Two unrelated cases of prenatal Shwachman-Diamond syndrome: a diagnosis complicated by a rare clinical presentation and a pseudogene

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by a triad of bone marrow dysfunction, skeletal abnormalities, and exocrine pancreatic dysfunction. The most common features in affected children are failure to thrive, short stature, and neutropenia resulting in recurrent infections. SDS poses several diagnostic challenges, especially during fetal life. First, not all features are seen during pregnancy, e.g. pancreatic dysfunction. As a result, prenatal and postnatal phenotypes may be different, and prenatal reports are scarce. Second, if patients present with severe skeletal features (a bell-shaped or long narrow thorax) during fetal life, the first suspected diagnosis is asphyxiating thoracic dystrophy (e.g. Jeune syndrome). Third, the molecular diagnosis is made by diagnosing biallelic loss-of-function pathogenic variants in the SBDS gene but molecular genetic analysis is hampered by the presence of a pseudogene (SBDSP1). These two genes are located in proximity on chromosome 7, and both mismapping and conversion events between the 2 loci resulting in a true mutation have been described.
We report two unrelated prenatal cases of SDS, presenting as a rare clinical presentation of asphyxiating thoracic dystrophy, where initial clinical molecular testing did not reveal the diagnosis. Further molecular testing after a multidisciplinary reassessment was able to reveal the diagnosis of SDS by germline biallelic pathogenic SBDS variants (c.258+2T>C p.(?) and c.184A>T p.Lys62Ter).