Treatment of inherited bone marrow failure syndromes beyond transplantation.

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

Guanine nucleotide exchange in the ribosomal GTPase EFL1 is modulated by the protein mutated in the Shwachman-Diamond syndrome.

Ribosome biogenesis in eukaryotes is a complex process that requires the participation of several accessory proteins that are not part of the mature particle. Efl1 is a yeast GTPase required for the cytoplasmic maturation of the 60S ribosomal subunit. Together with Sdo1, the yeast ortholog of the protein mutated in the Shwachman-Diamond Syndrome (SBDS), Efl1 releases the anti-association factor Tif6 from the surface of the 60S subunit allowing the assembly of mature ribosomes. We characterized the structural content and folding stability of the Saccharomyces cerevisiae and human EFL1 GTPases, as well as their enzymatic properties alone and in the presence of Sdo1 and SBDS, respectively. The human and S. cerevisiae EFL1 GTPases are composed of a mixture of α-helices and ß-sheets. Despite being orthologs, the yeast protein elicited a non-two state thermal unfolding behavior while the human EFL1 was highly resistant to thermal denaturation. Steady-state kinetic analyses indicated slow GTP hydrolysis for both EFL1 GTPases, with kcat values of 0.4 and 0.3min(-1) and Km for GTP of 110 and 180µM respectively. In the presence of the effector proteins, their kcat values remained unaltered while the Km decreased twofold suggesting that Sdo1 and SBDS act as nucleotide exchange factors.

Endocrine evaluation of children with and without Shwachman-Bodian-Diamond syndrome gene mutations and Shwachman-Diamond syndrome.

OBJECTIVE: To characterize the endocrine phenotype of patients with Shwachman-Diamond syndrome (SDS). STUDY DESIGN: Clinically indicated endocrine screening data from 43 patients with SDS or SDS-like presentation were analyzed according to sex, age, and genetic testing. In addition to 25 patients with biallelic Shwachman-Bodian-Diamond syndrome (SBDS) gene mutations, we evaluated 18 patients with cytopenias who were receiving pancreatic enzyme replacement but were without SBDS mutation. We performed a retrospective review of growth records and clinically indicated endocrine evaluations. RESULTS: Of patients with SBDS mutations, 2 had low stimulated growth hormone levels, 2 had mildly elevated thyrotropin levels, 5 had abnormal glucose levels, and 1 had an elevated follicle-stimulating hormone level (post transplantation). In contrast, 1 patient without SBDS mutations had postprandial hyperglycemia and 3 had mildly low free thyroxine levels without short stature. Endocrine abnormalities were identified in 19% of short patients and 26% of the whole group. Of patients with SBDS mutations, 56% had a height expressed in SD units from the mean for age and sex of <-1.8, in contrast to only 12% of patients without SBDS mutations (38% of the whole group). Body mass index z score was significantly greater in the group with SBDS mutations (P<.001). CONCLUSION: Although short stature was more common in patients with SBDS mutations, no consistent endocrine phenotype was observed in patients with SDS regardless of genetic testing.

Enfermedad metabólica ósea en prematuros bajo cuidados "Madre ganguro"

Se estudió la incidencia y severidad de la Enfermedad Metabólica osea (EMOP) en 30 prematruos de menos de 200 gramos de peso al nacer cuidados con el método "Madre Canguro", alimentados exclusivamente con leche de sus madres y suplementados diariamente con 400 U de vitamina D. Quince años fueron de peso adecuado para la edad gestacional. La edad gestacional promedio fue de 33,4 semanas; el peso promedio fue de 1623,3 g., la talla 40,97 cm., y el perímetro cefálico 29.1cm.. Ingresaron al programa madre canguro desde los 13,7 días. Se determinaron las velocidades de crecimiento de peso, talla y perímetro cefálico en tres períodos: de 0 a 4, 4 a 6 y de 6 a 13 semanas de vida. No encontramos diferencia estadísticamente significativa entre los grupos adecuados y peso bajo para la edad gestacional. Todos los lactantes presentaron crecimiento inicial muy lento hasta las seis semanas de vida, seguido de un aumento de la velocidad de crecimiento que se mantuvo hasta la décimo tercera semana. A las 4- 6 y 13 semanas de vida se dosificaron calcio fósforo, proteínas totales y fosfatasa alcalina séricos; y adicionalmente contenido mineral óseo por absorciometría bifotónica con emisión de rayos X. Las concentraciones de calcio, fósforo y proteínas totales fueron normales no hubo diferencias estadisticamente significativas entre los dos grupos. Encontrmos relación directa de los niveles de fosfatasa alcalina sérica con la edad posnatal. Reportamos EMOP por medición de contenido mineral óseo en 21 lactantes a las cuatro semanas (70 por ciento), 28 a las seis semanas (93,3 por ciento) y 30 a las 13 semanas (100 por ciento)