Hua Wang M.D., Ph.D, Subhadra Ramanathan M.S., Faith Hamamura M.D, PGY-2, Robin Clark M.D 

Case History: 

This is a 16-day-old male born at 36w4d via repeat C-section to a 38-year-old G9P3 mother. Prenatal history was significant for polyhydramnios, maternal UDS positive for marijuana use, and concern for cigarette smoking. Mother has a history of 4 spontaneous abortions and 2 ectopic pregnancies. GBS status was unknown. Prenatal labs were otherwise unremarkable. He was admitted to the referring hospital for one day and required CPAP due to acute respiratory distress and concern for cardiomegaly with a Grade III-IV murmur. Initial echocardiogram revealed a small patent ductus arteriosus, moderate to severe elevation of pulmonary pressures, mild dilatation of the right ventricle, and mild hypertrophy of the right ventricle that later resolved on repeat echocardiogram. Chest x-ray findings were significant for a small thoracic cage concerning for asphyxiating thoracic dystrophy. Genetics consultation was requested. 

Genetic Evaluation: 

The initial differential diagnoses included 1) Kagami-Ogata syndrome; 2) Asphyxiating thoracic dystrophy, or Jeune syndrome 3) Chromosome abnormality. 

Chromosome microarray analysis was normal, and a skeletal dysplasia gene panel was non-diagnostic. The patient was readmitted three months later due to 3 episodes of seizure-like activities. Genetics was again consulted. This time, uniparental disomy 14 testing was completed to evaluate for Kagami-Ogata syndrome and was negative. Trio Whole Exome Sequencing (WES) was then recommended. 

At five months of age, he failed to thrive and was being assessed for G-tube placement. 

Whole exome sequencing (WES) revealed that the patient has two different pathogenic variants (mutations), one on each copy of the SBDS gene (see Figure 4). The maternally inherited variant c.258+2T>C is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individuals with Shwachman-Diamond Syndrome. The paternally-inherited variant, c.183_184delinsCT, is predicted to result in premature protein termination (p.Lys62*). This variant has been reported in many patients with Shwachman-Diamond Syndrome when found with another pathogenic variant. Currently, in ClinVar, 11 pathogenic and 11 likely pathogenic variants are curated. 

Whole Exome Sequencing Result 

Discussion: 

SDS clinical presentations: 

SDS is a rare autosomal recessive, multisystem disease. SDS presents with exocrine pancreatic insufficiency, impaired hematopoiesis, and a predisposition for the development of leukemia. Skeletal, immunologic, hepatic, and cardiac disorders have been described. (1) 

Neutropenia is the most common hematologic abnormality affecting 88–100% of patients with SDS. Anemia has also been described in 42%–82% of patients. Thrombocytopenia has been reported in 24%–88% of patients. Patients with SDS have an increased risk for myelodysplasia and malignant transformation, particularly the development of acute myelogenous leukemia. Patients with SDS are susceptible to recurrent bacterial, viral, and fungal infections. Neutropenia is likely a contributing factor. SDS can present with exocrine pancreatic dysfunction of varying severities. This dysfunction is caused by the absence of acinar cells in early infancy leading to malabsorption, steatorrhea, failure to thrive, and low levels of fat-soluble vitamins A, D, E, and K. Patients with SDS have normal sweat chloride tests. This feature distinguishes them from patients with cystic fibrosis whose pancreatic defect involves the exocrine pancreatic ducts. Several case reports have described SDS associated with neonatal cardiac issues. (2, 3) 

The Skeletal Phenotype in Patients with SDS 

While pancreatic exocrine and bone marrow dysfunctions are considered universal features of SDS, the associated skeletal dysplasia is variable and not consistently observed. (4) The primary skeletal defect is abnormal growth plate development. The metaphyses are profoundly affected. Metaphyseal dysostosis has been reported in roughly 50% of the patients, is usually asymptomatic, and most commonly involves the femoral head. (5, 6) The knees, humeral heads, wrists, ankles, and vertebrae may also be affected. Rib-cage abnormalities are found in 30%–50% of patients, including narrow rib cage, shortened ribs with flared anterior ends, and costochondral thickening. Case reports have described respiratory failure in newborns due to these rib cage abnormalities. (2) 

Neonatal SDS 

While the diagnosis of SDS has classically relied on exocrine pancreatic dysfunction and bone marrow failure, a publication based on the North American SDS Registry reported that almost half of 37 individuals with genetically confirmed SDS did not have this classic combination of manifestations 

The typical clinical, laboratory, and imaging features of SDS are often lacking in the first months of life, which may delay diagnosis. (7) A few cases of SDS presentation and molecular diagnosis have been documented in the first months of life (8, 9) and misdiagnosed as asphyxiating thoracic dystrophy. (9) Our case presented with prominent skeletal phenotype with an X-ray image suggesting asphyxiating thoracic dystrophy. After the diagnosis was made, almost one year after the initial genetics consult, the laboratory workup showed he had moderate pancreatic insufficiency with low pancreatic elastase. He is on supplemental pancreatic lipase (Creon), started by peds GI right after diagnosis, and has no hematological abnormalities. 

Practical Applications 

1. Shwachman–Diamond syndrome (SDS, MIM 260400) is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, skeletal abnormalities, short stature, and a variety of other less common features. 
2. Pancreatic exocrine and bone marrow dysfunctions are considered universal features of Shwachman–Diamond syndrome (SDS), whereas the associated skeletal dysplasia is variable and not consistently observed. 
3. In addition to the pancreatic and bone marrow insufficiency, the skeletal manifestations should be considered an integral diagnostic feature of the syndrome and carefully assessed with a complete skeletal survey at presentation. 
4. The typical clinical, laboratory, and imaging features of SDS are often lacking in the first months of life, which may delay diagnosis. 
5. Skeletal dysplasia mimicking asphyxiating thoracic dystrophy with respiratory failure could be the major presentation in an infant with SDS. 
6. Whole exome sequencing is a powerful tool for the early diagnosis of SDS for atypical presentations essential for the neonate. 

References: 

1. Burroughs, L., Woolfrey, A., & Shimamura, A. (2009). Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am, 23(2), 233-248. doi:10.1016/j.hoc.2009.01.007 
2. Graham, A. R., Walson, P. D., Paplanus, S. H., & Payne, C. M. (1980). Testicular fibrosis and cardiomegaly in Shwachman’s syndrome. Arch Pathol Lab Med, 104(5), 242-244.
3. Savilahti, E., & Rapola, J. (1984). Frequent myocardial lesions in Shwachman’s syndrome. Eight fatal cases among 16 Finnish patients. Acta Paediatr Scand, 73(5), 642-651. doi:10.1111/j.1651-2227.1984.tb09989.x
4. Mäkitie, O., Ellis, L., Durie, P. R., Morrison, J. A., Sochett, E. B., Rommens, J. M., & Cole, W. G. (2004). Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS. Clin Genet, 65(2), 101- 112. doi:10.1111/j.0009-9163.2004.00198.x
5. Aggett, P. J., Cavanagh, N. P., Matthew, D. J., Pincott, J. R., Sutcliffe, J., & Harries, J. T. (1980). Shwachman’s syndrome. A review of 21 cases. Arch Dis Child, 55(5), 331-347. doi:10.1136/adc.55.5.331
6. Ginzberg, H., Shin, J., Ellis, L., Morrison, J., Ip, W., Dror, Y., . . . Durie, P. R. (1999). Shwachman syndrome: phenotypic manifestations of sibling sets and isolated cases in a large patient cohort are similar. J Pediatr, 135(1), 81- 88. doi:10.1016/s0022-3476(99)70332-x
7. Marsico, C., Scozzarella, A., Capretti, M. G., Carfagnini, F., Facchini, E., Arcuri, S., & Aceti, A. (2022). Atypical Findings of Shwachman-Diamond Syndrome in Early Infancy: A Diagnostic Challenge. JPGN Reports, 3(1), e165. doi:10.1097/pg9.0000000000000165
8. Saito-Benz, M., Miller, H. E., & Berry, M. J. (2015). Shwachman-Diamond syndrome (SDS) in a preterm neonate. J Paediatr Child Health, 51(12), 1228-1231. doi:10.1111/jpc.12941
9. Schaballie, H., Renard, M., Vermylen, C., Scheers, I., Revencu, N., Regal, L., . . . Meyts, I. (2013). Misdiagnosis as asphyxiating thoracic dystrophy and CMV-associated haemophagocytic lymphohistiocytosis in Shwachman- Diamond syndrome. Eur J Pediatr, 172(5), 613-622. doi:10.1007/s00431-012-1908-0

Disclosures: The authors have no disclosures