European Journal of

Eur J Pediatr (1983)140:34-40 Pediatrics �9 Springer-Verlag 1983

Progressive pseudorheumatoid arthritis of childhood (PPAC) A hereditary disorder simulating rheumatoid arthritis*

J. Spranger 1, C. Albert 1, F. Schilling 2, C: Bartsocas 3, and H. St/Jss 4

i Universit~its-Kinderklinik M, ainz, Federal Republic of Germany 2 Rheumaklinik Bad Kreuznach, Federal Republic of Germany 3 Children's Hospital, University of Athens, Greece 4 Pathologisches Institut, University of Erlangen, Federal Republic of Germany

Abstract. Five patients are described with a hereditary arthro- pathy affecting major and minor joints. The main features of this progressive connective tissue disorder are restricted joint mobility, osseous swelling of the interphalangeal and other joints, and platyspondyly. The condition is commonly mis- diagnosed as "chronic juvenile polyarthritis with Scheuer- mann disease". It differs from the rheumatoid-factor-negative polyarticular form of rheumatoid arthritis and other rheuma- toic spondylarthropathies by the absence of arthritic and other inflammatory changes, radiographically by the absence of de- structive and the presence of dysplastic bone changes. The disorder does not seem to respond to the usual forms of anti- rheumatoid treatment. Histological studies showed a peculiar, nest-like clustering of chondrocytes in the resting and growth cartilage suggesting that pathogenetically this is a primary disorder of the articular cartilage.

Key words: Rheumatoid arthritis - Chronic juvenile polyarthri- tis - Collagen diseases - Spondylarthropathies - Osteo- chondrodysplasia - Connective tissue diseases - Platyspondyly

Introduction

Primary disorders of the joints and muscles, if associated with restricted mobility and pain, have been loosely grouped as "rheumatic diseases" [6]: The rheumatic diseases of childhood are defined as disorders associated with inflammatory changes of the connective tissue throughout the body [8].

We describe a condition with clinical features of rheumatic disorders, notably the seronegative spondylarthropathies of childhood [9] but without signs of primary connective tissue inflammation. We present evidence that it is a progressive, probably hereditary, noninflammatory chondropathy affecting primarily the articular cartilage.

Case reports

Patient 1, E.P., a gM, was first seen at the age of 7 years with a complaint of generalized weakness. Her parents were 46 and 42-years-old, respectively, not consanguineous, of normal height and in good health. Three older brothers were healthy. A brother of the father's mother is said to have died from muscular atrophy.

* Supported by the Stiftung Volkswagenwerk Offprint requests to: Prof. J. Spranger, Univ.-Kinderklinik, Langen- beckstr. 1, D-6500 Mainz, FRG

The patient was born after an uneventful pregnancy with a weight of 4000g and a length of 56 cm. The early psychomotor development was normal. At 3 years she started to complain about weak legs and stiff joints. She walked slowly and tired easily. Usually, the symptoms were more severe in the morn- ing. Weakness and hypomobili ty increased, symptom-free intervals became shorter until, at the age of 7 years, she could no longer climb stairs, was barely able to feed herself and to tie her shoes. At that time she started to complain occasionally about pain in her calves. Her joints were never painful.

Physical examination showed a mentally normal, anxious girl with a height of 124 cm (50th centile) and a weight of 23.7 kg (50th centile). There was a violaceous hue to her cheeks and shanks; otherwise the skin was normal. The mobility of the large joints was reduced by 10~ ~ They appeared slightly prominent but there was no tenderness, no soft-tissue swel- ling, no redness, no sign of effusion. The patient could not extend her neck; cervical rotation was slightly and flexion was not restricted. Mobility of the dorsolumbar spine was modera- tely reduced in all planes. Flexion of the metacarpo-phalangeal joints was severely restricted and she was unable to close her fist. The middle and distal interphalangeal joints were mar- kedly distended (Fig. 1 b). The distention was caused by osse- ous hyperplasia of the bone ends (Fig. 2). The patient walked with short, stiff steps. Her spleen was palpated 1 cm below the left costal margin. The liver and lymph nodes were not enlarged. Ophthalmologic examination showed no signs ofiri- docyclitis. Neurologically, there was generalized muscular weakness, mild muscular hypotrophy with brisk reflexes and impaired fine motor coordination.

Radiographs showed irregular ossification of the vertebral bodies (Fig. 3 a), mild pelvic dysplasia, widened ends of the long and short tubular bones and generalized osteoporosis. There were no signs of bone destruction (Fig. 2). The joint spaces and the intervertebral disc spaces of the cervical spine were narrow.

Some pertinent laboratory findings are summarized in Table 1. Notably, there were no signs of systemic inflamma- tion. Creatinine phosphokinase was initially elevated on two occasions but normal thereafter. A synovial biopsy of the right knee gave normal results. A normal amount of synovial fluid did not show inflammatory cells. A muscle biopsy showed nonspecific type II fiber atrophy.

Salicylates and other noncorticoid anti-inflammatory drugs were ineffective. High-dose corticoid therapy resulted in only minor improvement of mobility and was discontinued.

Patient2, B.K., a girl, presented at the age of 9 years because of walking difficulties, morning stiffness and occasional pain in

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Fig.2. Patient 1, 8 years. The ends of the short tubular bones are widened. The contours of the carpal bones and the epiphyses of the distal radius and ulna are slightly irregular. Bone density is slightly diminished. Note the absence of lytic or erosive changes

Fig. 1. a Patient 3, 10 years. The patient stands with an anterior tilt of her pelvis caused by flexion contractures of her hips. b Patient l, 8 years. The interphalangeal joints appear swollen, c Patient 4, 16 years. The patient is unable to stand without support due to flexion contractures of her hip and knee joints. The leg musculature is hypo- trophic

the upper thighs, knees and ankles occuring after exercise and improving with rest.

Her parents, one older and two younger sisters were heal thy and of normal height. She was born with a weight of 3250g and a length of 50 cm. She sat at 12 months , spoke her first words at 18 months and walked wi thout support at 21 months . As an infant she had pertussis and a disorder diag- nosed as scarlet fever. At 3 years a waddling, stiff gait was noted. At 5 years, mobil i ty of the neck decreased and skeletal abnormali t ies were noted on radiographs leading to various diagnoses including rheumato id arthritis wi th Scheuermann disease, polymyosit is , enchondral dysostosis, and Morqu io disease.

Examina t ion showed an alert, cooperative girl with a he ight of 121 cm (below 3rd centile), weight of 23.5 kg (50th centile) and a sitting height of 65 can (20th centile for height). She had a stiff neck with markedly restricted extens ion and less severe restriction of f lexion and rotation. There was muscular weak- ness with normal ly preserved reflexes and she could not stand on one leg. She had considerable difficulties cl imbing stairs.

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Fig. 3. a Patient 1, 8 years, b Patient 3, 12 years. The films show defec- tive ossification of the anterior portions of the upper and lower plates of the vertebral bodies. The vertebral bodies are flattened

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Table 1. Laboratory findings in five patients with PPAC. (Multiple figures indicate repeated examinations; pathological findings in italics)

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Sex, age (years) f, 7-9 f, 9-13 f, 10 f, 16 f, 37-42 Sedimentation rate 7; 5; 8; 9; 40 9; 10; 26; 38; 9 15 11, 17 2; 37; 12; 28

SGOT (U/l) 13; 11; 9; 9 100; 3; 12 8 8 CPK (U/l) 71; 127," 20; 42 27; 34 21 40 IgM (mg/dl) 336 230; 266 91 60 ASR Neg 1 : 400 Neg Neg Waaler-Rose test Neg Pos. neg Neg Neg Neg Latex test Neg Neg Neg Neg Neg LE cells Neg Neg Neg Neg Rosette formation Neg Antinuclear antibodies Neg Neg Neg Neg Antimitochondrial antibodies Neg Neg Neg

Smooth muscle antibodies Neg Neg Neg Striated muscle antibodies Neg Neg

C50 complement 37 18 28 33 HLA type A2,3; B7,13 A28; Bw38,w51 Electromyogram Normal Normal Normal Muscle biopsy Type II fiber Inconclusive Normal

atrophy Synovial biopsy Normal

Fig. 4. Patient 2, 8 years. The lower portions of the ilia are broadened. The acetabular roofs are irregular and there is pronounced ossifica- tion of the capsular attachment

Her gait was broad-based and stiff with extended knees. The large joints were slightly prominent and had a full range of mobility. This decreased during the following years until, at 16 years there was only 20 ~ flexion-extension of the hips and ankles, respectively, without mobility in the other planes. Knees, shoulders elbows and wrists had a slightly better func- tion. The interphalangeal joints were distended due to widened ends of the adjoining bones without signs of soft tissue swelling. Liver, spleen, and lymph nodes were not enlarged. The skin was normal. Neurological examination was negative except for muscle weakness. The eyes were normal.

Audiometry showed neurosensory hearing loss on the left side.

Radiographs showed findings virtually identical to those in patient 1. The pelvis is depicted in Fig. 4. Some pertinent laboratory findings are summarized in Table 1.

During the next years, increasing stiffness of the spine and peripheral joints developed. She could no longer flex and oppose her thumbs and fully stretch her second to fifth fingers. A slightly reddened hue of the cheeks was occasionally noted. High-dose corticoid treatment and long-term azathioprine failed to improve the symptoms, as did numerous noncorticoid anti-inflammatory drugs and vigorous physiotherapy. At 16 years her height was 148 cm (below 3rd centile).

Patient 3, S.T., a 10-year-old girl was admitted because of walk- ing difficulties and a suspected neurodegenerative disorder. She was an adopted child of Greek origin and the only informa- tion about her early development was that she had been born with a weight of 2800 g and a length of 49 cm to a 17-year-old mother. In her third year of life it was noted that she walked with a broad base and everted feet and that she tired easily. A hand radiograph showed bony atrophy and shortened tubular bones. At 5.5 years her height was 103 cm (10th centile). Her gait was described as "spastic". Prominent interphalangeal joints were noted. Routine laboratory studies gave normal results. In the following years her gait deteriorated.

Physical examination showed a pleasant and cooperative girl with markedly impaired motor functions. She walked slowly with small steps. Her muscle strength was reduced. Mobility of the large joints except the knees was moderately reduced. Neck movements were limited. She had a round face without dysmorphic signs. There was a moderate spinal scolio- sis, lumbar hyperlordosis, and she stood with her trunk slightly bent forward (Fig. la). The interphalangeal joints were distended without signs of soft tissue swelling, inflammation or intraarticular fluid accumulation. The fingers could not be fully extended. Genua valga were present. The skin and sub-

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Fig. 5 a, b. Patient 3. Iliac crest biopsy. a Resting cartilage, b Growth plate. The chondrocytes are clustered in oval nest of densely staining material. Columnization is absent in the growth zone. Toluidin blue, orig. •

cutaneous tissue had a turgid feel. There were no corneal opacities, no signs of iridocyclitis and the texture of her hair was normal. Neurological examination showed normal cranial nerve function, normal muscle tone and motor coordination. Muscular strength was generally reduced. The tendon reflexes were brisk. The patient had difficulties in balancing and walk- ing due to restricted joint mobility and reduced muscle strength.

Laboratory studies gave normal results. In particular, there were no signs of a systemic inflammation (Table 1). Plasma and urine amino acids, glycosaminoglycans, a bone marrow spec- imen and a CAT scan of the brain were normal. A study of lysosomal enzymes in serum and leucocytes showed normal activities except for arylsulfatase A which was consistently in the heterozygous range. Skeletal radiographs showed changes identical to those in the other patients (Fig. 3B).

Patient 4, F.B,, a 16-year-old Arab girl was reportedly normal up to her eighth year when she began to tire more easily than before and started to walk with smaller steps. Her gait became awkward, her joints began to swell. Joint mobility decreased until finally she was no longer able to stand and walk without support.

Her parents are reportedly not consanguineous and in good health. One younger brother is said to have exactly the same symptoms. Four more brothers and one sister are living and well.

Physical examination showed a pleasant, cooperative girl who stood bent forward with the aid of crutches (Fig. 1C). Her height was 134 cm (below 3rd percentile) and her weight 34 kg. There was a mild scoliosis. Mobility of the cervical spine was slightly reduced. The hip j oints were in almost 90 ~ flexion. Her knees could be extended to approximately 120 ~ Mobility of the ankle joints was restricted to about 20 ~ flexion and extension. There was limited abduction of the shoulders and 160 ~ extension of the elbows. Mobility of the wrists was only slightly impaired. The fingers could not be fully flexed. The musculature of the legs was hypotrophic. Important negative findings included a normal skin, lack of hepatosplenomegaly, lack of lymph node swelling, normal sensory responses and cardiac function, nor- mal intelligence. Except for reduced muscle strength there were no neurologic abnormalities.

Radiographs showed changes identical to those in the other patients. The major laboratory findings are summarized in Table 1.

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Fig. 6. a Electron microscopy of one of the chondrocyte nests shows an abundance of fine fibers arranged in irregular whorls and spirals (glutaraldehyde-formol, orig. x 5400.) b Higher magnification of this area shows dense, curvilinear, labyrinthic structures interspersed between the partially striated collagen fibers (glutaraldehyde-formol x 18 000)

Patient 5, M.H., born 1936, was admitted to the Rheumaklinik Aachen in 1968 and 1975 because of painful, deformed and stiff joints with a diagnosis of "endochondral dysostosis".

Her parents were nonconsanguineous and of normal height. Her father died at 58 years from prostatic carcinoma; her mother was in good health. Three younger siblings were healthy with heights between 165 cm and 180 cm.

The patient 's early development was normal until the age of about 3 years when a waddling gait and easy fatiguability were noted. At 4 years, a bilateral tenotomy of the heel cords was performed. At 7 years the elbows became painful. Hip pain started at 12 years and bilateral realignment osteotomies were performed, leaving the patient unable to walk without support. Several years later, thickening of the finger joints was noted and a diagnosis of rheumatoid arthritis was made. Sub-

sequently, the wrists, elbows shoulders, hips, and knees became increasingly protuberant, stiff and painful. Mobility of the spine decreased. The disease progressed relentlessly in spite of numerous therapeutic trials. At the age of 32 years, the metacarpophalangeal joint of the left third finger became pain- ful with soft-tissue swelling, redness and increased tempera- ture. None of the other joints had ever shown similar signs of an arthritic flare-up.

Examination at the age of 42 years showed a mentally nor- mal, severely handicapped woman with a height of 144 cm and a weight of 49 kg. Mobility of the spine was severely restricted with complete fixation of the cervical spine in hyperextension and deviation to the right. Dorsal kyphosis and lumbar lordosis were accentuated. Mobility of the shoulder joints was reduced in all planes. Flexion/extension of the elbows was limited to

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Table 2. Major differential criteria between juvenile chronic poly- arthritis (rheumatoid arthritis) and PPAC

Rheumatoid arthritis PPAC

Course

Early Early manifestation manifestation takes mild and severe course course

Periarticutar soft tissue Yes No swelling

Synovitis (histol.) Yes No Systemic signs of Yes No

inflammation X-ray findings Destruction Dysplasia

600/54 ~ of the knees to 45~ ~ of the wrists to 40~ ~ Flexion and abduction of the hips were limited to 10 ~ The ankle joints were immobile. Extension and flexion of the finger joints were only mildly restricted. All joints were prominent without signs of soft-tissue involvement, effusion or abnormal position. They were painful in the morning, after exercise and on exter- nal pressure. The skin was normal. Liver, spleen, and lymph nodes were not enlarged. Neurologic examination was normal except for generalized muscular hypotrophic and weakness.

Radiographic examination showed generalized platyspon- dyly with narrow intervertebral disc spaces, partial synostosis of the cervical vertebrae, marked narrowing of all joint spaces with irregular articular surfaces and marked irregularity of sub- chondral bone structure but without erosive changes. Only few laboratory data were available (Table 1).

Special studies

Tests for serum rheumatoid factors and antibodies against various tissues were negative (Table 1). Muscle biopsies in patients 1 and 2 and a synovial biopsy in patient 1 gave normal or inconclusive results. A skin biopsy in patient 3 showed an increased number of mast cells, probably an unrelated allergic phenomenon [2].

An iliac crest biopsy was performed in patient 3. Histological examination showed an abnormal clustering

of chondrocytes in the resting and proliferative cartilage. The nests of chondrocytes were imbedded in material that stained deeply with PAS-Alcian blue and toluidin blue, less inten- sively with hematoxylyin-eosin (Fig. 5). The chondrocytes were polymorphous with pycnotic nuclei in many of them. In the growth zone columnization of the cells was defective. Capillary invasion, osteoid formation and mineralization seemed unaffected. Ulstrastructural studies showed chondro- cytes with large Golgi structure, intracytoplasmic vesicles and variably dilated cisterns of the endoplasmic reticulum. Some of the chondrocytes contained large vacuoles surrounded by osmiophilic deposits. The collagen fibers were of variable thickness and somewhat kinky. Within the nests of clustered chondrocytes the ground substance was irregular and there were spiral-like bundles of thin fibers, most of them without striation (Fig. 6).

Discussion

The main clinical features of PPAC are generalized, progres- sive impairment of joint mobility, osseous swelling of the

joints, best seen in the fingers and short stature in older patients. There are characteristic skeletal abnormalities, notably in the spine.

First symptoms appear between the ages of 3 and 8 years when walking difficulties, easy fatiguability and muscular weakness are noted. Tentative diagnoses at that stage include a polymyositis and muscular dystrophy. Increasing stiffness of the limb joints and spine, which tends to be more severe in the morning, and the increasing prominence of the joints then lead to a diagnosis of rheumatoid arthritis. When the spinal changes, the relentless course of the disease and its other dif- ferences from rheumatoid arthritis finally become apparent, the diagnosis is again changed to "endochondral dysostosis" or "bone dysplasia".

The differential diagnosis of PPAC includes most collagen diseases and the rheumatic diseases of childhood. Polymyo- sitis is suggested by muscular weakness and an occasional ele- vation of serum transaminases and creatinine phosphokinase. The course of the disease, its resistence to corticoids, normal electromyograms and normal muscle histology rule out that diagnosis. A turgid feel of the skin suggests scleroderma but there are no other signs of the disease and skin biopsies do not support the diagnosis. The lack of visceral involvement and the negative laboratory findings rule out lupus erythematodes, mixed connective tissue disease and the systemic forms of rheumatoid arthritis [1, 3, 6, 8, 9]. Ankylosing spondylitis does not usually begin before 8 years and affects more males than females [9]. Signs of arthritis or of involvement of the sacroiliac joints were not present in our patients, the cervical spine was more severely affected than the lower spine and HLA B 27 was negative in the patients in whom it was sought. There were no symptoms or signs to support a diagnosis of Reiter syndrome, arthritis of inflammatory bowel disease, psoriasis, or reactive arthritis.

Restricted mobility of multiple joints including those of the fingers and cervical spine, and growth retardation are common findings in the rheumatoid-factor-negative, polyarticular form of juvenile rheumatoid arthritis [9]. It occurs mostly in girls. PPAC differs from that form of rheumatoid arthritis by the absence of signs of soft tissue involvement and of laboratory signs of inflammatory disease. In particular, the erythrocyte sedimentation rate and CRP are mostly normal, there is no anemia or leucocytosis. The prominence of the joints is caused by osseous swelling of the bone ends. In fact, the digital changes recall those of "digital polyarthrosis" of the middle- aged women [6]. A synovial biopsy in one of our patients was normal. Radiologically, there are no signs of osseous erosion. Most importantly, the spinal abnormalities are not found in this or other forms of rheumatoid arthritis (Table 2). They are dysplastic in nature, i.e., they are caused by defects in bone formation and must not be confused with degenerative or destructive bone changes [3]. The pattern of osseous findings in PPAC is different from that in other osteochondrodys- plasias [101.

The disorder is not "new". It has previously be mentioned by us [11, 12] and others [5, 13]. Perri recognized the radio- graphic features of the disorder [7]. Some patients described in the older literature may have had the same condition [3, 4]. According to Dr.R. Wynne-Davies who observed 15 cases, mostly of Arab origin, PPAC may not be an exceptionally rare disorder [131.

PPAC has been observed in siblings of unaffected and con- sanguineous parents ([13], our patient 4) suggesting that it is a genetic disease with autosomal recessive inheritance. Its

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pathogenesis is obscure but the chondral abnormali t ies found in our patient suggest that cartilage is the site of primary in- volvement .

Acknowledgement. We thank Dr. A. Bopp, Medical Director of the Kursanatorium Salinental, Bad Kreuznach, for his permission to in- clude data from patient 5.

References

1. Coleman WP, Coleman WP, Derbes V, Holly HW, Nesbitt LT (1977) Collagen disease in children. J Am Med Ass 237 : 1095-1100

2. Gfinther O (1980) Allergische Reaktion vom Typ V. Kutane baso- phile Uberempfindlichkeit. In: Filip G (Hrsg) Allergologie, Bd I. Banaschewski, Mfinchen, S 456f.

3. Kahn MF, Corvol MT, Jurman SH, Couture B, Amouroux J, de Seze S (1970) Le rhumatisme chondrodysplasique. Sem H6p 46 : 1938-1953

4. Laplane R, Fontaine JL, Lagardere B, Sambucy F (1972) Nanisme syndesmoplasique familial. Arch Fran 9 Pddiatr 29:831-838

5. Maroteaux P (1981) Personal communication to the authors

6. Miilier W, Schilling F (1977) Differentialdiagnose rheumatischer Erkrankungen. Aesopus, Mtinchen Lugano

7. Perri G (1981) The radiological features of a new bone dysplasia. Pediatr Radiol 11 : 109-113

8. Schaller JG (1979) Rheumatic diseases of childhood. In: Vaughan VC, McKay RJ, Behrman RE (eds) Textbook of pediatrics. Saun- ders, Philadelphia

9. Schaller JG (1979) The seronegative spondylarthropathies of childhood. Clin Orthop 143 : 76-83

10. Spranger J, Langer LO, Wiedemann HR (1974) Bone dysplasias. Fischer, Saunders, Stuttgart Philadelphia

11. Spranger J, Albert C, Schilling F (1980) A progressive connective tissue disease with features of juvenile rheumatoid arthritis and osteochondrodysplasia. Europ J Pediatr 133 : 186

12. Spranger J, Albert C, Schilling F, Bartsocas C (1983) Progressive pseudorheumatoid arthropathy of childhood (PPAC): a here- ditary disorder simulating juvenile rheumatoid arthritis. Am J Med Genet 14 : 399-401

13. Wynne-Davies R, Hall C, Ansell BM (1982) Spondylo-epiphyseal dysplasia tarda with progressive arthropathy, J Bone Jt Surg 64-B : 442-445

Received October 26, 1982 / Accepted November 17, 1982