Unmasking Mucopolysaccharidosis Type I in a Patient With Wolf-Hirschhorn Syndrome: Diagnostic Overshadowing

Mucopolysaccharidosis Type I (MPS I) is a rare lysosomal storage disorder caused by α-l-iduronidase deficiency, leading to glycosaminoglycan accumulation and multisystem involvement. Wolf-Hirschhorn Syndrome (WHS) is a chromosomal disorder characterized by growth delay, dysmorphism, and developmental impairment. Because the IDUA gene is located within the 4p16.3 region, the coexistence of WHS and MPS I is biologically plausible but rarely documented. We describe a 2-year-old child of North African origin presenting with dysmorphic features, developmental delay, and thoracolumbar kyphosis. Chromosomal microarray analysis identified a 5.8 Mb deletion at 4p16.3-p16.2, confirming WHS at 17 months. However, additional clinical features remained unexplained. Incidentally, during a routine blood test, a blood smear revealed lymphocytes with metachromatic inclusions, raising suspicion of a lysosomal storage disorder. An enzymatic assay confirmed α-l-iduronidase deficiency, and molecular analysis identified biallelic pathogenic alterations in the IDUA gene located on chromosome 4p16.3, establishing the diagnosis of MPS I at 18 months. Enzyme replacement therapy was initiated at 19 months and was associated with stabilization of the somatic manifestations of MPS I, including improvement in respiratory symptoms. This observation highlights the risk of diagnostic overshadowing in rare diseases. A confirmed genetic diagnosis should not preclude further investigations when clinical features are discordant.