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1.  Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency 
Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56dim NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients’ fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients’ growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56dim subset in patients was associated with a lower rate of NK CD56bright cell proliferation, and the maturation of NK CD56bright cells toward an NK CD56dim phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.
doi:10.1172/JCI61014
PMCID: PMC3287233  PMID: 22354167
2.  Successful Use of Alternative Anticoagulants in the Management of Heparin-induced Thrombocytopenia with Thrombotic Complications 
Heparin is one of the most frequently used anticoagulants. It is easy to use, but can be associated with life-threatening side effects. One of these is heparin-induced thrombocytopenia syndrome (HITS), which develops in about 3–5% of patients exposed to heparin and is associated with thrombosis in 1% of cases. We report here the successful treatment of five patients with HITS who were treated with alternative anticoagulants namely danaparoid or hirudin. The median time between their exposure to heparin and onset of symptoms and or signs was 10.2 days (range 7–14 days). Platelet counts decreased to a mean of 38.4 x 109 /l (12–82 x 109/l). All five patients had evidence of thrombosis; four patients had clinical and radiological evidence of pulmonary emboli, one patient had confirmed deep vein thrombosis (DVT) and one patient had extensive skin necrosis of the thighs and abdomen. Platelet aggregation test were positive in two patients, inconclusive in one patient and negative in two patients. Two patients were anticoagulated with danaparoid and three with hirudin until their platelet counts returned to normal between 4 and 14 days (average 6 days) following the recognition of the syndrome. Our patients had significant morbidity, but no mortality. Immediate withdrawal of heparin is of paramount importance and introduction of alternative anticoagulant is necessary in the presence of thrombosis.
PMCID: PMC3210050  PMID: 22087382
Unfractionated heparin; Low-molecular weight heparin; Heparin-induced thrombocytopenia; Hirudin; Danaparoid; Case report; Oman
3.  A LARGE KINDRED WITH X-LINKED NEUTROPENIA WITH AN I294T MUTATION OF THE WISKOTT-ALDRICH SYNDROME GENE 
British journal of haematology  2008;144(1):120-126.
X-linked neutropenia (XLN, OMIM #300299) is a rare form of severe congenital neutropenia. It was originally described in a three-generation family with 5 affected members and with an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich-syndrome protein (WASP) (Devriendt, et al 2001).
Here, we report and describe a large three-generation family with XLN, with 10 affected males and 8 female carriers. A c.882T>C WAS gene mutation was identified, resulting in an I294T mutation. The infectious course is variable and mild in view of the deep neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced NK-cell counts also appear as consistent XLN features. However, inverted CD4/CD8 ratios were not found in this family, nor were cases identified with myelodysplastic syndrome or acute myeloid leukaemia. Female carriers exhibited a variable attenuated phenotype. Like L270P WASP, I294T WASP is constitutively active towards actin polymerisation In conclusion, this largest XLN kindred identified to date provides new independent genetic evidence that mutations disrupting the auto-inhibitory GBD of WASP are the cause of XLN. Reduced NK cells, low to low normal platelet counts and low to low-normal IgA levels are also features of XLN.
doi:10.1111/j.1365-2141.2008.07416.x
PMCID: PMC3125974  PMID: 19006568
neutropenia; X-linked; Wiskott-Aldrich syndrome protein
5.  Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms. 
Mediators of Inflammation  2004;13(3):181-187.
The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.
doi:10.1080/09511920410001713529
PMCID: PMC1781555  PMID: 15223609

Results 1-6 (6)