A 14-month-old boy presents with progressive developmental delay, coarse facial features, hepatosplenomegaly, and a thoracolumbar gibbus deformity. Audiometry reveals the pattern marked **B** in the diagram. Which of the following biochemical defects best explains both the hearing loss pattern and the systemic manifestations in this child?
A. Deficiency of iduronate-2-sulfatase (IDS) with X-linked inheritance and clear corneas
B. Deficiency of acid α-glucosidase with glycogen accumulation and normal lysosomal GAG storage
C. Deficiency of α-L-iduronidase (IDUA) with lysosomal accumulation of dermatan sulfate and heparan sulfate
D. Deficiency of galactocerebrosidase with demyelination and normal skeletal features
Explanation
Why option 0 is right
The pattern marked B — bilateral mixed hearing loss in the context of Hurler syndrome — is pathognomonic for MPS I-H. The mixed hearing loss (conductive + sensorineural) results from two mechanisms: (1) chronic serous otitis media and eustachian tube dysfunction from GAG deposition in middle ear structures (conductive component), and (2) direct cochlear involvement from lysosomal accumulation of glycosaminoglycans (sensorineural component). The biochemical defect is deficiency of α-L-iduronidase (IDUA), an autosomal recessive lysosomal enzyme encoded on chromosome 4p16.3, which normally degrades dermatan sulfate and heparan sulfate. When IDUA is deficient, these GAGs accumulate in lysosomes throughout the body — including the middle ear, cochlea, heart, skeleton, and CNS — causing the constellation of features: coarse facies, hepatosplenomegaly, gibbus deformity, corneal clouding, cardiac valve thickening, and progressive neurocognitive decline. This is the defining biochemical lesion of Hurler syndrome (Nelson Pediatrics 22e; Robbins 10e Ch 5).
Why each distractor is wrong
Option 1 (iduronate-2-sulfatase deficiency): This enzyme defect causes Hunter syndrome (MPS II), which is X-linked recessive, NOT autosomal recessive. Critically, Hunter syndrome presents with clear corneas (no corneal clouding), distinguishing it from Hurler. Hearing loss in Hunter is typically conductive only, not mixed. The clinical presentation in this case — with corneal involvement implied by the systemic severity and the mixed hearing loss pattern — is Hurler, not Hunter.
Option 2 (galactocerebrosidase deficiency): This causes Krabbe disease (globoid cell leukodystrophy), a lysosomal lipid storage disorder affecting myelin, not a mucopolysaccharidosis. Skeletal features (gibbus, dysostosis multiplex) are normal in Krabbe disease. Hearing loss is not a hallmark feature. The radiographic and skeletal findings in this case are incompatible with Krabbe.
Option 3 (acid α-glucosidase deficiency): This causes Pompe disease (glycogen storage disease type II), characterized by glycogen accumulation in muscle and heart, not GAG accumulation. Skeletal dysostosis, coarse facies, and mixed hearing loss are not features of Pompe disease. The clinical picture — especially the gibbus deformity and dysostosis multiplex — excludes this diagnosis.
High-YieldNEET PG
Hurler syndrome = IDUA deficiency → bilateral MIXED hearing loss (conductive + sensorineural) + corneal clouding + gibbus + cardiac valve disease + rapid neurocognitive decline. HSCT before age 2 is standard of care.
Nelson Pediatrics 22e; Robbins 10e Ch 5
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