Beyond osteopoikilosis: a blended skeletal dysplasia associated with dual LEMD3 and ANO5 variants

Abstract

Abstract Osteopoikilosis is a rare autosomal dominant sclerosing bone dysplasia caused by pathogenic variants in LEMD3, which is typically asymptomatic and incidentally detected on radiographs. Gnathodiaphyseal dysplasia is an extremely rare skeletal disorder characterized by diaphyseal sclerosis, bone fragility, and pathological fractures. The coexistence of 2 genetically distinct skeletal dysplasias in a single individual is exceptionally uncommon. A 15-year-old female presented with progressive gait disturbance and a right hip intertrochanteric fragility fracture. Radiological evaluation demonstrated widespread mixed sclerotic and geographic lytic lesions with predominant involvement of the appendicular skeleton. Serum 25-hydroxyvitamin D was reduced with secondary hyperparathyroidism, whereas the calcium–phosphate profile was normal. Bone biopsy revealed a fibro-osseous lesion. Clinical exome sequencing identified a heterozygous pathogenic nonsense variant in LEMD3, consistent with osteopoikilosis, and a heterozygous likely pathogenic missense variant in ANO5, associated with gnathodiaphyseal dysplasia. This case describes a rare blended skeletal phenotype associated with coexisting LEMD3 and ANO5 variants, presenting with osteopoikilosis, bone fragility, fibro-osseous histopathology, and mixed lytic–sclerotic skeletal lesions. The phenotype could not be fully explained by either disorder alone, highlighting the complexity of dual molecular diagnoses and the importance of comprehensive genetic evaluation in patients with unexplained skeletal lesions and pathological fractures