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, hematol- ogy, genotype, congenital, bone marrow transplantation. normalities, including metaphyseal dysostosis and epiphyseal dysplasia, has been found to be associ- ated 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. 11425, 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