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Shwachman-Diamond syndrome

Shwachman-Diamond syndrome (SDS) is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities, and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children. more...

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Clinical Features

This syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, haematologic abnormalities and growth retardation. Neutropenia may be intermittent or persistent and is the most common haematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia. Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients. More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients), and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographs from 15 patients indicated that all of them had at least one skeletal anomaly, though many were sub-clinical.


Initially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded with a normal sweat chloride test result. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either malabsorption, or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The gene responsible for the disease has been identified and genetic testing is now available. Though useful in diagnostics, a genetic test does not surmount the need for careful clinical assessment and monitoring of all patients.


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Emergence of an unusual bone marrow precursor B-cell population in fatal Shwachman-Diamond syndrome
From Archives of Pathology & Laboratory Medicine, 9/1/00 by Klupp, Nikolaus

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.

(Arch Pathol Lab Med. 2000;124:1379-1381)

The Shwachman-Diamond syndrome (SDS), first described in 1964,1 is a rare congenital disorder of unknown etiology for which an autosomal recessive trait of inheritance has been suggested.2,3 The complex of SDS is characterized by exocrine pancreatic insufficiency2,3 and growth retardation4 combined with bone marrow dysfunction, which is usually reflected by severe neutropenia.2 Children affected by SDS commonly present with failure to thrive, diarrhea, and recurrent bacterial infections3,4 in the absence of pulmonary disease. Ichthyotic skin rashes complicated by pyodermic skin rashes have also been reported in individual cases.2 As in other constitutional bone marrow failure syndromes, there is a predilection for hematologic diseases, such as aplastic anemia or clonal hematologic malignancies.5-7

We present the clinical and autopsy findings of 2 female siblings who were born to consanguine parents and who were both affected by this rare disease. We also provide details on the bone marrow abnormalities noted in these cases, which are likely to be associated with the persistent severe neutropenia encountered in one of the infants.


The 2 female infants were born to consanguine parents (firstdegree cousins). Parental history revealed 2 spontaneous abortions at 4 and 16 weeks of gestation, for which no autopsies had been performed. The children were born prematurely and were small for gestational age after unremarkable pregnancies. The clinical course was similar in both cases; the infants were referred to intensive care units soon after birth with suspected meconium plug syndrome. Cystic fibrosis was excluded by normal sweat tests. Physical examinations revealed facial dysmorphia and ichthyosis in both children. Laboratory investigations disclosed unremarkable hemoglobin levels, platelet counts, and total white blood cell counts. Differential counts, however, demonstrated severe intermittent (child 1) and persistent (child 2) granulocytopenia (Figure 1). The clinical course was aggravated by multiple episodes of staphylococcal pyodermic infections. Exocrine pancreatic insufficiency was confirmed on the basis of markedly lowered stool-elastase levels (74 (mu)g / g and 38 (mu)g / g for child 1 and child 2, respectively, normal range 200-500 (mu)g/g); child 1 also had low stool-chymotrypsin levels (4.6 U/mL, normal range >6 U/mL). Symptomatic therapeutic approaches, including parenteral nutrition, antibiotics, and substitution of pancreatic enzymes, failed to improve the clinical situation, and the infants died at the ages of 4 and 3.5 months due to respiratory infections. Autopsies were performed in both cases.


Histology and Immunohistochemistry

Three-micrometer-thick, formalin-fixed, paraffin-embedded tissue sections were stained with hematoxylin-eosin. For lymph node and bone marrow investigations, Giemsa, periodic acidSchiff, and the histochemical chloroacetate-esterase stain were also performed.

For immunohistochemical examinations of the bone marrow, paraffin-embedded serial sections were stained by applying a 3step immunoperoxidase technique, as described previously.8 The antibody panel used included CD34, neutrophilic elastase, myeloperoxidase, CD3, CD4, CDS, CDB, CD20, CD22, CD79a, terminal deoxynucleotidyl transferase (TdT), and CD10. All antibodies were obtained from Dakopatts (Glostrup, Denmark), except CD4, CDS, CD22, and CD10 (Novocastra, New Castle, United Kingdom) and CD34 (Immunotech, Marseilles, France).

Polymerase Chain Reaction Analysis for Immunoglobulin Gene Rearrangements

Genomic DNA extracted from paraffin tissue sections was analyzed for immunoglobulin heavy-chain (IgH) gene rearrangements using 4 primer pairs to the CDR3 region.9 Simultaneously amplified DNA from a case of B-cell chronic lymphocytic leukemia served as a positive control. A DNA mixture obtained from peripheral blood lymphocytes from 10 healthy individuals was used for a polyclonal control.


Gross Findings

Child 1 was a 4-month-old female infant with severe growth failure (length, 53 cm; weight, 2.555 g); facial dysmorphia and intensively scaling skin on the chest and face with pyodermic foci; and bilobation of the right lung, incomplete situs inversus abdominis with right-sided polysplenia, and a pancreas of normal size.

Child 2 was a 3.5-month-old female infant with severe growth failure (length 50 cm, weight 2.700 g); facial dysmorphia, brachycephaly, lamellar ichthyosis involving the whole integument, and pyodermic foci on scalp and buttocks; and polysplenia with a pancreas of normal size.

Sections of the pancreas from both infants revealed a normal architecture with a mild relative increase of endocrine tissue, but without fatty infiltration. Neither architectural alterations nor evidence for a neoplastic process were evident in sections of spleen, kidneys, adrenal glands, liver, and lymph nodes.

The bone marrow of child 2 was normocellular and displayed a regular myeloid-erythroid ratio (3:1). The myeloid series was left-shifted with a relative predominance of promyelocytes and myelocytes (Figure 2). Staining with antibodies against myeloperoxidase, chloroacetate-esterase, and neutrophilic elastase revealed no loss of the respective antigens in the myeloid population. Numerous lymphoid cells were diffusely distributed in the bone marrow interstitium, comprising approximately 40% of the total cellularity. Immunophenotypically, these cells reacted positively for CD79a and CD10, but were negative for CD20, CD22, TdT, and CD34, as well as T-cell markers.

The marked increase in immature bone marrow precursor B cells, the immature phenotype, and the resemblance of these B cells to blast cells of acute lymphoid leukemia led to molecular determination of the IgH gene status, which did not show a clonal rearrangement, thereby making a neoplastic lymphoproliferative process less likely.


The assumption of an autosomal recessive inheritance in SDS is based predominantly on reports of familial incidence.2-5 To our knowledge, however, consanguinity of the parents has never been reported to date. Shwachman-- Diamond syndrome affecting 2 siblings in the background of second-degree parental consanguinity strongly favors an autosomal recessive trait.

The most common hematologic abnormality associated with SDS is persistent or intermittent neutropenia"with defects in chemotaxis.10 In a manner similar to other bone marrow failure syndromes, SDS is associated with an increased risk for hematologic disorders.5-7 The exact pathogenic mechanism has not yet been defined. It has been speculated that the pluripotent hematopoietic stem cell may be defective7 and susceptible for chromosomal damage, leading to the emergence of malignant clones. Alterations in the neutrophil cytoskeletal/mictrotubular function appear to play an additional major role.2,10 Recently, an abnormal stromal microenvironment combined with a stem-cell defect has been demonstrated" using long-term bone marrow cultures. As in our case, the severity of peripheral neutropenia did not correlate with the cellularity of the bone marrow myeloid compartment. This discrepancy may be explained by ineffective granulopoiesis, similar to the situation encountered in myelodysplasia.

We also observed a marked increase of immature bone marrow precursor B cells. The emergence of these cells was interpreted as an increase of so-called hematogones,12 the term referring to a population of immature B cells found in the bone marrow of healthy young children,13 but more frequently in a variety of pathologic conditions, including hematologic disorders.14-16 Immunophenotypically, these cells are heterogeneous with respect to the expression of CD34, Ia antigens, TdT, and CD10, as well as either cytoplasmic or surface mu chains,15 thus representing a particular population at variable stages of B-cell maturation. Using molecular studies, hematogones have their IgH and T-cell receptor genes in a germline configuration, thus supporting the benign nature of this unique bone marrow population. Hematogones may be increased to values of more than 30% of the total cellularity, thus providing a rather alarming morphologic situation, because they may morphologically and phenotypically simulate blast cells of acute lymphoid leukemia. One has to be aware that postchemotherapy and post-bone marrow therapy specimens frequently are associated with the emergence of hematogones.15-17

Although the extent of hematogones has been elucidated in several pathologic settings, to our knowledge no reports on increased hematogones in SDS have been published to date. The clinical significance, as well as the exact function of these cells, is still obscure. One may speculate that these immature B cells may play a critical role in the regenerative regulation of hemopoiesis, as well as in immune functions in the context of chronic cytopenias. Clonal evolution of these cells resulting in overt leukemic processes has not yet been reported. An association between the increase of hematogones and the frequently encountered hematologic malignancies in SDS, therefore, seems quite unlikely. Moreover, the vast majority of acute leukemias associated with SDS are of myeloid origin,6 whereas lymphoid leukemias are noted only sporadically.7 It is therefore conceivable that the numerous immature B-cell precursors found in our case represent a transient, reactive, and regenerative population without any malignant potential in SDS. Therefore, immunophenotyping and molecular studies have potential value in the differential diagnosis of bone marrow changes in patients with primary bone marrow failures. This report adds SDS to the specfrom of conditions in which a prominent number of hematogones may be observed.


1. Shwachman H, Diamond LK, Oski FA, Khaw KT. The syndrome of pancreatic insufficiency and bone marrow dysfunction. J Pediatr. 1964;65:645-663.

2. Aggett PJ, Cavanagh NPC, Matthew DJ, Pincott JR, Sutcliffe J, Harries JT. Shwachman's syndrome: a review of 21 cases. Arch Dis Child. 1980;55:331347.

3. Ginzberg H, Shin J, Ellis L, et al. Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. Pediatr. 1999;135:81-88.

4. Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:1593-1602.

5. Dokal I, Rule S, Chen F, Potter M, Goldman J. Adult onset of acute myeloid leukemia (M6) in patients with Shwachman-Diamond syndrome.Br JHaematol. 1997;99:171-173.

6. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br J Haematol. 1996;94:279284.

7. Woods WG, Roloff JS, Lukens JN, Krivit W. The occurrence of leukemia in patients with the Shwachman syndrome. I Pediatr. 1981;99:425-428.

8. Chott A, Haedicke W, Mosberger I, et al. Most CD56+ intestinal lymphomas are CDS+CDS- T-cell lymphomas of monomorphic small to medium size histology. Am] Pathol. 1998; 153:1483-1490.

9. Sioutos N, Bagg A, Michaud GY, et al. Polymerase chain reaction versus Southern blot hybridization: detection of immunoglobulin heavy-chain gene rearrangements. Diagn Mol Pathol. 1995;4:8-13.

10. Azzara A, Carulli G, Ceccarelli M, Nucci C, Raggio R, Ambrogi F. In vivo effectiveness of lithium on impaired neutrophil chemotaxis in Shwachman-Diamond syndrome. Acta Hematol. 1991;85:100-102.

11. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood. 1999;94:3048-3054.

12. Vogel P, Erf LA, Rosenthal N. Hematological observations on bone marrow obtained by sternal puncture. Am J Clin Pathol. 1937;7:436-447.

13. Caldwell CW, Poje E, Helikson MA. B-cell precursors in normal pediatric bone marrow. Am] Clin Pathol. 1991;95:816-823.

14. Hirt A, Morell A, Frei H, Imbach P, Wagner HP. Proliferation of lymphoid precursor cells in the bone marrow of patients with various disorders of the immune system. Exp Hematol. 1988; 16:38-41.

15. Rimsza LM, Viswanatha DS, Winter SS, Leith CP, Frost JD, Foucar K. The presence of CD34+ cell clusters predicts impending relapse in children with acute lymphoblastic leukemia receiving maintenance chemotherapy. Am I Clin Pathol. 1998;110:313-320.

16. Vargas SO, Hasegawa SL, Dorfman DM. Hematogones as an internal control in flow cytometric analysis of suspected acute lymphoblastic leukemia. Pediatr Dev Pathol. 1999;2:371-376.

17. Kallakury BV, Hartmann DP, Cossman J, Gootenberg JE, Bagg A. Posttherapy surveillance of B-cell precursor acute lymphoblastic leukemia: value of polymerase chain reaction and limitation of flow cytometry. Am J Clin Pathol. 1999; 111:759-766.

Accepted for publication January 31, 2000.

From the Institutes of Forensic Medicine (Dr Klupp), Clinical Pathology (Drs Simonitsch and Amann), and Laboratory Medicine (Dr Mannhalter), Vienna Medical School, University of Vienna, Vienna, Austria.

Reprints: Nikolaus Klupp, MD, Institute of Forensic Medicine, Vienna Medical School, University of Vienna, Sensengasse 2, 1090 Vienna, Austria.

Copyright College of American Pathologists Sep 2000
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