Clinical characteristics.

Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement in the absence of inflammation. Onset – typically between ages three and six years – begins with the involvement of the interphalangeal joints. Over time, involvement of large joints and the spine causes significant joint contractures, gait disturbance, and scoliosis and/or kyphosis, resulting in abnormal posture and significant morbidity. Despite the considerable arthropathy, pain is not a major presenting feature of this condition. Initially height is normal; however, short stature (<3rd centile) becomes evident in adolescence as the skeletal changes progress.

Diagnosis/testing.

The diagnosis of PPD is established in a proband with characteristic radiographic features and/or identification of biallelic pathogenic variants in CCN6 (formerly WISP3) on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is supportive. Pain due to secondary osteoarthritis may respond to nonsteroidal anti-inflammatory drugs. Severe joint pain due to advanced osteoarthritis is treated by joint arthroplasty. Large joint stiffness is managed by physical therapy, activity modification, and walking aids. Small joint arthropathy is managed by an occupational therapist who may advise adaptive devices, modification of activity, and/or vocational training. Scoliosis and mild kyphosis may be treated with bracing. Surgical treatment for angular deformities of the lower limbs as per orthopedic surgeon.

Surveillance: Monitoring for orthopedic complications including bone deformity, secondary joint disease, spinal deformities, and pain. Annual evaluation by specialist(s) in skeletal dysplasia.

Agents/circumstances to avoid: Immobilization (e.g., casting).

Pregnancy management: Deformities of the pelvis may necessitate delivery by cæsarean section.

Genetic counseling.

PPD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CCN6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both CCN6 pathogenic variants have been identified in an affected family member.

Suggestive Findings

PPD should be suspected in individuals with the following clinical, laboratory, and radiologic features.

Clinical features

• Healthy at birth
• Onset of arthropathy early in childhood, usually between ages three and six years
• Enlargement of interphalangeal joints of hands (Figure 1)
• Progressive restricted mobility of all joints
• Gait abnormalities
• Genu valgum / genu varum
• Progressive hip disease (commonly coxa vara at the late stage)
• Articular pain
• Motor weakness and fatigability
• Spine involvement in late childhood and adolescence with thoracolumbar kyphoscoliosis that leads to short trunk
• Adult height below the third centile
• Absence of signs of inflammation

Figure 1.

Hands of individuals showing progressive swelling and limited range of movement of the interphalangeal joints A. Age 5 years

Laboratory features include normal erythrocyte sedimentation rate and C-reactive protein levels.

Radiologic features include spondyloepiphyseal dysplasia, generalized arthropathy, distinctive joint deformity of the hands (superficially resembling that of juvenile idiopathic arthritis), and diffuse osteoporosis at the late stage.

• Hands show enlarged epiphyses, widened metaphyses, and loss of or narrow joint spaces in the metacarpophalangeal and interphalangeal joints, particularly in the proximal interphalangeal joints (Figure 2) [Dalal et al 2012]. Camptodactyly is always present in adulthood.
• Pelvis. Hips show enlarged and flattened capital femoral epiphyses and short and wide femoral necks (Figure 3) [Dalal et al 2012, Garcia Segarra et al 2012]. Broadened ilia and irregular acetabular roofs are observed (Figure 3).
• Spine. Progressive irregularities in the ossification of vertebral endplates and platyspondyly with loss or narrowing of intervertebral disc spaces are observed in all (Figure 4). Anterior beaking of the vertebral bodies is seen in preadolescents [Garcia Segarra et al 2012].
• Shoulders and knees. Osteophytic formations and periarticular calcifications can be seen.

Figure 2.

Radiographs of hands showing large epiphyses and widened metaphyses of metacarpals and phalanges. Joint space is also reduced. A. Age 5 years

Figure 3.

Pelvic radiographs demonstrating reduced hip joint spaces, large capital femoral epiphyses, short and broad femoral necks, and irregular acetabular roofs. Iliac crests are also irregular in adolescence. A. Age 5 years

Figure 4.

Progressive platyspondyly due to erosion of the superior and inferior articular cartilages A. Age 5 years

Establishing the Diagnosis

The diagnosis of PPD can be established in a proband with characteristic radiographic features (see Suggestive Findings) and/or biallelic pathogenic variants in CCN6 (formerly WISP3) identified on molecular genetic testing (Table 1).

Note: Identification of biallelic CCN6 variants of uncertain significance (or identification of one known CCN6 pathogenic variant and one CCN6 variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of PPD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement, and the absence of signs of inflammation [Dalal et al 2012]. Progression of the disease severely affects gait and posture and causes significant morbidity.

PPD does not have any extraskeletal manifestations, such as craniofacial features or cognitive involvement.

To date, approximately 215 families with members affected with PPD have been identified with biallelic pathogenic variants in CCN6 [Dalal et al 2012, Garcia Segarra et al 2012, Bhavani et al 2015]. The following description of the phenotypic features associated with this condition is based on these reports.

Onset. Children with PPD are normal at birth and during infancy. Onset is typically between ages three and six years [Wynne-Davies et al 1982, Garcia Segarra et al 2012]; the range of onset age is from one year to 16 years [Delague et al 2005, Dalal et al 2012].

Initial presenting features in the majority are interphalangeal joint swelling, pain, and gait abnormalities. Joint deformities become manifest over time. Joint pain is rarely the presenting symptom and is disproportionately mild compared to the severity of arthropathy.

Joints. Enlargement, stiffness, and restricted range of movement in the hands start in the proximal interphalangeal joints and progress to the distal interphalangeal joints (Figure 1) [Garcia Segarra et al 2012]. These joints develop progressive contractures.

The joint enlargement, stiffness, and restricted range of movement gradually involve all large joints (e.g., knees, hips, wrists, and elbows) [Dalal et al 2012, Garcia Segarra et al 2012]. Hip involvement commonly manifests as coxa vara later in the disease course. The knees show either genu varum or genu valgum. Typically, the shoulder joints are not severely affected [Dalal et al 2012].

Spine. Scoliosis and/or kyphosis are noted in a majority of affected individuals during adolescence. Lordosis may also be seen. The neck is only occasionally involved [Dalal et al 2012].

Height. Height is initially normal; however, short stature becomes evident in some individuals as the skeletal changes progress. Adult height is typically below the third centile [Garcia Segarra et al 2012]. Flexion deformities at the hips and knees as well as spinal changes contribute in part to the short stature.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Mild variation in age of onset, severity, and progression noted in different families is not explained by the type of pathogenic variants or their locations.

Intrafamilial variation has been observed [Bhavani et al 2015].

Nomenclature

The name "progressive pseudorheumatoid dysplasia" reflects its resemblance to juvenile rheumatoid arthritis.

PPD was previously referred to as "spondyloepiphyseal dysplasia with progressive arthropathy" or "progressive pseudorheumatoid chondrodysplasia."

Prevalence

The prevalence of PPD has been estimated at one per million in the United Kingdom (prevalence category of <1-9:1,000,000) [Wynne-Davies et al 1982]. However, the disease may be underdiagnosed due to the overlap of clinical features with juvenile idiopathic arthritis. To date more than 215 families with molecularly confirmed PPD have been reported.

PPD is more frequent in communities with a high rate of consanguinity [Delague et al 2005, Dalal et al 2012]. The largest series has been published from India [Dalal et al 2012, Bhavani et al 2015].

PPD has also been observed among populations with a high rate of consanguinity in Kuwait, Lebanon, Iran, Jordan, Saudi Arabia, Syria, Palestine, and Morocco.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with progressive pseudorheumatoid dysplasia (PPD), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment is supportive. No specific therapy for PPD is available.

Surveillance

No specific guidelines for surveillance have been published.

Agents/Circumstances to Avoid

Avoid immobilization (e.g., casting).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Deformities of pelvis may necessitate delivery by cæsarean section in pregnant women who have PPD.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Progressive pseudorheumatoid dysplasia (PPD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one CCN6 [WISP3] pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CCN6 pathogenic variant and to allow reliable recurrence risk assessment. (In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred de novo in the proband or (2) uniparental isodisomy and consequent homozygosity for the pathogenic variant transmitted by a heterozygous parent [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CCN6 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Mild-to-moderate intrafamilial clinical variability may be observed in sibs who inherit biallelic CCN6 pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with PPD are obligate heterozygotes for a pathogenic variant in CCN6.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a CCN6 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the CCN6 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the CCN6 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for PPD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CCN6 encodes Wnt1 inducible signaling pathway protein 3 (WISP-3) (also called cellular communication network factor 6). WISP-3 comprises five functional domains: peptide signal sequence, insulin-like growth factor binding proteins (IGF-BP) like domain, von Willebrand factor type C (VWC) repeat domain, thrombospondin type I domain, and cysteine knot domain [Hurvitz et al 1999]. WISP-3 is a member of the CCN (connective tissue growth factor/cysteine-rich61/nephroblastoma overexpressed) family of growth factors [Pennica et al 1998]. WISP-3 regulates type II collagen and aggrecan expression by the activation of SOX9 transcription factors [Sen et al 2004] and plays a major role in cartilage homeostasis by inhibiting cell proliferation and promoting precursor cell differentiation of chondrocytes [Wang et al 2013].

Mechanism of disease causation. The pathophysiology of CCN6 variants resulting in PPD is not completely understood. However, studies show that WISP-3 expression is significantly reduced in the chondrocytes of individuals with PPD [Zhou et al 2007]. Mutated articular chondrocytes with very low levels of WISP-3 expression show an increased rate of proliferation, increased cell viability, and decreased apoptosis, suggesting that they are in an immature and hyper-proliferative state, which may explain the enlarged metaphyses observed in individuals with PPD. Mutated WISP-3 shows abnormal aggregation in the cytoplasm and cell membrane of chondrocytes [Wang et al 2013]. As mutated WISP-3 delays intracellular collagen synthesis and inhibits extracellular collagen secretion, the cartilage flexibility in individuals with PPD diminishes.

CCN6-specific laboratory technical considerations. Two deep intronic missense variants that caused alternative splicing were identified in fibroblast cDNA [Garcia Segarra et al 2012]. A 9-kb deletion encompassing the 5′ untranslated region and first exon was identified by quantitative real-time PCR [Neerinckx et al 2015].

Cancer and Benign Tumors

Loss or downregulation of WISP-3 is associated with breast cancers, colorectal cancers, and hepatocellular carcinoma as reduction of WISP-3 stimulates tumorigenesis. The COSMIC (Catalogue of Somatic Mutations in Cancer) database shows 1,290 unique CCN6 variants in tissues associated with cancers.

Acknowledgments

Indian Council of Medical Research – Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects (BMS 54/2/2013)

Department of Science and Technology – Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development (SB/SO/HS/005/2014)

Revision History

• 23 December 2020 (sw) Comprehensive update posted live
• 25 November 2015 (me) Review posted live
• 30 June 2015 (kmg) Original submission

Literature Cited

• Bhavani GS, Shah H, Dalal AB, Shukla A, Danda S, Aggarwal S, Phadke SR, Gupta N, Kabra M, Gowrishankar K, Gupta A, Bhat M, Puri RD, Bijarnia-Mahay S, Nampoothiri S, Mohanasundaram KM, Rajeswari S, Kulkarni AM, Kulkarni ML, Ranganath P, Ramadevi AR, Hariharan SV, Girisha KM. Novel and recurrent mutations in WISP3 and an atypical phenotype. Am J Med Genet A. 2015;167A:2481–4. [PubMed: 25988854]
• Dalal A, Bhavani G SL, Togarrati PP, Bierhals T, Nandineni MR, Danda S, Danda D, Shah H, Vijayan S, Gowrishankar K, Phadke SR, Bidchol AM, Rao AP, Nampoothiri S, Kutsche K, Girisha KM. Analysis of the WISP3 gene in Indian families with progressive pseudorheumatoid dysplasia. Am J Med Genet A. 2012;158A:2820–8. [PubMed: 22987568]
• Delague V, Chouery E, Corbani S, Ghanem I, Aamar S, Fischer J, Levy-Lahad E, Urtizberea JA, Mégarbané A. Molecular study of WISP3 in nine families originating from the Middle-East and presenting with progressive pseudorheumatoid dysplasia: identification of two novel mutations, and description of a founder effect. Am J Med Genet A. 2005;138A:118–26. [PubMed: 16152649]
• Garcia Segarra N, Mittaz L, Campos-Xavier AB, Bartels CF, Tuysuz B, Alanay Y, Cimaz R, Cormier-Daire V, Di Rocco M, Duba HC, Elcioglu NH, Forzano F, Hospach T, Kilic E, Kuemmerle-Deschner JB, Mortier G, Mrusek S, Nampoothiri S, Obersztyn E, Pauli RM, Selicorni A, Tenconi R, Unger S, Utine GE, Wright M, Zabel B, Warman ML, Superti-Furga A, Bonafé L. The diagnostic challenge of progressive pseudorheumatoid dysplasia (PPRD): a review of clinical features, radiographic features, and WISP3 mutations in 63 affected individuals. Am J Med Genet C Semin Med Genet. 2012;160C:217–29. [PubMed: 22791401]
• Hurvitz JR, Suwairi WM, Van Hul W, El-Shanti H, Superti-Furga A, Roudier J, Holderbaum D, Pauli RM, Herd JK, Van Hul EV, Rezai-Delui H, Legius E, Le Merrer M, Al-Alami J, Bahabri SA, Warman ML. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nat Genet. 1999;23:94–8. [PubMed: 10471507]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Neerinckx B, Thues C, Wouters C, Lechner S, Westhovens R, Van Esch H. A homozygous deletion of exon 1 in WISP3 causes progressive pseudorheumatoid dysplasia in two siblings. Hum Genome Var. 2015;2:15049. [PMC free article: PMC4785582] [PubMed: 27081554]
• Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D, Levine AJ. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A. 1998;95:14717–22. [PMC free article: PMC24515] [PubMed: 9843955]
• Sen M, Cheng YH, Goldring MB, Lotz MK, Carson DA. WISP3-dependent regulation of type II collagen and aggrecan production in chondrocytes. Arthritis Rheum. 2004;50:488–97. [PubMed: 14872491]
• Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
• Wang M, Man XF, Liu YQ, Liao EY, Shen ZF, Luo XH, Guo LJ, Wu XP, Zhou HD. Dysfunction of collagen synthesis and secretion in chondrocytes induced by wisp3 mutation. Int J Endocrinol. 2013;2013:679763. [PMC free article: PMC3614060] [PubMed: 23573089]
• Wynne-Davies R, Hall C, Ansell BM. Spondylo-epiphysial dysplasia tarda with progressive arthropathy. A "new" disorder of autosomal recessive inheritance. J Bone Joint Surg Br. 1982;64:442–5. [PubMed: 6807993]
• Zhou HD, Bu YH, Peng YQ, Xie H, Wang M, Yuan LQ, Jiang Y, Li D, Wei QY, He YL, Xiao T, Ni JD, Liao EY. Cellular and molecular responses in progressive pseudorheumatoid dysplasia articular cartilage associated with compound heterozygous WISP3 gene mutation. J Mol Med (Berl). 2007;85:985–96. [PubMed: 17483925]