• Shwachman–Diamond syndrome;
  • myelodysplastic syndrome;
  • isochromosome 7q;
  • bone marrow transplant


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References

Summary. We report on nine children with Shwachman–Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high-risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4·5 years +). The six non-transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.

Shwachman–Diamond Syndrome (SDS) is a rare autosomal recessive disorder affecting multiple organs with a wide range of clinical severity (Shwachman et al, 1964). It is characterized by exocrine pancreatic insufficiency, growth retardation, skeletal abnormalities and constitutional bone marrow failure, resulting in peripheral blood cytopenias. As a result, SDS patients are at high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). There also appears to be a strong association with chromosome 7 abnormalities, especially i(7)(q10) (Smith et al, 1996; Dror et al, 1998; Okcu et al, 1998). Monosomy 7 and deletions of 7q are common, and invariably poor prognostic markers in MDS/AML (Labal de Vinuesa et al, 1987, Shannon et al, 1989; Murray et al, 1996). However, i(7)(q10), representing a duplication of the q arm, has rarely been reported with the exception of SDS patients. Isochromosomes are formed by misdivision of the centromere, which is interesting, as Goobie et al (2001) have recently mapped the SDS gene to the peri-centromeric region of chromosome 7 [maximum multipoint LOD (log of the odds) score of 10]. The relevance of this discovery and whether or not the SDS gene is affected by i(7)(q10) formation is as yet unknown.

In childhood MDS, bone marrow transplantation (BMT) has become accepted as the treatment of choice with a disease-free survival of 50% (Guinan et al, 1989). However, SDS is a high-risk transplant group, of the 15 patients (including three of our patients) who have undergone BMT only six have survived (40%) and nine (60%) died from a variety of transplant-related causes (Tsai et al, 1990; Barrios et al, 1991; Smith et al, 1995; Arseniev et al, 1996; Bunin et al, 1996; Davies et al, 1997; Okcu et al, 1998; Faber et al, 1999). In addition, although BMT can replace faulty haematopoietic progenitors, the underlying stromal defect remains (Dror et al, 1998; Dror & Freedman, 1999). Clearly this is a very high-risk transplant group with a background of underlying organ failure, which may be exacerbated by current transplant conditioning regimes (Savilathi & Rapola, 1984; Okcu et al, 1998).

Here we report on nine SDS children, of whom seven acquired an i(7)(q10) and one had a derived chromosome 7 with a centromeric breakpoint near the proposed site of the SDS gene. We suggest that i(7)(q10) may be a relatively benign finding in SDS and should not be considered in the same poor prognostic group as other chromosome 7 abnormalities in MDS and AML, and, after reviewing the differing outcomes of BMT, question whether allogeneic BMT should be carried out if i(7)(q10) is the sole abnormality.

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References

The nine patients were studied at four different centres: Ninewells Hospital, Dundee (patients A1 and A2), Western General Hospital, Edinburgh (patients B1 and B2), National Centre for Medical Genetics, Dublin (patients C1, C2 and E) and Christie Hospital, Manchester (patients D1 and D2). Patients sharing the same letter are siblings (e.g. A1 and A2).

SDS. SDS was diagnosed on the basis of the following clinical features: failure to thrive (despite adequate nutritional intake) with weight on or below the third centile, absence of faecal tryptic activity, pancreatic insufficiency and recurrent infections. Depression of at least one haematopoietic cell line (neutropenia, thrombocytopenia or anaemia) was taken as evidence of haematological dysfunction. The presence of short stature and skeletal abnormalities were taken as further evidence of SDS. Cystic fibrosis was excluded.

MDS. MDS was defined as showing bone marrow dysplasia in at least two of the haematopoietic cell lines. Bone marrows were reviewed and classified according to the categories defined by the FAB (French–American–British) co-operative group (Bennet et al, 1982).

Independent prognostic scoring system (IPSS).  IPSS is calculated from cytogenetics, percentage blasts, haemoglobin level and platelet count. IPSS survival and prognostic data is based on elderly patients with MDS (Greenberg et al, 1997; Soléet al, 2000), therefore, where possible we have also included a Paediatric scoring system (PSS) based on childhood MDS (Passmore et al, 1995). The score is calculated from fetal haemoglobin (HbF), platelet count, neutrophil count, percentage blasts and cytogenetics.

Cytogenetics.  Bone marrow metaphases were prepared according to standard cytogenetic procedures (Czepulkowski et al, 1992). Karyotypes were described according to the International System for Chromosome Nomenclature (ISCN, 1995).

Fluorescence in situ hybridization (FISH). Slides containing metaphases spreads were prepared and denatured according to standard FISH protocols. Probes were hybridized and stringency washes carried out using standard procedures as recommended by the manufacturers. FISH signals were visualized using an Olympus BX 50 fluorescent microscope and images captured by macprobe imaging software (Applied Imaging International Ltd., Newcastle Upon Tyne, UK).

Probes.  The following probes were used: Williams syndrome critical region (WSCR) probe (7q11.23) FITC (fluorescein isothocyanate) (green) with D7S427 control probe (7q36) FITC (green) (Appligene Oncor, QBiogene, Middlesex, UK); whole chromosome 5 paint Cy3 (Red) (Cambio, Cambridge, UK); whole chromosome 7 paint FITC (green) (Cambio); chromosome 1/5/19 alpha satellite (D1Z7/D5Z2/D19Z3), Texas red (Appligene Oncor); chromosome 7 alpha satellite (D7Z1), FITC (green) (Appligene Oncor).

Clinical data

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References

Clinical data for all patients is presented in Table I.

Table I.  The clinical features of Shwachman–Diamond patients.
  • *

    These patients were considered to have only minor dysplastic features by the consultant and were therefore classified as RA.

  • IPSS Intermediate 1 = survival 3·3 years, Intermediate 2 = survival 1·2 years.

  • PSS 0 = 5 years survival > 60%, 1 = 5 years survival ∼20%.

  • NP, neutropenia; RA, refractory anaemia; TCP, thrombocytopenia; PCP, pancytopenia; A, anaemia; CL, clinodactyly; ST, small thorax; CT, costochondrial thickening; TD, thoracic dystrophy; MBLB, metaphyseal dysostosis of the long bones; SR, skin rash.

Failure to thrive+ ++++++ 
Skeletal Anomaly  CL, ST, CT, TDSTTD, CT, MDLBTD, MDLB  MDLB
Height Centile< 3rd< 3rd< 3rd< 3rd< 3rd< 3rdOn 3rdOn 3rd< 3rd
Weight Centile< 3rd< 3rd< 3rd< 3rdOn 3rd< 3rdOn 3rdOn 10th< 3rd
Respiratory Infections  + + ++ + +     
Recurrent Infections  SR+    +
Pancreatic deficit+++++ Resolved++ Diabetes++
Steatorrhoea++  +++  
Haematology stable+  ++++++
Transplant Outcome4·5y +DeadDead      
% Blasts< 1%< 1%< 1%< 1%< 1%< 1%< 1%< 1%< 1%
Fetal haemoglobin (%)10%10%N/AN/A10%10%10%10%10%
Platelets × 109/l< 100–11873152169714560119
Haemoglobin g/dl10·19·911·310·510·89·911·87·59·4
Neutrophils × 109/l0·60·31·21·00·90·40·90·74·2
Dysplastic featuresErythroidErythroid/ granulocyticErythroid/ granulocyticHypocellularErythroidErythroid/ granulocyticErythroidErythroidErythroid/ myeloid


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References

A summary of serial cytogenetics results on all patients is presented in Table II. The numbers in square brackets [] after the karyotype indicate the number of cells analysed.

Table II.  Summary of cytogenetic results.
  1. Numbers inside [] brackets = number of cells analysed, D = diagnostic sample.

A103/03/97 D45,XX,der(5;7)(p10;q10)[5]/46,XX[6]
Post transplant46,XX[30]
A209/06/97 D46,XX[20]
05/05/9846,XX,del (20)(q11)[4]/46,XX[18]
09/03/9946,XX,del (20)(q11)[6]/46,XX[44]
At transplant46,XX[30]
B112/03/93 D46,XX,i(7)(q10)[31]
B205/04/94 D46,XX,i(7)(q10)[19]/46,XX[15]
C104/10/99 D46,XY,i(7)(q10)[13]/46,XY[2]
C204/10/99 D46,XY[20]
D120/03/96 D46,XY,i(7)(q10)[7]/46,XY[5]
D220/03/96 D46,XX[20]
E10/08/98 D46,XY,i(7)(q10)[10]

Figure 1A shows the partial karyotype and ideogram of the der(5;7) (patient A1). Figure 1B shows the partial karyotype and ideogram of the i(7q) (patients A2, B1, B2, C1, D1, D2 and E).


Figure 1. FISH studies were carried out on patient A1 and her sister A2 to identify the precise breakpoint on the derived chromosome. (A) Partial karyotype and ideogram of (left to right) chromosome 5, chromosome 7 and the derived chromosome der(5;7) from patient A1. (B) Partial karyotype and ideogram of chromosome 7 (left) and the isochromosome 7q (right) seen in patients A2, B1, B2, C1, D1, D2 and E. (C) The der(5;7) (arrowed) with whole chromosome 7 paint (green) and chromosome 5 alpha-satellite (red) showing that 5 centromere is present on the rearranged chromosome of patient A1. The normal chromosome 7 (green) can be seen below. (The centromeres of chromosomes 1 and 19 also hybridized with this probe). (D) The der(5;7) (arrowed) painted with whole chromosome 5 paint (red), and the William syndrome critical region (WSCR) 7q11.2 and reference probe (green), revealed that the breakpoint in patient A1 was proximal to the WSCR at 7q11.23. The normal chromosome 5 (red) is on the right and the normal 7 (green) above. (E) The der(5;7) (arrowed) with alpha satellite probes for chromosome 5 (red) and 7 (green) showing centromeric fusion. (The centromeres of chromosomes 1 and 19 also hybridized with this probe). (F) The i(7)(q10) (arrowed) from patient A2 was confirmed with (WSCR) 7q11.2 and reference probe in green. The normal chromosome 7 (green) is on the right. FISH confirmed that the breakpoint on both sisters (patients A1 and A2) is at the centromere of chromosome 7. In C–F, an orange arrow indicates the abnormal chromosome.

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Patient A1.  Cytogenetic analysis of bone marrow revealed the presence of an abnormal clone 45,XX,der(5;7)(p10;q10) (Fig 1A, Table II). Breakpoints were confirmed by FISH (Fig 1C–E). Refractory anaemia (RA) was diagnosed on morphology and abnormal cytogenetics. The patient received a 1DQ mismatch bone marrow transplant in December 1997. Bone marrow morphology and cytogenetics became normal and she remains well 4·5 years+ later.

Patient A2.  Cytogenetic analysis showed 46,XX,i(7)(q10), this clone was replaced by 46,XX,del(20)(q11)(Table II). Patient A2 was well and had a normal karyotype when transplanted (9/10 mismatch DQ) but died 71 d later from infection.

Patient B1.  This patient remained well for 5 years despite RA and i(7)(q10) in all cells (Table II). At age 9 years, her clinical condition deteriorated with a systemic infection. She had been pancytopenic for some time and was refractory to platelet transfusion. She had bronchiectasis and renal impairment and was in poor condition when she received a matched BMT (10/10, mother), and died 1 month later from transplant-related complications (cardiac failure).


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References

Cytogenetic analysis of bone marrow from nine SDS children confirmed a high incidence of i(7)(q10), when combined with published SDS patients, a striking 75% have chromosome 7 abnormalities, 46% having i(7)(q10) alone (Table III). Patient A1 had a centromeric breakpoint and a similar patient has been reported (Smith et al, 1995), suggesting that these may represent variants of i(7)(q10). Subtle centromeric heteromorphism of chromosome 7 has also been reported (Sokolic et al, 1999). Whole arm rearrangements are thought to be associated with dosage effects rather than locus-specific disruption (Labal de Vinuesa et al, 1987). However, the possibility of a qualitative disruption of a critical gene must be re-evaluated, following the mapping of the SDS gene to the peri-centromeric region of chromosome 7 (Goobie et al, 2001). This is the first report of the mapping of a cancer predisposition gene to the breakpoint of an acquired chromosomal abnormality. Furthermore, the possibility of a chance association must be negligible given the high LOD score and the very specific nature of the acquired abnormality. Mutations in the SDS gene may predispose to isochromosome formation or i(7)(q10) formation may disrupt the gene. A full understanding awaits identification of the SDS gene itself.

Table III.  Clonal chromosome abnormalities in patients with Shwachman–Diamond syndrome.
Cytogenetic abnormalityDiagnosisAge (years)StatusReference
  1. NP, neutropenia; RA, refractory anaemia; RCP, refractory cytopenia; MF, myelofibrosis; TCP, thrombocytopenia; A, anaemia; PCP, pancytopenia; AML, acute myeloid leukaemia; MDS, myelodysplasia; RAEBT, refractory anaemia with excess blasts in transformation; RAEB, refractory anaemia excess blasts; ALL, acute lymphocytic leukaemia; MMD, mismatched; BMT, bone marrow transplant; MUD, matched unrelated; MSD, matched sibling.

46XX,i(7)(q10)/46,XXRA 1·5AlivePatient B2, present study
46,XY,i(7)(q10)/46,XYNP, TCP, A, PCP13AlivePatient C1, present study
46,XY,i(7)(q10)/46,XYNP, TCP 7AlivePatient D1, present study
46XX,i(7)(q10)/46,XXPCP 8AlivePatient D2, present study
46,XY,i(7)(q10)NP, TCP 7AlivePatient E, present study
46,XY,i(7)(q10)/46,XYRA 2AliveSmith et al (1996)
46,XY,i(7)(q11)RCP 6AliveDror et al (1998)
46,XY,i(7)(q10)/46,XY,del(20)(q11)/46,XYRCP 5AliveDror et al (1998)
46XX,i(7)(q10)[30]NP, TCP 6DeadMaserati et al (2000)
46XX,i(7)(q10)/46,XXNP16Dead d 71 post MMDPatient A2, present study
46XX,del (20)(q11)/46,XX
46XX,i(7)(q10)RA 3·5Dead d 31 post MMDPatient B1, present study
46XX,i(7)(q10)/46,XXHypocellular 8Dead 2 months post MMDDavies et al (1997)
45,XY,−7/46,XY,i(7)(q10)Hypoplasia, MF 9Dead d 32 post BMTOkcu et al (1998)
46,XY,der(7)t(4;7)(q31;q11)/46,XYRA > AMLM5 5Dead 1 years post BMTSmith et al (1995, 1996)
45XX,der(5;7)(p10:q10)/46,XXRA12Alive 3·5 years post MMDPatient A1, present study
46,XY,del(7)(q22q34)/47,XY,del(7)(q22q34),+21/46,XYNP > MDS (?)13Alive 12 months + post MUDKalra et al (1995), Davies et al (1997)
46XX,del(7)(q11.2q32)/46,XXRA11AliveSmith et al (1996)
46–47,XY,−2,−4,del(5)(q23q33),del(7)(q22),+2–3r,+2–4marRAEBT > AMLM642DeadSmith et al (1996)
45XX,t(6;13)(q21;q32),−7/46,XXPCP > MDS -AML 7·5Dead 2months post MUDKalra et al (1995), Davies et al (1997)
45,XY,−7,mar(18)AML 9Dead sepsisWoods et al (1981)
45,XY,−7RAEB 8Dead d 93 post MUDOkcu et al (1998)
47,XY,+1,del(9)(q22)RAEBT > AMLM5 9DeadSmith et al (1996)
46,XY,inv(14)(q11q32)MDS (?) 5Alive 18 months + post MSDFaber et al (1999)
46,XY,inv(9)MDS > AMLM424Dead 10 months post MSDArseniev et al (1996)
46,XY,add(11)(p?),−15,−22,+mar1,+mar2RAEBT > AMLM2 8DeadSmith et al (1996)
45–50,XY,−18,t(21;?)(q22;?),dic(22;?)(p11;?)/46,XYAML385 years +Seymour & Escudier (1993)
47,XY,+21,+4q,mar(1q)PCP > MDS > AMLM4 2·5DeadWoods et al (1981)
53,XY,+G,+GALL L1 1·5Alive 12 months +Woods et al (1981)

Although SDS patients are predisposed to myeloid disease, there is not the same clear relationship between chromosome 7 abnormalities and leukaemia, as seen in non-SDS patients. In many patients, the i(7)(q10) has been identified through routine monitoring and may previously have gone unnoticed in the absence of disease progression. There is compelling evidence to suggest that i(7)(q10), resulting in duplication of 7q, is cytogenetically and clinically distinct from other categories of chromosome 7 abnormality. MDS is commonly associated with monosomy 7, deletion of 7q, and complex abnormalities of 5q and 7q, where they define a poor prognostic group associated with rapid transformation to acute leukaemia (Johansson et al, 1991; Nowell, 1992). However, Anderson and Pederson-Bjergaard (2000) found no instances of i(7)(q10) in a total of 411 de novo and treatment-related MDS/AML patients, despite a high incidence of centromeric breaks.

SDS patients with i(7)(q10) do not show classic myelodysplastic features, do not appear to transform to AML and rarely develop secondary changes during disease progression.

Patients D1 and D2 had spontaneous reductions in clone size without treatment, and E had an improvement in bone marrow morphology with no change in level of the i(7)(q10) clone (Table II). Prior to transplant, patient B1 had i(7)(q10) for 5 years, and Maserati et al (2000) reported a similar patient with an i(7)(q10) clone for 9 years who eventually died of aplasia, not AML or MDS. This patient may provide some insight into the natural history of i(7)(q10) and would support our own patient data. Clearly these i(7)(q10) patients are inconsistent with the rapid expansion of an aggressive chromosome abnormality. No SDS children with i(7)(q10) have transformed to acute leukaemia and there is no evidence of additional abnormalities occurring within the i(7)(q10) clone, although separate minor del(20q) clones have been reported (patient A2 and Dror et al, 1998). Taken together, we believe there is evidence to suggest that isochromosome 7q is specific to SDS and is a different, much less aggressive, disease entity than other chromosome 7 abnormalities seen in MDS/AML. This of course has profound implications for the management of children with SDS.

As a result of the prior association of chromosome 7 abnormalities and poor prognosis, SDS children with i(7)(q10) may be offered transplants. However, the ethical decisions are difficult, SDS patients have a high incidence of transplant-associated problems; 46% survived for 9 months and 40% are still alive as far as we are aware (Savilathi & Rapola, 1984; Tsai et al, 1990; Okcu et al, 1998) (Table IV). If pulmonary function is compromised, and repeated infection and transfusion dependency are high, then transplant may be the only option; on the other hand, transplanting while a child is well and infection free may increase survival chances, but could risk transplant-related death. Faber et al (1999) suggested that early childhood transplants may be beneficial, as cardiotoxicity is reduced and treatment options are not yet limited by transformation to AML. While patient A1 and others in the literature show that transplants can be successful, none of these cases had an i(7)(q10) (Smith et al, 1995; Davies et al, 1997; Faber et al, 1999). Of the 13 i(7)(q10) SDS cases, four children (4/4) have died as a result of BMT (< 3 months post transplant), one of aplasia (Maserati et al, 2000), and eight non-transplanted cases are alive and have not transformed to acute leukaemia (Tables III and IV). Obviously a large collaborative study is required to determine the true prognostic significance of i(7)(q10) in SDS and how this may impact on patient management.

Table IV.  Bone marrow transplants in SDS patients.
DiagnosisTypeComplicationsIndications for transplantSurvivalReference
  1. NP, neutropenia; MDS, myelodysplasia; RA, refractory anaemia; AML, acute myeloid leukaemia; RAEB, refractory anaemia excess blasts; MMD, mismatched; MPD, matched parent; MUD, matched unrelated; MSD, matched sibling; GVHD, graft-versus-host disease; PH, pulmonary haemorrhage; CA, clonal abnormality.

NPMMDAdenovirusCADead 71 dPatient A2, present study
MDS (RA)MPDCardiac failureCA, pulmonary/ renal impairmentDead 1 monthPatient B1, present study
MDS (RA)MMDGVHD, PHCA, myelofibrosisDead 32 dOkcu et al (1998)
HypocellularMMDRespiratory distressCA, hypocellularDead 2 monthsDavies et al (1997)
MDS (RA)MMDNoneCAAlive 52 months +Patient A1, present study
AML M5aMUDGraft rejectionCA, AML M5Dead 12 monthsSmith et al (1995)
Hypocellular, dysplastic changesMUDNoneCA, hypocellularAlive 12 months +Davies et al (1997)
MDS unclassifiedMUDGraft failed, InfectionCA, hypocellularDead 2 monthsDavies et al (1997)
AplasiaMSDCardiac failureRepeated pyrogenic infectionDead 23 dTsai et al (1990)
AplasiaMSDGVHDPneumonia, renal failureAlive 9 months +Barrios et al (1991)
AplasiaMMDVeno-occlusive diseaseTransfusion dependent,Alive 10 months +Bunin et al (1996)
MDS (RAEB)MUDGVHDCADead 93 dOkcu et al (1998)
MDS hypoplasia, dyserythropoesisMUDNoneCA, Pyrogenic infection.Alive 18 months +Faber et al (1999)
MDS > AMLM4MSDCytomegalovirus,Severe transfusion dependentDead 10 monthsArseniev et al (1996)
AMLMUDHepatic/cardiac dysfunctionCAAlive 97 d +Seymour & Escudier (1993)

Accumulated evidence strongly suggests that i(7)(q10) is specific to SDS, represents a different disease entity from other chromosome 7 abnormalities in myeloid leukaemia and should not be considered in the same poor risk category. Although SDS children are at high risk of developing MDS/AML, they are prone to lethal transplant complications and transplant decisions should not be based on the presence of i(7)(q10) alone in the absence of other signs of haematological disease progression.


  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Clinical data
  6. Cytogenetics
  7. Transplant patients
  8. Discussion
  9. References
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