Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91 phox and p22 phox , which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47 phox and p67 phox . A fifth subunit, p40 phox , plays an important role in phagocytosisinduced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40 phox , in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40 phox R105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40 phox -deficient granulocytes, with premature loss of p40 phox R105Q from phagosomes. Thus, p40 phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease. IntroductionSuperoxide production by the phagocyte NADPH oxidase during the respiratory burst is an essential component of the innate immune response. The active enzyme is assembled from a membrane-bound flavocytochrome b, a heterodimer composed of gp91 phox and p22 phox subunits, and cytosolic regulatory components p47 phox , p67 phox , p40 phox , and the Rac GTPase. 1,2 Genetic defects in the NADPH oxidase cause chronic granulomatous disease (CGD), characterized by absent or markedly reduced enzyme activity, recurrent bacterial and fungal infections, and granulomatous inflammation that can involve multiple organs, including the genitourinary and gastrointestinal tracts. 1,3 Recent retrospective studies report clinical and genetic findings on more than 900 patients. [4][5][6][7] Although there is some ethnic and regional variation, approximately two-thirds of CGD patients have recessive mutations in the X-linked CYBB gene encoding gp91 phox , and the remainder have autosomal recessive defects in CYBA, NCF1, or NCF2, encoding p22 phox , p47 phox , or p67 phox , respectively. Mutations involving p40 phox or Rac have not been reported as causes of CGD. An infant with a dominant-negative mutation in the hematopoietic-specific Rac2 GTPase was reported, with partial oxidase defects, markedly impaired leukocyte migration and adhesion, and a clinical picture that resembled leukocyte adhesion deficiency rather than CGD. 8,9 In the majority of CGD cases, the gen...

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Introduction: BAY 94-9027, a site-specifically PEGylated, B-domain-deleted recombinant factor VIII (FVIII) with extended half-life, demonstrated efficacy for bleed prevention and treatment in previously treated adolescents and adults with severe haemophilia A. Aim:To assess BAY 94-9027 in children with severe haemophilia A. Methods:In the two-part PROTECT VIII Kids study, boys <12 years with <1% FVIII and >50 exposure days (EDs) to FVIII were enrolled in two cohorts (<6 years; 6-<12 years) and treated with BAY 94-9027 prophylaxis twice-weekly, every 5 days, or every 7 days at physician discretion for ≥50 EDs (Part 1) or twice-weekly for 12weeks (Part 2). Annualized bleeding rate (ABR) was a primary efficacy endpoint; FVIII inhibitor development was the primary safety variable.Results: At study completion, 25 patients had been treated twice-weekly, 28 in the every-5-day group, and 8 in the every-7-day group. Median ABR for all bleeds was 2.9 (Part 1) and 2.4 (Part 2) and similar in younger and older patients; median ABR for joint bleeds was 0 for both cohorts. In the last 90 days' treatment, median ABR was 0 for younger and older patients (Part 1). Of 149 reported bleeds, 93% were treated with ≤2 infusions. Twelve patients, the majority <6 years (n = 11), discontinued due to apparent loss of efficacy or hypersensitivity. No FVIII inhibitors developed. Conclusions:In PROTECT VIII Kids, which allowed tailoring of prophylaxis to individual clinical response, BAY 94-9027 was efficacious for bleed prevention and treatment in previously treated children with severe haemophilia A. K E Y W O R D Schildren, factor VIII, haemophilia A, polyethylene glycol, prophylaxis e56 |

From this the largest published comprehensive cohort of IBMFSs, it can be concluded that recent advances have led to successful genotyping of about half of the patients. Establishing a genetic diagnosis is still challenging and there is a critical need to develop novel diagnostic tools.

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.

The Self-PBQ generates comparable BSs to the expert-administered PBQ and is a reliable, reasonably sensitive screening tool to incorporate into the assessment of children presenting to a hematologist for the investigation of an inherited bleeding disorder.