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Progressive Pseudorheumatoid Dysplasia

Synonyms: Progressive Pseudorheumatoid Arthropathy of Childhood, Progressive Pseudorheumatoid Chondrodysplasia, SEDT-PA, Spondyloepiphyseal Dysplasia Tarda with Progressive Arthropathy

, MSc, , MS, , MD, DM, , MD, DM, and , MD, DM.

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Estimated reading time: 14 minutes


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.


Although radiologic examination has high accuracy in the diagnosis of PPD, the definitive diagnosis is established in a proband with identification of the characteristic radiologic findings and biallelic pathogenic variants in CCN6 (formerly WISP3) on molecular genetic testing.


Treatment of manifestations: Treatment is supportive. Pain due to secondary osteoarthritis may respond to NSAIDs. Other anti-inflammatory medications may have limited efficacy in the treatment, but are best avoided in view of their significant side effects. Physical therapy may help preserve joint mobility. Surgical intervention, including realignment of the lower limbs, joint arthroplasty, and/or treatment of spinal stenosis may be necessary.

Surveillance: Monitoring for orthopedic complications including bone deformity, secondary joint disease, spinal deformities, and pain.

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

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

Genetic counseling.

PPD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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.


Progressive pseudorheumatoid dysplasia (PPD) is a distinctive form of spondyloepiphyseal dysplasia with predominant joint disease.

Formal diagnostic criteria are lacking at present.

Suggestive Findings

Progressive pseudorheumatoid dysplasia should be suspected in individuals with the following clinical and radiologic findings.

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 3rd centile
  • Absence of signs of inflammation
  • Normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels
Figure 1. . Hands of individuals show progressive swelling and limited range of movement of the interphalangeal joints.

Figure 1.

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

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 show large epiphyses and widened metaphyses of metacarpals and phalanges.

Figure 2.

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

Figure 3. . Pelvic radiographs demonstrate reduced hip joint spaces, large capital femoral epiphyses, short and broad femoral necks, and irregular acetabular roofs.

Figure 3.

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

Figure 4.

Figure 4.

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

Establishing the Diagnosis

In general, radiologic examination is highly accurate in the diagnosis of PPD. The diagnosis of progressive pseudorheumatoid dysplasia is confirmed in a proband with identification of biallelic pathogenic variants in CCN6 (formerly WISP3) on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and genomic testing.

Single-gene testing. Sequence analysis of CCN6 is performed first. If only one or no pathogenic variant is found, sequence analysis of cDNA from cultured skin fibroblasts may be performed to detect splicing aberrations resulting from intronic pathogenic variants [Garcia Segarra et al 2012] (see Molecular Genetics).

Targeted analysis for pathogenic variants can include the following:

  • c.156C>A (p.Cys52Ter) is the most frequent pathogenic variant in Turkish patients and accounts for approximately 28% of pathogenic variants worldwide [Author, review of the literature].
  • c.1010G>A (p.Cys337Tyr) and c.233G>A (p.Cys78Tyr) are the most common pathogenic variants in the Indian population.

A multigene panel that includes CCN6 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes CCN6) fails to confirm a diagnosis in an individual with features of PPD. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Progressive Pseudorheumatoid Dysplasia

Gene 1MethodProportion of Probands with Characteristic Radiographic Findings in Whom Pathogenic Variants 2 Are Detectable by Method
CCN6Sequence analysis 3Nearly 100% 4

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Among the pathogenic variants were three intronic variant alleles identified by fibroblast cDNA sequence analysis; two of the three are deep intronic pathogenic variants [Garcia Segarra et al 2012].

Clinical Characteristics

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.

Clinical Features

Onset. Children with PPD are normal at birth and during infancy. The age of onset is typically between three and six years [Wynne-Davies et al 1982, Garcia Segarra et al 2012]; the range 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 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 (i.e., 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 as the skeletal changes progress. Adult height is typically below the 3rd 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].


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

PPD was previously referred to as spondyloepiphyseal dysplasia with progressive arthropathy.


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 160 families with molecularly confirmed PPD have been reported.

PPD is more frequent in endogamic communities [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 been observed among populations with a high rate of consanguinity in Kuwait, Lebanon, Iran, Jordan, Saudi Arabia, Syria, Palestine, and Morocco.

Differential Diagnosis

Juvenile idiopathic arthritis and all skeletal dysplasias with epiphyseal and spondylar involvement are to be considered in the differential diagnosis of progressive pseudorheumatoid dysplasia (PPD).

Juvenile idiopathic arthritis (JIA) is the disorder most commonly confused with PPD. The main differentiating features:

  • Joint inflammation (tenderness and warmth) in JIA
  • Elevation of ESR and CRP in JIA and not in PPD. However, in some instances elevation of these acute reactants in JIA can be minimal.
  • In JIA, joint destruction seen on radiographs. In PPD radiographs show dysplasia along with epiphyseal enlargement and platyspondyly.

X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) develops in adolescence or adulthood and is characterized by disproportionate short stature, platyspondyly with a distinctive posterior hump of the vertebral bodies, and osteoarthritis without involvement of peripheral joints. X-linked SEDT is caused by mutation of TRAPPC2 (SEDL).

In the mucopolysaccharidoses (MPSs) the vertebral deformities (hook-shaped vertebral bodies with inferior beaking or platyspondyly with central beaking) and progressive joint limitation are similar to those of PPD. Extraskeletal manifestations observed in the MPSs (e.g., coarse facies, corneal clouding, hepatomegaly, intellectual disability) are not present in PPD. (See MPS I, MPS II, MPS IV A, MPS IVB, and Mucopolysaccharidoses: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.)

Atypical forms of COL2A1-related spondyloepiphyseal dysplasias may share features of PPD:

  • Czech dysplasia (OMIM 609162), also called progressive pseudorheumatoid dysplasia with hypoplastic toes, is characterized by early-onset osteoarthritis and hypoplastic 3rd, 4th, and 5th toes. Radiologic features (including platyspondyly with irregular endplates and usually anterior-posteriorly elongated vertebral bodies, coxa vara, short femoral neck, and narrow joint spaces) resemble those of PPD. However, normal stature and short postaxial toes in Czech dysplasia are distinguishable features. Czech dysplasia is caused by heterozygous pathogenic variants in COL2A1 (usually the p.Arg275Cys pathogenic variant) and is inherited in an autosomal dominant manner.
  • Spondyloepimetaphyseal dysplasia, Strudwick type (OMIM 184250) shares some features with PPD. Individuals with this condition are very short and present in infancy. Spondyloepimetaphyseal dysplasia, Strudwick type is caused by mutation of COL2A1 and is inherited in an autosomal dominant manner.

Spondylometaphyseal dysplasia, corner fracture type, also known as Sutcliffe type, may resemble some phenotypic variants of PPD.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with progressive pseudorheumatoid dysplasia (PPD), the following evaluations are recommended:

  • Complete skeletal survey, if not already done as part of the diagnostic evaluation
  • Referral to a pediatric orthopedic surgeon or specialist in treating bone dysplasias
  • Consultation with a clinical geneticist and/or genetic counselor or a multidisciplinary skeletal dysplasia team

Treatment of Manifestations

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

Pain due to secondary osteoarthritis may respond to NSAIDs. Other anti-inflammatory medications including steroids and immunosuppressive drugs (cyclosporine and methotrexate) have a limited role in treatment and are best avoided in view of their significant side effects.

Physical therapy may help preserve joint mobility. Immobilization (e.g., casting) should be avoided.

Most joint involvement requires intervention by an orthopedist and/or physical therapist.

  • Angular deformities of lower limbs. The indications for surgical correction are to restore normal alignment of the lower limbs and to alleviate gait disturbance, instability, and/or pain.
  • Progressive joint stiffness
    • 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.
  • Joint pain. Severe joint pain due to advanced osteoarthritis is treated by joint arthroplasty (i.e., hip and knee replacement). Early hip replacement (second decade of life) can be successful in relieving pain and restoring the ability to ambulate.
  • Progressive stiffness and deformities of the spine
    • Scoliosis and mild kyphosis can be managed with bracing.
    • Spinal canal stenosis can be managed with decompression, fusion, and instrumentation.


No specific guidelines for surveillance have been published.

Recommendations include the following:

  • Monitoring for orthopedic complications including bone deformity, secondary joint disease, spinal deformities, and pain
  • Evaluation by a specialist in skeletal dysplasia or a multidisciplinary skeletal dysplasia clinic every year

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 cesarean section in pregnant women who have PPD.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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., carriers of one CCN6 [WISP3] pathogenic variant).
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has 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.
  • Heterozygotes 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 (Heterozygote) 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, clarification of carrier status, and discussion of the availability of prenatal 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 testing for a pregnancy at increased risk and preimplantation genetic testing for progressive pseudorheumatoid dysplasia are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Arthritis Foundation
    1330 W. Peachtree Street
    Suite 100
    Atlanta GA 30309
    Phone: 800-283-7800 (toll-free); 404-872-7100
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    1 AMS Circle
    Bethesda MD 20892-3675
    Phone: 877-226-4267 (toll-free); 301-565-2966 (TTY)
    Fax: 301-718-6366
  • International Skeletal Dysplasia Registry
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Progressive Pseudorheumatoid Dysplasia: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CCN66q21Cellular communication network factor 6WISP3 databaseCCN6CCN6

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Progressive Pseudorheumatoid Dysplasia (View All in OMIM)


Gene structure. CCN6 (formerly WISP3) consists of five exons. Ensembl lists 11 transcripts, produced as a result of alternative splicing (GRCh38). The most commonly used and clinically relevant reference sequence is NM_003880.3 with a length of 1,235 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 60 pathogenic variants have been reported in CCN6. Missense variants, deletions, nonsense variants, duplications, and splice site variants as well as complex variants such as indels have been described. Additionally, two deep intronic missense variants that caused alternative splicing were identified in fibroblast cDNA [Garcia Segarra et al 2012].

The most common pathogenic variant observed across all ethnicities is p.Cys52Ter (~28%).

Two other pathogenic variants observed only in the Indian population are p.Cys337Tyr in exon 5 and p.Cys78Tyr in exon 2.

Table 2.

CCN6 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. CCN6 encodes a 354-amino acid protein, Wnt1 inducible signaling pathway protein 3 (WISP-3), of approximately 40-kd molecular weight. 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].

Abnormal gene product. 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.

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 45 unique CCN6 variants in tissues associated with cancers.


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]
  • 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]
  • 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]

Chapter Notes


  • 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

  • 25 November 2015 (me) Review posted live
  • 30 June 2015 (kmg) Original submission
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