 |
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
This rare genetic syndrome is characterized by pancreatic insufficiency, neutropenia, and in some patients, metaphyseal dysostosis. Bone marrow failure may also occur. Rare cases may benefit from a bone marrow transplant.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE Rare GEOGRAPHY
Shwachman-Diamond syndrome in a Mexican family.Belkind-Gerson J, Ontiveros-Nevares P, Ocampo-Roosens V, Sandoval-Juarez D.
Departamento de Gastroenterologia, Hospital del Nino Morelense Macaria Than de Rivapalacio, Cuernavaca, Morelos, Mexico.
Arch Med Res 2001 Jul-Aug;32(4):318-23 Abstract quote Shwachman-Diamond Syndrome (SDS) is an inherited condition with multisystemic abnormalities including pancreatic exocrine dysfunction, neutropenia, short stature, and skeletal abnormalities.
In this report, we describe the case of a 14-year-old female with a history of neutropenia, pancreatic exocrine insufficiency and pancreatic endocrine sufficiency, pancreatic lipomatosis (10), and the development of myeloid leukemia. Postmortem examination revealed a high probability of SDS.
We also describe the clinical findings in the patient's six siblings, suggesting this as a familial form of SDS. Because the gene(s) responsible for this syndrome have not yet been identified, genetic confirmation is not yet possible. This is the first report in the literature of a Mexican family with probable SDS.
DISEASE ASSOCIATIONS CHARACTERIZATION IMMUNE DEFECTS
Immune function in patients with Shwachman-Diamond syndrome.Dror Y, Ginzberg H, Dalal I, Cherepanov V, Downey G, Durie P, Roifman CM, Freedman MH.
Division of Haematology and Oncology, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Br J Haematol 2001 Sep;114(3):712-7 Abstract quote Shwachman-Diamond syndrome (SDS) is an inherited multisystem disorder characterized by exocrine pancreatic dysfunction and varying degrees of cytopenia. In addition, various immunological abnormalities have been noted.
To clarify the issue of immunological competence or incompetence in SDS, we prospectively studied immune function in 11 patients with SDS. Seven suffered from recurrent bacterial infections and six from recurrent viral infections. Varying degrees of impairment were readily identified. All patients had neutropenia; total lymphocyte counts, however, were normal in all except one patient. Nine patients had B-cell defects comprising one or more of the following abnormalities: low IgG or IgG subclasses, low percentage of circulating B lymphocytes, decreased in vitro B-lymphocyte proliferation and a lack of specific antibody production. Seven out of nine patients studied had at least one T-cell abnormality comprising a low percentage of total circulating T lymphocytes or CD3+/CD4+ cell subpopulations or decreased in vitro T-lymphocyte proliferation. Five out of six patients studied had decreased percentages of circulating natural killer cells. Moreover, neutrophil chemotaxis was significantly low in all the patients studied. These data point to a major immunodeficiency component in SDS that places patients at heightened risk of infections, even if neutrophil numbers are protective.
This finding broadens the definition of the syndrome substantially: it suggests that the SDS marrow defect occurs at the level of an early haematological-lymphocytic stem cell or that a combined marrow and thymic stromal defect accounts for the aberrant function of haematopoietic and lymphopoietic lineages.
LIVER DISEASE
Shwachman-Diamond sydnrome and chronic liver disease.Liebman WM, Rosental E, Hirshberger M, Thaler MM.
Clin Pediatr (Phila) 1979 Nov;18(11):695-6, 698 Abstract quote Clinically inapparent persistent chronic liver disease in a 15-month-old male patient with Shwachman-Diamond syndrome is presented.
Cryptic hepatic involvement may be an unrecognized feature of the syndrome and should be evaluated in all cases.
PREGNANCY
Pregnancy in bone marrow failure syndromes: Diamond-Blackfan anaemia and Shwachman-Diamond syndrome.Alter BP, Kumar M, Lockhart LL, Sprinz PG, Rowe TF.
Division of Pediatric Hematology/Oncology, University of Texas Medical Branch, Galveston, USA.
Br J Haematol 1999 Oct;107(1):49-54 Abstract quote Pregnancy in bone marrow failure syndromes has risk to mother and fetus. There are fewer than 30 reports of cases with Diamond-Blackfan anaemia (DBA), and none with Shwachman-Diamond syndrome (SD).
We report two DBA and one SD cases. One DBA mother received transfusions intra-partum, and the other only post-partum. Both required caesarean sections (C-sections) for failure of labour to progress and severe pre-eclampsia respectively. Both subsequently resumed pre-pregnancy steroid-induced control of anaemia. approximately 40% of DBA pregnancies required maternal transfusions; 25% delivered by C-section. The SD patient also had Ehlers-Danlos (ED) syndrome and urticaria pigmentosa (UP). Her blood counts were adequate until week 38, when the platelet count dropped and a C-section was performed.
Pregnancy management in marrow failure disorders requires obstetricians with expertise in high-risk pregnancies, and haematologists with experience with marrow failure syndromes.
PATHOGENESIS CHARACTERIZATION APOPTOSIS
Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway.Dror Y, Freedman MH.
Department of Pediatrics, Division of Hematology and Oncology, Research Institute, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
Blood 2001 May 15;97(10):3011-6 Abstract quote Shwachman-Diamond syndrome (SDS) is an inherited bone marrow disorder with varying cytopenias and a strong predilection to myelodysplastic syndrome (MDS) and acute myeloid leukemia. Previously, it was found that the percentage of CD34(+) cells in bone marrow and the in vitro colony formation from CD34(+) cells of patients with SDS were markedly reduced. For these reasons, and because apoptosis is central in the pathogenesis of bone marrow dysfunction in MDS, this study was initiated to delineate the role of apoptosis in the pathogenesis of the marrow failure.
Eleven children with SDS were studied. Compared to normal controls, patients' marrow mononuclear cells plated in clonogenic cultures showed a significantly higher tendency to undergo apoptosis. The defect in SDS was found in patients with and without MDS. Patients showed a more prominent decrease in colony formation and increased apoptosis after preincubation with activating anti-Fas antibody. Fas expression on marrow cells from patients was significantly higher than from normal controls. The difference between patients and controls for Fas expression was also significant for the following cell fraction subpopulations: CD34(-)/CD38(-), CD34(-)/CD38(+), and CD34(+).
In conclusion, SDS hematopoietic progenitors are intrinsically flawed and have faulty proliferative properties and increased apoptosis. Bone marrow failure in SDS appears mediated by increased apoptosis as the central pathogenetic mechanism. This increased propensity for apoptosis is linked to increased expression of the Fas antigen and to hyperactivation of the Fas signaling pathway.
p53 Protein Overexpression in Bone Marrow Biopsies of Patients With Shwachman-Diamond Syndrome Has a Prevalence Similar to That of Patients With Refractory Anemia
M. Tarek Elghetany, MD and Blanche P. Alter, MD, MPHFrom the Department of Pathology, University of Texas Medical Branch, Galveston, Tex (Dr Elghetany); and the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, Bethesda, Md (Dr Alter)
Arch Pathol Lab Med 2002;Vol. 126, No. 4, pp. 452–455. Abstract quote Context.—Shwachman-Diamond syndrome (SDS) is a rare inherited disorder characterized by pancreatic insufficiency, neutropenia, and in some patients, metaphyseal dysostosis. Patients with SDS are at a high risk for development of bone marrow failure, myelodysplastic syndrome, and acute leukemia. The p53 gene plays a major role in cell-cycle regulation, particularly in the presence of a genetic alteration in DNA, a critical step for the initiation of leukemogenesis. p53 gene up-regulation and p53 protein overexpression may occur as a cellular reaction to significant DNA damage. Shwachman-Diamond syndrome and refractory anemia patients have close similarities in the prevalence of acute leukemia and in cell-cycle changes in bone marrow cells. This similarity was further investigated for p53 protein overexpression using archived tissue from patients with hematologic diseases having various leukemic propensities, including SDS and refractory anemia.
Methods.—Immunohistochemical staining for p53 protein overexpression was performed on bone marrow biopsies from 9 patients with SDS. These specimens were compared with biopsies from 71 patients with acquired hematologic disorders with variable risk levels for leukemia, including acquired aplastic anemia (n = 14), refractory anemia (n = 46), and various acquired cytopenias (n = 11), as well as 37 control subjects.
Results.—p53 protein overexpression was identified only in patients with SDS and in patients with refractory anemia; these groups exhibited comparable prevalences of 78% and 72%, respectively. None of the patients with acquired aplastic anemia, acquired cytopenias, or in the control group showed overexpression of p53 protein.
Conclusion.—The prevalence of p53 protein overexpression in SDS is significantly different from that in acquired aplastic anemia and acquired cytopenias, but it is similar to the prevalence in refractory anemia. We speculate that p53 protein overexpression in this bone marrow failure syndrome may represent an early indicator of significant DNA genetic alteration, which is a crucial step in the process of leukemogenesis.
CHROMOSOME DEFECTS
Discordant detection of monosomy 7 by GTG-banding and FISH in a patient with Shwachman-Diamond syndrome without evidence of myelodysplastic syndrome or acute myelogenous leukemia.Sokolic RA, Ferguson W, Mark HF.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Cancer Genet Cytogenet 1999 Dec;115(2):106-13 Abstract quote The myelodysplastic syndromes (MDS) are a group of hematologic disorders commonly affecting elderly persons and often leading to acute myelogenous leukemia (AML). Although rare in children, when MDS does occur, it is frequently part of a congenital disorder such as Shwachman-Diamond syndrome (SDS). Monosomy 7 and/or deletion of part or all of 7q are poor prognostic signs in MDS and AML, although the pathophysiologic relationship between this finding and MDS or AML is unclear. Shwachman-Diamond syndrome is an inherited illness characterized by exocrine pancreatic insufficiency and by congenital neutropenia. Patients with SDS are at increased risk of developing myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Because monosomy 7 is a poor prognostic sign in MDS and AML, establishing its presence is important. However, different methods of detection of monosomy 7 may lead to different results in some patients.
We present the case of a 10-year-old girl known to have SDS, who had a bone marrow aspiration and biopsy done to rule out MDS and AML. By light microscopy, the patient's bone marrow was unremarkable. GTG-banding showed the following karyotype: 45,XX,-C[3]/47,XX,+C[1]/46,XX[45]. Fluorescence in situ hybridization (FISH) was performed with a chromosome 7-specific alpha-satellite probe (D7Z1). Almost all (373 of 376) cells exhibited only one chromosome 7 signal. A second marrow aspiration done 6 months later showed an essentially normal karyotype by GTG-banding. Fluorescence in situ hybridization with the same chromosome 7 probe showed 230 of 250 cells to be monosomic for chromosome 7. A whole chromosome 7 painting probe demonstrated disomy for chromosome 7 in 90 of 90 cells; however, subtle heteromorphism in the centromeric regions of the 2 copies of chromosome 7 was noted in some cells.
This case demonstrates that FISH and GTG-banding can give discordant results, that the two should be viewed as complementary technologies, and that both have a place in a full karyotypic analysis. Furthermore, this case demonstrates for the first time that heteromorphism and/or subtle structural abnormalities of chromosome 7, previously associated with MDS and AML, can exist without clinical or morphologic signs of these illnesses. It will be of interest to further study the relationship, if any, between SDS and various structural abnormalities of chromosome 7 in MDS and AML, and to elucidate the molecular mechanisms of pathogenesis, physiology, and treatment of these disorders.
Shwachman-Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7.Goobie S, Popovic M, Morrison J, Ellis L, Ginzberg H, Boocock GR, Ehtesham N, Betard C, Brewer CG, Roslin NM, Hudson TJ, Morgan K, Fujiwara TM, Durie PR, Rommens JM.
Program in Genetics and Genomic Biology, Research Institute, and Departments of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada.
Am J Hum Genet 2001 Apr;68(4):1048-54 Abstract quote Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities.
A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children.
Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.
STEM CELL DEFECT
Shwachman-Diamond syndrome: An inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment.Dror Y, Freedman MH.
Division of Hematology and Oncology and the Research Institute, The Hospital for Sick Children, and the University of Toronto, Toronto, Ontario, Canada.
Blood 1999 Nov 1;94(9):3048-54 Abstract quote Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant myeloid transformation, is an important model for understanding genetic determinants in hematopoiesis.
To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34(+) cells on bone marrow aspirates. SD CD34(+) cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34(+) cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34(+) cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia.
We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.
LABORATORY/RADIOLOGIC/
OTHER TESTSCHARACTERIZATION RADIOLOGIC
Shwachman-Diamond syndrome: clinical, radiological and sonographic aspects.Berrocal T, Simon MJ, al-Assir I, Prieto C, Pastor I, de Pablo L, Lama R.
Department of Pediatric Radiology, La Paz Children's Hospital, Madrid, Spain.
Pediatr Radiol 1995;25(4):289-92 Abstract quote Six children with Shwachman-Diamond syndrome have been diagnosed and treated in our hospital since 1986. We describe the radiological and sonographic findings of this rare disease which is characterized by metaphyseal chondrodysplasia, neutropenia and pancreatic exocrine insufficiency.
It presents with variable extremity shortening, "cup" deformation of the ribs, metaphyseal widening and hypoplasia of the iliac bones, and increased echogenicity of the pancreas without change in size. We discuss the differential diagnosis and review the literature.
Pancreatic lipomatosis in the Shwachman-Diamond syndrome. Identification by sonography and CT-scan.Robberecht E, Nachtegaele P, Van Rattinghe R, Afschrift M, Kunnen M, Verhaaren R.
Pediatr Radiol 1985;15(5):348-9 Abstract quote The typical pathological finding in the pancreas of patients with the Shwachman-Diamond syndrome is fatty infiltration.
In this report it is emphasized that this lipomatosis can be demonstrated by non-invasive techniques, using abdominal ultrasound and CT-scan.
LABORATORY MARKERS
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL Pancreatic lipomatosis VARIANTS
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL VARIANTS SKELETAL
Duplication of distal thumb phalanx in Shwachman-Diamond syndrome.Dror Y, Durie P, Marcon P, Freedman MH.
Division of Hematology and Oncology, The Hospital for Sick Children and the University of Toronto, Ontario, Canada.
Am J Med Genet 1998 Jun 16;78(1):67-9 Abstract quote Shwachman-Diamond syndrome (SDS) comprises of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. We report on a child with SDS and duplication of distal thumb phalanx. This combination has not been reported previously.
We suggest that supernumerary thumb is likely a rare skeletal manifestation of SDS and that SDS should be considered in the differential diagnosis of patients with bone marrow failure and duplication of the thumb along with Blackfan-Diamond/Aase syndrome and Fanconi's anemia.
SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION SPECIAL STAINS IMMUNOPEROXIDASE
Expression of CD5 on hematogones in a 7-year-old girl with Shwachman-Diamond syndrome.Jelic TM, Raj AB, Jin B, Kurczynski EM, Tolaymat N, Chang HH.
Department of Pathology, Charleston Area Medical Center, WV 25304, USA.
Pediatr Dev Pathol 2001 Sep-Oct;4(5):505-11 Abstract quote We report increased numbers of hematogones in a 7-year-old girl with pancytopenia due to Shwachman-Diamond syndrome. Her hematogones expressed the T-cell marker CD5 as well as CD19, CD10, and CD20, and terminal deoxynucleotidyl transferase and HLA-DR. These findings suggest that hematogones are precursors of both CD5-positive B cells and CD5-negative B cells.
Thus CD5-positive B cells in bone marrow may be derived from bone marrow stem cells, and not from the residual fetal B cells of yolk sac/liver origin.
The finding of CD5 expression on hematogones also raises the possibility that neoplastic B cells of chronic lymphocytic leukemia, which characteristically co-express CD5 and CD19, may be derived from CD5-positive B-cell precursors in bone marrow and not from mature B cells in lymph nodes.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES PANCREATIC DISEASE
Pancreatic disease in children and young adults: evaluation with CT.Vaughn DD, Jabra AA, Fishman EK.
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA.
Radiographics 1998 Sep-Oct;18(5):1171-87 Abstract quote In children with pancreatic disease, computed tomography (CT) has a primary role in the evaluation of pancreatitis, trauma, and malignancy. At CT, pancreatic abnormalities may manifest as pancreatic enlargement (tumor, acute pancreatitis), pancreatic atrophy (cystic fibrosis, chronic pancreatitis), cystic lesions (pseudocysts, congenital simple cysts, autosomal dominant polycystic kidney disease, von Hippel-Lindau disease, cystic fibrosis, cystic neoplasms), or fatty replacement (cystic fibrosis, Shwachman-Diamond syndrome, history of steroid therapy, Cushing syndrome, Johanson-Blizzard syndrome, obesity). CT is the best modality for evaluation of pancreatitis, allowing detection of pancreatic abnormalities as well as abnormal extrapancreatic fluid collections.
In children who have undergone blunt abdominal trauma, CT has been shown to be the best initial imaging study, being more sensitive than ultrasound for detection of pancreatic injury. In neoplastic conditions, CT demonstrates the extent of disease, enables characterization of the tissue components of the tumor, and allows accurate posttreatment follow-up.
Although the various diseases of the pancreas may have overlapping appearances at CT, the correct diagnosis can often be made on the basis of the CT findings in combination with the clinical history, laboratory data, and the patient's age.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS MALIGNANCIES
Haematological abnormalities in Shwachman-Diamond syndrome.Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P.
Department of Haematology, Great Ormond Street Hospital for Children NHS Trust, London
Br J Haematol 1996 Aug;94(2):279-84 Abstract quote We have analysed the haematological parameters in 21 patients with Shwachman-Diamond syndrome (SDS) seen over a 25-year period at our institution. Neutropenia, although present in all patients, was intermittent in two-thirds, constant in the rest and was associated with impaired chemotaxis in all of those patients tested. Fetal haemoglobin (HbF) was elevated in 80% of the patients at some stage, and anaemia and thrombocytopenia was documented in 66% and 24% respectively.
Bone marrow samples were taken in over half of the patients. Myelodysplastic syndrome (MDS) developed in seven (33%) patients, five of whom had acquired clonal structural chromosome abnormalities in their bone marrows. In five of the patients with MDS (24%) transformation to acute myeloid leukaemia occurred. Like other constitutional bone marrow failure syndromes. SDS has a predilection to leukaemic transformation hitherto assumed to be in the region of 5-10%.
The data presented here suggest that this figure probably represents an underestimate. Shwachman-Diamond syndrome is an interesting model of leukaemia development and greater understanding of the clinical spectrum of this rare disorder should produce further insights into its pathobiology.
Malignant myeloid transformation with isochromosome 7q in Shwachman-Diamond syndrome.Dror Y, Squire J, Durie P, Freedman MH.
Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Ontario, Canada.
Leukemia 1998 Oct;12(10):1591-5 Abstract quote Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, various degrees of cytopenia, and a striking tendency to develop myelodysplastic syndrome and acute myeloblastic leukemia. Isochromosome 7 [i(7q)] is a rare non-random cytogenetic abnormality of myeloid cells in hematological malignancy.
We report two cases of Shwachman-Diamond syndrome in which patients developed myelodysplastic syndrome and i(7q), detected by G-banding karyotype analysis and fluorescence in situ hybridization. Three other children have been previously reported to have myelodysplastic syndrome in association with i(7q); two of them had Shwachman-Diamond syndrome. Isochromosome 7q may be a fairly specific marker of myeloid malignant transformation in this syndrome and play a role in its pathogenesis.
Emergence of an unusual bone marrow precursor B-cell population in fatal Shwachman-Diamond syndrome.Klupp N, Simonitsch I, Mannhalter C, Amann G.
Institutes of Forensic Medicine, Vienna Medical School, University of Vienna, Austria.
Arch Pathol Lab Med 2000 Sep;124(9):1379-81 Abstract quote The Shwachman-Diamond syndrome (SDS) is a rare congenital disorder for which inheritance by an autosomal recessive trait has been suggested. Shwachman-Diamond syndrome is defined by exocrine pancreatic insufficiency combined with severe neutropenia. Moreover, SDS patients are at risk to develop neoplastic hematologic diseases.
We describe 2 SDS-affected daughters of consanguine parents who were born 1 year apart, at 35 and 36 weeks of gestation, and who died at the age of 4 and 3.5 months, respectively, due to respiratory infections. Histologic bone marrow evaluation of the second-born child revealed a diffuse proliferation of immature B cells, which comprised 40% of the total cellularity. These cells were identified as precursor B cells by immunophenotyping studies (CD79a(+)/CD10(+)/CD20(-)/CD22(-)/CD34(-)/ terminal deoxynucleotidyl transferase(-)). Molecular determination of the immunoglobulin heavy-chain gene status did not reveal clonality. The emergence of this peculiar B-cell population was interpreted as a marked increase of hematogones.
Although the clinical significance and the exact function of hematogones is still obscure, they may play a critical regenerative role in the regulation of hemopoiesis, but without malignant potential in SDS. Immunophenotyping and molecular studies, therefore, have potential value in the differential diagnosis of primary bone marrow failures. This report adds SDS to the spectrum of conditions in which a prominent number of hematogones may be observed.
TREATMENT BONE MARROW TRANSPLANTATION
Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis.Faber J, Lauener R, Wick F, Betts D, Filgueira L, Seger RA, Gungor T.
Division of Immunology/Haematology, University Children's Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland.
Eur J Pediatr 1999 Dec;158(12):995-1000 Abstract quote Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by exocrine pancreas insufficiency, metaphyseal dysostosis and bone marrow dysfunction. Recurrent severe bacterial infections and susceptibility to leukaemia are the major causes of morbidity and mortality occurring preferentially in patients with pancytopenia and features of myelodysplasia.
Here we report a patient with SDS leading to recurrent bacterial infections and a deteriorating condition since early infancy. Extensive investigations disclosed severe pancytopenia, myelodysplasia and a clonal cytogenetic abnormality, inv(14)(q11q32), as risk factors of leukaemic transformation. He therefore underwent allogeneic geno-identical bone marrow transplantation which resulted in correction of all haematological and immunological abnormalities within an 18-month follow up period.
Conclusion Bone marrow transplantation may be considered early as a valuable treatment option especially in high risk Schwachman-Diamond syndrome patients anticipating malignant transformation, life-threatening severe infections or further organ damage.
Successful unrelated bone marrow transplantation for Shwachman-Diamond syndrome.Cesaro S, Guariso G, Calore E, Gazzola MV, Destro R, Varotto S, Zanesco L, Messina C.
Paediatric Oncology-Hematology Clinic, University of Padova, Italy.
Bone Marrow Transplant 2001 Jan;27(1):97-9 Abstract quote A 5-year-old boy with Shwachman-Diamond syndrome underwent unrelated HLA-identical bone marrow transplantation for severe pancytopenia.
Conditioning was with busulfan, thiotepa and cyclophosphamide plus rabbit anti-lymphocyte serum. Engraftment for neutrophils and platelets was observed on days +18 and +41, respectively. Transplant-related side-effects were mild and transient. After a follow-up of 32 months, the patient is alive and enjoys a normal life, off any immunosuppressives. Immunological and hematological reconstitution is complete while other phenotypic characteristics (pancreatic insufficiency, short stature, femur dysostosis) are stable.
Although experience in this field is scarce, we speculate that bone marrow failure in Shwachman-Diamond syndrome (even if not linked to the appearance of clonal disorders or leukemic transformation) is an indication for bone marrow transplantation and may be associated with a better outcome.
Successful allogeneic hematopoietic stem cell transplantation (HSCT) for Shwachman-Diamond syndrome.Fleitz J, Rumelhart S, Goldman F, Ambruso D, Sokol RJ, Pacini D, Quinones R, Holida M, Lee N, Tannous R, Giller R.
University of Colorado Health Science Center, and The Children's Hospital, Denver, CO 80218, USA.
Bone Marrow Transplant 2002 Jan;29(1):75-9 Abstract quote Shwachman-Diamond syndrome (SDS) is a rare genetic disorder characterized by pancreatic insufficiency, short stature, skeletal abnormalities and bone marrow dysfunction. Patients with SDS have varying degrees of marrow aplasia, which can be severe or progress to leukemic transformation. While allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for the hematologic disturbances of SDS, a recent review of the literature reveals few survivors. Poor outcome with HSCT is often related to excessive cardiac and other organ toxicity from transplant preparative therapy.
We describe two young children with SDS who developed aplastic anemia and subsequently underwent successful allografting using a non-cardiotoxic conditioning regimen. Case 1 received marrow from an HLA-identical sibling while case 2 received partially matched umbilical cord blood from an unrelated donor. Both patients are presently alive and well with sustained donor engraftment and excellent hematopoietic function at 36 and 22 months post-HSCT.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
Last Updated 3/25/2002
Send mail to psdermpath@earthlink.net with questions or comments about this web site.