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Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc.

Wiskott-Aldrich syndrome (WAS),

Two distinct syndromes that link α-thalassemia and intellectual disability (ID) have been described: ATR-X, due to mutations in the ATRX gene, and ATR-16, a contiguous gene deletion syndrome in the telomeric region of the short arm of chromosome 16. A critical region where the candidate genes for the ID map has been established. In a pediatric patient with Hemoglobin H disease, dysmorphic features and ID, 4 novel and clinically relevant Copy Number Variants were identified. PCR-GAP, MLPA and FISH analyses established the cause of the α-thalassemia. SNP-array analysis revealed the presence of 4 altered loci: 3 deletions (arr[hg19]Chr16(16p13.3; 88,165-1,507,988) x1; arr[hg19]Chr6(6p21.1; 44,798,701-45,334,537) x1 and arr[hg19]Chr17(17q25.3; 80,544,855-81,057,996) x1) and a terminal duplication (arr[hg19]Chr7(7p22.3-p22.2; 4,935-4,139,785) x3). The -α(3.7) mutation and the ∼1.51 Mb in 16p13.3 are involved in the alpha-thalassemic phenotype. However, the critical region for ATR-16 cannot be narrowed down. The deletion affecting 6p21.1 removes the first 2 exons and part of intron 2 of the RUNX2 gene. Although heterozygous loss of function mutations affecting this gene have been associated with cleidocranial dysplasia, the patient does not exhibit pathognomonic signs of this syndrome, possibly due to the fact that the isoform d of the transcription factor remains unaffected. This work highlights the importance of searching for cryptic deletions in patients with ID and reiterates the need of the molecular analysis when it is associated to microcytic hypochromic anemia with normal iron status.

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Hereditary Spherocytosis (HS) is the most common cause of non-immune hemolytic anemia in Argentine people of European ancestry, it is characterized by chronic hemolysis, which is reduced or abrogated by splenectomy.. Because of the risk of postsplenectomy sepsis, especially among children under 5 years old, partial splenectomy has been advocated as an alternative. This procedure seems to ensure prolonged reduction but not complete elimination of hemolysis and it is possible some regrowth of the splenic remnant and a secondary total splenectomy must be performed in some patients (pts). This problem is worse especially when pts. live in rural areas and a close observation is necessary. We analyzed retrospectively the evolution of 83 pediatric pts with HS with low resources, other health priorities and in some cases an underling nutritional deficit. Diagnostics was made in a public hospital between October 1971 and December 2002 and the last control was in December 2004. The pts. Median age at diagnostic was 4.7 years (14 days to 14 years). Severe forms were observed in 18%, mild in 20% and moderate in 62%. Twenty four pts were phenotypically sporadic. Biochemical analysis (SDS-PAGE) were performed in 30 pts and/or family members, combined spectrin- ankirin deficiency were observed in most of them. Sixty-nine hemolytic crisis was observed in 30 pts (37.5%). and 17.5% developed an aplastic crisis. Fifty-two pts. (65%) received 249 Red Blood Cell Transfusions (Trs), 36% between 1 and 2, 22.5% 3 to10, and 6% between 10 to 34 Trs. Gallstones were observed in 4 PTs (5%). Total splenectomy was performed in 46 of 83 pts (55%), median age: 7 years (4–15) 42 pts had conventional and 4 have undergone laparoscopyc procedure. Ninety six per cent of pts were splenectomized after age of 5. The median time from diagnostic to splenectomy was 1 year (0.2–8.9). All pts were immunized against Pneumococcus, Haemophilus, and Meningococus and received prophylactic antibiotics. With a median follow up of 18.5 years (3–30 y) after splenectomy all pts showed a significant clinical improvement and no further transfusion requirement. In all cases the hemoglobin increased (median pre and post splenectomy 8.6/13gr/dl) and reticulocyte counts decreased (8 / 1.4%). We do not observe procedure relate mortality, sepsis, thrombosis, and aplastic or hemolytic crisis post-splenectomy. On the basis of our experience we favor the total splenectomy performed by a training team in countries with low resources and in pts with deficient hygienic and housing conditions that inhabit in places with long distances from centers to ensure wider access to training health care providers.

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