Shwachman–Diamond Syndrome

In 1964, five patients showing evidence of exocrine pancreatic insufficiency and leucopenia were described (Shwachman et al, 1964). The syndrome, later termed Shwachman–Diamond syndrome (SDS), was described earlier by Nezelof & Watchi (1961) and a few months later by Bodian et al (1964). Burke et al (1967) and Pringle et al (1968) observed associated skeletal changes of the metaphyseal dysostosis type, which became the third fundamental feature of the syndrome. Aggett et al (1980) described 21 cases of SDS in detail and defined the scope of the syndrome as currently understood. SDS has also been called ‘Shwachman syndrome’, ‘Shwachman–Bodian syndrome’ and ‘congenital lipomatosis of the pancreas. Although SDS is a rare disorder, it is the most common cause of pancreatic insufficiency in children next to cystic fibrosis and probably the third most common inherited bone marrow failure syndrome after Fanconi’s anaemia and Diamond–Blackfan anaemia. It mainly involves the pancreas, bone marrow and skeleton, but the liver, kidneys, teeth and immune system may also be affected (Aggett et al, 1980; Mack et al, 1996; Ginzberg et al, 1999; Dror et al, 2001). Haematologically, SDS is characterized by varying degrees of cytopenia and a high risk of development of myelodysplastic syndrome (MDS) and leukaemia, making it an important model for genetic determinants of bone marrow failure and leukaemia. Studies of family pedigrees support an autosomal recessive mode of inheritance (Ginzberg et al, 1999). The SDS locus has recently been mapped to the centromeric region of chromosome 7 (7p10–7q11) (Goobie et al, 2001). The gene responsible for this complex, pleiotropic phenotype should be identified soon, and the molecular basis for the multisystem features, bone marrow failure and leukaemic transformation may be clarified. SDS manifests itself in many and various combinations, shown in Table I. Results of two retrospective studies (Mack et al, 1996; Smith et al, 1996) and a cross-sectional multicentre study (Ginzberg et al, 1999) have recently been published, adding significantly to our understanding of the clinical phenotype and probably representing the spectrum of clinical findings fairly accurately. Neutropenia. Neutropenia is the most common haematological abnormality, occurring in 88–100% of patients and has been identified as early as the neonatal period. In most cases the neutropenia is intermittent and fluctuates within the same patient from severely low to normal levels. Cyclic patterns without detailed information on the timing of cycling have also been reported (Dokal et al, 1997). However, cyclical haematopoiesis was not observed in the series described by Aggett et al (1980), Mack et al (1996) or Smith et al (1996) or among 16 SDS patients followed at our institution (unpublished observations). Impaired neutrophil chemotaxis. SDS neutrophils may have defects in mobility, migration and chemotaxis in most (Cipolli et al, 1999; Maserati et al, 2000) or all patients (Smith et al, 1996; Dror et al, 2001). Alterations in neutrophil cytoskeletal/microtubular integrity and function may play a prominent role in causing the defective chemotaxis. Rothbaum et al, (1982) demonstrated abnormal distribution of concanavalin-A receptors on polymorphonuclear leucocytes. Lithium appears to restore chemotaxis when used in vitro (Azzaràet al, 1988) and in vivo (Azzaràet al, 1991). Anaemia. Anaemia with low reticulocytes was recorded in up to 80% of patients in the reports reviewed. It was usually mild and normochromic-normocytic. However, macrocytosis has been described (Woods et al, 1981a) and three of 16 SDS patients we studied had macrocytic red blood cells (unpublished observations). Fetal haemoglobin was elevated in 80% of patients (Dror & Freedman, 1999). The elevation of heterogeneously distributed fetal haemoglobin reflects ‘stress’ haematopoiesis and/or ineffective erythropoiesis related to apoptosis and is also seen in all types of MDS. Thrombocytopenia. Thrombocytopenia, defined by platelets < 150 × 109/l, was seen in 24% to 88% of patients. Easy bruising may occur. Fatal bleeding while the patients had moderate to severe thrombocytopenia has also been reported (Nezelof & Watchi, 1961; Caselitz et al, 1979; Woods et al, 1981a; Gretillat et al, 1985; Okcu et al, 1998; Maserati et al, 2000). Pancytopenia. Trilineage cytopenia occurs in 10–65% of patients. Both anaemia and thrombocytopenia are usually mild to moderate in these cases but neutropenia tends to be more severe. Pancytopenia in SDS with hypoplasia of three bone marrow lineages might carry a poor prognosis, with a higher chance of developing symptomatic severe aplasia, advanced MDS or acute myeloid leukaemia (AML) (Mack et al, 1996). Severe aplasia requiring transfusion has been reported (Woods et al, 1981a; Tsai et al, 1990; Barrios et al, 1991). In the series reported by Aggett et al (1980), four of the 21 patients were transfusion dependent. Bone marrow findings. The severity of cytopenia does not always correlate with bone marrow cellularity. Varying degrees of marrow hypoplasia and fat infiltration are the usual findings (Aggett et al, 1980; Dror & Freedman, 1999), but marrows showing normal or even increased cellularity have also been observed (Smith et al, 1996; Ginzberg et al, 1999). Single-lineage hypoplasia is usually myeloid and occurs in 15–50% (Mack et al, 1996; Ginzberg et al, 1999). Left-shifted granulopoiesis or maturation arrest was also described (Aggett et al, 1980; Ginzberg et al, 1999). Scattered mild dysplastic changes in the erythroid, myeloid and megakaryocytic precursors are commonly seen in bone marrows of SDS patients and form part of the syndrome. These changes represent disordered haematopoiesis and may fluctuate. Prominent dysplasia is less common and, if it occurs, signifies malignant myeloid transformation. Myelodysplastic syndromes. Several findings suggest that SDS is a myelodysplastic disorder from its inception. MDS is defined as a preleukaemic, clonal, stem-cell disease with peripheral blood cytopenia, ineffective haematopoiesis and varying degrees of bone marrow cellularity and dysplasia (Harris et al, 1999). SDS easily meets at least five of these seven criteria: it is a stem-cell disorder with peripheral cytopenia, ineffective haematopoiesis, varying degrees of bone marrow cellularity and carries a significant risk of leukaemia. The fact that all marrow cells harbour two copies of the mutated SDS gene and that clonal marrow cytogenetic abnormalities are common probably satisfies the clonality criterion. In addition, scattered mild dysplastic changes in the erythroid, myeloid and megakaryocytic precursors are part of the syndrome. Finally, a close relationship between SDS and MDS is reflected in similar defects in marrow-stromal support of normal haematopoiesis (Dror & Freedman, 1999), increased apoptosis mediated through the Fas pathway (Dror & Freedman, 2001), similar prevalence of P53 protein overexpression to refractory anaemia patients (Elghetany & Alter, 2001) and high cluster-to-colony ratios (Dror et al, 1998a). Therefore, according to a newly devised classification system of childhood MDS (Mandel et al, 1999, 2002; Table III), we consider SDS as refractory cytopenia and when we refer to malignant myeloid transformation in SDS we mean more advanced MDS stages. Until recently, no comprehensive, all-inclusive classification scheme for paediatric MDS was available. We therefore developed the CCC system, which incorporates the ‘Category’ of MDS (denovo, syndromic or therapy-related), the ‘Cytology’ (refractory cytopenia, RC; refractory cytopenia with dysplasia, RCD; refractory cytopenia with ring sideroblasts, RCRS; and refractory cytopenia with excess blasts, RCEB) and the ‘Cytogenetics’. Therefore, when we refer to malignant myeloid transformation in SDS, we mean stages beyond RC/CG– (RC without cytogenetic abnormalities): RC/CG+ (RC with cytogenetic abnormalities), RCD, RCRS, RCEB or leukaemia. Forty such cases have been reported in SDS (Nezelof & Watchi, 1961; Huijgens et al, 1977; Strevens et al, 1978; Caselitz et al, 1979; Aggett et al, 1980; Woods et al, 1981a,b; Gretillat et al, 1985; MacMaster & Cummings, 1993; Seymour & Escudier, 1993; Kalra et al, 1995; Passmore et al, 1995; Smith et al, 1995, 1996; Arseniev et al, 1996; Mack et al, 1996; Davies et al, 1997; Dokal et al, 1997; Dror et al, 1998b; Okcu et al, 1998; Faber et al, 1999; Sokolic et al, 1999; Maserati et al, 2000; Spirito et al, 2000; Cesaro et al, 2001) (Table IV). Twenty-five patients with SDS with cytogenetic abnormalities and/or morphological dysplasia and/or an increase in bone marrow blasts (5–30%) have been reported at a mean age of 11·8 years (median, 8 years; range, 2–42). Seventeen of the 25 were males, seven were females, and was not patients with SDS were with malignant myeloid transformation at the of leukaemia at a mean age of 16 years (median, years; range, abnormalities have been reported in 25 SDS patients in various stages of malignant myeloid RCD, RCEB and (Table of had an cytogenetic described in or acute leukaemia patients without SDS et al, high in SDS patients that it is a fairly clonal in this syndrome and is probably related to the of the SDS gene on (Goobie et al, 2001). The relationship between the SDS gene and the which also involves at may be when the gene is and chromosome 7 abnormalities were described in an patients and and or part of the of chromosome These cases suggest that a of patients with SDS also chromosome 7 However, 7 or of its are also of patients with inherited bone marrow failure MDS or neutropenia and thrombocytopenia et al, cytogenetic abnormalities have also been described in SDS at various disease stages (Table The of the cytogenetic abnormalities in SDS be with of patients. It is that among the patients with no to RCEB or has been In four patients with the chromosome 7 with RCEB and three with with these or to from earlier stages of MDS. has been associated with morphological dysplasia in SDS transfusion in and severe neutropenia requiring in a These findings may a of in this seven SDS cases have been reported with cytogenetic abnormalities without prominent marrow dysplasia or an increase in blasts these two had two developed morphological dysplasia or followed a more severe clinical developed and two not be Therefore, the of a clonal cytogenetic in bone marrow may be of clinical and is for patients with clonal marrow but without symptomatic cytopenia or increased is morphological types of MDS have been described in SDS patients. without RC/CG+ was reported in of be for disease three had clinical of four developed and had of evidence of in a patient with SDS to was In the five reported cases with RCEB without RC/CG+ or RCD, three patients to and two not be patient developed RCEB from RC/CG+ and on to was reported in SDS patients males, not at a mean age of years (median, years; range, reports were the reported cases of were by an MDS et al, 1977; Strevens et al, 1978; Woods et al, Gretillat et al, 1985; Seymour & Escudier, 1993; Arseniev et al, 1996; Smith et al, 1996; Dokal et al, while in the the malignant myeloid transformation was at the (Nezelof & Watchi, 1961; Caselitz et al, 1979; Aggett et al, 1980; Woods et al, MacMaster & Cummings, 1993; Mack et al, 1996; Dokal et al, 1997; Spirito et al, 2000). The risk is probably between and types of leukaemia have been described in SDS in three in in in in acute leukaemia in three and leukaemia in It is that was common in SDS, occurring in of reports of acute leukaemia are et al, 1978; Woods et al, Gretillat et al, these children might have been as the early in SDS may be to malignant as is seen in with MDS et al, 1997). The leukaemia in an SDS patient reported by Caselitz et al might have been as as as the does not the for the of this leukaemia carries a poor In the cases reported or after a with patients of refractory disease or The three and months after and after of the three patients with acute leukaemia of refractory disease or and after The patient with leukaemia of The of in SDS patients for severe neutropenia has that the might have a role in malignant transformation. myeloid transformation in SDS patients while on has been reported et al, 1997; et al, 2000). is no evidence to the in the leukaemic does not cause and no relationship has been between the development of and the or the of et al, 2000). may be an that the patient and for the malignant to may the to malignant myeloid transformation in the SDS or malignant that be for SDS is among the many inherited bone marrow failure with a to MDS and leukaemia. such as neutropenia and Diamond–Blackfan anaemia this its prevalence with SDS are to and and is a of this disorder, early in The and defects in SDS neutrophils to these reports and defects in patients with the syndrome have been & et al, 1978; Aggett et al, 1979; et al, et al, In a study of immune function in patients with SDS (Dror et al, 2001), we identified varying degrees of patients had defects or more of the low or low of in vitro in to and and a of or of patients studied had at least abnormality, a low of or an or an low to and of patients studied had of was observed in therefore to be a of the syndrome. Varying severity of pancreatic to is a of severity is not with haematological or skeletal abnormalities (Ginzberg et al, 1999). of pancreatic with normal and the of and the which is through a These abnormalities are also reflected by the low in of patients (Ginzberg et al, 1999), low in (Aggett et al, low et al, 2001) and fat in a (Aggett et al, 1980; Ginzberg et al, 1999). that the is with increased The may be by fibrosis or lipomatosis of the pancreas, which easily be by et al, et al, 1985; MacMaster & Cummings, The of pancreatic and are in of patients. These to and and The most severe of pancreatic insufficiency are seen in (Ginzberg et al, 1999). up to of SDS patients in and with normal fat In these pancreatic be by an abnormal pancreatic in all patients and by low in The children are to or even of children with SDS have metaphyseal which most involves the and is usually et al, Aggett et al, These changes be seen on but may not be after months of third to of children with SDS have with and a In a few these abnormalities may to and failure in the et al, et al, skeletal & Aggett et al, (Ginzberg et al, 1999) and (Dror et al, or et al, 1999). to is common in SDS patients and is by various metaphyseal pancreatic and is at the but by age and later of patients are the for with pancreatic most patients to a normal but the for and (Mack et al, 1996). is in most and abnormalities of the liver, or elevated are seen in of most in and to with The disease is usually mild and of cause is not understood. of dysplasia, increased risk of and disease may also occur. pancreas, system and were reported to be (Aggett et al, 1980; & et al, 1999; Ginzberg et al, 1999). The of the disease is not and in are related to and the same patients of pancreatic causing in the of and are to in severity but are have been reported after symptomatic aplasia The of patients with MDS and has been described the basis of a & the of SDS patients as more is no or genetic for the of Therefore, we currently the disorder by of clinical and features, which might be or to more cases of SDS had been reported in the et al the as cystic fibrosis for the The of to with SDS is (Ginzberg et al, 1999). The is in the few years of on of the SDS the evidence of exocrine pancreatic and haematological abnormalities (Ginzberg et al, 1999). skeletal or abnormalities of the are findings of the Table the clinical for the of SDS as used at our should be to cystic fibrosis cause of pancreatic with an abnormal disease insufficiency and cytopenia, marrow ring and and myeloid and hypoplasia and cytopenia, and metaphyseal common in the with two or three affected have been described and, in rare of patients not related to are in the of between and (Ginzberg et al, 2000). These support an autosomal recessive mode of et al no in the neutrophil gene in three patients with reported with abnormalities in SDS, et al observed a and in an However, and were as for the SDS gene by studies of of SDS with two or three affected children (Goobie et al, 1999). In we an increased of in SDS (Dror et al, We that the locus was important in the of malignant myeloid transformation in SDS and that was a for in a of with SDS, et al identified chromosome 7 that with the significant a that the The was with at at a of from all by et al, support for the with a locus for However, the of is The on in SDS are et al and et al increased of chromosome in a the not increased to However, in et al and et al were to these studies in the and early bone marrow and in most patients with SDS, findings with a defective for the marrow failure et al, 1979; Woods et al, 1981a; et al, In addition, et al that marrow was as by of and of from peripheral blood normal when on or were shown and and of peripheral blood with marrow not The that were in SDS and in vitro as the clinical The of cells was normal and a of the of or of granulopoiesis be recently, we that SDS is characterized by marrow with an abnormal bone marrow in of its to support and marrow we marrow by normal marrow cells SDS or normal (Dror & Freedman, 1999). cells from the were In to the abnormality, bone marrow from patients with SDS is characterized by of which have a to of all lineages in vitro (Dror & Freedman, 1999). The the myeloid and The of marrow cells and to in vitro are probably related to increased to Bone marrow cells in an increased of cells in < and a of cells < (Dror & Freedman, 2001). The increased apoptosis was to of marrow cells to an with higher apoptosis and normal Fas on marrow cells from patients was significantly higher in normal The between patients and in Fas was also significant for the and that the abnormal apoptosis early haematopoiesis (Dror & Freedman, 2001). We recently in SDS patients to the increased apoptosis is also reflected in increased with normal mean of marrow cells was significantly et al, The for malignant myeloid transformation in MDS and the molecular in this are not understood. We recently from four patients with malignant myeloid transformation RC/CG+ and with of the SDS patients followed at our institution (Dror et al, 1998a). The not patients with malignant myeloid transformation from the SDS severity of peripheral cytopenia, fetal haemoglobin of marrow from marrow cluster-to-colony marrow of apoptosis cells in marrow cells and and P53 and were normal in all the SDS gene is its role in causing the as as and abnormalities should be Several be The SDS gene is probably for the development and of the cells and of various may be or in apoptosis of and cells and The SDS gene on the centromeric region of chromosome 7 is to be an important in in SDS patients. the SDS gene is in chromosome 7 abnormalities in these patients is not it might also be in in 7 syndromes. However, as a of its autosomal recessive inheritance and no increased of among of SDS a gene be is by a of a and as a to in the and as such as an and a in of a patient with SDS should of the patient and the family and with to and and skeletal should blood mean peripheral blood fetal haemoglobin and and pancreatic function should be and/or of the pancreas. and skeletal are It is important to of cytopenia, such as and on the immune function and neutrophil chemotaxis may in the of studies with and without or are to anaemia. Bone marrow and are for and should of studies and and in SDS be defined as requiring These severe cytopenia < 8 < × 109/l, neutrophil < × myelodysplastic syndrome RCEB (5–30%) and acute leukaemia The of is to risk for developing In SDS, these severe aplasia, a cytogenetic and of RCEB and with low may early and However, the to for is as no are to suggest that is are and patients with and by cytogenetic abnormality, with RCEB and with with low are the and of bone marrow and In addition, the of or with cytogenetic without which may cause significant and to the to a and haemoglobin bone marrow with and of cluster-to-colony and The reported of transformation were and if a is it should probably after and at The with which the should be is not but probably on the severity of the bone marrow findings. In cases without the patient be seen a in the with blood and bone marrow We a and peripheral blood In cases of severe cytopenia, patients should probably be seen in the months with and peripheral blood Bone marrow and may be months to to a or to malignant myeloid transformation. The at this is from a or an which may be In cases of and severe patients should be with with the probably from the neutrophil are higher × 109/l, the of and neutrophil chemotaxis should be and a to patients as or and anaemia may with an for neutropenia has been in a neutrophil et al, 1993; & 1996; Davies et al, 1997). was also shown to be in patient et al, 1996) but not in & 1996). low in of not haemoglobin & Escudier, few patients have in the of anaemia. et al, and (Woods et al, Tsai et al, 1990; Seymour & Escudier, have been of the abnormalities seen in SDS, the risk of might be even higher it is in the seen in anaemia patients is et al, 2000). Several patients with have shown haematological (Woods et al, patient on & In cases of and RCRS, the patient should be seen in the at least with and Bone marrow may be patient is severely and should be as a patient with severe aplasia, as In cases of from a or is as as Several may be in cases with SDS and symptomatic MDS as to transfusion and a or have been used in patients with MDS but have not been reported in inherited bone marrow failure syndromes. In cases of leukaemia, the patient should be on to to a should be of the high risk of the for the haematological in of we on a of patients with SDS cases with the same clinical phenotype and from the same even if the had not that the same patients had been for the of these patients is that the usual clinical is which be with and also be on a basis for patients with advanced and marrow these four had severe aplasia (unpublished Tsai et al, 1990; Barrios et al, et al, seven had MDS et al, 1997; Okcu et al, 1998; Faber et al, 1999; Cesaro et al, 2001) and four had & Escudier, 1993; Smith et al, 1995; Arseniev et al, 1996; Dokal et al, 1997). of the patients with severe aplasia of was reported to be at months and the patient with severe aplasia from an was reported and at months et al, the of the patient was not (unpublished observations). patients an MDS with RCEB) (Table IV). had and was reported at the had two were reported at and and the four patients were at an two of was reported and at The three are more common in SDS patients or in patients with the same blood but without an patients with SDS have been with or with with or without In this from related to the severe aplasia, and failure and The poor of patients with SDS after be in three the of a marrow that is not by the and might be by the increased to and in apoptosis in various or and at an advanced disease The for patients for or should probably severe cytopenia < 8 neutrophil < × 109/l, < × MDS RCEB cytogenetic and leukaemia. is usually similar to for cystic and and, usually but not and are usually may with age as a of in may be for metaphyseal which should be and may and may be for patients with may be or blood and and should be and/or and or may be to the risk of may from and In cases of severe should be as it may and months is of severe of an may be Several clinical and in SDS The clinical and risk for the development of to be for and of for to be clarified. Studies should be to the of such as in the of cells and the severity of We to the for the of SDS patients to and and a or for The SDS gene has to be and its function clarified. the gene protein normal haematopoiesis and from apoptosis is not The and of molecular malignant myeloid transformation be The relationship between the SDS gene on and the which also involves at to be study was in part by from the Shwachman–Diamond of and the The was with the of The for We are to all of the SDS

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