Our long term goal is to characterize the clinical phenotype, molecular pathogenesis, and medical complications of congenital neutropenia syndromes with the goal of improving medical management and establishing better treatments for these life-threatening disorders. Although these syndromes are rare, they provide important insights into neutropenia that can be broadly applied to the general population. We propose here to build upon the resources established by The Severe Chronic Neutropenia International Registry (SCNIR or Registry) to develop a complementary registry and repository for Shwachman-Diamond syndrome (SDS). The SCNIR was originally established in 1994 to collect clinical data on patients with congenital, cyclic, and idiopathic neutropenia treated with granulocyte-colony stimulation factor (G-CSF). Over the years it has expanded to include patients with a variety of causes of chronic neutropenia including patients not treated with G-CSF to establish the natural history, evolution and basic mechanisms for these disorders. While the SCNIR includes data on some SDS patients in its """"""""congenital"""""""" category, SDS patients currently are infrequently referred to and not included in the SCNIR, because, for yet unknown reasons, their degree of neutropenia is quite variable. The current registry structure also does not collect information on many clinical aspects of SDS, particularly the immunological, gastrointestinal and other non-hematological aspects of SDS. For example, in SDS not only are neutrophil numbers low but neutrophil functions such as chemotaxis are also impaired.1,2 Additionally, SDS patients manifest immunological abnormalities.3 Patients with SDS have an increased risk of developing severe aplastic anemia.4 The gastrointestinal manifestations, which are often the SDS patients'dominant problem, particularly in early childhood, are not being systematically followed by the SCNIR. The risk and predictors of leukemic evolution are also not known because the population of patients being followed is relatively small. These many features distinguishing SDS from other congenital neutropenia syndromes warrant the development of a complementary SDS registry designed to collect these additional data. The recent identification of the SBDS gene, which is mutated in over 90% of SDS patients, renders the establishment of an SDS tissue repository both timely and essential for investigations into the molecular function(s) of this gene. Finally, the educational efforts of the Registry need to be broadened to address issues specific to SDS patients.
The specific aims of this grant are as follows: 1. Design a database to collect comprehensive information on the clinical phenotype of SDS. Since this is a disorder of neutrophil function as well as neutrophil number, and multiple organ systems in addition to the neutrophils are affected, registry forms will be designed specifically for the study of SDS. 2. Expand recruitment of all patients with SDS regardless of G-CSF treatment and collect longitudinal information to understand the evolution of the clinical phenotype over time. Longitudinal data are critical for the determination of the frequency of complications and the elucidation of risk factors for outcomes such as life-threatening infections, leukemia, or osteoporosis. An understanding of the long-term effects of treatments such as hematopoietic stem cell transplant also require longitudinal study. 3. Establish a bank of biological materials (i.e., blood and bone marrow cells, DNA, RNA and serum) as a shared resource to study the genetic and molecular basis of Shwachman-Diamond syndrome and the evolution of some patients to aplastic anemia, myelodysplasia and leukemia. 4. Develop educational resources to disseminate information about the diagnosis, consequences, and treatment of Shwachman-Diamond syndrome to physicians, patients, and families.
Although SDS is a rare disorder, it provides unique insights into general mechanisms contributing to neutropenia, neutrophil dysfunction, immunologic abnormalities, and leukemogenesis in the general population. These studies will also improve the medical management of non-SDS patients with neutropenia.
| Myers, Kasiani C; Bolyard, Audrey Anna; Otto, Barbara et al. (2014) Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 164:866-70 |
| Burwick, Nicholas; Shimamura, Akiko; Liu, Johnson M (2011) Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome. Semin Hematol 48:136-43 |
| Huang, James N; Shimamura, Akiko (2011) Clinical spectrum and molecular pathophysiology of Shwachman-Diamond syndrome. Curr Opin Hematol 18:30-5 |
