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• MLOF used an innovative approach to genotype 3000 hemophilia patients identifying likely causative variants in 98.4% of patients.• Hemophilia genotyping should include structural variation, F8 inversions (for hemophilia A), and consideration of gene-wide approaches.Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia treatment centers (HTCs). Genotyping was performed centrally using nextgeneration sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years.Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel.Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild-moderate disease. Novel DNA variants accounted for ;30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected .1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.

Three child population groups from the Madrid area were studied for anti-HAV antibodies. Analysis was carried out with respect to age and socio-environmental factors. The population understudy was composed of 156 children, with ages ranging from 1 to 14 years; they were stratified in three socio-environmental groups (white-family unit, gypsy-family unit and orphanage), and also divided into subgroups according to age. As a whole, an age-related increase in prevalence was found. The overall seroprevalence by socio-environmental groups was: gypsy-family unit 63%, orphanage 46%, and white-family unit 23%. Significant differences between groups appeared from seven years on, being more marked among the eldest subgroups. Among the factors evaluated, hygienic-sanitary conditions and overcrowding influenced the high prevalence rate found in the gypsy-family unit subjects, whereas overcrowding appeared to be responsible for the higher prevalence in orphanage residents, as compared to white-family unit children.

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Adrenocortical tumors are rare in childhood and adolescence. Virilization, alone or in combination with signs of overproduction of other adrenal hormones, is the most common clinical presentation. Here we report an unusual case of an AfricanAmerican female adolescent presenting with idiopathic acquired generalized anhidrosis, dysregulation of body temperature, absence of adult body odor and dry skin in the face of a virilizing para-adrenocortical adenoma. Virilization signs regressed soon after removal of the tumor, but normalization of the 3 α -androstenediol glucuronide (3 α -AG) took longer compared to other measurable androgens; accompanied by anhidrosis. The association of remitting anhidrosis with normalized levels of 3 α -AG suggests it might be a possible mechanism for anhidrosis. High 3 α -AG levels might implicate the increased peripheral conversion of weak pro-androgens with different biochemical structure. We recommend obtaining 3 α -AG beside other androgens in virilized patients with atypical dermatological symptoms in the face of hyperandrogenism.

Introduction: Approximately 20% of children diagnosed with ITP have chronic thrombocytopenia, some requiring immunosuppressive treatments. The TPO receptor agonist romiplostim could be a treatment option for symptomatic children with ITP. Methods: In this phase 3, double-blind study, children with ITP for ≥6 months were randomized to weekly romiplostim or placebo (2:1) for 24 weeks, with the dose adjusted weekly from 1-10 μg/kg to target platelet counts of 50-200×109/L. Platelet response was defined as platelet counts ≥50×109/L any week of weeks 2-25 (excluding 4 weeks after rescue medication use). The 1° endpoint, durable platelet response, was defined as ≥6 weekly platelet responses during the final 8 weeks, weeks 18-25. Overall platelet response was defined as ≥4 weekly platelet responses during weeks 2-25. Antibodies to romiplostim or TPO were assayed at baseline and weeks 12 and 25. The Kid's ITP Tool (KIT), in which higher scores reflect improved quality of life, was administered to children and their parents. Results: Patients (n = 62) had median (range) age 9.5 (3-17) years, ITP duration 2.1 (0.5-10.7) years, and baseline platelet counts 18 (1-94) × 109/L; 44% were male. Sixty-six percent of patients were Caucasian, 13% African American, 8% Asian, and 15% other. For the 1° endpoint, measured in the final 8 weeks after 16 weeks of dose titration, rates of durable platelet response were romiplostim: 52% and placebo: 10% (p < 0.002) (Table). Rates of overall platelet response were romiplostim: 71% and placebo: 20% (p = 0.0002), and rates of any platelet response were romiplostim: 81% and placebo: 55% (ad hoc p = 0.03). For romiplostim, the median (range) time to firstplatelet response was 4.5 (1-20) weeks and the median average weekly dose was 3.9 (0.9-8.1) μg/kg. Median platelet counts with romiplostim were ≥50×109/L from week 8 on (Figure). In the final 8 weeks, non-cutaneous bleeding rates were romiplostim: 33% and placebo: 47%, and rescue medication use rates were romiplostim: 24% and placebo: 30%. Over the course of the study, the rates of grade ≥3 bleeding were romiplostim: 5% and placebo: 11%; rates of any bleeding and non-cutaneous bleeding were similar for romiplostim and placebo. We also examined a composite bleeding episode endpoint, defined as clinically significant bleeding, ie, CTCAE grade ≥2, OR the use of rescue medication to prevent such bleeding. The rate for these episodes for weeks 2-25 was less with romiplostim than placebo (8.1 vs 18.4 per 100 patient-weeks, p<0.0001). No patients withdrew due to adverse events (AE). Rates of serious AEs (SAEs) were romiplostim: 23.8% (10 patients) and placebo: 5.3% (1 patient). SAEs with romiplostim consisted of 2 cases each of contusion, epistaxis, and headache, and 1 case each of petechiae, thrombocytosis, nephrotic syndrome, nausea, vomiting, bronchiolitis, fever, urinary tract infection, and seizure. These SAEs often occurred with related comorbidities. Only the headache and thrombocytosis SAEs, which occurred in the same patient, were considered treatment-related by the investigator. There were no thrombotic events, no malignancies observed, and no findings indicating bone marrow dysplasia or fibrosis in the only bone marrow biopsy performed. None of the 42 romiplostim-treated patients developed neutralizing antibodies to either romiplostim or TPO. The parent impact score of the KIT showed significant quality-of-life improvement with romiplostim (p = 0.04) in the mixed-effects repeated measures analysis using a general linear model. Conclusions: In children with symptomatic ITP of ≥6 months duration, romiplostim was effective in inducing high rates of durable and overall platelet responses. There were no new safety signals. By the final 8 weeks of the study, noncutaneous bleeding was decreased with romiplostim. Romiplostim may be a viable treatment option for children with symptomatic chronic ITP. Table. Placebo (N = 20) Romiplostim (N = 42) Durable platelet response, x/n (%), all patients 2/20 (10%) 22/42 (52%) P < 0.002 By baseline age · 1 to <6 years 1/4 (25%) 3/8 (38%) · 6 to <12 years 1/9 (11%) 10/18 (56%) · 12 to <18 years 0/7 (0%) 9/16 (56%) Overall platelet response, x/n (%), all patients 4/20 (20%) 30/42 (71%) P = 0.0002 By baseline age · 1 to <6 years 2/4 (50%) 5/8 (63%) · 6 to <12 years 1/9 (11%) 15/18 (83%) · 12 to <18 years 1/7 (14%) 10/16 (63%) Figure 1. Figure 1. Disclosures Tarantino: Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties: royalties; Amgen, Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Romiplostim is indicated for use in adults with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in children with ITP is investigational.. Bussel:Amgen, Cangene, GlaxoSmithKline (GSK), Genzyme, IgG of America, Immunomedics, Ligand, Eisai, Shionogi and Sysmex: Research Funding; Portola: Consultancy; Amgen, GSK, Ligand, Shionogi, and Eisai: Other: Advisory board. Blanchette:Baxter Corporation, Bayer Healthcare, Novo Nordisk, Pfizer: Honoraria; Baxter Corporation, Bayer Healthcare: Research Funding; Baxter Corporation, Bayer Healthcare, Novo Nordisk, Pfizer; Data Safety Monitoring Board Baxter Corporation, Octapharma: Other: Advisory board; Baxter Corporation, Octapharma: Other: Data Safety Monitoring Board. Morales:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Carpenter:Amgen Inc.: Employment, Other: Stockholder. Nie:Amgen Inc.: Employment, Other: Stockholder. Eisen:Amgen Inc.: Employment, Other: Stockholder.

INTRODUCCIÓNEl síndrome de lisis tumoral (SLT) comprende el conjunto de alteraciones metabólicas que aparecen secundariamente a la masiva liberación al espacio extracelular de sustancias intracelulares, procedentes de una rápida destrucción de célu-las tumorales (1-4). La presentación más habitual es en relación con aquellas neoplasias que tienen un recambio celular más alto, como son las neoplasias hematológicas tipo linfoma de Burkitt, linfoma linfoblástico y leucemia linfoblástica aguda (1-4). También, aunque mucho más raramente, se ha descrito en neoplasias no hematológicas como el cáncer de pulmón, de mama y otros (1-5). Las características del SLT son hiperuricemia, hiperpotasemia, hiperfosfatemia e hipocalcemia (1-4). La insuficiencia renal aparece también en la mayoría de los casos (1-4). Generalmente el proceso se desencadena tras el tratamiento oncológico, especialmente tras la poliquimioterapia, pero también la administración de glucocorticoides, de interferón o la radioterapia, pueden ser sus desencadenantes (1-4). La presentación espontánea puede considerarse excepcional (1-4) y son muy pocos los casos recogidos en la literatura. (4,(6)(7)(8). Presentamos el caso de una paciente que falleció por un SLT espontáneo diagnosticándo-se post-mortem de LHN de alto grado a través de punción aspiración con aguja fina de adenopatía cervical. CASO APORTADOMujer de 77 años diagnosticada de hipertensión arterial esencial, hipercolesterolemia, insuficiencia renal crónica leve, hiperuricemia, insuficiencia cardiaca en estadio III de la NYHA y portadora de un marcapasos cardiaco definitivo desde hacía 5 años. Seguía tratamiento habitual con atenolol, captopril, alopurinol y torasemida. Ingresó en el hospital refiriendo intenso cansancio y aparición de múltiples adenopatías en el cuello desde hacía menos dos semanas. En las últimas 48 horas había sufrido un empeoramiento muy acusado siendo incapaz de deambular. Refirió pérdida de apetito y pérdida de peso no cuantificada en los últimos meses. Negó fiebre, dolor torácico o disnea. Tampoco había presentado náuseas ni vómitos ni diarrea. En la exploración física presentaba [0212-7199 (2005) RESUMENPresentamos el caso de una mujer de 77 años sin antecedentes de proceso neoplásico que ingresa por la aparición en pocas semanas de múltiples adenopatías cervicales y que fallece a las pocas horas presentado hiperuricemia, hipocalcemia, hiperpotasemia, hiperfosfatemia e hiperazotemia. La citología y estudio molecular de una muestra de una adenopatía cervical fueron compatibles con de linfoma no Hodgkin de estirpe B de alto grado. Se trataría por tanto de un síndrome de lisis tumoral espontáneo como debut de un linfoma no Hodgkin.