Progressive pseudorheumatoid dysplasia confirmed by whole-exon sequencing in a Chinese adult before corrective surgery

Progressive pseudorheumatoid dysplasia (PPD) is an autosomal recessive disease characterized by spondyloepiphyseal dysplasia associated with progressive joint deformities, pain, stiffness, and swelling mainly in the spine and hip joints [1]. PPD is caused by mutation in the Wnt1-inducible signaling pathway protein 3 (WISP3) gene, which consists of five exons and encodes a 354 amino acid protein [2]. WISP3 belongs to the connective tissue growth factor (CCN) gene family, and the encoded protein plays an essential role in skeletal growth and cartilage homeostasis [3]. This disease is usually misdiagnosed as juvenile idiopathic arthritis or juvenile rheumatoid arthritis (JRA), and patients can receive many years of unnecessary treatment before correct diagnosis [4].

Whole-exon sequencing (WES) is useful for identifying rare monogenic inherited diseases [5], and the reducing cost of WES has improved the feasibility of its clinical use [6]. In this study, we employed WES to explore the potential causative genes in a Chinese PPD patient who underwent spinal surgical treatment twice.

At the first admittance to our hospital, the diagnosis of the proband was not clear. Mucolipidosis type IV was suspected according to clinical presentations. Both physical examination and imaging indicated lumbar canal stenosis at that time, so we performed decompressive laminectomy and posterior-lateral fusion from L2 to S1. A pedicle screw internal fixation system was used (Synthes GmbH, USS II, Switzerland Inc.; Fig. 5), but the left pedicle of L5 was maldeveloped making it impossible to implant a screw (Fig. 3). Hypertrophic ligamentum flavum and herniated discs from L2 to S1 were confirmed during the surgery. The herniated discs of L4–5 and L5–S1 were ossified which caused cauda equina compression (Fig. 3). The dura at the L5–S1 level was hypertrophic and rigid. After the operation, leg pain was decreased and the VAS score was decreased to 1 without any surgical complications. With the help of rehabilitation training, the proband regained the ability to walk with the help of crutches. Bony fusion of the facet joints from L2 to S1 was achieved in the follow-up (Fig. 5).

Five years after the surgery, the patient began to feel stiffness and weakness of the lower extremities. His symptoms progressed for several months, and he lost ambulatory ability again. Physical examination revealed positive Babinski sign, hypesthesia below the xiphoid level, hypermyotonia, and extensive muscle weaknesses of the lower extremities. Magnetic resonance imaging showed extensive canal stenosis from T2 to L2 (Fig. 6). Kyphosis of the middle thoracic spine increased compression of the spinal cord, and Frankel classification was grade B. The proband underwent surgery again, during which decompressive laminectomy from T2 to L2 was performed and kyphosis correction was achieved by resecting the facet joints with circumferential decompression at the T5–6 level. We also removed the L2 pedicle screws and connected the segmental instrumentation (Synthes GmbH, USS II, Switzerland Inc.) with the previous internal fixation. Zonesthesia and hypermyotonia of the lower extremities improved postoperatively, but muscle weakness did not improve. At the latest follow-up, 1 year after the second surgery, the Frankel classification was still grade B.

Before the second surgery, WES was performed and a conclusive diagnosis of PPD was developed. WES covered 99.8% of target regions with a mean depth of on-target reads of × 105. A total of 44,397 raw variant calls were detected, and after removing variants with low quality (see the “Methods” section), 39,924 remained. Using the 1000 Genomes and ExAc databases, 1486 were selected as rare variants, 79.0% of which were excluded as known SNPs. Also excluded were 140 synonymous variants, while 71 benign or neutral variants were filtered out by PolyPhen-2 and SIFT. One rare variant (c.395G>A/p.C132Y) located in exon 3 of WISP3 was identified as associated with skeletal dysplasia. Sanger sequencing confirmed this homozygous mutation co-segregated with affected family members (Fig. 4). This mutation resulted in the substitution of a cysteine with a tyrosine at position 132 and was predicted by Polyphen-2 as probably damaging with a score of 1.0 and damaging by SIFT with a score of 0. As shown in Fig. 4, this amino acid change affected a highly conserved residue.

PPD is a rare autosomal recessive disease, with an estimated population incidence in the UK of one per million [1]. In this study, we presented a family showing PPD and a patient undergoing spinal surgery twice. WES identified a missense mutation in WISP3, enabling a definitive diagnosis. We believe that this is the first presentation of a PPD patient receiving spinal surgery twice.

Patients with PPD are asymptomatic after birth and during early childhood, with symptoms often appearing between the age of 4 and 6 years [7, 8]. Because PPD patients are asymptomatic in the first years of life, the disease is usually misdiagnosed as mucolipidosis type IV and juvenile rheumatoid arthritis [9]. The typical clinical manifestations and radiographic findings in PPD include progressive deformities, pain, stiffness, and swelling of multiple joints, notably in the wrists, fingers, hips, and knees, with the absence of destructive bone changes [7]. To date, there is still no radical treatment for PPD and surgical treatment can be performed in individuals who might benefit. In our patient, the hypogenetic spine presented coin-like flat vertebral bodies, short pedicles, and kyphosis. These deformities resulted in developmental spinal canal stenosis. The degenerative changes, such as disc herniation and hypertrophic ligamentum flavum, worsened the spinal canal stenosis and gradually led to clinical symptoms. Spinal surgery aiming to decompress the spinal canal was inevitable if non-surgical intervention failed. Our patient also had developmental spinal canal stenosis and conspicuous spinal symptoms. He underwent lumbar spine and thoracic spine surgery successively. Available reports on the treatment for PPD focus more on hip joint replacement surgery, and this is the first reported sequential lumbar and thoracic spinal surgery. Meanwhile, vertebral body deformities, maldevelopment of the pedicles and segmental kyphosis, increased the difficulty of the spinal surgery. We noticed that muscle weakness did not improve after the second surgery, indicating the importance of early diagnosis and rehabilitation intervention.

WISP3 belongs to the CCN family, which encodes multimodular mosaic proteins. To date, 51 mutations have been identified in WISP3, including missense, nonsense, frameshift, and exon-deletion mutations (the Human Gene Mutation Database (HGMD)), indicating that loss of WISP3 function leads to PPD. Our study is consistent with another report of a Chinese patient with a similar phenotype and a WISP3 p.C132Y mutation [10], which indicates this variant as a mutation hotpoint in the Chinese population. WISP3 functions in the synthesis of chondrocyte saccharin and collagen type II [11], which are the major components of cartilaginous tissue. The loss of WISP3 function can result in cartilage lesion.

WES enabled us to conclusively diagnose PPD in this patient and may provide wider clinical use in this field. With its decreasing cost, WES is increasingly used for diagnostic purposes in the clinical setting with a 25.2% diagnosis rate in a consecutive patient cohort [5]. With appropriate data filtering and pedigree mapping, WES can help develop diagnoses, especially in rare Mendelian diseases like PPD, which will help prevent the administration of unnecessary treatments [12]. Our study further verified the value of WES in the diagnosis of PPD. With the diagnosis of PPD, we were able to develop proper surgical strategy and anticipate complexity of surgery before the second procedure. Due to coin-like flat vertebral bodies of PPD, precisely applying pedicle screw should be pre-designed before surgery [13]. And since developmental spinal canal stenosis was induced by short pedicles in PPD, associated cervical, thoracic, and lumbar neurological symptoms may deteriorate over time with degenerative changes. As a result, spinal decompression range should be decided not only on the radiological imaging, but also on clinical manifestations. Favorable prognosis in PPD patients was also composed by patient education in early intervention of myelopathy and anti-osteoporosis medications.

In conclusion, our study describes a PPD patient who underwent spinal surgery twice. Meanwhile, WES was used efficiently to identify causative mutations in PPD, thus informing a definitive diagnosis and enabling individualized surgical strategy.