Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction, and skeletal abnormalities (1). The frequency of the disease varies between 1:100,000 and 1:200,000, and the male:female ratio is 1.8:1. The most common mutations are 258+2T>C and 183-184TA>CT (2). Serum pancreatic trypsinogen and isoamylase levels are useful markers for evaluating pancreatic insufficiency (3); however, low levels of fecal elastase can be detected in some patients. Neutropenia is the most commonly observed hematologic abnormality in patients with SDS. Patients with SDS have a high risk of developing myelodysplastic syndrome and acute myeloblastic leukemia (4). Patients with SDS generally have skeletal abnormalities that develop after birth and vary with age. The primary skeletal defects are related to abnormal development of the growth plates, particularly the metaphyses. Metaphyseal dysostosis has been reported in roughly 50% of patients with SDS and is commonly found in the femoral head, and the humeral heads, wrists, knees, and ankles may be affected (5). Rib cage abnormalities, including a narrow rib cage, are found in 30% to 50% of patients, and these have been reported to cause respiratory failure in newborns. Furthermore, slipped femoral epiphysis, supernumerary thumbs, syndactyly, clinodactyly, kyphosis, and scoliosis have been reported in patients with SDS (6).
Our patient was the first child of healthy, unrelated parents. She was born at 40 weeks gestation with a birth weight of 2870 g (10th–25th percentile). The patient was admitted to our hospital because of failure to thrive and poor weight gain at her 6-month follow-up. Labor was induced at 20 weeks gestation because of symmetrical fetal growth retardation (5th percentile) and the suspicion of shortening of the upper and lower limbs. Tests for cytomegalovirus, rubella, Toxoplasma, herpes simplex virus IgM-IgG, and VDRL for syphilis were negative; thus, congenital infections were ruled out. No structural or chromosomal abnormalities were detected in the fetal karyotype analysis of amniotic fluid obtained by amniocentesis. The telomere fluorescent in situ hybridization analysis did not detect cryptic translocations or deletions. The results of the molecular genetic analysis for achondroplasia and hypochondroplasia mutations in the FGFR3 gene were negative. At 6 months of age, the patient's height, weight, and head circumference were below the 3rd percentile. On physical examination, the birth length of all extremities was below −2 SDS. Other features were unremarkable on examination. The results of the laboratory tests revealed that γ-glutamyl transferase (178 IU/L), aspartate aminotransferase (242 IU/L), and alanine aminotransferase (286 IU/L) were elevated. Activated partial thromboplastin time, albumin levels, and other serum biochemical parameters were within the normal range. At 6 months of age, the child's blood count was evaluated retrospectively, and intermittent neutropenia was documented. During this period, neutrophil counts were 1800, 900, 2100, and 900 cells/mm3. At the time of referral, the patient's hemoglobin was 12 g/dL, white blood cell count was 9600 cells/mm3, neutrophil count was 920 cells/mm3, and platelet count was 272,000 cells/mm3. Bone marrow aspirate findings showed normoactive erythroid precursors, mild hypogranulation, and dysplastic changes in myeloid precursors. The bone marrow showed normal cellularity, and maturation of the myeloid series ruled out congenital neutropenia. The patient's Hb-F level was normal for her age. When the patient presented with increased fat loss and failure to thrive, the result of the steatocrit was 4.1 (0.74–1.4), the fecal elastase level was <50 μg/g, and the serum trypsinogen level was low (<8.2 μg/L). These results were suggestive of severe pancreatic insufficiency. The chloride sweat test used to diagnose cystic fibrosis was normal on 3 trials, and no significant single-point mutations of the cystic fibrosis gene were detected. The computed tomography (CT) scan detected scattered fatty infiltration of the pancreatic head, corpus, and tail, which is associated with SDS (Fig. 1). CT scan was applied to the patient and it did not reveal any abnormalities in liver (Fig. 2). X-ray imaging revealed a narrow thorax. Although metaphyseal changes on the costochondral junctions were not detected on the spinal x-ray, the metaphyseal dysostosis of the femoral head and distal femur was more remarkable than that of the upper limbs (Figs. 3 and 4). O-bain deformity (genu varum deformity) of the lower extremities was observed (Fig. 4). Metaphyseal irregularity was found on the proximal humerus, distal radius, and ulna (Fig. 5). Bone age was determined to be 0 years, and delayed ossification of the carpals and metacarpals was observed. The vitamin D level was normal (90.4 μg/L). DNA sequence analysis of the SBDS gene, the causative gene for SDS, revealed compound heterozygosity for c. 258+2T>C and c. 183–184TA>CT, the 2 most common mutations responsible for SDS, thus confirming the diagnosis of SDS.
Our patient's pancreas and bone marrow disorders and associated anomalies developed in week 20 of intrauterine life. Skeletal abnormalities in patients with SDS vary with age and may be detected later in life. The most common deformity is abnormal development of the metaphyseal growth plates (7). Makitie et al (6) reported that skeletal deformities developed within the first 2 years of life in patients with SDS. In our case, shortness of the upper and lower extremities and metaphyseal disorders were detected prenatally, and genetic analysis of the fetal amniotic fluid revealed no achondroplasia or hypochondroplasia mutations.
The patient developed diarrhea at 6 months of age and was referred to our hospital for failure to thrive at the age of 9 months. We examined the patient's skeletal abnormalities, and the x-ray examination revealed metaphyseal dysostosis of the femoral head and distal femur, proximal humerus, and distal radius and ulna. Delayed ossification of the carpals and metacarpals was observed. Skeletal deformity was not detected on x-ray images of the skull, spine, thoracic cage, proximal and distal tibia, or metatarsal bones. After confirmation of the SDS diagnosis, review of patient's intrauterine imaging revealed abnormalities of the femoral head and proximal humerus.
In contrast to previous observations, our findings suggest that the skeletal changes characteristic of SDS can be present in the intrauterine period of life. Our findings suggest that SDS should be considered as a potential cause of prenatally diagnosed bone disorders such as achondroplasia and hypochondroplasia.
1. Boocock GR, Morrison JA, Popovic M, et al. Mutation in SBDS are associated with Shwachman–Diamond syndrome. Nat Genet
2. Goobie S, Popovic M, Morrison J, et al. Shwachman–Diamond syndrome with exocrine pancreatic dysfunction and bone marrow failure maps to the centromeric region of chromosome 7. Am J Hum Genet
3. Ip WF, Dupuis A, Ellis L, et al. Serum pancreatic enzymes define the pancreatic phenotype in patients with Shwachman–Diamond syndrome. J Pediatr
4. Dokal I, Rule S, Chen F, et al. Adult onset of acute myeloid leukaemia (M6) in patients with Shwachman–Diamond syndrome. Br J Haematol
5. Aggett PJ, Cavanagh NPC, Matthew DJ, et al. Shwachman's syndrome. A review of 21 cases. Arch Dis Child
6. Makitie O, Ellis L, Durie PR, et al. Skeletal phenotype in patients with Shwachman–Diamond syndrome and mutations in SBDS. Clin Genet
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7. 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. J Pediatr