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A case of progressive pseudorheumatoid arthropathy of‘childhood’ with the diagnosis delayed to the fifth decade

A. CEFLE,1 K. CEFLE,2 M. TUNACI,3 S . OZTURK, 2 S . PALANDUZ2

Kocaeli University,1 Medical Faculty, Department of Internal Medicine, Division of Rheumatology, Kocaeli, Istanbul

University,2 Istanbul Medical Faculty, Department of Internal Medicine, Division of Medical Genetics, IstanbulxUniversity,3 Istanbul Medical Faculty, Department of Radiology, Istanbul, Turkey

SUMMARY

Progressive pseudorheumatoid arthropathy of childhood

(PPAC) is a rare single gene disorder which is frequently

misdiagnosed as juvenile rheumatoid arthritis. It is char-

acterised with arthralgia, joint contractures, bony swelling

of metacarpophalangeal and interphalangeal joints and

platyspondyly. Clinical and laboratory signs of joint

inflammation such as synovitis, a high erythrocyte sedi-

mentation rate and an elevated C-reactive protein level are

usually absent. Although the disease begins early in life

(usually between 3 and 8 years of age), the diagnosis may

be delayed. In the present case report, we describe a male

patient diagnosed with PPAC at the age of 46 years,

although he had been exhibiting the typical radiological

and clinical features of the disease since the age of 7 years.

Keywords: Progressive pseudorheumatoid arthropathy of

childhood

ª 2006 Blackwell Publishing Ltd

I N T R O D U C T I O N

Progressive pseudorheumatoid arthropathy of childhood

(PPAC) is a single gene disorder which is inherited in an

autosomal recessive manner. Alternative names of the dis-

ease are ‘spondyloepiphyseal dysplasia tarda (SEDT) with

progressive arthropathy’ and ‘progressive pseudorheumatoid

dysplasia’ (1). Although the frequency of the disease is not

known exactly, it is estimated to be one per million in Uni-

ted Kingdom. The main clinical features are arthralgia, joint

contractures, enlarged metacarpophalangeal and interphalan-

geal joints, platyspondyly and short stature. The onset of

the disease is usually between 3 and 8 years of age, and it is

frequently diagnosed erroneously as juvenile rheumatoid

arthritis (JRA). In the present case report, we describe a

male patient diagnosed with PPAC as late as at the age of

46 years, although he had been displaying the typical clin-

ical and radiological features of the disease since childhood.

C A S E

A 46-year-old male patient was admitted due to back and hip

pain of 4 years’ duration. His history was remarkable for

‘swelling’ of the interphalangeal and metacarpophalangeal

joints accompanied with a decrease in joint mobility which

had begun at the age of 7 years. He also described ‘enlarge-

ment of knees’ during the following years and a gradual

decrease of mobility involving nearly all the joints (knees,

shoulders, hips, servical and thoracal spine). He had also

joint pain mainly during physical activity, occasionally

intensifying also at rest and necessitating administrations of

non-steroidal anti-inflammatory drugs. He denied other

signs of arthritis including erythema and soft tissue swelling.

He had been evaluated in various hospitals without a defin-

ite diagnosis. For the last 4 years, the hip and back pain

worsened to the point of limiting daily activities without a

satisfactory response to non-steroid anti-inflammatory drugs.

The patient was born from a first-cousin marriage.

Remarkably, his sister and mother had a ‘joint disease’ with

many similarities: swelling of interphalangeal joints and knees

beginning in childhood, gradual limitation of mobility of

both peripheral and axial joints and back and hip pain.

The height of the patient was 146 cm, and the weight

was 56 kg. On physical examination, the neck and the

trunk were found to be shortened. Flexion contractures and

bony enlargement of proximal and distal interphalangeal

joints were noted (Figures 1 and 2). Also bilateral wrist,

elbow, shoulder, knee and hip movements were limited.

Physical examination was normal otherwise.

The results of a urine analysis, complete blood count and

routine blood chemistry (including serum creatinine, calcium,

phoshorus alkaline phosphatase, aspartate aminotransferase

and alanine aminotransferase) were normal. The thyroid-

stimulating hormone, follicule-stimulating hormone, luteinis-

ing hormone and testosterone levels were normal. The

Correspondence to:Dr Kivanc Cefle, Istanbul Universitesi, Istanbul Tip Fakultesi, Ic

Hastaliklari AD, Tibbi Genetik BD, 34093 Capa, Istanbul, Turkey

Tel.: þ 90 212 414 23 22

Fax: þ 90 212 532 42 08

Email: [email protected]

CASE REPORT d o i : 1 0 . 1 1 1 1 / j . 1 7 4 2 - 1 2 4 1 . 2 0 0 5 . 0 0 6 6 2 . x

ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1306–1309

erythrocyte sedimentation rate was 24 mm ⁄ h; C-reactive pro-

tein was in the normal range. The rheumatic facor was

negative. Echocardiographic and ophtalmological examina-

tion was unremarkable.

Plain radiographs of the hands showed bony enlargement of

metacarpophalangeal, proximal interphalangeal joints and joint

narrowing.Theknee jointswereenlarged similarly.Radiographs

of the spine (dorsal and lumber region) revealed osteophyitic

degeneration, decreased vertebral height (platyspondyly) and

narrowing of the intervertebral space (Figures 3, 4 and 5).

Coxofemoral joints were found to be heavily sclerosed with

narrowing of the joint space. Analysis of bone mineral density

by dual energy X-ray absorptometry (DEXA) showed a lomber

T-score of )3.65 and Z score of )3.28. Femoral T and Z scores

were 8.87and10.26, respectively.

The patient was diagnosed with PPAC based on the typical

clinical (childhood onset, bony swelling of interphalangeal

joints, gradual decrease in joint mobility, disabling hip and

back pain, lack of overt signs of arthritis and absence of

synovial involvement) and laboratory findings (osseous enlarge-

ment of joints and platyspondyly on skeletal radiograms,

normal erythrocyte sedimentation rate and C-reactive protein

level).

D I S C U S S I O N

PPAC was first described in 1983 by Spranger et al. (2) in five

patients as a hereditary arthropathy affecting ‘major and

minor joints’ (2). It is a rare hereditary disorder with auto-

somal recessive inheritance characterised by bony enlargement

of interphalangeal and metacarpophalangeal joints, flexion

Figure 1 Flexion deformity and ‘apparent’ swelling of proximal

interphalangeal joints

Figure 2 Bony enlargement of metacarpophalangeal and

proximal interphalangeal joints

Figure 3 X-ray of the hands revealing ‘swelling’ of the

metacarpophalangeal and proximal interpahalangeal joints. General

narrowing of the joint spaces; irregularity of the first metacarpop-

galangeal joint on the left

Figure 4 X-ray showing osseous enlargement of the knees with

extremely narrowed joint spaces. Sclerosing and irregularity of

joint contours are noted

A CASE OF PROGRESSIVE PSEUDORHEUMATOID ARTHROPATHY 1307


deformities of fingers, reduced mobility of knees and coxofe-

moral joints and platyspondyly; severe involvement of the

joints may be disabling. Although apparently rare in western

countries with an incidence of one per million in United

Kingdom, it is probably more frequent in Middle East and

Gulf States with more than two-thirds of the reported patients

belonging to Arab and Mediterranean populations (3,4). To

our knowledge, this is the third case report of a patient with

PPAC from Turkey (5,6).

Initial mapping studies assigned the gene responsible for

the disease to the long arm of chromosome 6. However,

examination of COL10A1, which is a candidate gene in this

region, did not reveal any mutations (7,8). Using a positional

candidate approach, Hurvitz et al. (4) found homozygous

mutations in the WISP gene which also resides in 6q. WISP

is a member of CCN gene family which encodes cysteine-rich

secreted proteins with roles in cell growth and differentiation.

However, the exact mechanism of the disease is not clear at

the present.

The clinical course of the present patient is typical for the

disease. Joint involvement, characterised with painless swel-

ling of interphalangeal joints, had begun when he was 7 years

old. Although joint symptoms most commonly begin

between 3 and 8 years of age, skeletal findings may be present

even at birth (9). In this patient, severe pain, which occurred

as a relatively late symptom, affected mainly hips and the

back, and it was unresponsive to non-steroidal anti-inflamma-

tory drugs. Osteoarthritic degeneration of the coxofemoral

joints, which is revealed by intense sclerotic changes seen on

plain radiographs, may become an indication for hip replace-

ment (10). An interesting feature of the present case is the

decreased bone mineral density of the lomber vertebrae.

Because the patient did not display any clinical and laboratory

signs of other disorders associated with osteoporosis, we sug-

gest that the decreased bone density may be a direct conse-

quence of PPAC. However, the exact mechanism of this

relation is unclear at the present. On the other hand, the

increased bone mineral density of the femoral neck is

explained with the heavy osteosclerosis.

PPAC is frequently confused with JRA. There are at least

five case reports describing its striking similarity to JRA

(2,6,10–12). The main reasons of confusion appear to be

early onset at childhood, swelling and restriction of peripheral

and axial joints. However, the absence of arthritic and other

inflammatory findings, especially synovitis and radiological

absence of destructive joint changes, should alert the clinician

in excluding JRA and considering other diagnostic possibilities.

It should also be emphasised that joint swelling is osseous in

nature and is not due to synovial involvement. Furthermore, a

normal erythrocyte sedimentation rate and a normal level of

C-reactive protein may be additional clues in excluding JRA in

addition to platyspondyly, which is highly unusual for JRA.

A second diagnostic possibility to consider in the present case

could be SEDT. SEDT is an X-linked recessive disease mainly

involving the spine and hips. Recently, it has been found that

SEDT is associated with mutations in the ‘SEDL’ gene on the X

chromosome (13). Short stature with a disproportionally short

trunk, flattening of the vertebrae, short neck, pain and stiffness

of hips and osteoarhtritic degeneration of the coxofemoral

joints are main features of the syndrome. Although these are

also shared by the case under discussion, involvement of small

joints with stiffness and periarticular osseous enlargement are

not compatible with a diagnosis of SEDT.

The patient discussed here had been followed with unclear

diagnoses in other hospitals before. However, characteristic

history, bony enlargement of interpahalangeal joints, sparing

of the synovium and absence of past or present signs and

symptoms of inflammation made the diagnosis of PPAC

straightforward, and JRA was excluded easily. Also, the involve-

ment of joints other than axial skeleton and presence of

female members of the family exhibiting similar signs rule

out SEDT, which is X-linked.

We conclude that, from the practical point of view, although

PPAC is a disease which begins early in life, the diagnosis may

be delayed and should be considered in adult patients also. A

remote history of JRA should not be a reason to exclude PPAC,

because PPAC is frequently misdiagnosed as JRA.

R E F E R E N C E S

1 Online Mendelian Inheritance in Man, Omim (TM). Johns

Hopkins University, Baltimore, MD. MIM Number 208230:

8 ⁄ 27 ⁄ 1999: World Wide Web URL. http://www.ncbi.nlm.nih.

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Figure 5 Lateral X-ray view of the thoracal vertebrae shows

platyspondyly, narrowing and irregularity of intervertebral spaces

1308 A CASE OF PROGRESSIVE PSEUDORHEUMATOID ARTHROPATHY


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Paper received April 2005, accepted July 2005

A CASE OF PROGRESSIVE PSEUDORHEUMATOID ARTHROPATHY 1309
