Prenatal Shwachman‐Diamond Syndrome: Diagnostic Challenges in Two Unrelated Cases With a Rare Clinical Presentation and Pseudogene Interference, and a Review of the Literature

This report describes two unrelated prenatal cases of Shwachman-Diamond syndrome (SDS) presenting primarily with severe skeletal anomalies. SDS is a rare autosomal recessive disorder characterized by a triad of bone marrow dysfunction, skeletal abnormalities, and exocrine pancreatic dysfunction. The most common postnatal features include faltering growth, short stature, and neutropenia resulting in recurrent infections. Prenatal presentations could be scarce as the most common features are typically not apparent before birth. Molecular diagnosis of SDS relies on the identification of biallelic loss-of-function pathogenic variants in the SBDS gene. However, molecular genetic analysis is hampered by the presence of a pseudogene (SBDSP1), which can lead to misalignment or gene conversion events. In both reported cases, initial genetic testing was inconclusive. Subsequently, through clinical phenotype reassessment and expanded molecular analysis, the diagnosis of SDS by germline pathogenic SBDS variants (c.258+2T>C p.(?) and c.184A>T p.Lys62Ter) was established. These cases underscore the diagnostic complexity of SDS in prenatal settings and the necessity of comprehensive molecular analysis when facing severe skeletal anomalies suggesting small thoracic skeletal dysplasia and are further supported by an added literature review that expands the prenatal phenotype.