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ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is typically an autosomal recessive, early-onset, life-threatening immune disorder. Loss-of-function mutations in STX11 have been found to impair NK cell degranulation and cytotoxicity. Here, we describe two unrelated infants of Punjabi descent presenting with FHL and carrying a novel, homozygous STX11 frameshift mutation [c.867dupG]. Western blot analysis indicated absence of syntaxin-11. Unexpectedly, degranulation by NK cells from one of the patients was not impaired, although patient NK cells showed mildly and significantly decreased cytotoxicity, respectively. Importantly, these observations imply that STX11 should be sequenced in HLH patients even when impaired NK cell degranulation is not found.
Pediatric Blood & Cancer 04/2011; 56(4):654-7. · 1.89 Impact Factor
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Christine A. Macartney MB, MRCP, FRCPath,
FRCP Sheila Weitzman MB BCh,
Stephanie M. Wood PhD,
Deepak Bansal MD,
FRCPC MacGregor Steele MD,
Marie Meeths MD,
Mohamed Abdelhaleem MD, PhD, FRCPC,
Yenan T. Bryceson PhD,
Christine A. Macartney,
Sheila Weitzman,
Stephanie M. Wood,
Deepak Bansal, MacGregor Steele,
Marie Meeths,
Mohamed Abdelhaleem,
Yenan T. Bryceson
[show abstract]
[hide abstract]
ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is typically an autosomal recessive, early-onset, life-threatening immune disorder. Loss-of-function mutations in STX11 have been found to impair NK cell degranulation and cytotoxicity. Here, we describe two unrelated infants of Punjabi descent presenting with FHL and carrying a novel, homozygous STX11 frameshift mutation [c.867dupG]. Western blot analysis indicated absence of syntaxin-11. Unexpectedly, degranulation by NK cells from one of the patients was not impaired, although patient NK cells showed mildly and significantly decreased cytotoxicity, respectively. Importantly, these observations imply that STX11 should be sequenced in HLH patients even when impaired NK cell degranulation is not found. Pediatr Blood Cancer 2011;56:654–657. © 2010 Wiley-Liss, Inc.
Pediatric Blood & Cancer 03/2011; 56(4):654 - 657. · 1.89 Impact Factor
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Juan D Matute,
Andres A Arias,
Nicola A M Wright,
Iwona Wrobel,
Christopher C M Waterhouse,
Xing Jun Li,
Christophe C Marchal,
Natalie D Stull,
David B Lewis, MacGregor Steele,
James D Kellner,
Weiming Yu,
Samy O Meroueh,
William M Nauseef,
Mary C Dinauer
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ABSTRACT: 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 phagocytosis-induced 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.
Blood 09/2009; 114(15):3309-15. · 9.90 Impact Factor
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Juliana T Teo,
Robert Klaassen,
Conrad V Fernandez,
Rochelle Yanofsky,
John Wu,
Josette Champagne,
Mariana Silva,
Jeffrey H Lipton,
Jossee Brossard,
Yvan Samson,
Sharon Abish, Macgregor Steele,
Kaiser Ali,
Uma Athale,
Lawrence Jardine,
John P Hand,
Elena Tsangaris,
Isaac Odame,
Joseph Beyene,
Yigal Dror
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ABSTRACT: Unclassified inherited bone marrow failure syndromes are a heterogeneous group of genetic disorders that represent either new syndromes or atypical clinical courses of known inherited bone marrow failure syndromes. The relative prevalence of the unclassified inherited bone marrow failure syndromes and their characteristics and the clinical and economic challenges that they create have never been studied.
We analyzed cases of inherited bone marrow failure syndrome in the Canadian Inherited Marrow Failure Registry that were deemed unclassifiable at study entry.
From October 2001 to March 2006, 39 of the 162 patients enrolled in the Canadian Inherited Marrow Failure Registry were registered as having unclassified inherited bone marrow failure syndromes. These patients presented at a significantly older age (median: 9 months) than the patients with classified inherited bone marrow failure syndrome (median: 1 month) and had substantial variation in the clinical presentations. The hematologic phenotype, however, was similar to the classified inherited bone marrow failure syndromes and included single- or multiple-lineage cytopenia, severe aplastic anemia, myelodysplasia, and malignancy. Grouping patients according to the affected blood cell lineage(s) and to the presence of associated physical malformations was not always sufficient to characterize a condition, because affected members from several families fit into different phenotypic groups. Compared with the classified inherited bone marrow failure syndromes, the patients with unclassified inherited bone marrow failure syndromes had 3.2 more specific diagnostic tests at 4.5 times higher cost per evaluated patient to attempt to categorize their syndrome. At last follow-up, only 20% of the unclassified inherited bone marrow failure syndromes were ultimately diagnosed with a specific syndrome on the basis of the development of new clinical findings or positive genetic tests.
Unclassified inherited bone marrow failure syndromes are relatively common among the inherited bone marrow failure syndromes and present a major diagnostic and therapeutic dilemma.
PEDIATRICS 08/2008; 122(1):e139-48. · 4.47 Impact Factor
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ABSTRACT: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome that has the potential to progress to pancytopenia and acute myeloid leukemia. Hematopoietic stem-cell transplantation (HSCT) is presently the only curative treatment approach. We used a reduced intensity transplantation regimen in a CAMT patient with aplastic anemia and monosomy 7 who had no matched related donor. The patient had rapid and durable engraftment with minimal complications and is well 24 months post-transplantation. Thus, reduced intensity conditioning might be a feasible approach to stem-cell transplantation in patients with CAMT who do not have a related donor and who are at increased risk of toxicity from standard conditioning regimens.
Pediatric Blood & Cancer 09/2005; 45(2):212-6. · 1.89 Impact Factor
