001, OR=9.57, 95%CI 2.59-35.3), hospitalizations (p=045, OR=4.01; 95%CI 1.10-14.67], and need for chronic treatment (p=006, OR=5.5; 95%CI 1.57-19.54) were higher in affected FDRs than in unaffected ones. CONCLUSIONS: The symptoms were not more severe in familial than sporadic SIgAD cases. Nonetheless, the elevated prevalence of affected FDRs with significant morbidity may justify routine screening of close family members of these patients.

[Recurrent meningitis due to anatomical defects: The bacteria indicates its origin]. / Meningitis recurrente por defectos anatómicos: la bacteria indica su origen.

INTRODUCTION: Recurrent meningitis is a rare disease. Anatomical abnormalities and immunodeficiency states are predisposing factors. Four cases, in which immunodeficiency was excluded, are presented. The causal microorganism led to the detection of the anatomical defect responsible for the recurrences. PATIENTS AND METHODS: Retrospective review of 4 cases with clinical diagnosis of recurrent bacterial meningitis. RESULTS: Case 1: a thirty month-old boy with unilateral hearing loss, diagnosed with Mondini abnormality by magnetic resonance imaging (MRI) after 2 episodes of Haemophilus influenzae meningitis. Surgical repair after third recurrence. Case 2: fourteen year-old girl diagnosed by MRI with cribriform plate defect after 3 episodes of meningitis due to Streptococcus pneumoniae. Ventriculoperitoneal shunt was placed. Case 3: girl with meningitis due to Staphylococcus aureus at 2 and 7 months. MRI shows occipital dermal sinus requiring excision. Complication with cerebellar abscesses because of a coexisting dermoid cyst. Case 4: child with meningitis due to Streptococcus bovis at 9 days and Enterococcus faecium, Klebsiella pneumoniae and Escherichia coli at 7 months, with positive cultures to Citrobacter freundii and E. faecium later on. Spinal MRI led to the diagnosis of Currarino syndrome with CSF fistula, which was surgically repaired. The 4 patients had undergone image studies reported as normal during the first episodes. CONCLUSIONS: In patients with recurrent meningitis the possibility of an anatomical defect should be considered. The isolated microorganism should help to locate it. It is essential to know the normal flora of the different anatomical sites. The definitive treatment is usually surgical.

[Imported infectious diseases in tertiary hospital]. / Patología infecciosa importada en hospitales terciarios.

INTRODUCTION: An Imported Diseases Clinic was created in the hospital in 2009. The aim of this study was to asses its contribution in terms of capacity, quality of care and teaching offered. PATIENTS AND METHODS: A retrospective study was conducted from 2009 to 2011, analyzing: A) development of knowledge by means of protocols and publications created, and subject taught; B) capacity and quality of care offered by the analysis of patients seen, the adequacy of the protocols and accessibility. The patients were classified into 3 groups. Group 1: immigrant patient screening, group 2: patient consultation after tropical or sub-tropical travel, group 3: screening of vertical transmission of imported disease. RESULTS: Six protocols have been developed and disseminated on the unit website, as well as 5 scientific publications. A total of 316 patients were evaluated: 191 included in group 1 (29 Adopted and 162 Immigrants), 57 in group 2 (94.7% Visiting Friends and Relatives and 81.5% without a pre-travel consultation). They consulted due to, gastrointestinal symptoms (52.6%) and fever (43.8%), with 68 included in group 3 at risk of imported disease by vertical transmission (62 Trypanosoma cruzi, 1 Human T Lymphotropic Virus and 5 Plasmodium spp.). The overall adherence to the protocols was about 77.1%. DISCUSSION: Infectious Diseases Units must adapt to the reality of the population and be flexible in its structure. Periodic assessment of the quality of care offered is essential, as well as an evaluation on the need for additional studies.

[Spectrum of primary immunodeficiencies in a tertiary hospital over a period of 10 years]. / Espectro de las inmunodeficiencias primarias en un hospital de tercer nivel en un periodo de 10 años.

INTRODUCTION: More than 200 primary immunodeficiencies (PID) have been described and about 60% present during childhood. Early diagnosis and treatment have been shown to improve patient outcome. AIM: Analysis of patients with a PID diagnosed in a paediatric tertiary care hospital-referral centre over a period of 10 years. PATIENTS AND METHODS: Medical records of all paediatric patients followed up in our unit were retrospectively reviewed. Clinical and epidemiological features, laboratory tests, therapy and outcome were analysed. RESULTS: One hundred and eighty nine patients were followed up in this period of time. Antibody disorders were the most common diagnosis. In our series, clinical presentation at diagnosis were: recurrent respiratory infections in selective IgA deficiency and common variable immunodeficiency (CVID) patients, failure to thrive and opportunistic infections (mainly viral infections) in patients with severe combined immunodeficiency (SCID), skin abscesses (Staphylococcus aureus, Serratia spp.) and complicated pneumonia (Aspergillus spp., Rhodococcus equi) in chronic granulomatous disease, congenital heart disease and consistent phenotype in 22q11 deletion syndrome, skin abscesses and ecthyma gangrenosum in severe congenital neutropenia and opportunistic infections and sepsis (Pseudomonas aeruginosa) in children with X-linked agammaglobulinaemia (XLA). Lymphoproliferative disorders were common in CVID. No malignancies were observed during this period. One patient with XLA developed chronic encephalitis. All patients with CVID and XLA were receiving immunoglobulin replacement therapy (8 intravenous and 14 (since 2006) subcutaneous route) and in all but two SCID patients, stem cell transplantation was performed. Outcome was good in most of them except 8 SCID (2 prior and 6 after transplantation), 3 Wiskott-Aldrich syndrome, 1 complete DiGeorge, 1 chronic granulomatous disease and 1 ataxia-telangiectasia patients who died during follow-up. CONCLUSION: The vast majority of patients included in this series presented with typical clinical features; therefore, basic knowledge of these entities in primary care and collaboration with hospital referral centres should allow a large number of PID in children to be diagnosed at an early stage, leading to proper treatment and monitoring, and therefore improvement of patient prognosis.

[Evaluation of a program for assessing adherence to antiretroviral treatment]. / Evaluación de un programa de valoración de adherencia al tratamiento antirretroviral.

INTRODUCTION: Poor adherence to antiretroviral treatment (ART) is the commonest cause of treatment failure in children and adults living with HIV, and this is especially important during adolescence. Therefore, any analysis of ART effectiveness in children should include an evaluation of adherence to ART. The aim of this study is to assess the usefulness of an ART adherence monitoring program in an HIV-infected paediatric population. PATIENTS AND METHODS: An observational and cross-sectional study was performed, within the framework of the "Health Education Program for Optimising Adherence in Paediatric Patients with HIV", which is part of the "I am not alone" project. Adherence was assessed simultaneously by different methods: personal interview, therapeutic drug monitoring, pharmacy dispensing records and evolution of viral load and T CD4+ lymphocyte count. RESULTS: Twenty patients were included (50% female, median age 14.5 years). Percentage of self-reported full adherence was 90% (95% CI: 70-97.2%); however, the median adherence percentage according to pharmacy dispensing records was significantly lower (83.3%, SD=32.88). The average of drugs and dosage forms per day were 3.5 (SD=0.83) and 5.5 (SD=2.72), respectively. There was an inverse relationship between the number of dosage forms per day and adherence scores (F=13.8; P=.002). No single method was statistically related to adherence, although therapeutic drug monitoring showed a trend towards significance. CONCLUSIONS: Global adherence to ART was high and was easier with simpler regimens. Self-reported adherence overestimated real adherence to ART in our cohort. The simultaneous use of different methods to assess adherence is recommended in HIV-infected children.

[Consensus Document on the differential diagnosis and therapeutic approach to recurrent fever by the Paediatric Infectology Society and the Paediatric Rheumatology Society]. / Documento de Consenso de la Sociedad de Infectología Pediatrica y la Sociedad de Reumatología Pediatrica sobre el diagnóstico diferencial y el abordaje terapéutico de la fiebre recurrente.

Recurrent fever is a relatively common problem during childhood. Diagnosis is often easy and related to mild viral infections. However a small proportion of these cases originate from an underlying non-infectious process that is generally difficult to diagnose. In this paper we describe the differential diagnosis of recurrent or periodic fever versus other processes, with especial attention to autoinflammatory disorders (AD). AD are alterations of innate immunity, and they have been recently classified as an immunodeficiency. Anyhow, since infections are not present, these processes are different to the classic primary immunodeficiency. An important part of AD is of known genetic aetiology. The symptoms originate from an underlying inflammatory process and can have different clinical expressions. One of the most relevant groups is the hereditary syndromes of periodic fever. This group of diseases associates recurrent fever and several clinical symptoms with a relative periodicity, separated by intervals free or almost free of symptoms. We include the diagnostic criteria for some processes as well as the characteristics that should, eventually, lead to a genetic study. Although treatment should be individualised, we also include some general recommendations.