Progressive pseudorheumatoid dysplasia

Alternate names

Spondyloepiphyseal dysplasia tarda-progressive arthropathy syndrome; Progressive pseudorheumatoid arthropathy of childhood; PPAC; Spondyloepiphyseal dysplasia tarda - progressive arthropathy; PPD; SEDT-PA; Arthropathy, progressive pseudorheumatoid, of childhood; Spondyloepiphyseal dysplasia tarda with progressive arthropathy; Progressive pseudorheumatoid chondrodysplasia

Definition

Progressive pseudorheumatoid disyplasia (PPD) is a disorder of bone and cartilage that affects many joints. It manifests between the age of 3 and 6 years with joint pain and progressive joint stiffness.

Summary

• This condition is characterized by breakdown (degeneration) of the cartilage between bones (articular cartilage).
• This cartilage covers and protects the ends of bones, and its degeneration leads to pain and stiffness in the joints and other features of PPRD.
• PPRD is often mistaken for another joint disorder that affects young people called juvenile rheumatoid arthritis.
• However, the joint problems in juvenile rheumatoid arthritis are associated with inflammation, while those in PPRD are not.

Epidemiology

• PPRD has been estimated to occur in approximately 1 per million people in the United Kingdom.
• The condition is thought to be more common in Turkey and the Middle East, although its prevalence in these regions is unknown.
• The condition in all regions is likely underdiagnosed because it is often misdiagnosed as juvenile rheumatoid arthritis.

Cause

• PPRD is caused by mutations in the CCN6 gene.
• The function of the protein produced from this gene is not well understood, although it is thought to play a role in bone growth and cartilage maintenance.
• The CCN6 protein is made in cells called chondrocytes, which produce and maintain cartilage.
• This protein is associated with the production of certain proteins that make up cartilage, but its role in their production is unclear.
• CCN6 may also help control signaling pathways involved in the development of cartilage and bone and may help regulate the breakdown of cartilage components.

Gene mutatios

• CCN6 gene mutations lead to an altered protein that may not function.
• Loss of CCN6 protein function likely disrupts normal cartilage maintenance and bone growth, leading to the cartilage degeneration and joint problems that occur in PPRD.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Onset

PPRD usually begins in childhood, between ages 3 and 8.

Signs and symptoms

• The first indications are usually an abnormal walking pattern, weakness and fatigue when active, and stiffness in the joints in the fingers and in the knees.
• Other signs and symptoms that develop over time include permanently bent fingers (camptodactyly), enlarged finger and knee joints (often mistaken as swelling), and a reduced amount of space between the bones at the hip and knee joints.
• Hip pain is a common problem by adolescence.
• Affected individuals have flattened bones in the spine (platyspondyly) that are abnormally shaped (beaked), which leads to an abnormal front-to-back curvature of the spine (kyphosis) and a short torso.
• At birth, people with PPRD are of normal length, but by adulthood, they are usually shorter than their peers.
• Affected adults also have abnormal deposits of calcium around the elbow, knee, and hip joints and limited movement in all joints, including those of the spine.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Gait disturbance(Abnormal gait)
• Joint stiffness(Stiff joint)
• Methylmalonic acidemia
• Short stature(Decreased body height)

30%-79% of people have these symptoms

• Abnormality of the knee
• Enlarged interphalangeal joints(Enlarged hinge joints)
• Flattened epiphysis(Flat end part of bone)
• Kyphosis(Hunched back)
• Osteoarthritis(Degenerative joint disease)
• Sclerotic vertebral endplates
• Scoliosis

Diagnosis

PPD should be suspected in individuals with the following clinical, laboratory, and radiologic features.[1].

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

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.

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

Treatment

• 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.[2].

NIH genetic and rare disease info

• NIH info on Progressive pseudorheumatoid dysplasia

Progressive pseudorheumatoid dysplasia is a rare disease.

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