Diagnosis Of Shwachman-Diamond Syndrome Research Articles

Clinical and genetic characteristics of Chinese patients with Shwachman Diamond syndrome: a literature review of Chinese publication.

Shwachman Diamond syndrome (SDS) is a rare autosomal recessive genetic disorder and due to its complex and varied clinical manifestations, diagnosis is often delayed. The purpose of this study was to investigate the clinical manifestations and genetic characteristics of SDS in Chinese patients, in order to increase pediatricians' awareness of SDS and to allow early diagnosis. We conducted a search to identify patients presenting SBDS gene pathogenic variant in two Chinese academic databases. We analyzed and summarized the epidemiology, clinical features, gene pathogenic variants, and key points in the diagnosis and treatment of SDS. We reviewed the clinical data of 39 children with SDS from previously published articles. The interval from the onset of the first symptoms to diagnosis was very long for most of our patients. The age of presentation ranged from 1day to 10years (median: 3months). However, the age of diagnosis was significantly delayed, ranging from 1month to 14years (median: 14months). Hematological abnormalities were the most common presentation, 89.7% (35/39) at the beginning and 94.9% (37/39) at diagnosis of SDS. Diarrhea was the second most common clinical abnormality at the time of diagnosis. 59% (23/39) of patients had a typical history of persistent chronic diarrhea. Furthermore, hepatic enlargement or elevation of transaminase occurred in 15 cases (38.5%). 56.4% patients (22/39) had a short stature, and 17.9% (7/39) patients showed developmental delay. Additionally, twenty patients had compound heterozygous pathogenic variants of c.258 + 2T > C and c.183_ 184TA > CT. Children with SDS in China had high incidence rates of chronic diarrhea, cytopenia, short stature, and liver damage. Furthermore, SBDS c.258 + 2T > C and c.183_ 184TA > CT were the most common pathogenic variants in patients with SDS. The diagnosis of SDS can be delayed if the clinical phenotype is not recognized by the health care provider.

Outcomes of Hematologic Complications in Shwachman Diamond Syndrome: High Risk Features and Implications for Surveillance

Background Shwachman Diamond syndrome (SDS) is characterized by genetic predisposition to bone marrow failure and TP53-mutated myeloid malignancies. Data are scarce to guide surveillance strategies. Objectives This study aims to characterize the presentation and outcomes of hematologic complications in 218 patients with SDS with the goal of informing surveillance. Design/Method Data was obtained from medical records of 218 study subjects with biallelic mutations in SBDS/DNAJC21/ EFL1, or heterozygous mutations in SRP54 consented to the SDS Registry or the Bone Marrow Failure/MDS study which are longitudinal prospective cohort studies. Results The median age of the study cohort was 12.2 years (yr) (range 0.1-52.8 yr). Of 204 patients with SBDS mutations, 12 developed severe BMF requiring transplant (median age 2.9 yr, range 0.4-39.5), 16 developed MDS (median age 15.9 yr, range 0.5-45), 11 developed AML (median age 27.7 yr, range 9.4-47.3) and 2 developed lymphoma (ages 17.0 and 23.8 yr). Of the 48 subjects with SBDS mutations who were adults >18 years (median 25.5, range 18.5-52.8), 16 (33%) developed a myeloid malignancy. Of 20 patients with an SRP54 mutation, 1 developed AML at age 15.2. One patient with biallelic EFL1 mutations died of BMF at age 0.7 yr. Further analysis focused on patients with SBDS mutations. Five patients with MDS and 1 patient with AML were on G-CSF at the time of malignancy diagnosis. Only 2 patients who developed AML had had surveillance, but neither included somatic mutation analysis. The diagnosis of SDS was unrecognized prior to malignancy diagnosis for 5 with MDS (age range 13.8 to 21.5 yr) and 2 with AML (age 37.8 and 47.3 yr). Three patients were diagnosed with MDS on surveillance marrow exam. All patients with AML presented with symptoms which led to diagnosis. Of the 16 patients who initially presented with MDS, 5 progressed to AML. Median survival for those who presented with MDS was 1.3 yr (range 0.2-14.9). Ten were deceased, 4 were alive with median follow up of 3.4 yr (range 1.0-14.9). Two additional patients were <100 days out from HSCT. Of 9 patients with MDS who proceeded to HSCT without prior cytoreductive therapy, 4 were alive with a median follow up of 3.1 yr (range 0.2-14.4) post-HSCT, 5 were deceased from treatment related mortality (TRM) (n=2), relapsed/refractory disease (n=2) or osteosarcoma at 10 years post-HSCT (n=1). Of 6 patients who received cytoreductive therapy, 3 died prior to HSCT with active disease (n=2) or TRM (n=1). Of the 3 who proceeded to HSCT post-cytoreductive therapy, 2 are alive at 0.1 and 0.7 yr post HSCT, and 1 died of TRM. One patient who received no therapy died 7.7 years post-diagnosis. Median survival following AML diagnosis was 1 year (range 0.2-5.6). Of the 11 patients with AML, 8 died with relapsed/refractory disease, 1 died of TRM, and 2 survive in remission at 2 and 5.6 years post-AML diagnosis. Of the two patients who proceeded directly to HSCT, one is alive 5.6 years post-HSCT. Nine patients received a variety of cytoreductive regimens for AML, including AraC/Idarubicin, hypomethylating agents +/- venetoclax, of whom 6 were able to proceed to HSCT. None of the 9 adult patients >18 years with SBDS mutations and AML survived. Eight patients with SDS undergoing surveillance marrow exams developed high risk features (HRF), including progressive dysplasias, dropping blood counts with rising marrow cellularity, high risk clonal cytogenetic abnormalities, and large or rapidly growing TP53 clones. Median age of patients with HRF was 19.7 yrs (range 1.3-40.9). All 6 patients transplanted for HRF are alive and well with a median follow up of 1.8 yr (0.1-4.5) post-BMT (Figure 1); 2 patients are currently undergoing evaluation for HSCT. None of the patients transplanted for HRF developed grade 3 or 4 GVHD. One patient with a large TP53 clone prior to transplant is alive without a detectable TP53 clone 0.9 years post-BMT. Conclusions AML carries a poor prognosis for patients with SBDS mutations, so early referral for novel therapies should be considered. Marrow surveillance including morphology, cytogenetics, FISH, and somatic mutation analysis identified patients who developed HRF. Survival was excellent for patients transplanted for HRF. Although SDS is rare and patient numbers are small, these data show that regular comprehensive marrow surveillance can identify HRF to inform the need for closer monitoring or transplant prior to progression to malignancy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MDS and AML in Shwachman-Diamond Syndrome: Clinical Features and Outcomes

Genetic predisposition to MDS and AML is recognized in a growing subset of patients, but data to inform medical management and outcomes are sparse. Shwachman-Diamond syndrome (SDS) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML). The aim of this multi-institutional retrospective study was to investigate clinical features, treatment, and outcomes of 37 patients with SDS who developed MDS or AML. Diagnosis of SDS was established by SBDS genetic testing (n=30), exocrine pancreatic dysfunction (n=5), or data were unavailable (n=2). Nine individuals presented with AML (4 male, 5 female), 26 with MDS (13 male and 13 female), one male with refractory cytopenia (RC), and one male with isolated persistent somatic TP53 mutation. Eight of 26 MDS patients, had MDS-EB1 or EB2 at diagnosis, of whom two progressed to AML. Three patients initially presenting with early MDS progressed to MDS-EB1, MDS-EB2, or AML. Median age (years) at diagnosis of early MDS was 13.8 (range 0.5-28.8), for MDS-EB1/2 was 16 (range 9-30) and for AML was 33 (range 5.5-47). Nine patients with MDS and 1 patient with AML were receiving G-CSF chronically prior to diagnosis of MDS/AML.Complex cytogenetics, (>3 cytogenetic abnormalities per clone), were noted in 8/9 AML cases. One AML patient presented with normal cytogenetics. Complex clonal cytogenetic abnormalities were noted in 5 of 6 patients with MDS-EB1/EB2 for whom reports were available. Cytogenetic data were available for 16 MDS cases and clonal abnormalities were noted in 10. Aberrations involving chromosome 7 were most common. The patient with the somatic TP53 mutation had normal cytogenetics. Centralized bone marrow pathology review is currently ongoing.Follow up data were available for 8 patients with AML; 6 are deceased. Six received chemotherapy with intent to proceed to hematopoietic stem cell transplant (HSCT), of whom 5 failed to achieve remission and died with disease without proceeding to transplant. One AML patient proceeded to HSCT with progressive disease post-chemotherapy, but died with relapsed disease. One patient proceeded to HSCT without prior chemotherapy and was in remission at day 30 post-HSCT. The sole long-term surviving AML patient achieved remission with chemotherapy and underwent HSCTs with 3 separate stem cell infusions due to primary graft failure after the initial two infusions. He remains alive in remission more than 4 years after diagnosis. Notably this surviving AML patient was the only AML patient with normal cytogenetics at diagnosis.Follow up data are available for 6 of 8 patients presenting with MDS-EB1/EB2, 4 of whom are deceased. One patient who presented with MDS-EB1 is alive with relapsed disease after HSCT and one patient is in remission 100 days after HSCT.Follow up data are available for 17 of 18 early MDS patients, 7 of whom are deceased including three who had progressed to MDS-EB1, MDS-EB2, or AML. Four of the 7 deceased patients had received a HSCT. One individual with MDS died of hepatic failure unrelated to MDS. Seven MDS patients are alive in remission after HSCT without prior chemotherapy. Treatment was not reported for an additional 2 surviving patients. One patient receiving a hypomethylating agent is alive with stable disease 4.8 years from diagnosis. The patients with RC and with a TP53 clonal abnormality are alive at 6.5 years and 1.7 years from diagnosis respectively.In summary,prognosis is poor for patients with SDS who develop AML or MDS-EB1/2, with few long-term survivors due to resistant disease and treatment-related complications. Outcomes are better if transplanted for MDS prior to acquisition of increased blasts, with 10 of 17 (59%) subjects surviving (median follow up 6 years, range 1.5-11.2). AML often presents in adulthood highlighting the need for continued surveillance of SDS patients with bone marrow examinations including cytogenetics and FISH. These data demonstrate the importance of early detection of clonal evolution in this leukemia predisposition syndrome. Better markers for risk stratification are needed to identify patients who would benefit from early transplant prior to advanced clonal disease. Novel therapeutic strategies, such as targeted therapies, are urgently needed to improve outcomes of SDS patients with advanced MDS or AML. DisclosuresDiNardo:Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Norkin:Celgene: Honoraria, Research Funding. Shimamura:TransCellular Therapeutics: Other: Spouse is majority shareholder .

Large Genomic Deletions in Shwachman-Diamond Syndrome

▪Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) with gastrointestinal manifestations (pancreatic insufficiency) and cytopenias, primarily neutropenia. Skeletal dysplasias and short stature are frequent. Patients with SDS are at significantly increased risk of myelodysplastic syndrome and acute myeloid leukemia. More than 90% of patients have autosomal recessive inheritance of germline pathogenic variants in SBDS, a ribosome biogenesis gene. The most common variants are c.258+2T>C (disrupts the donor splice site of intron 2, leading to an 8bp deletion and a premature protein truncation due to a frameshift); and c.183_184TA>CT (introduces an in-frame stop codon). To date, the vast majority of pathogenic alleles reported have been single nucleotide variants (SNVs) or small insertions/deletions. Rare cases have been reported with SBDS exon 3 deletions.The National Cancer Institute's IBMFS study is a longitudinal cohort study with 521 families enrolled, including 54 SDS or SDS-like families. Through clinical testing or whole exome sequencing all but nine families have had their disease-causing alleles identified. Three of the nine families had a known single pathogenic variant in SBDS. Array comparative genomic hybridization (aCGH) was uninformative in all but one.We initially focused on the family with a known SBDS c.258+2T>C and potential deletion on aCGH. The 27 year-old (yo) male proband was diagnosed with SDS at 5yo due to a history of malabsorption, requiring pancreatic enzyme supplementation, failure to thrive (FTT), short stature and neutropenia. He also has metaphyseal dysplasia, scoliosis, psychomotor retardation and learning disability. A bone marrow (BM) biopsy at 21yo showed hypoplasia with mild dysplastic changes and a del20q clone. aCGH showed a possible large deletion, but the resolution was too low to determine exact breakpoints. Therefore, long-range Single Molecule, Real-Time (SMRT) Sequencing (PacBio Systems) was undertaken. This identified a read spanning a 19kb deletion with exact coordinates (hg19: chr7:66,436,397-66,455,294), and was confirmed with polymerase chain reaction and Sanger sequencing. This deletion removes part of intron 4, all of exon 5 and the 3'UTR of SBDS. Western blotting for SBDS showed significant decrease in protein production from cultured fibroblasts. This deletion in combination with the known SBDS variant and western blot is consistent with the SDS phenotype in this patient.We then designed a targeted SMRT sequencing panel consisting of the four published SDS genes: SBDS, EFL1, DNAJC21 and SRP54 to evaluate the remaining families. The second proband evaluated was a 19yo female heterozygous for the SBDS c.258+2T>C variant. She had a history of malabsorption requiring enzyme supplementation and FTT in childhood. She has short stature, deformity of the distal metaphysis of the ulnae, and ongoing neutropenia with a hypocellular BM but no cytogenetic clones. Targeted SMRT sequencing identified a deletion in SBDS which deletes all of exon 3 and part of the surrounding introns (872bp, hg19: chr7: 66,457,992-66,458,863). Western blotting for SBDS showed a decrease in protein production in cultured fibroblasts consistent with a diagnosis of SDS. Sequencing of the family members indicated the deletion was paternal in origin, while the SNV was maternal.A deletion of SRP54 was identified in two affected siblings from a third family; both siblings have a history of neutropenia and mild BM dysplasia. The deletion encompasses exon 8 of SRP54, which encodes part of the G-domain, critical for SRP54 cotranslational function, and is near other reported autosomal dominant pathogenic variants. One affected individual in this family also has a single SBDS c.183_184TA>CT variant, but had normal SBDS protein levels by western blot. In this family, the SBDS variant is likely not disease causing as individuals with heterozygous pathogenic variants of SBDS are generally asymptomatic, but rather the dominant SRP54 deletion is the disease causing genetic alteration in this SDS-like family.No large deletions or insertions were identified in DNAJC21. Analysis of EFL1 is on-going. These cases illustrate the advantages of using long-read sequencing methodologies to identify large deletions which are not readily found using short-read sequencing, and identify large deletions as a novel mechanism of SDS inheritance. DisclosuresNo relevant conflicts of interest to declare.

Germline and Somatic Genetic Characterization of Shwachman-Diamond Syndrome

The North American Shwachman-Diamond Syndrome Registry (SDSR) opened in 2008 to improve our understanding of the natural history of Shwachman-Diamond Syndrome (SDS), improve medical outcomes, and facilitate research. The diagnosis of SDS was defined by either biallelic SBDS gene mutations or by the clinical combination of exocrine pancreatic dysfunction with bone marrow failure. Median age of study subjects is 11.2 years (range, 0.6-52.8). SBDS genetic reports were available for 168 subjects. Eighty-one had biallelic SBDS mutations, while 48 individuals lacked SBDS mutations. Ongoing characterization of SBDS mutation-negative individuals has identified subgroups of SDS individuals meeting clinical diagnostic criteria as outlined above, as well as a more heterogenous subgroup with features of SDS but in whom a clinical diagnosis could not be confirmed by classic diagnostic criteria. Amongst those with biallelic SBDS mutations, cytopenias were noted in all but 1 subject. Intermittent neutropenia was noted in 97% (n=70/72) and was the most frequent hematologic abnormality. Anemia was noted in 53% (n=39/73) and thrombocytopenia in 64% (n=48/75). Congenital anomalies were seen in 50% (n=39/78).The mutational spectrum of SBDS was explored. In 80 of 81 patients harboring biallelic SBDS mutations, the c.258+2 T>C intron 2 splice donor mutation was found in at least one of the two mutant SBDS alleles. In these cases, the mutation spectrum of the second mutant SBDS allele included missense mutations, splice site mutations, and truncating mutations. The one patient lacking the intron 2 splice donor mutation had a c.183_184delTAinsCT mutation together with a c.523 C>T mutation in SBDS confirmed to be in trans. This results in the combination of a truncating p.Lys62X mutation with a p.R175W missense mutation at a conserved residue predicted to be deleterious. This patient presented with neonatal severe aplastic anemia requiring platelet and red cell transfusions with neutrophil counts of 0-200 unresponsive to G-CSF. The marrow showed irregular islands of cartilage surrounded by osteoid consistent with a disorder of bone formation. A low level of SBDS protein is expressed by the c.258+2T>C variant, so the absence of this hypomorphic allele may have contributed to this exceptionally severe phenotype.Bone marrow reports were available for 67 subjects with biallelic SBDSmutations. Marrow hypocellularity was noted in 79% (n=49/62). Mild morphologic marrow dysplasia was observed in 58% (n=35/60). Clonal abnormalities developed in 36%. The most common clonal abnormality was del20q in 16% (n=10/64). Isochromosome 7 was noted in 2% (n=1/64). Three individuals developed AML at ages 19.5, 38, and 39 years. Eleven (14%) have undergone hematopoietic stem cell transplantation (HSCT), 10 for MDS or AML and 1 for severe aplastic anemia.Given the frequency of del20q clones in SDS, we studied clinical features of the 10 SDSR subjects with del20q clones. Median age of this group was 17 years (range, 10.8-29.3). Congenital anomalies were noted in 80% (n=8/10). Frequency of cytopenias was similar to that of non-del20q subjects, with neutropenia, anemia and thrombocytopenia seen in 90%, 50%, and 80% respectively. Bone marrow pathology reports were available for 9 subjects. All were noted to have hypocellular marrows as well as mild marrow dysplasia. In many patients, the clone was persistent or grew over time, with longest duration of 14.6 years. Progression to MDS was reported in 3 subjects who initially had an isolated del20q clone. Two developed an additional loss of chromosome 7. Progressive marrow dysplasia and falling blood counts were seen in two subjects. All three were treated with HSCT at 5.4, 5.7 and 7 years. Deletion of 20q in SDS has been hypothesized to result in a milder hematologic phenotype due to compensatory deletion of eIF6. eIF6 binds to the nascent 60S ribosomal subunit and sterically inhibits joining of the 60S to the 40S ribosomal subunits. SBDS functions to facilitate release of eIF6 thus promoting assembly of the mature 80S ribosome. These data from the SDSR suggest that SDS patients with del20q clones remain at risk for clonal evolution. Higher patient numbers are needed to quantitate risk of MDS in SDS patients with del20q.The SDSR continues to expand and mature as a resource for biological and clinical studies in this rare disorder advancing our understanding of marrow failure and clonal evolution. DisclosuresDavies:Novartis: Honoraria. Dale:Amgen: Consultancy, Honoraria, Research Funding.

Shwachman-Diamond Syndrome

Exocrine pancreatic insufficiency and diarrhea have been hallmarks in the diagnosis of Shwachman-Diamond syndrome (SDS). We report 2 cases of genetically confirmed SDS in patients who presented with an unusual phenotype. Patient #1 presented with pancytopenia without other system involvement, while patient #2 presented with severe neutropenia, anemia, and a bifid thumb. Neither patient had diarrhea or malabsorption. Both patients had the classic heterozygous mutations c183_184 TA>CT and c.258+2 T>C in the Shwachman-Bodian-Diamond syndrome gene. Incomplete phenotypes may be more common than previously recognized in bone marrow failure syndromes; gastrointestinal symptoms should not be considered a prerequisite for SDS.

Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation

Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.

Diagnosis of Shwachman-Diamond Syndrome in a 24-Year-Old Woman with Abdominal Pain and Fatty Replacement of the Pancreas

Diagnosis of Shwachman-Diamond Syndrome in a 24-Year-Old Woman with Abdominal Pain and Fatty Replacement of the Pancreas

Shwachman-Diamond Syndrome: Clinical Phenotypes

The clinical phenotype of Shwachman-Diamond syndrome (SDS) is extremely heterogeneous, showing a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormality and growth retardation. At diagnosis, especially when made in infancy, symptoms of pancreatic insufficiency are always present. This condition could be considered as a transient pancreatic insufficiency. In fact, several studies have shown that, with advancing age, about 40–60% of patients become pancreatic sufficient. Observations on the evolution of pancreatic activity lead us to believe that the diagnosis of SDS must be considered even in the absence of signs and symptoms of pancreatic insufficiency. Intermittent neutropenia is the most common haematological finding in SDS, but more of the bone marrow cellular elements can be involved. In recent years, recombinant human granulocyte colony-stimulating factor has been used in some SDS subjects with severe neutropenia and frequent infection. The major haematological problem in the disease is the appearance of acute myeloid leukaemia; however, its prevalence is difficult to establish. Growth retardation is a typical manifestation. Weight and length are deficient at birth and remain below normal over time. Some studies show that SDS patients present short stature rather than malnutrition and this would suggest an inherent growth problem. A broad spectrum of skeletal abnormalities has been found to be associated with this syndrome. Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings. Elevated liver enzymes and hepatomegaly are present in the first years of life with subsequent improvement without complications. Developmental delay, learning disorders and attention deficit disorders are also reported.