Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: a Rare Presentation of Shwachman-Diamond Syndrome

Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: A Rare Presentation of Shwachman-Diamond Syndrome

Taco W. Kuijpers, MD, PhD*; Eline Nannenberg, MD‡; Marielle Alders, MSc‡; Robbert Bredius, MD, PhD§; and Raoul C. M. Hennekam, MD, PhD*‡

ABSTRACT. Clinical Findings. Aplastic anemia was aly have been observed in the first years of life, with diagnosed at birth for a first child from healthy noncon- subsequent improvement without complications sanguineous parents. The girl had hypoglycemia, which (similar to the pancreatic insufficiency).3 Intermittent normalized within 2 months. Cow milk allergy was sus- neutropenia is the most common hematologic find- pected initially, because of skin lesions and diarrhea, ing in SDS. Hematologic manifestations other than followed by severe growth retardation. Clinical and ra- diologic symptoms gradually became typical for Shwach- neutropenia include anemia, increased fetal hemo- man-Diamond syndrome. Two common mutations in the globin levels, thrombocytopenia, and aplastic ane- -SBDS gene (183-184TA3CT [K62X] and IVS2(258)؉2T3 mia.2,4,5 As with other constitutional BM failure syn C [C84fs]) were found. dromes, there is a tendency toward malignant Results. Bone marrow transplantation from a myeloid transformation. Recombinant human gran- matched unrelated donor was unsuccessful. The genetic ulocyte colony-stimulating factor (G-CSF) has been information from the deceased patient enabled us to used for some SDS subjects with severe neutropenia perform prenatal molecular studies during the subse- but is not recommended because of the risk of acute quent pregnancy, successfully predicting a nonaffected child. myeloid leukemia, although the exact prevalence of Conclusions. This report describes for the first time the disease and its induction by G-CSF are difficult to 2 the hematologic abnormalities of congenital aplastic ane- establish. mia and prolonged neonatal hypoglycemia as the pre- Growth retardation is a typical manifestation. senting symptoms of Shwachman-Diamond syndrome. Weight and length are deficient at birth and remain The finding of common mutations in the presence of below normal with time. Some patients with SDS these symptoms at birth suggests the lack of a clear present with short stature only, rather than malnu- phenotype-genotype relationship in this syndrome. Pe- trition or malabsorption, which suggests an inherent e e diatrics 2004;114: 387– 391. URL: http://www.pediatrics. growth problem. A broad spectrum of skeletal ab- org/cgi/content/full/114/3/e387; aplastic anemia, hematology, genotype, congenital, bone marrow transplantation. normalities, including metaphyseal dysostosis and epiphyseal dysplasia, has been found to be associated with this syndrome. Additional clinical features ABBREVIATIONS. SDS, Shwachman-Diamond syndrome; CHH, include immune dysfunction, liver disease, renal tu- cartilage/hair hypoplasia; DKC, dyskeratosis congenita; G-CSF, granulocyte colony-stimulating factor; BM, bone marrow; BMT, bular defects, insulin-dependent diabetes mellitus, 6,7 bone marrow transplantation; PCR, polymerase chain reaction. and psychomotor retardation. No unifying pathogenic mechanism has yet been shown to be responsible for SDS, although the ge- hwachman-Diamond syndrome (SDS) (Online netic basis of this rare disease was recently de- Mendelian Inheritance in Man no. 260400) is a scribed.8 Indirect lines of evidence indicate that the Srare autosomal recessive disorder that usually orthologs may function in RNA metabolism. manifests itself in infancy or early childhood. The YLR022c has been clustered with genes encoding disease is extremely heterogeneous, showing a wide RNA-processing enzymes.9 Restriction digestion or variety of abnormalities and symptoms. It is charac- sequencing of polymerase chain reaction (PCR) terized mainly by exocrine pancreatic insufficiency, products from affected individuals showed that short stature, and bone marrow (BM) dysfunction.1–3 ϳ75% of alleles associated with SDS were the result Several studies have shown that, with advancing age, 40% to 60% of patients exhibit pancreatic suffi- of gene conversion, which was confined to a short ciency. Elevated liver enzyme levels and hepatomeg- segment with a maximal size of 240 base pairs. Ap- proximately 90% of affected individuals carry at least 1 converted allele, and 60% carry 2 converted alleles. From *Emma Children’s Hospital and ‡Department of Clinical Genetics, Alleles from affected individuals without conversion Institute for Human Genetics, Academic Medical Center, Amsterdam, Netherlands; and §Leiden University Medical Center, Leiden, Netherlands. mutations had other changes in the coding region of Accepted for publication Apr 8, 2004. SBDS, which led to frameshift and missense chang- DOI: 10.1542/peds.2003-0651-F es.8 We present an unusual case of congenital aplas- Reprint requests to (T.W.K.) Emma Children’s Hospital, Academic Medical tic anemia combined with transient hypoglycemia Center (G8-205), Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: during early infancy with a diagnosis of SDS, which [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- was confirmed by the identification of 2 common emy of Pediatrics. mutations in the SBDS gene.

http://www.pediatrics.org/cgi/content/full/114/3/Downloaded from www.aappublications.org/newse387 PEDIATRICS by guest on September Vol. 11428, 2021 No. 3 September 2004 e387 METHODS abnormalities. The 32-year-old white mother and the Hematologic Studies 31-year-old father were both healthy. At the 39th Morphologic analyses demonstrated hypocellular BM in week of gestation, contractions started spontane- smears, which was confirmed with BM biopsies. No excess colla- ously. During the delivery fetal distress developed, gen or signs of fibrosis, disturbed BM stroma development, or prompting a cesarean section. A pale girl with a birth disorganized hematopoiesis was observed. Absolute numbers of weight of 2790 g (10th percentile), length of 38 cm progenitor B cells (CD19ϩ, CD10ϩ, CD24ϩ), T cells (CD2ϩ, CD3ϩ, Ͻ ϩ ϩ Ϫ ϩ ϩ ( 3rd percentile), and occipital-frontal circumfer- CD4 , CD8 ), natural killer cells (CD3 , CD16 , CD56 ), and myeloid cells (CD15ϩ, CD14ϩ, CD16ϩ, CD65ϩ) were determined ence of 35 cm (10th percentile) was born; she expe- with standard fluorescence-activated cell-sorting procedures. Col- rienced respiratory failure, which necessitated artifi- ony-forming units of the erythroid and granulocyte/macrophage cial respiration. The patient had low hemoglobin progenitors were determined in 10- to 14-day semisolid cultures levels and hypoglycemia (Table 1), which were im- and compared with normal age-matched values. mediately corrected. Chest radiographs did not show Histochemical Analyses any defects (in particular, no abnormal ribs, verte- Histochemical and immunophenotypic analyses of the liver brae, or humeri). and muscle were conducted with standard staining procedures, No firm diagnosis was made at that time. with a streptavidin-biotin complex method for paraffin-embedded Kleihauer tests to determine fetomaternal blood loss sections and a 3-step, indirect, immunoperoxidase method, with yielded negative results. The girl was weaned from 3-amino-9-ethylcarbazole as a substrate, for frozen sections. Elec- the ventilator but, for unknown reasons, exhibited tron microscopy was performed with the tissue samples simulta- ϳ neously, with Karnovsky embedding. periods of tachypnea for 8 weeks. Ultrasono- graphic evaluations of the head yielded normal re- Molecular Studies sults. Echocardiography showed nonclosure of the Genomic DNA from peripheral mononuclear cells and fibro- foramen ovale, with moderate left-to-right shunting. blasts from the patient were extracted with standard methods. The The pulmonary artery pressure was 35 mm Hg. SBDS gene was amplified in separate PCRs with primer sets Microbiologic cultures all yielded negative results. identical to those described by Boocock et al,8 with essentially the same genomic PCR conditions as described. Direct sequencing Serologic tests for congenital infections yielded neg- was performed with an ABI PRISM Big Dye terminator v1.1 cycle ative results, as did PCR tests for cytomegalovirus, sequencing kit (Applied Biosystems, Foster City, CA), and PCR parvovirus B19, herpes simplex virus, and Epstein- products were separated in 1% SeaKem (FMC BioProducts, Rock- Barr virus. The patient experienced persistent peri- land, ME) gels, purified with a Qiagen gel extraction kit (Qiagen, Hildena, Germany), and sequenced automatically (ABI3100 se- ods of unexplained hypoglycemia, with transient quencer; Applied Biosystems). lactate acidemia (peak: 5.4 mmol/L). She was exten- sively evaluated for metabolic disorders, in particu- CLINICAL REPORT lar mitochondrial disorders, but no clues were found The proband was the first child of a nonconsan- in a liver biopsy, muscle biopsy, and mitochondrial guineous couple with no family history of congenital DNA analysis. The patient was treated with decreas-

TABLE 1. Hematologic and Immunologic Blood Values of the Propositus Birth 2 wk 12 mo* Hematologic findings Hb, mmol/L 2.8† 4.2† 5.5† Hct, L/L 0.23 0.33 Reticulocytes (106 cells/mL) 2.6 8.2 MCV, fL 106 102 Platelets (106 cells/mL) 75 21 50 Leukocytes (106 cells/mL) 1.8 4.2 4.4 Metamyelocytes, % 2 Bands formed, % 1 2 Neutrophils, % 8 8 16 Monocytes, % 5 11 10 Lymphocytes, % 87 80 75 Chemical findings Bilirubin, ␮mol/L 63 166 6 ALAT, IU/L 110 66 ASAT, IU/L 94 40 LDH, IU/L 414 576 0.7 Creatinine, ␮mol/L 32 Glucose, mmol/L 0.9 2.2 4.4 Immunologic findings Lymphocytes (106 cells/mL) 3.4 3.3 CD3ϩ T cells (106 cells/mL) 3.1 3.0 CD3ϩ/CD4ϩ Th cells (106 cells/mL) 2.5 2.1 CD3ϩ/CD8ϩ Tc cells (106 cells/mL) 0.6 0.9 CD19ϩ B cells (106 cells/mL) 0.2† 0.4 CD16/CD56ϩ NK cells (106 cells/mL) 0.03† 0.05 Hb indicates hemoglobin; Hct, hematocrit; MCV, mean corpuscular volume; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; LDH, lactate dehydrogenase; Th, T helper; NK, natural killer; Tc, cytotoxic cells. * With crythropoietin (400 E/kg) and G-CSF (30 ␮g/kg, 3 times per wk, subcutaneously). † Outside the normal range of values for lymphocyte counts.

e388 CONGENITAL APLASTICDownloaded ANEMIA from www.aappublications.org/news IN SDS by guest on September 28, 2021 Fig 1. Hypocellular BM smear at 1 week of age. In A, 3 normoblasts, 2 lymphocytes, and a fully differentiated neutrophilic granulocyte can be observed. In B, 2 myelocytes and signs of some dyserythropoiesis, as indicated by a small cytoplasmic bridge between 2 adjacent normoblasts (arrow) in the same smear, can be observed.

ing amounts of diazoxide until glucose levels were donor. Before admission, there were no signs of in- completely normalized. fections or hemorrhagic diathesis. Fanconi anemia was considered because of the Examination at admission showed a pale dystro- aplastic anemia (Fig 1) but was excluded because of phic girl, with weight of 6980 g (Ͻ3 SD) and height of normal mitomycin C test results. Neonatal lupus was 68 cm (Ͻ3 SD). The tonsils were present, and the excluded because of the absence of autoantibodies in lymph nodes were not enlarged. There was hepato- the mother and the newborn. Thrombopoietin levels megaly but no enlargement of the spleen. The patient were strongly increased (786 kU/L; normal: Ͻ40 had no clinical jaundice. No proof of a recent (viral) kU/L); the absence of mutations in the MPL gene infection was obtained. The BM was hypocellular, made severe congenital amegakaryocytic thrombocytopenia unlikely. Moreover, plasma levels of folic acid and vitamin B12 were normal; ferritin levels increased within the first 3 months, from 24 to 890 ␮g/L, after 4 erythrocyte transfusions. Chromosomal analysis indicated a normal female pattern (46, XX). At the age of 4 months, the patient was discharged with tube feeding and erythropoietin treatment (400 U/kg, administered subcutaneously, twice weekly). She was thought to have a cow milk allergy because of persistent diarrhea and small, itchy, eczematous, skin lesions on the limbs, chest, and back. Growth failure became more evident during follow-up monitoring. Insulin-like growth factor-1, growth hormone, and thyroid hormone tests produced normal results. Metaphyseal dysplasia was noted radiologi- cally (Fig 2), which led to the suspicion of SDS. Although stools seemed well formed and of normal consistency, fat malabsorption was detected (78%), and elastase in fecal samples was repeatedly determined to be undetectable (Ͻ15 ␮g/g). Pancreatic enzymes were administered orally, but substitution was without effect on the patient’s de- creased growth rate during follow-up monitoring. The patient experienced recurrent pneumonia and diarrhea, recovering rapidly with rehydration and antibiotic treatment. Subcutaneous administration of G-CSF was initiated with a dose of 10 ␮g/kg; with time, the dose was increased to 30 ␮g/kg, to main- tain the patient’s absolute neutrophil count above ␮ 500 to 600 cells per L. At the age of 14 months, the Fig 2. Metaphyseal dysplasia on a radiograph of the hips and patient was admitted for allogeneic BM transplanta- knees of the proband at 8 months of age. At that time, features of tion (BMT) with BM cells from a matched unrelated proportional short stature were present.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/114/3/ by guest on September 28, 2021 e387 e389 Fig 3. Sequence analysis of exon 2 of the SBDS gene in the patient. WT represents a control sample (wild-type). Both alleles of the patient were affected; she carried the mutations 183-184TA3CT (on 1 allele) and 258ϩ2T3C (on the other allele). without much erythropoiesis. The myeloid lineage Analysis of SBDS genomic sequences in each of the was hypoplastic; megakaryocytes were not detected. parents confirmed the presence of the genetic Clonal derangements and myelodysplasia were ex- changes in the heterozygous condition, ie, 183- cluded on the basis of morphologic, immunopheno- 184TA3CT, resulting in a stop codon (K62X), in the typing, and cytogenetic studies (eg, monosomy 7 or mother and IVS2(258)ϩ2T3C, leading to a C84 i7q). frameshift splicing event, in the father. Immunologic studies indicated no defects. Lym- Recently, the mother became pregnant again and phocyte proliferation tests yielded largely normal asked for prenatal diagnosis. A chorionic villus bi- results with activation with mitogens or combined opsy showed that the fetus was a carrier of the CD3/CD28 receptor signaling (data not shown). A IVS2(258)ϩ2T3C (C84fs) mutation only, and a normal-sized thymus was observed with computed healthy boy was born. tomography; no lung abnormalities or scarring was observed. Echocardiography showed normal ana- DISCUSSION tomic dimensions and good ventricular contractions, Several short stature-skeletal dysplasias can be as- with normal fractional shortening for age. Liver and sociated with varying degrees of hematologic defi- kidney functions were normal at that time. Microbi- ciency or immunodeficiency.10–15 BM failure syn- ologic cultures and PCR tests yielded negative re- dromes almost always occur in childhood until sults for several viruses (ie, all herpes viruses, human adulthood, with symptoms related to the predomi- immunodeficiency virus, and parvovirus B19) in nant cytopenia, and often culminate in multilineage nose washings, feces, urine, and/or blood. failures with time. Congenital BM failures have been The patient received 2.5 ϫ 108 nucleated cells per characterized primarily as single-lineage failures, kg. Graft-versus-host disease prophylaxis consisted as seen in Kostmann syndrome or other variants of of methotrexate and cyclosporine A. Posttransplan- severe chronic neutropenia,16 congenital amega- tation supportive care consisted of total gastrointes- karyocytic thrombocytopenia or thrombocytopenia tinal decontamination in a strict protective (sterile) with absent radii syndrome,11,17,18 or Diamond- environment. Hematologic engraftment failed. On Blackfan anemia.12 the 30th day after BMT, circulatory insufficiency be- The presentation of SDS for our patient was highly came evident during Escherichia coli sepsis. A second unusual. The SBDS gene product is presumed to infusion of donor BM was performed on the 47th function in RNA processing. This function and its day. Thereafter, the patient experienced clinical gas- clinical implications are reminiscent of those of the troenteritis and a systemic adenovirus infection that RMRP gene, which, when defective, causes carti- worsened her condition, with rapidly increasing vi- lage/hair hypoplasia (CHH) and impairs hemato- ral DNA concentrations. She died on the 69th day, as logic and immunologic functions.8,19,20 However, the a result of multiple-organ failure. growth failure in SDS is proportional and differs Sequence analysis showed that the patient was from the disproportional growth in CHH. Moreover, compound heterozygous for 2 common mutations in the exocrine pancreas insufficiency is most typical exon 2 of the SBDS gene (Fig 3). These mutations for SDS, whereas Hirschsprung disease may coincide were previously identified among SDS patients.7 with CHH.2,14 Dyskeratosis congenita (DKC) also is

e390 CONGENITAL APLASTICDownloaded ANEMIA from www.aappublications.org/news IN SDS by guest on September 28, 2021 caused by a defect in RNA processing.21,22 The de- 3. Ginzberg H, Shin J, Ellis L, et al. Shwachman syndrome: phenotypic fective protein, dyskerin, in X-linked DKC is associ- manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr. 1999;135:81–88 ated not only with H/ACA small nucleolar RNA but 4. Barrios NJ, Kirkpatrick DV. Successful cyclosporin A treatment of aplas- also with human telomerase RNA, which was found tic anaemia in Shwachman-Diamond syndrome. Br J Haematol. 1990;74: to be defective in autosomal DKC.23 Telomerase adds 540–541 simple sequence repeats to chromosome ends by 5. Woods WG, Krivit W, Lubin BH, Ramsay NK. Aplastic anemia associated with the Shwachman syndrome: in vivo and in vitro observations. using an internal region of its RNA as a template. Am J Pediatr Hematol Oncol. 1981;3:347–351 Interestingly, shortened telomeres have been demon- 6. Aggett PJ, Cavanagh NPC, Matthew DJ, Pincott JR, Sutcliffe J, Harries strated in the leukocytes of patients with SDS,20,24 JT. Shwachman’s syndrome: a review of 21 cases. Arch Dis Child. 1980; although it remains to be shown whether this results 55:331–347 from defective telomerase activity or hyperprolifera- 7. Mack DR, Forstner GG, Wilchanski M, Freedman MH, Durie PR. Sh- wachman syndrome: exocrine pancreatic dysfunction and variable phe- tion. notypic expression. Gastroenterology. 1996;111:1593–1599 Overt BM failure at birth has never been observed 8. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are in SDS, although aplastic anemia, with transfusion associated with Shwachman-Diamond syndrome. Nat Genet. 2003;33: dependence, has been noted at older ages during 97–101 childhood and adolescence.5,6 In contrast to our case, 9. Koonin EV, Wolf YI, Aravind L. Prediction of the archaeal exosome and its connections with the proteasome and the translation and transcrip- the symptoms of pancreatic insufficiency are sug- tion machineries by a comparative-genomic approach. Genome Res. gested to be most prominent in SDS at the time of 2001;11:240–252 diagnosis and especially during infancy, although 10. Tishkowitz MD, Hodgson SV. Fanconi anemia. J Med Genet. 2003;40: they resolve with time for Ͼ50% of patients.1–3 In our 1–10 11. Hall JG. Thrombocytopenia with absent radius (TAR) syndrome. J Med case, the diagnosis of SDS was finally established at Genet. 1987;24:79–83 the age of 6 months, because of the combined hema- 12. Dianzani I, Garelli E, Ramenghi U. Diamond Blackfan anaemia: an tologic abnormalities, growth failure with metaphy- overview. Paediatr Drugs. 2000;2:345–355 seal dysplasia, mild hepatitis, and fat malabsorption, 13. MacDermot KD, Winter RM, Wigglesworth JS, Strobel S. Short stature/ with undetectable elastase and chymotrypsin in the short limb skeletal dysplasia with severe combined immunodeficiency and bowing of the femora: report of two patients and review. J Med feces. The BM failure reacted marginally to the ad- Genet. 1991;28:10–17 dition of growth factors such as erythropoietin and 14. Ma¨kitie O, Kaitila I. Cartilage-hair hypoplasia: clinical manifestations in G-CSF. 108 Finnish patients. Eur J Pediatr. 1993;152:211–217 Although BMT or hematopoietic stem cell trans- 15. Hong R. Associations of the skeletal and immune systems. Am J Med Genet. 1989;34:55–59 plantation has been attempted for treatment of the 16. Kuijpers TW. Clinical symptoms and neutropenia: the balance of neu- hematologic disturbances of SDS, few survivors have trophil development, functional activity, and cell death. Eur J Pediatr. been reported to date.25–28 Poor outcomes are often 2002;161(suppl 1):S75–S82 related to excessive cardiac and other organ toxicity 17. Ihara K, Ishii E, Eguchi M, et al. Identification of mutations in the c-mpl resulting from the conditioning regimen before gene in congenital amegakaryocytic thrombocytopenia. Proc Natl Acad Sci USA. 1999;96:3132–3136 transplantation and a stromal cell defect that is part 18. Germeshausen M, Ballmaier M, Welte K. Implications of mutations in of the syndrome. hematopoietic growth factor receptor genes in congenital cytopenias. Ann N Y Acad Sci. 2001;938:305–320 CONCLUSIONS 19. Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage- The female patient presented here exhibited con- hair hypoplasia. Cell. 2001;104:195–203 genital aplastic anemia, which was diagnosed after 6 20. Thornley I, Dror Y, Sung L, Wynn RF, Freedman MH. Abnormal telo- months as SDS. The early onset of the hematologic mere shortening in leucocytes of children with Shwachman-Diamond symptoms is unusual for SDS. Transient diabetes syndrome. Br J Haematol. 2002;117:189–192 mellitus in early infancy was described for a single 21. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis con- 29 genita is caused by mutations in a highly conserved gene with putative case of SDS, but our patient experienced transient nucleolar functions. Nat Genet. 1998;19:32–38 hypoglycemia instead. In addition, the patient 22. Yaghmai R, Kimyai-Asadi A, Rostamiani K, et al. Overlap of dyskera- showed extreme proportional dwarfism once the me- tosis congenita with the Hoyeraal-Hreidarsson syndrome. J Pediatr. taphyseal dysplasia became apparent. 2000;136:390–393 Taken together with the findings of Boocock et al,8 23. Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. the common mutations in the present case and our Nature. 2001;413:432–435 analysis of 10 additional SDS cases (T.W. Kuijpers, 24. Dror Y, Ginzberg H, Dalal I, et al. Immune function in patients with M. Alders, and R.C.M. Hennekam, unpublished ob- Shwachman-Diamond syndrome. Br J Haematol. 2001;114:712–717 servations) suggest that a clear genotype-phenotype 25. Maserati E, Minelli A, Olivieri C, et al. Isochromosome (7)(q10) in Shwachman syndrome without MDS/AML and role of chromosome 7 relationship may not exist in SDS. This would be in anomalies in myeloproliferative disorders. Cancer Genet Cytogenet. 2000; agreement with the lack of concordance in hemato- 121:167–171 logic findings among affected siblings and the wide 26. Hsu JW, Vogelsang G, Jones RJ, Brodsky RA. Bone marrow transplan- variability within families.3 tation in Shwachman-Diamond syndrome. Bone Marrow Transplant. 2002;30:255–258 ACKNOWLEDGMENT 27. Cesaro S, Guariso G, Calore E, et al. Successful unrelated bone marrow We are grateful to Clemens Mellink for the cytogenetic testing. transplantation for Shwachman-Diamond syndrome. Bone Marrow Transplant. 2001;27:97–99 28. Fleitz J, Rumelhart S, Goldman F, et al. Successful allogeneic hemato- REFERENCES poietic stem cell transplantation (HSCT) for Shwachman-Diamond syn- 1. Smith OP. Shwachman-Diamond syndrome. Semin Hematol. 2002;39: drome. Bone Marrow Transplant. 2002;29:75–79 95–102 29. Filippi L, Tronchin M, Pezzati M, et al. Shwachman syndrome in a 2. Dror Y, Freedman MH. Shwachman-Diamond syndrome. Br J Haematol. preterm newborn associated with transient diabetes mellitus. J Pediatr 2002;118:701–713 Gastroenterol Nutr. 2002;34:219–223

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Congenital Aplastic Anemia Caused by Mutations in the SBDS Gene: A Rare Presentation of Shwachman-Diamond Syndrome Taco W. Kuijpers, Eline Nannenberg, Marielle Alders, Robbert Bredius and Raoul C. M. Hennekam Pediatrics 2004;114;e387 DOI: 10.1542/peds.2003-0651-F

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