Infantile Osteopetrosis with a CLCN7 Variant: An Educational Case Highlighting Integrated Diagnosis and Variant Interpretation
TL;DR
This report presents an educational case emphasizing the importance of integrated clinical, radiological, and laboratory evaluation, and highlights the challenges in interpreting variants of uncertain significance in clinical practice.
Abstract
Background Infantile osteopetrosis is a rare inherited disorder caused by defective osteoclast-mediated bone resorption, resulting in increased bone density and marrow failure. The CLCN7 gene encodes a chloride channel essential for osteoclast acidification. Case Presentation A 4-month-old male presented with failure to thrive, pallor, hepatosplenomegaly, and recurrent infections. Examination revealed frontal bossing and hypotonia. Laboratory evaluation showed anemia and persistent hypocalcemia (6.8 mg/dL; reference 8.5–10.5 mg/dL). Skeletal survey demonstrated diffuse osteosclerosis with a characteristic “bone-within-bone” appearance. Differential diagnoses, including storage disorders and leukemia, were excluded. Clinical exome sequencing identified a homozygous CLCN7 missense variant, c.613G>A (p.Gly205Arg), classified as a variant of uncertain significance (VUS) based on ACMG/AMP criteria (PM2, PP3). Conclusion Diagnosis in this case was primarily clinico-radiological, with genetic findings providing supportive evidence. This report presents an educational case emphasizing the importance of integrated clinical, radiological, and laboratory evaluation, and highlights the challenges in interpreting variants of uncertain significance in clinical practice.