Severe Phenotype in an Indian Family With Progressive Pseudorheumatoid Arthropathy of Childhood.

Progressive pseudorheumatoid arthropathy of childhood (PPAC) is a rare autosomal recessive progressive condition that affects the cartilage of joints and bones. The symptoms of PPAC include stiffness of the joints, bony swelling of the toes and fingers, short stature, kyphosis, and muscle weakness. The radiologic manifestations are often mistaken for juvenile rheumatoid arthritis and include platyspondyly, widened metaphyses, flattened epiphyses, and large femoral heads. The disease is caused by variants in the WISP3 (also known as CCN6) gene, which encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. We describe three affected female siblings in an Indian family with PPAC, all of whom manifest a severe phenotype of the disease. The girls all walked with a crouching gait from severe joint contractures. Radiographic findings included generalized periarticular osteopenia and widened metaphyses. The radiographs of the hands and feet showed similar changes with narrow joint spaces, widened metaphyses, and flattened epiphyses. Elbows and knees revealed gracile bones, and contractures with severe muscle atrophy. Spine films were significant for marked beaking, lumbar vertebrae anterior narrowing, irregular end plates and rotational scoliosis. X-rays of the hips revealed deformed femurs, coxa vara, and large flat epiphyses. All affected individuals were compound heterozygotes for two pathogenic variants in the WISP3/CCN6 gene, a novel nonsense variant (c.172A>T [p.Lys58*]) and a 2-base pair deletion (c.740_741delGT [p.Cys247Leufs*31]). This combination of a nonsense and frameshift variant has not previously been reported and may be the explanation for the severe clinical manifestation of PPAC in this family. Further investigation into the mechanism of the disease may provide promising therapies to modify disease progression.