Late diagnosis of a truncating WISP3 mutation entails a severe phenotype of progressive pseudorheumatoid dysplasia

Abstract

Rare diseases are often misdiagnosed or receive a delayed diagnosis; thus, unfortunately, affected individuals may not receive optimal medical management. Here, we report a case of two siblings with a severe phenotype of progressive pseudorheumatoid dysplasia (PPD). Their onset of symptoms began at the age of 3 yr. Both were neglected in the past, and the patients presented with a very severe phenotype and unmitigated natural history. PPD is a rare autosomal recessive skeletal dysplasia characterized by progressive joint stiffness, swelling, and pain. Because of observed muscle wasting, weakness, and the lack of laboratory testing, the case had been initially misdiagnosed by the local physicians. We aimed to provide diagnostic support by a targeted next-generation sequencing gene panel (Illumina TruSight One) for Mendelian diseases (Mendeliome), and we identified a homozygous frameshift mutation in the gene WISP3 (c.868_869delAG, p.Ser290Leufs*12). Thus, early diagnosis and intervention may have decreased the severity and complication of the disease.

Keywords: joint swelling; progressive joint destruction.

Figure 1.

Clinical photos and radiologic images of the patient. (A) Enlargement of elbows, widening of the thoracic wall, and severe contractures of the fingers are visible. Note that the posture of the patient is altered because of severe joint involvement. (B) X-ray analysis of the whole body. Increased anteroposterior diameter of thoracic wall, platyspondyly, and irregularity of end plates. An anteroposterior radiograph of the hips showed narrowing of joint spaces and mild sclerotic and cystic changes on the acetabulum and the head of the femur. A hand radiograph demonstrated severe enlargement and cystic changes on proximal interphalangeal (PIP), distal interphalangeal (DIP), and metacarpophalangeal (MCP) joints and carpal bones and metaphyseal cupping of the radius and ulna. Foot and ankle radiographs also showed severe enlargement and cystic changes of tarsal and metatarsal joints. A bilateral knee radiograph revealed narrowing of joint spaces and secondary osteoporosis.

Figure 2.

Family pedigree and Sanger sequencing chromatograph. (A) The pedigree of a Yemeni family with PPD showing the consanguinity; the arrow indicates the index case P1. Case P2 underwent exome sequencing. (B) Sanger sequencing chromatograph confirming the mutation detected by Mendeliome (c: 868_869delAG, p.S290Lfs*12). This mutation has been reported in compound heterozygosity with another missense mutation in one Italian family (Garcia Segarra et al. 2012).