Sixth International Congress on Shwachman-Diamond Syndrome

Agenda

*Presentation times are subject to change.

Tuesday, June 28

SESSION I: Clinical Features of Shwachman-Diamond Syndrome

Pancreatic Defects in Shwachman-Diamond Syndrome

PR Durie, MD^{1, 2}, WF Ip, MASc¹, L Ellis, RN¹, JM Rommens, PhD^{1, 2}

¹The Research Institute, The Hospital for Sick Children, Toronto, Canada
²University of Toronto, Toronto, Canada

Although it appears to be a universal manifestation of Shwachman-Diamond Syndrome (SDS), the clinical spectrum of exocrine pancreatic dysfunction is broad and varies among individuals including sibs. Most commonly SDS presents in infancy with failure to thrive and secondary to pancreatic insufficiency and recurrent infections. Exocrine pancreatic dysfunction of varying severity appears to be a universal manifestation of SDS. The SDS exocrine pancreas shows normal ductular architecture and islets, absent or sparse acinar cells and extensive fatty replacement. Cross-sectional imaging may reveal a small shrunken pancreas or pancreatic enlargement due to lipomatosis. The suggestion that SDS is a syndrome primarily affecting acinar cells is bolstered by analysis of the results of hormonally stimulated pancreatic function studies, which reveal absent or deficient enzyme secretion, but preserved ductal function, which is reflected by fluid and electrolytes. Most infants with SDS have signs and symptoms of fat maldigestion due to pancreatic insufficiency. Approximately 50% of SDS patients show moderate improvement in pancreatic acinar capacity, to allow normal digestion of fat and protein without the need for enzyme replacement therapy. Because the exocrine pancreas has a large reserve capacity, the absence of signs and symptoms of pancreatic maldigestion steatorrhea does not exclude pancreatic acinar dysfunction or the diagnosis of SDS. Those who become “pancreatic sufficient” with advancing age, show an increase in serum immunoreactive trypsinogen. In contrast, the values remain low in those who remain “pancreatic insufficient”. The age-related changes observed for serum trypsinogen does not hold true for all pancreatic enzymes. For example, all patients with SDS have low serum pancreatic isoamylase activities irrespective of age. The independent age-related changes of the two enzymes has proven to be of great value as a clinical marker of exocrine pancreatic function and as diagnostic marker of the SDS pancreatic phenotype

Advances in Imaging Studies of Shwachman-Diamond Syndrome

Sanna Toiviainen-Salo, MD, PhD, Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland

This presentation focuses on the use of different imaging modalities in assessment of various clinical and phenotypic features in Shwachman-Diamond syndrome, including pancreatic, hepatic, cardiac, skeletal, and brain involvement. The advanced applications of conventional imaging modalities such as ultrasound, magnetic resonance imaging, and bone densitometry have provided versatile tools to assess the characteristics of various organs involved in SDS. The findings and implications of the current literature are reviewed and novel methods are discussed.

SESSION II: Surveillance, Management, and Treatment of Shwachman-Diamond Syndrome

Hematologic Complications of SDS

Akiko Shimamura, MD, PhD
Fred Hutchinson Cancer Research Center; Seattle Children’s Hospital, Seattle, Washington

Marrow failure and malignant transformation are potentially life-threatening hematologic complications of Shwachman-Diamond syndrome (SDS). In the SDS clinical statement published in 2002 by Rothbaum et al., neutropenia is defined as an ANC<1500 and thrombocytopenia as platelet count <150K. Anemia is defined as a hemoglobin or hematocrit that falls below normal ranges for age and gender. Cytopenias may be mild, severe, or intermittent. A subset of patients develop aplastic anemia. Cytogenetic clones often arise in patients with SDS. Del20(q) and isochromosome 7 are frequently observed and in isolation do not portend imminent malignant transformation. The definition of MDS in patients with inherited marrow failure syndromes is challenging since the World Health Organization (WHO) criteria are not applicable. The diagnosis of Myelodysplastic Symdrome (MDS) is typically reserved for patients deemed to be at high risk for malignant transformation. Data are sparse to guide clinical management of Acute Myelogenous Leukemia (AML). The role of pre-transplant cytoreductive chemotherapy for AML remains to be clarified for SDS patients. Indications for hematopoietic stem cell transplantation include severe or symptomatic cytopenias, MDS, and AML. Encouraging results with reduced intensity conditioning regimens have been reported but patient numbers are still small with limited follow up. Given the risks of transplant-related morbidity and mortality, preemptive transplants are not currently standard of care. Since treatment outcomes are superior if initiated prior to the development of leukemia or complications from severe marrow failure, regular monitoring of blood counts and bone marrow exams with cytogenetics are recommended. Molecular cytogenetic approaches warrant consideration. Data collection on Registries and treatment on SDS protocols are critical to improve outcomes.

Management of Adults with Shwachman-Diamond Syndrome (SDS)

Monica Bessler, MD, PhD ^1,2 and Kim Overby, MD MBE ^1,2

¹The Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
²The Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Shwachman-Diamond syndrome (SDS) is a rare, autosomal-recessive disorder that is usually identified in infancy and is characterized by exocrine pancreatic insufficiency, short stature, and bone marrow failure. Additional clinical features include: metaphyseal dysostosis, growth failure, osteopenia, immune dysfunction, renal defects, liver disease, diabetes mellitus, psychomotor deficiencies, and a predisposition to malignant myeloid transformation during the second and third decade of life. Existing care guidelines reflect our knowledge of this disease during childhood however an increasing number of individuals are surviving to adulthood. Much less is known about the natural history and care needs of these individuals as adults. As a result, both the adult health care system and informal care providers are generally ill prepared to care for these individuals as adults. Furthermore, the transition to adulthood poses many general and disease-specific challenges for these youth. Many are lost to follow-up compromising not only health outcomes but also efforts to better understand the natural history of this condition across the lifespan. The Children’s Hospital of Philadelphia and the Department of Medicine at the University of Pennsylvania are currently developing a transition and ongoing care program for these individuals. This initiative will help address the medical and non-medical needs of these youth by providing individualized needs assessment and supports, assistance with self-management and advocacy skills, and care coordination during and after transition to the adult-oriented health care system. This program will also provide an opportunity to expand our knowledge of the natural history of SDS across the lifespan and extend care guidelines for the management of SDS in adults.

Understanding Neurocognitive Functioning in SDS

Elizabeth N. Kerr, PhD, The Hospital for Sick Children, Toronto, Canada

It has been demonstrated that individuals with Shwachman-Diamond Syndrome (SDS) are at risk for neurocognitive and neuropsychiatric issues. Specifically, a spectrum of intellectual functioning, with an overall downward shift from the norm, as well as weaknesses in visual processing, attention and executive functioning have been documented. In addition, a large proportion of individuals with SBDS mutations present with neuropsychiatric issues (Kerr et al., 2010). A recent objective has been to assess functioning longitudinally; several case studies will be presented. The documented difficulties are believed to be primary consequences of SBDS dysfunction on the brain. Preliminary neuroimaging studies indicate that SDS is associated with disturbances in white matter tracts (Kamoda et al., 2005; Todorovic-Guild et al. 2006., Toivianinen-Salo et al., 2008). Examination of neurocognitive correlates of white matter deficits in common diseases will be presented as a basis to further our understanding of possible implications in SDS; to date, neurocognitive functioning has not been directly linked to imaging status in SDS. Future studies are needed to understand the degree to which abnormal white matter is related to cognitive performance in SDS and to investigate the relationship between white matter integrity and SDS-specific clinical variables.

SESSION III: International Shwachman-Diamond Syndrome Registries

Update on the North American Shwachman-Diamond Syndrome Registry

SDS Registry Investigators (alphabetical)

David Dale, MD, University of Washington
Stella Davies, MBBS, PhD, Cincinnati Children’s Hospital
Richard Harris, MD, Cincinnati Children’s Hospital
Akiko Shimamura, MD PhD Fred Hutchinson Cancer Research Center

Research Nurses

Audrey Anna Bolyard, RN, BS, University of Washington
Theresa Cole, RN, Cincinnati Children’s Hospital

Research Coordinators

Satabdi Chakrabarti, Fred Hutchinson Cancer Research Center
Joan Moore, Cincinnati Children’s Hospital

The North American Shwachman-Diamond Syndrome Registry (SDSR) opened for accrual in December of 2008. Participants in the SDSR are asked to send in medical records and fill out a questionnaire annually. Data collected include hematology, oncology, gastroenterology, skeletal abnormalities, other physical findings, genetic testing, and infection history. Fifty one subjects were <18 years of age (median age 8.7, range 2.3-17.3), with a male:female ratio of 1.7:1. Ten subjects were > 18 years of age (median age 22.8, range 18.7-61.6), with a male:female ratio of 1:2.3. SBDS genetic analysis has been submitted for 35 subjects thus far. 33 of 35 harbor SDBS mutations. Two of 35 had no SBDS mutations detected but were phenotypically consistent with SDS as demonstrated by exocrine pancreatic dysfunction and marrow failure. A wide range of congenital anomalies were reported in patients with SDS. 34 subjects have submitted CBC data: 22 with SBDS mutations, 2 negative for SBDS mutations and the remainder lacked SBDS genetic data. Of the 22 with SBDS mutations, neutropenia was noted in 13 (5 severe), thrombocytopenia in 9 (1 severe), macrocytosis in 3, and anemia in 10 (1 severe). Four patients had reductions in all three lineages. Of the two subjects without SBDS mutations, one had neutropenia and one had thrombocytopenia. Bone marrow reports are available for 21 patients of whom 17 had SBDS mutations. 5/17 patients had marrow hypoplasia, 3/17 patients had marrow dysplasia. 7/17 showed clonal abnormalities: 5 with del(20q), 1 with iso(7q), 1 with monosomy 7. No subjects have reported malignancy.

National Cancer Institute SDS and Bone Marrow Failure Registry

Blanche P. Alter, MD, MPH¹, Neelam Giri, MD¹, Sharon A. Savage, MD¹, Christian P. Kratz, MD¹, Philip S. Rosenberg, PhD²

¹Clinical Genetics Branch^, National Cancer Institute, Rockville, Maryland
²Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland

The National Cancer Institute (NCI) Inherited Bone Marrow Failure Syndrome (IBMFS) cohort began in 2002 and is reported through 2010. The major IBMFS are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA) and Shwachman-Diamond syndrome (SDS). All have very high risks of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), as well as solid tumors in FA, DC, and DBA. The purpose of this retrospective/prospective cohort is to quantify the types and incidences of neoplasms in this cancer-prone group. We enroll participants (including first degree relatives) from North America. Standard screening tests are employed (chromosome breakage for FA, telomere length for DC, ADA for DBA, pancreatic enzymes for SDS); genetic mutations are identified where possible. Patients with acquired disorders are not included, and those called “other” have had known IBMFS rigorously excluded. There are currently >400 affected participants, and >900 family members. The observed/expected ratio for all cancers in FA is ~40-fold, DC ~11-fold, and not yet significant in DBA or SDS. The sequence from the worst to the best for overall survival, survival free of cancer, and survival free of bone marrow failure is: FA, DC, DBA, SDS. Cytogenetic clones were more frequent in FA, followed by DC, then SDS; there were none in DBA. Clones in SDS included del(20)(q) and monosomy 7; MDS was rare. Longitudinal studies are ongoing in order to learn whether there is prognostic significance to the presence or type of clones and/or myelodysplastic syndrome (MDS), with regard to evolution to MDS or AML.

Risk Factors for Severe Chronic Cytopenia, In Shwachman-Diamond Syndrome: A French Survey

J Donadieu¹, B Beaupain¹, S. Beaufils², O Fenneteau³, C Bellanné-Chantelot⁴ and the French Severe Chronic Neutropenia Registry*

¹French Severe Chronic Registry, AP-HP Hôpital Trousseau, Paris, France

Aim: To study risk factors for severe cytopenia; (either clonal or not clonal) in Shwachman-Diamond syndrome (SDS).

Methods: 101 patients with SDS and SBDS mutations were enrolled in the French SCN registry.

Results: During a total follow-up of 1401 person-years, 21 cases severe cytopenia (Hb < 7 gr/l Plat < 20 G/l) was observed and classified in myelodysplasia / leukemia / (n=9) and chronic not clonal multi cytopenia (n=9) and in 3 cases by myelodysplasia was preceded by a prolonged not clonal cytopenia. Severe hematological complications were responsible for 13 of the 15 deaths observed in the cohort. The p.[Lys62X]+[Cys84fs] genotype was present in 60% of the kindred. Only severe gastrointestinal complications, low median baseline (i.e. measured at routine examinations) hematological values (absolute neutrophil count (ANC) < 0.5 G/l, platelets < 100 G/l, hemoglobin < 9 g/dl) were associated with a severe hematological complications. The genotype had no discernable prognostic value.

Conclusion: Our study suggests that patients with profound cytopenia at baseline should be considered at a high risk of secondary leukemias. Patients with major nutritional impact of the disease have also a higher risk of SC, suggesting a link between nutritional status and such haematological events.

The Canadian Inherited Marrow Failure Registry

Zlateska B., Hashmi S.K., Klaassen R., Fernandez C.V., Yanofsky R., Wu J., Champagne J., Silva M., Lipton J.H., Brossard J., Samson Y., Abish S., Steele M., Ali K. Dower N., Athale U., Jardine L., Hand J.P., Beyene J., Dror Y.

From the Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology and Cell Biology Program, Research Institute, The Hospital for Sick Children and the University of Toronto, Ontario and the Canadian Inherited Marrow Failure Registry, Canada

The Canadian Inherited Bone Marrow Failure Registry (CIMFR) is a multicenter study, which was approved by the Institutional Ethics Board of all 17 the participating institutions. Patients have been prospectively enrolled since January 2001 after written consent was obtained from the patients or guardians. The participating centers care for >95% of the eligible pediatric IBMFS population in Canada. Patient information are collected at registration and updated every year or two. SDS is the third most prevalent disease on the CIMFR. Compound heterozygosity for mutations in SBDS was found in 81% of patients tested. The most common mutations were 258+2T>C, 183-184TA>CT and 183-184 TA>CT+258+2T >C. At diagnosis, 74% of SDS patients had neutropenia, 58% had anemia and 38% had thrombocytopenia. At a median age of 26 months, 24% of SDS patients developed severe aplastic anemia. At a median age of 20 years, 18% of the SDS patients developed clonal and malignant myeloid transformation. Eighty-five percent of patients had pancreatic dysfunction; 67% of whom required enzyme replacement therapy. Analysis of genotype-phenotype correlation revealed that compared to patients with SBDS mutations, the wild type SBDS patients had significantly lower hemoglobin levels, higher HgF, higher incidence of severe aplastic anemia, more frequent need for hematological treatment, but milder pancreatic dysfunction. Comparison between patients with one truncation (e.g. c.183-184TA>CT) and one hypomorphic mutation (e.g. c.258+2T>C) to patients with two hypomorphic mutations revealed no differences with regard to age of presentation, age of diagnosis, Hg, HgF, MCV, platelets, neutrophils, severe aplastic anemia and clonal marrow cytogenetic abnormalities.

In summary, SDS patients commonly present with pancytopenia; however, patients may present with unique features such as neutropenia with either high MCV or high HgF. SDS patients with no mutations in the SBDS gene have a more severe hematological disease with higher risk of severe aplastic anemia but a milder pancreatic disease compared to the patients with mutated SBDS.

A Prospective Haematological Survey Of Italian Patients Affected By Shwachman-Diamond Syndrome: Results Of A Ten Years Multicentric Study

D.Longoni², L. Sainati¹, G. Basso¹, A. Biondi², S. Fenu³, S. Francescato¹, M. Zecca⁴, C. Bugarin², M. Cipolli⁶, C. Danesino⁵, A Di Meglio¹, G. Tridello¹, A. Leszl¹, E. Maserati⁸, A. Minelli⁵, E. Nicolis⁶, F. Pasquali⁸, F. Poli i<sup>7

1</sup>Clinica Pediatrica Università di Padova, Fondazione Città della Speranza, Italy
²Clinica Pediatrica, Fondazione MBBM, Università Milano-Bicocca, AO San Gerardo, Monza, Italy
³ Clinica di Ematologia Università La Sapienza Roma, Italy
⁴ Ematologia Pediatrica Ospedale S.Matteo Pavia, Italy
⁵ Genetica Medica, Università e IRCCS San Matteo, Pavia, Italy
⁶ Centro fibrosi cistica, Ospedale Civile Maggiore Verona, Italy
⁷ Ospedale Burlo Garofalo, Trieste, Italy
⁸ Dip. Scienze Biomediche Sperimentali e Cliniche – Università dell’Insubria, Varese, Italy

Introduction: SDS patients have an increased risk to develop severe aplasia, myelodysplasia and leukemia. The appearance of dysplastic features and clonal cytogenetic abnormalities increases the incidence of these complications and the treatment of choice is haematopoietic stem cell transplantation (HSCT) but the timing is controversial because few information about haematological history are available.

Methods: A national centralized network has been created for the haematological follow-up of SDS patients: whole peripheral blood count, molecular investigation, marrow morphological and cytogenetic analysis and clonogenic assays were scheduled according the guidelines recommended during the First International Meeting on SDS. SDS patients were recruited since 1997 to 2007 and follow-up has been up-dated at December 2010. 50 patients were recruited with median age at first observation 7.5 years. SBDS gene mutations were detected in 42/50 patients.

Results: The majority of the patients presented anaemia; 62% and 84% of the patients was thrombocytopenic and neutropenic, respectively.
Aplastic or hypoplastic marrow was detected in 2% and 17% of the samples respectively. Megacaryocytes were absent end severally reduced in 26% and 35% of the cases respectively. Myelodysplastic changes were observed in 38% of the cases. 70% of the patients showed impaired clonogenic ability. In 20/42 cases a clonal cytogenetic evolution has been detected; 5 cases presented clinical evolution: 2 SAA, 2 MDS and 1 AML; 2/5 died, 3/5 are alive 6, 9 and 11 years after BMT. One third of patients are clinically stable despite clonal and displastic abnormalities.

Conclusion: Cytopenia, dysplastic features and clonal abnormalities are frequent in SDS patients, and can be associated with a long steady clinical state. Malignant evolution is a rare complication and HSCT should be considered only in a little number of patients.

Shwachman-Bodian-Diamond Syndrome (Sbds): Data from the European Branch of The Severe Chronic Neutropenia Registry (SCNIT)

C Zeidler, P Lohse, I Schäfer, KW Sykora and K Welte for the European Branch of the Severe Chronic Neutropenia Registry

The SCNIR Europe has collected clinical data on 503 patients with different types of severe chronic neutropenia (congenital neutropenia and idiopathic neutropenia) since 1994. Out of the 503 patients 297 patients suffer from different types of congenital neutropenia (CN) and 66 from cyclic neutropenia (CyN). The CN subtypes include 46 patients with Shwachman-Diamond syndrome (SDS), 68 patients with ELANE mutations, 25 patients with HAX1 mutations, 21 patients with Gykogen storage disease type 1b, 8 patients with G6PC3 mutations and other rare disorders. An overall incidence of secondary leukemia of more than 10 percent is documented in patients with congenital neutropenia which belongs to the premalignant bone marrow failure syndromes. With the identification of new causative gene mutations the number of genetic subgroups is still increasing. We assessed the incidence and outcome of leukemic transformation in CN patients with known gene mutations in ELANE, HAX1, G6PT, G6PC3, WAS, SBDS, TAZ1 and p14 or no identified mutation, respectively, by analyzing all available data from the European Branch of the Severe Chronic Neutropenia Registry (SCNIR). For comparison we also analyzed patients with cyclic neutropenia (CyN) with or without ELANE mutations.

Here we report our long term clinical data on the 46 SDS patients: The gender ratio is 20 female to 26 male. 29 patients are alive, 3 expired, 1 patient is lost to follow up.

Severe Neutropenia (ANC <500/µl) is reported in all patients receiving subsequent G-CSF treatment (n= 11). The G-CSF dose ranges from 0.4 to 7.5µg/kg/day. The median G-CSF dose in SDS patients is 3.41 µg/kg/d.

MDS-like leukemic transformation occurred in 4 patients (2 male/2 female) out of the 46 SDS patients (8,7 %) at an age of 5, 7, 13 and 16 years and was highest in the patients with HAX1-CN (20%) or ELANE-CN (16.2%).

All SDS patients with leukemic transformation had additional cytogenetic abnormalities (monosomy 7 or complex aberrant karyotype). 3 patients received SCT from unrelated donors (2 MUD, 1 haploident.). In addition SCT has been performed in 6 non-leukemic SDS patients due to pancytopenia, non-response and planned lung transplantation.

SBDS gene analysis has been performed in 28 of the 46 SDS patients: Compound heterozygous mutations (183 TA>CT/258+2T>C) have been found in 19 of the 28 patients. Five patients revealed rare mutations in one allele; in one patient no SBDS mutation was detected.

SESSION IV: Genetics and Disease Models of Shwachman-Diamond Syndrome

Genetics and Disease Models of Swhachman-Diamond Syndrome

JM Rommens^1,2, M.E. Tourlakis^1,2, H. Liu^1,2, R. Gandhi², J. Zhong², W. Ip⁴, L. Ellis⁴, P.R. Durie<sup>3,4

1</sup> Department of Molecular Genetics, University of Toronto, Toronto, Canada
2 Program in Genetics & Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada
³ Department of Pediatrics, University of Toronto, Canada
4 Programs in Physiology & Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Canada

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder with clinical features of exocrine pancreatic dysfunction, skeletal abnormalities and bone marrow failure. Neurobehavioral and learning components are also evident as primary manifestations. The major gene that causes SDS, SBDS, was identified by positional cloning using family studies. Common recurring mutations that lead to premature truncation or aberrant splicing have arisen by gene conversion events to comprise the majority of all patient mutations (76%), with over forty additional rare mutations also reported to date. It is evident that complete loss of SBDS function is not compatible with life as no patient has been described with two null alleles. The possibility that additional genes may lead to SDS remains an open question, and although introduction of molecular genetic testing of SBDS has complemented clinical assessment, improved and more discriminating disease definitions continue to be needed. Disease models with null, disease-associated and conditional Sbds alleles have revealed a general theme of hypocellularity and growth deficiency that is broadly consistent with a ribosomal deficiency that was first suggested from studies of the yeast ortholog, known as SdoI. Further, disease pathology in different organs, including those most afflicted in SDS, demonstrate responses to stresses that parallel critical growth and developmental stages of these organs. Questions regarding the basic functions of Sbds, the specificity of organ involvement and the basal and developmental aspects of disease phenotypes are current avenues of research.

P53-Dependent Ribosomal Stress Response Underlies the Developmental Defects In A Drosophila Model Of Shwachman-Diamond Syndrome

Shengjiang Tan, Li Jin, Alan J. Warren
MRC Laboratory of Molecular Biology and Department of Haematology, University of Cambridge, Cambridge, United Kingdom

The SBDS protein cooperates with the GTPase elongation factor-like 1 (EFL1) to catalyze a conserved late cytoplasmic step in the maturation of nascent 60S ribosomal subunits. Specifically, SBDS and EFL1 jointly evict the anti-association factor eIF6 from the intersubunit interface of pre-60S ribosomal subunits to allow ribosomal subunit joining. However, the molecular mechanisms underlying the developmental abnormalities associated with SBDS deficiency remain unknown. Here, we show that Drosophila Sbds (dSbds) is essential for larval growth and development. Ectopic expression of wild-type eIF6 enhances the growth defect of hypomorphic dSbds mutant flies by exacerbating the defect in ribosomal subunit joining. By contrast, transgenic over-expression of dominant gain-of-function eIF6 suppressor mutants completely rescues the lethal phenotype caused by dSbds deficiency. Strikingly, we demonstrate that genetic ablation of p53 rescues the cell-cycle arrest, apoptosis and developmental abnormalities associated with loss of dSbds function. Taken together, our data reveal for the first time the presence of a ribosomal stress surveillance pathway in Drosophila that activates p53 in an Mdm2-independent manner. Our findings provide insight into the etiology of the developmental defects that result from loss of dSbds function and further strengthen the hypothesis that small molecules that mimic the effects of eIF6 suppressor mutations may have utility in the treatment of Shwachman-Diamond syndrome.

Shwachman Diamond Syndrome is a P53-Independent Ribosomopathy

Elayne Provost¹, Foram Asher², Xiaogang Zhong¹, Michael Parsons¹ and Steven D Leach^1
1Department of Surgery, Johns Hopkins University, Baltimore, Maryland
²Human Genetics, Johns Hopkins University, Baltimore, Maryland

Mutations in the human Shwachman-Bodian Diamond Syndrome (SBDS) gene cause chronic neutropenia, exocrine pancreas dysfunction and skeletal defects. Although the precise cellular function of SBDS is unknown, it has been implicated in ribosome biogenesis. Diseases that affect ribosome biogenesis, termed ribosomopathies, are generally understood to do so through a p53-dependent mechanism. We used morpholino knock down of the zebrafish orthologue of sbds to recapitulate the disease phenotype. Knock down of SBDS in zebrafish resulted in a loss of neutrophils, a small exocrine pancreas and a disrupted skeletal architecture. To assess whether these phenotypes were due to a p53-dependent mechanism, we knocked down p53 and assessed rescue of the phenotype. Knock down of both SBDS and p53 by coinjection of morpholino did not rescue the SBDS phenotype. This was confirmed genetically using a p53 null zebrafish line. Additionally, we show another isoform of p53, D113p53, when knocked down by morpholino, did not rescue the phenotype. We conclude Shwachman Diamond Syndrome is a p53-independent ribosomopathy.

*Additional abstracts coming soon

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