Chapter 8 Joints

Alessandro Castriota-Scanderbeg, M.D.

Joints develop secondarily in the mesenchyme com- Joint Contracture, Joint Stiffness prised between the developing ends of two adjacent bones (mesenchymal interpose) at about 5 1/2 weeks. ᭤ [Limitation (loss) of (active and passive) The mesenchyme is converted to form fibrous tissue, joint motion] hyaline cartilage, or fibrocartilage, depending on whether the developing joint is a fibrous joint, a syn- The issue discussed in the current section encom- chondrosis, or a symphysis, respectively.At the site of passes a heterogeneous group of conditions, both in- a synovial joint, while the primitive mesenchyme of herited and acquired, isolated and associated with the interzone undergoes liquefaction and cavitation, syndromic and nonsyndromic malformation spec- giving rise to the articular cavity, its peripheral con- tra, localized to one joint and generalized. An intro- densation results in formation of the joint capsule duction to the contractural abnormalities developing (Resnick et al.1995).This process is completed by ap- after birth is first provided, followed by a discussion proximately 7 weeks of fetal age, and by 8 weeks of the congenital forms, which represent the main fo- movements of the limbs about the joint are appear- cus of the section. ing. Motion is essential for the normal development Flexion contracture and joint stiffness may occur of joints and contiguous structures. As discussed in as late manifestations of conditions causing joint more detail in the following pages, congenital limita- and/or surrounding tissue infiltration (sarcoidosis, tion or loss of joint function may be caused by factors amyloidosis), hemorrhage (trauma, hemophilia), or that either are intrinsic to the joint, or are extrinsic inflammation (rheumatoid arthritis, systemic lupus but inhibit fetal movements. erythematosus, dermatomyositis, scleroderma, gout, calcium pyrophosphate dihydrate crystal deposition disease, eosinophilic fasciitis) (Waugh et al. 1980; Reference Kane-Wanger et al.1992). Induration and sclerosis of the tendons and ligaments, subcutaneous tissue, and Resnick D, Manolagas SC, Niwayama G, Fallon MD. Histogene- muscles of a given joint may all be responsible for sis, anatomy, and physiology of bone. In: Resnick D (ed.) loss of the full range of joint motion. Joint contrac- Diagnosis of bone and joint disorders.W.B. Saunders Com- pany, Philadelphia, 1995 (3rd ed.), pp. 609–51 ture can also follow electrical or thermal burns, pro- longed immobilization (Woo et al. 1975), or end- stage degenerative arthropathy. In amyloidosis,joint Abnormalities of Joint Motion contracture may be related to articular and periartic- ular amyloid deposition, muscle or nerve involve- The articular abnormalities discussed in this section ment, or a combination of factors. Every joint can be may occur in association with a great variety of condi- affected, including those in the fingers (Bussiere et al. tions and therefore remain totally nonspecific in many 1976). Several patterns of joint involvement, often cases.Nevertheless,even if the specific diagnosis cannot followed by flexion contracture, may occur in pa- be determined, a systematic approach to these defects tients with diabetes mellitus, including periarthritis may help to identify broad categories of disorders, to (stiff shoulder due to capsular fibrosis and thicken- rule out certain diseases, and to provide insight into the ing) (Bridgman 1972), cheiroarthropathy (contrac- anatomical status of individual joints in the body. tures at the proximal interphalangeal joints, less This section summarizes the most relevant clini- commonly at other sites, in the absence of palmar cal and radiographic patterns of joint involvement, fascial thickening, tentatively attributed to connec- offering existing knowledge of the mechanisms lying tive tissue abnormalities, vascular changes, neuropa- behind the altered joint function whenever possible. thy, and myopathy) (Choulot et al. 1980), Dupuytren’s 474 Chapter 8 · Joints

b c

a d

Fig. 8.1 a–d. Progressive pseudorheumatoid arthropathy. a In and interphalangeal joints, and flexion contractures of the fin- a 13-year-old girl. Note fixed flexion deformity of the knees, gers. There is also diffuse osteoporosis. c Observe severe hips, elbows and fingers. b–d In a 17-year-old boy. b There is platyspondyly, irregular end-plates, and anterior vertebral enlargement of the proximal and distal ends of phalanges, beaking. d Note premature osteoarthritis, deformed femoral joint space narrowing in the carpal, metacarpo-phalangeal, capital epiphyses, and coxa vara. (From Kaibara et al. 1983) contracture (interphalangeal joint contracture of the 8 years with waddling gait, muscle weakness, and 4th and 5th fingers due to thickening of the palmar painful swelling of multiple joints, particularly in the fascia) (Noble et al. 1984), and flexor tenosynovitis hands. Initial symptoms, i.e., morning stiffness and (interphalangeal joint contracture due to a constrict- decreased mobility of the cervical spine, suggest ed flexor tendon sheath). Multiple joint stiffness and rheumatoid arthritis, but synovitis is absent, the sed- large-joint contractures are manifestations of the imentation rate is within normal range, and rheuma- autosomal recessive progressive pseudorheumatoid toid factor tests are negative. Moreover, soft tissues arthropathy (OMIM 208230), a rare skeletal dysplasia around the joints are not involved, and swelling of with progressive arthropathy mimicking rheumatoid the finger joints is caused by osseous expansion of arthritis (Wynne-Davies 1982; Adak et al. 1998). The the ends of the phalanges. Arthropathy is character- disease generally manifests between the ages of 3 and istically progressive, and affected patients become Abnormalities of Joint Motion 475

crippled because of multiple joint contractures, with fixed flexion deformity of the hips, knees, and el- bows. Roentgenographic changes include general- ized osteoporosis; bulbous enlargement of both ends of the phalanges in the hands; platyspondyly, Scheuermann-like lesions, and kyphoscoliosis in the spine; long bone epiphyseal dysplasia with prema- ture osteoarthritis; and multiple flexion deformities (Fig. 8.1a–d). Universal platyspondyly results in short stature. The head and face are normal (Kaibara et al. 1983; Spranger et al. 1983). Spondylo-epiphyseal dysplasia (Stanescu type) shares several clinical and radiographic features with progressive pseudorheu- matoid dysplasia, including multiple joint swelling and stiffness, progressive joint contractures, platy- spondyly, bulbous widening of the phalanges, and premature osteoarthritis (Fig. 8.2a,b). However, nor- mal height, coxa valga, lack of vertebral tonguing, and autosomal dominant inheritance unambiguously identify patients with Stanescu type of dysplasia (Nishimura et al. 1998). Paradoxical joint stiffness may occur in conditions with joint laxity, such as Ehlers-Danlos syndrome, Marfan syndrome,and ho- mocystinuria. In these disorders, ligamentous laxity and recurrent dislocations lead to precocious os- teoarthritis (during the 3rd or 4th decade of life) and, possibly, to flexion joint contracture. Commonly in- volved joints are the hands, knees, and shoulders (Lewkonia and Pope 1985; Beighton and Horan 1969). Another potential mechanism is persistent joint effu- sion and hemarthrosis from repetitive subclinical trauma, again caused by ligamentous and capsular a laxity (Osborn et al. 1981). It is of interest for the dif- ferential diagnosis that joint contracture occurs only in the 5th digits of the hands in Marfan syndrome, whereas it occurs in multiple digits, the elbows, and the knees in homocystinuria (Brenton et al. 1972). Congenital joint contractures may be divided in two broad groups,depending on whether the ultimate cause is intrinsic or extrinsic to the developing fetus (Jones 1997). Intrinsic factors include neurological abnormalities, such as anencephaly, microcephaly, hydranencephaly, unilateral cerebral hypoplasia, holoprosencephaly, meningomyelocele, anterior mo- tor horn cell degeneration, aberrant myelin forma- b tion, and several others (Hageman et al. 1985, 1988, Fig. 8.2 a,b. Spondyloepiphyseal dysplasia, Stanescu type in the 1994; Gorgen-Pauly et al. 1999; Borochowitz et al. 14-year-old boy whose case is illustrated in Fig. 4.32. a Note rela- 1991; Kobayashi et al. 1995; Novotniy 1998); muscle tively short trunk, flexion contracture of knees, hips, and elbows, abnormalities, such as fetal myopathies, myotonic and genu valgum. The boy’s height is normal. b Note bulbous ex- dystrophy (Steinert syndrome), myotonic chondro- pansion of both ends of the phalanges with megaepiphyses, flex- dystrophy (Schwartz-Jampel syndrome), and muscle ion of distal interphalangeal joints, and premature osteoarthri- tis. These changes are indistinguishable from those of progres- agenesis (Jobsis et al. 1999; Hageman et al. 1986; sive pseudorheumatoid dysplasia. (From Nishimura et al. 1998) Wieacker et al. 1985); and joint and/or contiguous tis- 476 Chapter 8 · Joints

births, and can be seen in isolation or in association with other abnormalities. Over 150 syndromic and nonsyndromic conditions manifest with multiple congenital joint contractures at birth, and the etiolog- ic and genetic basis of these is very heterogeneous (Hall 1985; Ladda et al. 1993; Froster-Iskenius et al. 1988; Herva et al.1988; Lowry et al.1985).In a study of 350 patients with various kinds of congenital contrac- tures, 135 (38%) were found to have a specific syn- drome termed amyoplasia (see discussion below); 80 patients (23%) had mental or developmental retarda- a tion (11 of these had abnormal karyotypes, about half of them being chromosomal mosaics) (Reed et al. 1985); 11 patients (3%) had multiple limb pterygia (7 of which were instances of the autosomal recessive multiple pterygium syndrome) (Hall et al.1982b),and 15 patients (4%) had had a possible teratogenic expo- sure during fetal life (infection, maternal drug or tox- in ingestion, chronic maternal illness, or direct physi- cal insult) (Hall and Reed 1982). Regardless of the eti- ology, joint contractures are secondary to fetal akinesia, suggesting that function is an integral part of normal joint development. The clinical phenotype varies according to the underlying etiology, but some features, including equinovarus deformity of the foot, ulnar deviation of the hand, carpotarsal fusions, hip dislocation, patella malposition and dislocation, and scoliosis are common to all types (Hall 1985; Poznan- ski and La Rowe 1970). A practical approach to the etiology of arthrogry- posis that is useful for estimation of the recurrence risk (including the empiric recurrent risk if a specif- b ic diagnosis cannot be reached) and natural history Fig. 8.3 a,b. Amyoplasia (arthrogryposis multiplex congenita) and for decisions on possible therapeutic strategies, in the 11-year-old boy whose case is illustrated in Fig. 4.38b. consists in identifying children with limb involve- Note a fixed flexion of both hands at the wrist, b equinovarus ment only, those with involvement of the limbs and deformity, and gracile appearance of the tubular bones, espe- cially the fibula. The abnormalities were bilateral and symmet- other body areas (trunk,craniofacial or visceral),and rical. Additional findings in this boy were bilateral hip sublux- those with involvement of the limbs in association ation (Fig. 4.38b) and scoliosis with severe central nervous system dysfunction (Hall 1984, 1989). Examples of the first group (limb involve- ment only) include familial camptodactyly, amyo- sue problems, such as lack of joint development, syn- plasia, trismus-pseudocamptodactyly syndrome, and ostosis, congenital skin anomalies (restrictive der- distal arthrogryposis.Camptodactyly,a peculiar type mopathy), aberrant fixation of joints (diastrophic of localized joint contracture involving the proximal dysplasia), and aberrant soft tissue fixations (pop- interphalangeal joints of the fingers, is discussed in liteal pterygium syndrome). In contradistinction, ex- Chapter 6. Amyoplasia (OMIM 108110) is a sporadic trinsic factors act through a mechanical restriction of disorder characterized by the absence of limb mus- the fetus, such as fetal crowding and constraint from cles and their replacement by fibrous and fatty tissue. any cause (multiple births, oligohydramnios) (Hall This is the condition usually meant when the term 1985).As the term is applied currently, arthrogryposis ‘arthrogryposis multiplex congenita’ is used.At birth, is not a disease itself, but a birth defect consisting in limb positioning is typical: internal rotation of the multiple nonprogressive joint contractures of prena- shoulders, extension of elbows, and flexion of the tal onset.The defect occurs in approximately 1 in 3000 hands at the wrists. Severe equinovarus deformities Abnormalities of Joint Motion 477

Examples of the second group (involvement of limbs plus other body areas) include congenital con- tractural arachnodactyly, multiple pterygium syn- drome, and Schwartz-Jampel syndrome. Congenital contracture arachnodactyly (Beals syndrome, OMIM 121050) is phenotypically similar to the Marfan syn- drome, with arachnodactyly, dolichostenomelia, pro- gressive kyphoscoliosis, abnormal ears (resembling cabbage leaves), patellar dislocation, and congenital contractures of both hands. With increasing age, the clenched hands of the newborn improve, turning in- to camptodactyly. Contractures of other joints, espe- cially of elbows, are present to varying degrees.A dif- ference from Marfan syndrome is that the aorta and Fig. 8.4. Arthrogryposis, distal type I in a 4 1/2-year-old boy. the eyes are not affected. Mutations occurring in two Note clenched hands with medially overlapping fingers and ul- nar deviation of the fingers. Flexion deformities and contrac- structurally related genes encoding large fibrillin tures similar to those in the hands were evident in the feet (not proteins, the FBN1 gene located at 15q15–21.3 and shown). No other skeletal or visceral anomalies were present the FBN2 gene located at 5q23–31, cause the Marfan syndrome and the congenital contracture arachno- dactyly, respectively (Lee et al. 1991; Putnam et al. of the feet and contractures at knees and hips are 1995; Babcock et al. 1998). The autosomal recessive usually present. The face is typically round, with a multiple pterygium syndrome (Escobar syndrome, frontal midline capillary hemangioma and slightly OMIM 265000) features multiple pterygia, campto- small jaw. Intelligence is normal. Symmetrical limb dactyly and syndactyly. Pterygia occur in the neck, involvement (four limbs, 63%; lower limbs, 24%; up- axilla, elbow, popliteal fossa, fingers, and intercrural per limbs, 13%) and absence of other major malfor- areas. Affected patients are short, with a characteris- mations are typical (Hall et al. 1983a). Radiographic tic facies (down-slanting palpebral fissures, ptosis of manifestations include gracile bones, fibular hy- eyelids, hypertelorism, epicanthal folds, microg- poplasia, scoliosis, dislocation of hip and patella nathia, down-turned corners of the mouth, sad ex- (Fig. 8.3a,b). Identical twins are differently affected pression, low-set ears). Additional features include (Hall et al. 1983b). ‘Arthrogryposis multiplex con- talipes equinovarus and/or rocker-bottom feet, geni- genita, distal type,’ is a designation for congenital tal anomalies (cryptorchidism, absence of labia ma- contractures with major involvement of the hands jora), and musculoskeletal anomalies (multiple flex- and feet. Arthrogryposis, distal type I (OMIM 108120), ion contractures, scoliosis, kyphosis, vertebral fu- a condition of autosomal dominant inheritance with sions, rib anomalies, absent patella). Occasionally, variable expression, manifests at birth with tightly radial head and hip dislocation, diaphragmatic her- clenched fists with medially overlapping fingers, nia, and cardiac defects are also present. Intelligence ulnar deviation, and positional foot deformities is normal (Hall et al. 1982b; Escobar et al. 1978). (Fig. 8.4). Contractures at other major joints are vari- Schwartz-Jampel syndrome (chondrodystrophia my- able. Intelligence is normal, and there are no associ- otonica, OMIM 255800), also of autosomal recessive ated visceral anomalies. Camptodactyly replaces inheritance, is characterized by myotonia, blepharo- clenched fists in adult life (Hall et al. 1982a). Arthro- phimosis, and joint contractures. A primary muscle gryposis, distal type II (OMIM 108130) occurs in var- disorder with hypotonia is possibly responsible for ious combinations and patterns with other defects, most of the clinical features. In fact, early diagnosis including fused cervical vertebrae, webbed neck, and treatment with carbamazepine can resolve my- kyphoscoliosis, congenital hip dislocation, cleft lip otonia and prevent the development of the classic and palate, micrognathia, ptosis, trismus, a unique clinical picture. Manifestations of the disorder in- hand position, dull normal intelligence, and short clude short stature, expressionless fixed face, pursed stature (Hall et al. 1982a; Reiss and Sheffield 1986; lips, narrowed palpebral fissures, small mandible, Kawira and Bender 1985).Although the pathogenesis myopia, spinal malalignment, pectoral deformity, ac- of these disorders remains obscure, abnormal ten- etabular dysplasia, and bowed long bones (Schwartz don attachments have been implicated (Hall et al. and Jampel 1962; Squires and Prangley 1996). Mental 1982a). retardation is present in 25% of cases. The disease 478 Chapter 8 · Joints course is one of progressive muscle weakness and 1. Multiple flexion deformities; widening of meta- joint contractures reaching a plateau in mid-child- physes and epiphyses of the phalanges; platy- hood. spondyly; premature osteoarthritis; osteoporosis Examples of the third group of arthrogrypotic dis- (progressive pseudorheumatoid arthropathy) orders (limb involvement plus central nervous sys- 2. Flexion contracture of the interphalangeal joint of tem problems) are the Marden-Walker syndrome the 5th digits; arachnodactyly; dolichostenomelia; and the Pena-Shokeir syndrome. Clinical manifesta- patella dislocation (Marfan syndrome) tions in Marden-Walker syndrome (OMIM 248700), 3. Multiple, symmetrical joint contractures, com- an autosomal recessive disorder, include fixed facial monly involving all four limbs (shoulders, elbows, expression, blepharophimosis, and joint contrac- hands, wrists, knees and hips); severe foot equino- tures. Central nervous system defects include agene- varus; absent limb muscles; gracile bones; fibular sis of corpus callosum, cerebellar hypoplasia, brain hypoplasia; scoliosis; hip and patella dislocation stem hypoplasia, hydrocephalus, and Dandy-Walker (amyoplasia) malformation. Micrognathia, decreased muscle mass 4. Congenital contractures of the fingers and toes, with hypotonia, microcephaly, and mental retarda- isolated (arthrogryposis, distal type I) or associat- tion are also part of the syndromic spectrum. Death ed with fused cervical vertebrae, kyphoscoliosis, within the first months of life is relatively common, congenital hip dislocation, cleft lip and palate, and occurring as a secondary event of aspiration, sepsis, micrognathia (arthrogryposis, distal type II) or cardiac failure (Marden and Walker 1966). ‘Pena- 5. Arachnodactyly; dolichostenomelia; progressive Shokeir’ is often used as an aspecific label for a clini- kyphoscoliosis; patellar dislocation; congenital cal phenotype caused by decreased intrauterine contractures of both hands, camptodactyly (con- movement, regardless of the specific cause. There- genital contracture arachnodactyly) fore, the designations ‘Pena-Shokeir phenotype’ and 6. Multiple flexion contractures; multiple pterygia; ‘fetal akinesia/hypokinesia sequence’ may be used camptodactyly and syndactyly; characteristic fa- interchangeably (Hall 1986). The Pena-Shokeir phe- cies (multiple pterygium syndrome) notype occurs in a group of etiologically heteroge- 7. Joint contractures; myotonia; blepharophimosis neous disorders. When fully expressed, this pheno- (Schwartz-Jampel syndrome) type is characterized by polyhydramnios, intrauter- 8. Joint contractures; fixed facial expression; ble- ine growth retardation, pulmonary hypoplasia, pharophimosis (Marden-Walker syndrome) craniofacial and limb anomalies, multiple congenital 9. Multiple congenital joint contractures; pulmonary contractures, short umbilical cord, and lethality hypoplasia; unusual facies; lethality (Pena-Shokeir (Herva et al. 1985). Polyhydramnios is the result of syndrome) failure of normal deglutition, lung hypoplasia, or de- ficient function of the diaphragm and intercostal Associations muscles. The short umbilical cord and the multiple • Aarskog syndrome joint contractures are caused by the absence of fetal • Aase-Smith syndrome movements. Hence, overlap with arthrogryposis • Achondroplasia multiplex congenita is recognized. The unusual fa- • Acromesomelic dysplasia cies and lethality in Pena-Shokeir allow the differen- • Addison disease tial diagnosis. Furthermore, interphalangeal sublux- • Adducted thumb syndrome ation has been reported as a potentially specific sign • Amyloidosis of Pena-Shokeir (Houston and Shokeir 1981). Over- • Amyoplasia congenita disruptive sequence lap is also recognized between the Pena-Shokeir phe- • Antley-Bixler syndrome notype and trisomy 18 (Jones 1997). • Apert syndrome • Aplasia cutis congenita Radiographic Synopsis • Arthrogryposis, distal, types I and II Evaluation of the skeleton aims at verifying whether • Arthrogryposis-advanced skeletal maturation- joint fixation is due to an anatomic anomaly (for ex- unusual facies ample, congenital synostosis) or to a deficit of joint • Camptodactyly-ichthyosis syndrome function in the absence of primary structural causes. • Catel-Manzke syndrome In joint contractures occurring as part of a primary • Caudal dysplasia sequence disease the radiographic findings are those of the un- • Cerebro-oculo-facio-skeletal syndrome derlying disease process. • CHILD syndrome Abnormalities of Joint Motion 479

• Chondrodysplasia punctata (recessive, X-linked • Metaphyseal chondrodysplasias dominant) (Jansen, McKusick, Schmid) • Chromosomal abnormalities (trisomy 8,trisomy 9, • Metatropic dysplasia mosaic, 13, trisomy 18, XXXXY, deletion 11q, • Mietens-Weber syndrome duplication 4p, duplication 10q, duplication 15q) • Moore-Federman syndrome • Cockayne syndrome • Mucolipidoses • Contractural arachnodactyly, congenital • Mucopolysaccharidoses (Beals syndrome) (Hunter, Hurler, Morquio, Maroteaux-Lamy) • De Lange syndrome • Multiple epiphyseal dysplasia • Dermo-chondro-corneal dystrophy of François • Multiple pterygium syndrome • Diabetes mellitus (Escobar syndrome) • Diastrophic dysplasia • Multiple synostoses syndrome • Digitotalar dysmorphism (facio-audio-symphalangism) • Duchenne muscular dystrophy • Myhre syndrome • Dyggve-Melchior-Clausen syndrome • Nail-patella syndrome • Dyschondrosteosis • Neu-Laxova syndrome • Dysplasia epiphysealis hemimelica • Oligohydramnios sequence • Dyssegmental dysplasia • Oto-palato-digital syndrome type I • Epidermolysis bullosa dystrophica • Pachydermoperiostosis • Exostoses • Pallister-Hall syndrome • Fabry disease • Parastremmatic dwarfism • Farber disease • Pelvic dysplasia-arthrogrypotic lower limbs • Femoral hypoplasia-unusual facies syndrome • Pena-Shokeir syndrome • Fetal-alcohol syndrome • Pleonosteosis (Leri) • FG syndrome • Popliteal pterygium syndrome • Fibrochondrogenesis • Progeria • Fibrodysplasia ossificans progressiva • Progressive pseudorheumatoid chondrodysplasia • Fluorosis • Pseudoachondroplasia • Flynn-Aird syndrome • Pseudodiastrophic dysplasia • Freeman-Sheldon syndrome • Pyle metaphyseal dysplasia • Frontometaphyseal dysplasia • Restrictive dermopathy • Geleophysic dysplasia • Rigid spine syndrome • German syndrome • Rutledge lethal congenital anomaly syndrome • GM1 gangliosidosis • Saethre-Chotzen syndrome • Golden-Lakim syndrome • Schwartz-Jampel syndrome • Goodman camptodactyly syndrome • Scleroderma • Gordon syndrome • Seckel syndrome • Hecht syndrome • Shprintzen-Goldberg syndrome • Hemophilia • Sjögren-Larsson syndrome • Homocystinuria • Spondylocostal dysplasia, Jarcho-Levin • Hypochondroplasia • Spondyloepiphyseal dysplasia congenita • Infantile multisystem inflammatory disease • Spondyloepiphyseal dysplasia (Stanescu) • Killian/Teschler-Nicola syndrome • Spondylometaphyseal dysplasia (Kozlowski) • Klein-Waardenburg syndrome • Stewart-Bergstrom syndrome • Kniest dysplasia • Stickler syndrome • Kuskokwim syndrome • Trismus pseudocamptodactyly syndrome (Hecht) • Kyphomelic dysplasia • Tumoral calcinosis • Leri-Weill dyschondrosteosis • Weaver syndrome • Macrodystrophia lipomatosa • Weill-Marchesani syndrome • Mandibuloacral dysplasia • Winchester syndrome • Marden-Walker syndrome • Zellweger syndrome • Melorheostosis 480 Chapter 8 · Joints

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Muscle weakness and congenital contractures in a case of arthrogryposis (X-linked infantile spinal muscular atro- congenital myasthenia. J Pediatr Orthop 1986; 6: 227–31 phy) maps to human chromosome Xp11.3-q11.2. Hum Mol Hageman G, Ippel EP, Beemer FA, de Pater JM, Lindhout D, Genet 1995; 4: 1213–6 Willemse J. The diagnostic management of newborns with Ladda RL, Zonana J, Ramer JC, Mascari MJ, Rogan PK. Con- congenital contractures: a nosologic study of 75 cases.Am J genital contractures, ectodermal dysplasia, cleft lip/palate, Med Genet 1988; 30: 883–904 and developmental impairment: a distinct syndrome. Am J Hageman G, Hoogenraad TU, Prevo RL. The association of Med Genet 1993; 47: 550–5 cortical dysplasia and anterior horn arthrogryposis: a case Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, report. Brain Dev 1994; 16: 463–6 Tsipouras P, Ramirez F, Hollister DW. Linkage of Marfan Hall JG. 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Teratogens associated with congenital con- syndrome. Am J Dis Child 1966; 112: 225–8 tractures in humans and in animals. Teratology 1982; 25: Nishimura G, Saitoh Y, Okuzumi S, Imaizumi K, Hayasaka K, 173–91 Hashimoto M. Spondyloepiphyseal dysplasia with accumula- Hall JG, Reed SD, Greene G. The distal arthrogryposes: delin- tion of glycoprotein in the chondrocytes: spondyloepiphyseal eation of new entities – review and nosologic discussion. dysplasia, Stanescu type. Skeletal Radiol 1998; 27: 188–94 Am J Med Genet 1982a; 11: 185–239 Noble J, Heathcote JG, Cohen H. Diabetes mellitus in the aeti- ology of Dupuytren’s disease. J Bone Joint Surg Br 1984; 66: 322–5 Abnormalities of Joint Motion 481

Novotny EJ.Arthrogryposis associated with connatal Pelizaeus- Ankylosis can be due to calcium deposition in Merzbacher disease: case report. Neuropediatrics 1988; 19: the joint or in the soft tissues surrounding the joint.A 221–3 number of inflammatory and connective tissue disor- Osborn TG, Lichtenstein JR, Moore TL, Weiss T, Zuckner J. Ehlers-Danlos syndrome presenting as rheumatic manifes- ders are recognized in which joint ankylosis may be tations in the child. J Rheumatol 1981; 8: 79–85 part of the clinical spectrum.In advanced rheumatoid Poznanski AK, La Rowe PC. Radiographic manifestations of arthritis, the proliferative granulation tissue – or pan- the arthrogryposis syndrome. Radiology 1970; 95: 353–8 nus,the pathological hallmark of the disease – can ex- Putnam EA, Zhang H, Ramirez F, Milewicz DM. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congen- tend across the joint bridging the articular cavity. By ital contractural arachnodactyly. Nat Genet 1995; 11: 456–8 calcification of the dystrophic tissue that bounds the Reed SD,Hall JG,Riccardi VM,Aylsworth A,Timmons C.Chro- articular cartilages of opposing bones, the initial fi- mosomal abnormalities associated with congenital con- brous ankylosis is transformed into bony ankylosis. tractures (arthrogryposis). Clin Genet 1985; 27: 353–72 The disease has a predilection for the synovial articu- Reiss JA, Sheffield LJ. Distal arthrogryposis type II: a family with varying congenital abnormalities. Am J Med Genet lations of the appendicular skeleton, especially those 1986; 24: 255–67 in the hands and feet, wrist, knee, elbow, glenohumer- Schwartz O, Jampel RS. Congenital blepharophimosis associat- al and acromioclavicular joints. However, the at- ed with a unique generalized myopathy.Arch Ophthal 1962; lantoaxial joint and apophyseal joints of the cervical 68: 52–7 spine can also be involved. Bony proliferation with in- Spranger J, Albert C, Schilling F,Bartsocas C, Stoss H. Progres- sive pseudorheumatoid arthritis of childhood (PPAC): a tra-articular bony ankylosis frequently occurs in the hereditary disorder simulating rheumatoid arthritis. Eur J seronegative spondyloarthropathies (ankylosing Pediatr 1983; 140: 34–40 spondylitis, psoriasis, and Reiter’s disease), a group of Squires LA, Prangley J. Neonatal diagnosis of Schwartz-Jampel inflammatory disorders sharing radiologic and syndrome with dramatic response to carbamazepine. Pedi- pathological similarities with rheumatoid arthritis, atr Neurol 1996; 15: 172–4 Waugh W, Newton G, Tew M. Articular changes associated but with prominent involvement of the cartilaginous with a flexion deformity in rheumatoid and osteoarthritic articulations (discovertebral junctions, symphysis knees. J Bone Joint Surg Br 1980; 62: 180–3 pubis, manubriosternal joint) and entheses (tendi- Wieacker P,Wolff G,Wienker TF,Sauer M.A new X-linked syn- nous and ligamentous attachments in the calcaneus, drome with muscle atrophy, congenital contractures, and pelvis, femoral trochanters, humerus, patella, etc.). oculomotor apraxia. Am J Med Genet 1985; 20: 597–606 Woo SL, Matthews JV,Akeson WH, Amiel D, Convery FR. Con- The sites primarily affected by ankylosing spondylitis nective tissue response to immobility. Correlative study of are the joints and entheses of the axial skeleton.Psori- biomechanical and biochemical measurements of normal asis has a variable distribution, but is essentially a and immobilized rabbit knees. Arthritis Rheum 1975; 18: polyarticular disorder of appendicular joints, with 257–64 prominent involvement of the interphalangeal articu- Wynne-Davies R, Hall C,Ansell BM. Spondylo-epiphyseal dys- plasia tarda with progressive arthropathy: a ‘new’ disorder lations of the hands and feet. In Reiter’s disease, of autosomal recessive inheritance. J Bone Joint Surg Br asymmetrical involvement of the joints in the lower 1982; 64: 442–5 extremities, sacroiliitis, spondylitis, and calcaneal en- thesopathy are common manifestations. Intra-articu- lar bony ankylosis is relatively common in juvenile Ankylosis chronic arthritis, including the juvenile-onset adult type (seropositive) of rheumatoid arthritis, seronega- ᭤ [Joint fixation] tive juvenile chronic arthritis (Still’s disease), and ju- venile-onset ankylosing spondylitis, and also in septic Although ankylosis and synostosis are often used as arthritis. In the spine, obliteration of intervertebral synonyms, each term implies a distinct mechanism of disc spaces and bony bridging resulting in ankylosis joint fixation. Synostosis indicates a failure of joint of contiguous vertebrae also occurs in some cases of formation, while the true meaning of ankylosis is alkaptonuria, X-linked hypophosphatemia, calcium supervening fixation of a previously normally de- pyrophosphate dihydrate (CPPD) crystal deposition veloped joint. The radiographic and pathological disease (Brem 1982),and (occasionally) severe degen- aspects related to the presence of synostosis at specif- erative osteoarthritis. ic articular sites are discussed elsewhere in this book. A mixed pattern of intra-articular and periarticu- Similarly, congenital disease processes manifesting lar soft tissue (tendons, tendon sheaths, capsule, bur- with multiple synostoses, such as Antley-Bixler syn- sae) calcification (Resnick et al. 1977; Albert and Ott drome, Apert acrocephalosyndactyly, and multiple 1984) is characteristic of scleroderma, a generalized synostosis syndrome, are also not included here. disorder of connective tissue that affects the skin, 482 Chapter 8 · Joints

Bennett and O’Connell 1978; Notman et al. 1975; Alarcon-Segovia 1981). Ankylosis at the capitate- trapezoid articulation could possibly have clinical significance (Halla and Hardin 1978). As anticipated, ankylosis can also be due to bridg- ing heterotopic calcific or ossific deposits within the soft tissues surrounding the joint even when the joint itself is not primarily affected. Examples include trau- ma (myositis ossificans), neurological injury, postsur- gical scars,and thermal and electrical burns (Fig. 8.5). Thermal and electrical injuries affect the elbow,shoul- der, and hip most frequently, irrespective of their proximity to the burn site. If the joint is directly dam- aged by the burn intra-articular fusion may ensue. Progressive heterotopic ossification of muscles, tendons, ligaments, fasciae, aponeuroses and, occa- sionally, the skin in combination with bilateral short hallux is the clinical and pathological hallmark of fibrodysplasia (or myositis) ossificans progressiva syndrome (OMIM 135100), an inheritable connective tissue disorder (McKusick 1972). The inheritance pattern is autosomal dominant (the disease gene maps to 4q27-q31) (Feldman et al. 2000; Lucotte et al. 2000), with almost full penetrance for short hallux and wide variability for fibrodysplasia (McKusick 1972; Jones 1997). Most cases are sporadic, represent- ing spontaneous fresh mutations (Rogers and Geho 1979; Connor and Evans 1982; Connor et al. 1993) probably related to paternal age (Rogers and Chase Fig. 8.5. Electrical burn in a 34-year-old man. Note extra-ar- 1979; Tuente et al. 1967). The prevailing pathogenetic ticular heterotopic ossification leading to lateral osseous bridging of the hip. (From Balen et al. 2001) theory,which is not shared by all investigators (Smith 1998), is one of primary involvement of the fibrous tissue, with secondary extension to the striate mus- lungs, gastrointestinal tract, heart, kidney, and mus- cles through the contiguous fascial coverings (McKu- culoskeletal system. Articular involvement is com- sick 1972; Reinig et al. 1986; Kalukas and Adams mon in scleroderma, with preferential locations in 1985). Histological changes at the involved sites the fingers, wrists, and ankles. Erosive arthritis of the include edema, fibroblast proliferation, muscular distal interphalangeal joints (Resnick 1995; Baron et cell degeneration, and deposition of abnormal colla- al. 1982; Bassett et al. 1981), articulations that are not gen, which subsequently undergoes mineralization commonly involved in rheumatoid arthritis, of the (Cramer et al. 1981; Kaplan et al. 1993). The newly proximal interphalangeal, metacarpophalangeal, 1st formed bone is entirely identical to normal membra- carpo-metacarpal, and inferior radioulnar joints, nous bone. The initial clinical presentation includes which can culminate in bony ankylosis, can all be swelling, local warmth, pain, and fever, mimicking an seen in scleroderma (Jamieson et al. 1985; Resnick et infection, a trauma, or a neoplasm. Common sites of al. 1978; Bjersand 1968). Ankylosis of such major initial heterotopic ossification are neck (sternoclei- joints as the elbows and hips also occurs (Huyck and domastoid), shoulder girdle, spine, and pelvis. The Hoffman 1982). Mixed connective tissue disease is the distal extremities are involved late in the course of designation for a condition characterized by overlap- the disease.An entire muscle or group of muscles can ping clinical features of scleroderma, systemic lupus be replaced by bone. The smooth muscles are spared. erythematosus, dermatomyositis, and rheumatoid Joint ankylosis is caused by ossification of the sur- arthritis and by a feature revealed by laboratory in- rounding tissues, as opposed to a primary articular vestigations in all cases: the presence of antibodies to abnormality.Various postural deformities develop as RPN, a soluble ribonucleoprotein (Sharp et al. 1972; the result of joint ankylosis. Ankylosis of the tem- Abnormalities of Joint Motion 483

a b c

Fig. 8.6 a–e. Fibrodysplasia ossifi- cans progressiva. a In a 17-year-old male youth. Note short great toe with interphalangeal fusion. The phalanges are in mild valgus devia- tion. b–e In a 6-year-old girl. b Bony outgrows arising from the tibial metaphysis and reminiscent of os- teochondromas. Note also mature trabecular heterotopic ossification bone in the axilla (c), iliopsoas mus- cles (d), and nuchal ligament (e). d e (From Mahboubi et al. 2001) poromandibular joint limits nutrition, while involve- current remissions and exacerbations (Cohen et al. ment of the hips leaves the patient wheelchair bound 1993). Radiographic manifestations include bilateral (Connor and Evans 1982; Cohen et al. 1993). Hearing short hallux (90%), often with interphalangeal fu- loss is common. Most patients experience symptom sions; hallux valgus; short thumbs (about 50%); onset at about 5 years of age. Restricted mobility of cylindrical columns of solid new bone replacing an a single or of multiple joints is apparent within entire muscle or group of muscles; ‘pseudoexostoses’ 15 years in the vast majority of patients (Cremin et al. at the insertions of tendons, ligaments, and fasciae; 1982). The natural history of the disease is one of re- progressive intervertebral fusions (especially in the 484 Chapter 8 · Joints cervical spine); and ossification of the spinal liga- 5. Erosive arthritis of the distal and proximal inter- ments (Fig. 8.6a–e). Occasionally X-rays show short phalangeal joints, metacarpophalangeal joints, 1st middle phalanges of the 5th fingers and toes with carpometacarpal joints, and inferior radioulnar clinodactyly; malformed cervical vertebrae; broad joints; tuftal resorption; skin atrophy; soft tissue femoral necks; cortical thickening of both tibias; calcification (scleroderma) broad mandibular condyle; spina bifida; scoliosis; 6. Bilateral short hallux; short thumbs (less com- and lumbar spinal stenosis (Cremin et al. 1982; mon); heterotopic ossification of striate muscles; Thickman et al. 1982). The trabecular pattern of the ‘pseudoexostoses’ at insertion points of tendons, heterotopic bone in this condition allows its distinc- ligaments, fasciae, and aponeuroses; ankylosis tion from other disorders with periarticular calcium of spine, shoulders, hips, temporomandibular deposition, including idiopathic calcinosis univer- joints, etc. (fibrodysplasia ossificans progressiva salis, dermatomyositis, idiopathic tumoral calcinosis, syndrome) and disorder of calcium metabolism, in which the dense lesions remain calcific and do not mature into Associations trabecular bone.Disorders such as Klippel-Feil,Still’s • Alkaptonuria disease,and ankylosing spondylitis,which share sim- • Ankylosing spondylitis ilarities with fibrodysplasia progressive ossificans at • Calcium pyrophosphate dihydrate (CPPD) crystal the spinal level, can be easily ruled out by ascertain- deposition disease ing the absence of the typical anomalies involving • Degenerative osteoarthritis the great toes, which are present and potentially rec- • Fibrodysplasia ossificans progressiva syndrome ognizable at birth in all cases of fibrodysplasia ossifi- • Hemophilia cans progressiva (Smith et al. 1996). • Juvenile chronic arthritis • Mixed connective tissue disease Radiographic Synopsis • Neurological injury 1. Symmetrical involvement of the synovial joints of • Osteogenesis imperfecta the appendicular skeleton (hands, feet, wrists, • Psoriasis knees, elbows, and shoulders most involved); soft • Reiter’s disease tissue swelling; osteoporosis; joint space narrow- • Rheumatoid arthritis ing; marginal bony erosions; subchondral cyst for- • Scleroderma mation; joint ankylosis, deformity, and dislocation • Septic arthritis (rheumatoid arthritis) • Surgical scars 2. Synovial and cartilaginous articulations involved; • Thermal and electric burns preferential involvement of the joints in the axial • Trauma skeleton (sacroiliac, apophyseal, discovertebral, • Winchester syndrome and costovertebral articulation); characteristic • X-linked hypophosphatemia pattern of spinal ascent; involvement of entheses; joint space narrowing and erosion; marginal scle- rosis; bone formation within joint capsule, ten- References dons, and ligaments; joint ankylosis (ankylosing spondylitis) Alarcon-Segovia D. Mixed connective tissue disease-a decade 3. Synovial and cartilaginous articulations involved; of growing pains. J Rheumatol 1981; 8: 535–40 Albert J, Ott H. Unusual articular abnormalities in scleroder- asymmetrical involvement of the appendicular ma. Clin Rheumatol 1984; 3: 323–7 (upper and lower limb) and axial joints; promi- Balen PF, Helms CA. Bony ankylosis following thermal and nent involvement of the interphalangeal articula- electrical injury. Skeletal Radiol 2001; 30: 393–7 tions of hands and feet; osteolysis of terminal Baron M, Lee P, Keystone EC. The articular manifestations of phalanges; bone formation within joint capsule, progressive systemic sclerosis (scleroderma). Ann Rheum Dis 1982; 41: 147–52 tendons, and ligaments; intra-articular bony anky- Bassett LW,Blocka KL, Furst DE, Clements PJ, Gold RH. Skele- losis (psoriasis) tal findings in progressive systemic sclerosis (scleroder- 4. Synovial and cartilaginous articulations involved ma). AJR Am J Roentgenol 1981; 136: 1121–6 with findings reminiscent of psoriasis; asymmet- Bennett RM, O’Connell DJ. The arthritis of mixed connective rical involvement of the appendicular (lower tissue disease. Ann Rheum Dis 1978; 37: 397–403 Bjersand AJ. New bone formation and carpal synostosis in limb) and axial joints; calcaneal enthesopathy; scleroderma. A case report. Am J Roentgenol Radium Ther resolution of some lesions (Reiter’s disease) Nucl Med 1968; 103: 616–9 Abnormalities of Joint Motion 485

Brem JB.Vertebral ankylosis in a patient with hereditary chon- Resnick D, Greenway G, Vint VC, Robinson CA, Piper S. Selec- drocalcinosis: a chance association? Arthritis Rheum 1982; tive involvement of the first carpometacarpal joint in scle- 25: 1257–63 roderma. AJR Am J Roentgenol 1978; 131: 283–6 Cohen RB, Hahn GV, Tabas JA, Peeper J, Levitz CL, Sando A, Rogers JG, Chase GA. Paternal age effect in fibrodysplasia ossi- Sando N, Zasloff M, Kaplan FS. The natural history of het- ficans progressiva. J Med Genet 1979; 16: 147–8 erotopic ossification in patients who have fibrodysplasia Rogers JG, Geho WB. Fibrodysplasia ossificans progressiva. A ossificans progressiva: a study of forty-four patients. J Bone survey of forty-two cases. J Bone Joint Surg Am 1979; 61: Joint Surg Am 1993; 75: 215–9 909–14 Connor JM, Evans DA. Fibrodysplasia ossificans progressiva. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed The clinical features and natural history of 34 patients. connective tissue disease-an apparently distinct rheumatic J Bone Joint Surg Br 1982; 64: 76–83 disease syndrome associated with a specific antibody to an Connor JM, Skirton H, Lunt PW. A three generation family extractable nuclear antigen (ENA). Am J Med 1972; 52: with fibrodysplasia ossificans progressiva. J Med Genet 148–59 1993; 30: 687–9 Smith R, Athanasou NA, Vipond SE. Fibrodysplasia (myositis) Cramer SF, Ruehl A, Mandel MA. Fibrodysplasia ossificans ossificans progressiva: clinicopathological features and progressiva: a distinctive bone-forming lesion of the soft natural history. Q J Med 1996; 89: 445–56 tissue. Cancer 1981; 48: 1016–21 Smith R. Fibrodysplasia (myositis) ossificans progressiva. Cremin B, Connor JM, Beighton P. The radiological spectrum Clinical lessons from a rare disease. Clin Orthop 1998; 346: of fibrodysplasia ossificans progressiva. Clin Radiol 1982; 7–14 33: 499–508 Thickman D, Bonakdar-Pour A, Clancy M, van Orden J, Feldman G, Li M, Martin S, Urbanek M, Urtizberea JA, Fardeau Steel H. Fibrodysplasia ossificans progressiva. AJR Am J M, LeMerrer M, Connor JM, Triffitt J, Smith R, Muenke M, Roentgenol 1982; 139: 935–41 Kaplan FS, Shore EM. Fibrodysplasia ossificans progressi- Tuente W,Becker PE, von Knorre GV.Zur Genetik der Myositis va, a heritable disorder of severe heterotopic ossification, ossificans progressiva. Humangenetik 1967; 4: 320–51 maps to human chromosome 4q27–31. Am J Hum Genet 2000; 66: 128–35 Halla JT, Hardin JG. Clinical features of the arthritis of mixed connective tissue disease. Arthritis Rheum 1978; 21: 497– Joint Laxity, Joint Hypermobility 503 Huyck CJ, Hoffman GS. Bony ankylosis of the hips in progres- ᭤ [Hyperextensible joints, increased range sive systemic sclerosis.Arthritis Rheum. 1982; 25: 1497–500 of joint motion] Jamieson TW, de Smet AA, Stechschulte DJ. Erosive arthropa- thy associated with scleromyxedema. Skeletal Radiol 1985; 14: 286–90 The osseous surfaces of a synovial articulation are Jones KL. Smith’s recognizable patterns of human malforma- bound together by a fibrous capsule externally rein- tions.W.B. Saunders Company, Philadelphia, 1997 (5th ed.), forced by a variety of supporting structures (ten- p. 492 dons, aponeuroses, fasciae, and ligaments) and, at Kalukas BA, Adams RD. Disease of muscles. Harper & Row, some joint sites, by accessory intra-articular liga- Philadelphia, 4th ed., 1985, p. 659 Kaplan FS, Tabas JA, Gannon FH, Finkel G, Hahn GV, Zasloff ments (e.g., the cruciate ligaments of the knee). The MA. The histopathology of fibrodysplasia ossificans pro- fibrous capsule represents the outer layer of the artic- gressiva: an endochondral process. J Bone Joint Surg Am ular capsule (the inner layer being the synovial mem- 75: 1993; 220–30 brane) and is composed of parallel and interlacing Lucotte G, Bathelier C, Mercier G, Gerard N, Lenoir G, Semonin thick bundles of connective tissue. The ligaments are O, Fontaine K. Localization of the gene for fibrodysplasia ossificans progressiva (FOP) to chromosome 17q21–22. tough bands of connective tissue that resist excessive Genet Counsel 2000; 11: 329–34 or abnormal motion and are therefore essential to Mahboubi S, Glaser DL, Shore EM, Kaplan FS. Fibrodysplasia the maintenance of joint stability (Resnick and Ni- ossificans progressiva. Pediatr Radiol 2001; 31: 307–14 wayama 1995). McKusick VA. Fibrodysplasia ossificans progressiva. In: McKu- In disorders of the connective tissue with joint sick VA (ed.) Heritable disorders of connective tissue. C.V. Mosby Company, St. Louis, 1972 (4th ed.), p. 687 laxity, the articular capsule, the ligaments, and the Notman DD, Kurata N, Tan EM. Profiles of antinuclear anti- periarticular supporting tissues are all involved by bodies in systemic rheumatic diseases. Ann Intern Med the primary mesenchymal defect. In the Ehlers-Dan- 1975; 83: 464–9 los syndromes, a group of disorders with impaired Reinig JW, Hill SC, Fang M, Marini J, Zasloff MA. Fibrodyspla- collagen synthesis (Beighton et al. 1969; McKusick sia ossificans progressiva: CT appearance. Radiology 1986; 159: 153–7 1972; Prockop and Kivirikko 1984; Kivirikko and Ris- Resnick D. Scleroderma (progressive systemic sclerosis). In: teli 1966) characterized by disorganization of colla- Resnick D (ed.) Diagnosis of bone and joint disorders.W.B. gen bundles and abnormal shortening of the colla- Saunders Company, Philadelphia, 1995 (3rd ed.), p. 1199 gen chains (Svane 1966; Rybka and O’Hara 1967), Resnick D, Scavulli JF, Goergen TG, Genant HK, Niwayama G. Intra-articular calcification in scleroderma. Radiology joint hyperextensibility,skin fragility/hyperelasticity, 1977; 124: 685–8 and vascular fragility with bleeding diathesis are car- 486 Chapter 8 · Joints dinal features, whereas primary osseous abnormali- 15q21) result in Marfan syndrome (Tsipouras et al. ties are absent.Ligamentous and capsular laxity leads 1992; Kainulainen et al. 1990; Sarfarazi et al. 1992). to kyphoscoliosis, pes planus, spondylolisthesis, and Fibrillin is a component of elastin fibrils, which are genu recurvatum (Beighton et al. 1969; Lewkonia and found in the tunica media of the aorta, periosteum, Pope 1985; Bannerman et al. 2000; Pyeritz 2000). and ligaments (Tsipouras et al. 1992). Marfan syn- Other organs and systems are involved to variable drome and congenital contractural arachnodactyly, a extents, including the eye, gastrointestinal tract, milder disorder without major involvement of the bronchopulmonary tree, genitourinary system, and eyes and aorta, are phenotypically and genetically re- cardiovascular system (Schippers and Dittler 1989). lated disorders.However,while the mutant gene in the Unlike Marfan syndrome and homocystinuria, Marfan syndrome (FBN1) is located on chromosome dolichostenomelia is not an obligatory finding. The 15, the disease locus in congenital contractural label ‘Ehlers-Danlos syndrome’ refers in fact to a arachnodactyly (FBN2) is located on chromosome 5. group of nine syndromes (Beighton et al. 1998) that Similarly, isolated mitral valve prolapse does not ap- share the same complex of clinical abnormalities, pear to be linked to the fibrillin gene on chromosome while differing in both genetic and biochemical char- 15. Manifestations of ligamentous laxity and joint hy- acteristics. Unclassified forms and overlapping syn- permobility include scoliosis (frequent), pes planus dromes (e.g., Ehlers-Danlos type VII and osteogene- deformity (frequent) (Pyeritz and McKusick 1981), sis imperfecta) exist (Ainsworth and Aulicino 1993; joint dislocation (patellas, hips, clavicles, mandible), Hartsfield and Kousseff 1990; Wordsworth et al. 1991; joint deformation (genu recurvatum, patella alta), Hamada et al. 1992). Both active and passive joint and premature osteoarthritis (Magid et al. 1990; hypermobility of severe degree is observed in type I Pennes et al.1985; Walker et al.1969).Atlantoaxial dis- (OMIM 130000), type III (OMIM 130020), and type location is rare (Levander et al.1981).Homocystinuria VII (OMIM 130060) (Lacour 1998; Giunta et al. 1999; (OMIM 236200) is a heterogeneous group of inherit- McKusick 1974) Ehlers-Danlos syndrome. Sponta- ed disorders of the connective tissue, with abnormal- neous dislocations are common and correlate with ities involving the central nervous system (variable the degree of laxity (Beighton and Horan 1969a). mental retardation, seizures); the vasculature (fibrous Sites of dislocation are both small and large joints, medial degeneration of the aorta and other arteries, including the hands, the radial head, the hip, and arterial and venous thrombosis); the eyes (bilateral the patellofemoral, glenohumeral, temporomandibu- lens subluxation, myopia, less frequently cataracts lar, sternoclavicular, and acromioclavicular joints and optic atrophy); the skeleton (slim long bones, (McKusick 1972; Beighton and Horan 1969b; Horton arachnodactyly, pectus carinatum or excavatum, pes et al. 1980; Carter and Wilkinson 1964). Recurrent cavus, kyphoscoliosis, osteoporosis, multiple contrac- dislocations cause premature degenerative joint dis- tures); the skin (thin skin, malar flush, prominent ve- ease (Osborn et al. 1981). Persistent effusions or nous markings, ‘cigarette paper’ scars); and the hair hemarthroses, which are also thought to result from (fine, sparse, dry, and light) (Schoonderwaldt et al. repetitive subclinical trauma caused by ligamentous 1981; Isherwood 1996; Beals 1969). Manifestations of and capsular laxity, may contribute to the precocious joint laxity, such as genu valgum and patella alta, are occurrence of degenerative joint disease. Secondary not consistently present (Brenton et al. 1972; Skovby changes of the articular constituents, with articular 1989; Smith 1967; Hurwitz et al. 1968; Leonard 1973) cartilage degeneration, capsular thickening, and and, a point that is of interest for the differential diag- contractures, can be responsible for switching from nosis against Marfan syndrome, they coexist with joint laxity to joint stiffness in the advanced stages flexion contractures of the fingers, elbows and knees (Beighton and Horan 1969a). The carpometacarpal (in Marfan syndrome, contracture occurs in the 5th joint of the thumb is particularly vulnerable (Gold- digit only) (Beals 1969; Brenton et al. 1972). Other dis- man 1995; Gamble et al. 1989). In Marfan syndrome tinctive features in homocystinuria include mental (OMIM 154700) the eye, the skeleton, and the cardio- retardation, malar flush, vascular thromboses, and ec- vascular system are primarily involved. Despite wide topia lentis at birth (Goldman 1995). Ligamentous variability of the clinical phenotype, ectopia lentis, laxity and bone fragility are characteristic clinical as- aortic root dilatation or dissection, dolichosteno- pects of osteogenesis imperfecta (OMIM 166200, melia, and dural ectasia are consistent features of the 166210, 166220, 259420), an inherited connective tis- syndrome (Tsipouras 1992; Tsipouras et al. 1992; sue disorder with a defect in fibrillar type I collagen Morse et al. 1990; Joseph et al. 1992). Mutations in the synthesis (Stoltz et al. 1989; Marini 1988; Rosenstock gene encoding fibrillin (FBN1, locus maps to 15q15– 1968; Brenner et al. 1989a, b), a major component of Abnormalities of Joint Motion 487 the bone organic matrix (Nerlich et al. 1993). Type I 2. Ectopia lentis; aortic dilatation/dissection; do- collagen is also highly represented in ligaments, ten- lichostenomelia; dural ectasia; joint dislocation; dons, fasciae, sclerae, and teeth. As stated earlier, kyphoscoliosis; pes planus; genu recurvatum; Ehlers-Danlos type VII is another disorder related to patella alta; premature osteoarthritis (Marfan syn- mutations of type I collagen. Blue sclerae, a common drome) finding in osteogenesis imperfecta, can also occur in 3. Ectopia lentis; mental retardation; vascular throm- Ehlers-Danlos type VII (Cohn and Byers 1990; Pope et bosis; dolichostenomelia; arachnodactyly, joint al. 1989; Byers 1990; Sykes 1993). Despite these simi- contractures; patella subluxation; pes cavus; larities, and the occurrence in patients with osteogen- kyphoscoliosis; thin skin; sparse fine hair (homo- esis imperfecta of the clinical abnormalities that are cystinuria) typical for connective tissue disorders, including joint 4. Joint laxity; multiple fractures; kyphoscoliosis; laxity and hypermobility, no increase in the preva- genu valgum (osteogenesis imperfecta) lence of dislocations has been reported in osteogene- sis imperfecta (Gertner and Root 1990). Similarly, Associations bleeding is less constant and severe in osteogenesis • Aarskog syndrome imperfecta than in Ehlers-Danlos syndromes (Gert- • Achard syndrome ner and Root 1990; Beighton et al. 1983; Ramser et al. • Acromesomelic dysplasia 1966). Joint laxity is most prominent in osteogenesis • Bannayan-Riley-Ruvalcaba syndrome imperfecta type I and type III of the Sillence classifi- • Borjeson-Forssman-Lehmann syndrome cation (Sillence et al.1979).Severe kyphoscoliosis and • Chromosome XXXXY syndrome genu valgum may arise from ligamentous and capsu- • Coffin-Lowry syndrome lar laxity or fracture deformities, or a combination of • Coffin-Siris syndrome the two. Joint laxity, familial (articular hypermobility • Cohen syndrome syndrome, OMIM 147900), a condition formerly in- • Cutis laxa cluded under the Ehlers-Danlos umbrella (Ehlers- • Cutis laxa-growth deficiency syndrome Danlos syndrome type XI), is now recognized as a • Deafness and metaphyseal dysostosis separate disorder of autosomal dominant inheritance • Down syndrome characterized by joint laxity and congenital hip dislo- • Ehlers-Danlos syndromes cation (Horton et al. 1980) and not including the skin • FG syndrome changes that are part of the spectrum of the Ehlers- • Floating-Harbor syndrome Danlos syndromes (Beighton et al. 1998). Recurrent • Focal dermal hypoplasia (Goltz-Gorlin syndrome) dislocation of other joints, including the patella and • Fragile X syndrome the shoulder, may also be observed. Ligamentous and • Geroderma osteodysplastica hereditaria capsular laxity, with dislocated hips at birth and ear- • Hajdu-Cheney syndrome ly-onset, progressive kyphoscoliosis, is also observed • Hallermann-Streiff syndrome in spondyloepimetaphyseal dysplasia with joint laxity • Homocystinuria (OMIM 271640). Joint laxity and dislocation (at- • Hypermobility syndrome lantoaxial, hip) are prominent findings in Down syn- • Hypochondroplasia drome (OMIM 190685). In this regard, the dispute • Johanson-Blizzard syndrome prompted by the ‘triple jeopardy’of the upper cervical • Joint laxity-idiopathic scoliosis spine (atlantoaxial subluxation, hypoplastic posterior • Kabuki syndrome arch of C1, and atlanto-occipital instability) on • Langer-Giedion syndrome whether or not children with Down syndrome should • Larsen syndrome be screened radiographically remains unresolved • Lenz-Majewski syndrome (Kriss 1999). • LEOPARD syndrome • Lowe syndrome Radiographic Synopsis • Marfan syndrome 1. Joint hyperextensibility; skin fragility/hyperelas- • Marfanoid hypermobility syndrome ticity; vascular fragility; joint dislocation; kypho- • Megaepiphyseal dysplasia-wrinkled skin-aged scoliosis; pes planus; spondylolisthesis; genu re- appearance curvatum; premature osteoarthritis (Ehlers-Dan- • Metaphyseal chondrodysplasia, McKusick los syndrome) • Metatropic dysplasia • Mitral valve prolapse, isolated 488 Chapter 8 · Joints

• Mucopolysaccharidosis IV A (Morquio) Byers PH. Brittle bones – fragile molecules: disorders of colla- • Multiple endocrine neoplasia, type 2b gen gene structure and expression. Trends Genet 1990; 6: • Nail-patella syndrome 293–300 • Carter CO,Wilkinson JA.Genetic and environmental factors in Osteogenesis imperfecta, type I the etiology of congenital dislocation of the hip. Clin Or- • Osteoporosis-pseudoglioma syndrome thop 1964; 33: 119–28 • Pallister-Killian syndrome Cohn DH, Byers PH. Clinical screening for collagen defects in • Pseudoachondroplasia connective tissue diseases. Clin Perinatol 1990; 17: 793–809 Gamble JG, Mochizuki C, Rinsky LA. Trapeziometacarpal ab- • Robinow syndrome • normalities in Ehlers-Danlos syndrome. J Hand Surg [Am] Rubinstein-Taybi syndrome 1989; 14: 89–94 • Seckel syndrome Gertner JM, Root L. Osteogenesis imperfecta. Orthop Clin • Shprintzen syndrome North Am 1990; 21: 151–62 • Spondyloepimetaphyseal dysplasia Giunta C, Superti-Furga A, Spranger S, Cole WG, Steinmann B. Ehlers-Danlos syndrome type VII: clinical features and with joint laxity • molecular defects. J Bone Joint Surg Am 1999; 81: 225–38 Spondyloepiphyseal dysplasia Goldman AB. Heritable diseases of connective tissue, epiphy- • Stickler syndrome seal dysplasias, and related conditions. In: Resnick D (ed.) • The 3-M syndrome Diagnosis of bone and joint disorders.W.B. Saunders Com- • Tricho-rhino-phalangeal dysplasia, type 2 pany, Philadelphia, 1995 (3rd ed.), pp. 4095–162 • Hamada S, Hiroshima K, Oshita S, Doi T,Ono K. Ehlers-Danlos Velo-cardio-facial syndrome syndrome with soft-tissue contractures. J Bone Joint Surg • Wrinkly skin syndrome Br 1992; 74: 902–5 • Zimmermann-Leband syndrome Hartsfield JK Jr, Kousseff BG. Phenotypic overlap of Ehlers- Danlos syndrome types IV and VIII.Am J Med Genet 1990; 37: 465–70 Horton WA, Collins DL, DeSmet AA, Kennedy JA, Schimke RN. References Familial joint instability syndrome. Am J Med Genet 1980; 6: 221–8 Ainsworth SR, Aulicino PL. A survey of patients with Ehlers- Hurwitz LJ, Chopra JS, Carson NA. Electromyographic evi- Danlos syndrome. Clin Orthop 1993; 286: 250–6 dence of a muscle lesion in homocystinuria. Acta Paediatr Bannerman RM, Graf CJ, Upson JF. Ehlers-Danlos syndrome. Scand 1968; 57: 401–4 Br Med J 1967; 3: 558–9 Isherwood DM. Homocystinuria. BMJ 1996; 313: 1025–6 Beals RK. Homocystinuria.A report of two cases and review of Joseph KN, Kane HA, Milner RS, Steg NL, Williamson MB Jr, the literature. J Bone Joint Surg Am 1969; 51: 1564–72 Bowen JR. Orthopedic aspects of the Marfan phenotype. Beighton P,Horan F.Orthopaedic aspects of the Ehlers-Danlos Clin Orthop 1992; 277: 251–61 syndrome. J Bone Joint Surg Br 1969a; 51: 444–53 Kainulainen K,Pulkkinen L,Savolainen A,Kaitila I,Peltonen L. Beighton P, Horan FT. Surgical aspects of the Ehlers-Danlos Location on chromosome 15 of the gene defect causing syndrome.A survey of 100 cases. Br J Surg 1969b; 56: 255–9 Marfan syndrome. N Engl J Med 1990; 323: 935–9 Beighton P, Price A, Lord J, Dickson E. Variants of the Ehlers- Kivirikko KI, Risteli L. Biosynthesis of collagen and its alter- Danlos syndrome. Clinical, biochemical, haematological, ations in pathological states. Med Biol 1976; 54: 159–86 and chromosomal features of 100 patients.Ann Rheum Dis Kriss VM. Down syndrome: imaging of multiorgan involve- 1969; 28: 228–45 ment. Clin Pediatr 1999; 38: 441–9 Beighton P, Spranger J, Versveld G. Skeletal complications in Lacour JP. Type I Ehlers-Danlos syndrome. Ann Dermatol osteogenesis imperfecta. A review of 153 South African pa- Venereol 1998; 125: 926 tients. S Afr Med J 1983; 64: 565–8 Leonard MS. Homocystinuria: a differential diagnosis of Mar- Beighton P,de Paepe A,Steinmann B,Tsipouras P,Wenstrup RJ. fan’s syndrome. Oral Surg Oral Med Oral Pathol 1973; 36: Ehlers-Danlos syndromes: revised nosology, Villefranche, 214–9 1997. Ehlers-Danlos National Foundation (USA) and Levander B, Mellstrom A, Grepe A. Atlantoaxial instability in Ehlers-Danlos Support Group (UK). Am J Med Genet 1998; Marfan’s syndrome. Diagnosis and treatment. A case re- 77: 31–7 port. Neuroradiology 1981; 21: 43–6 Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, Lewkonia RM, Pope FM. Joint contractures and acroosteolysis Muller PK. Osteogenesis imperfecta: insufficient collagen in Ehlers-Danlos syndrome type IV.J Rheumatol 1985; 12: synthesis in early childhood as evidenced by analysis of 140–4 compact bone and fibroblast cultures. Eur J Clin Invest Magid D, Pyeritz RE, Fishman EK. Musculoskeletal manifesta- 1989a; 19: 159–66 tions of the Marfan syndrome: radiologic features. AJR Am Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, J Roentgenol 1990; 155: 99–104 Muller PK. Biochemical analysis of callus tissue in osteoge- Marini JC. Osteogenesis imperfecta: comprehensive manage- nesis imperfecta type IV.Evidence for transient overmodi- ment. Adv Pediatr 1988; 35: 391–426 fication in collagen types I and III. J Clin Invest 1989b; 84: McKusick VA. Heritable disorders of connective tissue. C.V. 915–21 Mosby Company, St. Louis (4th ed.), 1972, p. 292 Brenton DP, Dow CJ, James JI, Hay RL, Wynne-Davies R. McKusick VA. Multiple forms of the Ehlers-Danlos syndrome. Homocystinuria and Marfan’s syndrome. A comparison. Arch Surg 1974; 109: 475–6 J Bone Joint Surg Br 1972; 54: 277–98 Abnormalities of Joint Position 489

Morse RP,Rockenmacher S, Pyeritz RE, Sanders SP,Bieber FR, genes on chromosomes 15 and 5. The International Marfan Lin A, MacLeod P, Hall B, Graham JM Jr. Diagnosis and Syndrome Collaborative Study. N Engl J Med 1992; 326: management of infantile Marfan syndrome. Pediatrics 905–9 1990; 86: 888–95 Tsipouras P.Marfan syndrome: a mystery solved. J Med Genet Nerlich AG, Brenner RE, Wiest I, Lehmann H, Yang C, Muller 1992; 29: 73–4 PK, von der Mark K. Immunohistochemical localization of Walker BA, Beighton PH, Murdoch JL. The marfanoid hyper- interstitial collagens in bone tissue from patients with var- mobility syndrome. Ann Intern Med 1969; 71: 349–52 ious forms of osteogenesis imperfecta. Am J Med Genet Wordsworth BP, Ogilvie DJ, Sykes BC. Segregation analysis of 1993; 45: 258–9 the structural genes of the major fibrillar collagens pro- Osborn TG, Lichtenstein JR, Moore TL, Weiss T, Zuckner J. vides further evidence of molecular heterogeneity in type Ehlers-Danlos syndrome presenting as rheumatic manifes- II Ehlers-Danlos syndrome. Br J Rheumatol 1991; 30: 173–7 tations in the child. J Rheumatol 1981; 8: 79–85 Pennes DR, Braunstein EM, Shirazi KK. Carpal ligamentous laxity with bilateral perilunate dislocation in Marfan syn- Abnormalities of Joint Position drome. Skeletal Radiol 1985; 13: 62–4 Pope FM, Daw SC, Narcisi P, Richards AR, Nicholls AC. Prena- tal diagnosis and prevention of inherited abnormalities of There are five different clinical situations that are collagen. J Inherit Metab Dis 1989; 12: 135–73 consistently associated with joint subluxation and/or Prockop DJ, Kivirikko KI, Tuderman L, Guzman NA. The dislocation: (a) trauma; (b) inflammatory joint dis- biosynthesis of collagen and its disorders (second of two eases; (c) disorders with muscular imbalance; (d) parts). N Engl J Med 1979; 301: 77–85 Prockop DJ, Kivirikko KI. Heritable diseases of collagen. disorders with joint laxity; and (e) disorders with de- N Engl J Med 1984; 311: 376–86 fective development of the osseous components of Pyeritz RE. Ehlers-Danlos syndrome. N Engl J Med 2000; 342: the joint.A discussion of the clinical and radiograph- 730–2 ic manifestations of joint subluxation/dislocation re- Pyeritz RE, McKusick VA. Basic defects in Marfan syndrome. lated to trauma and inflammatory disorders is be- N Engl J Med 1981; 305: 1011–2 Ramser JR, Villanueva AR, Pirok D, Frost HM. Tetracycline- yond the scope of this book. Among the latter, only based measurement of bone dynamics in 3 women with rheumatoid arthritis is mentioned here, because of osteogenesis imperfecta. Clin Orthop 1966; 49: 151–62 its frequency and relevance in the clinical practice Resnick D, Niwayama G. Articular anatomy and histology. In: (Fig. 8.7). Resnick D (ed.) Diagnosis of bone and joint disorders.W.B. The broad designation of ‘muscular imbalance’ is Saunders Company, Philadelphia, 1995 (3rd ed.), p. 661 Rosenstock HA. Osteogenesis imperfecta. JAMA 1968; 203: meant to include several unrelated disorders, all of 740–1 which are characterized by incompetence of the mus- Rybka FJ, O’Hara ET. Surgical significance of the Ehlers-Dan- cular function at a given joint. Muscular incompe- los syndrome. Am J Surg 1967; 113: 431–4 tence, that is, absence, atrophy, fibrosis, flaccidity, or Sarfarazi M, Tsipouras P,Del Mastro R, Kilpatrick M, Farndon spasticity of a muscle from any cause, results in mal- P,Boxer M, Bridges A, Boileau C, Junien C, Hayward C et al. A linkage map of 10 loci flanking the Marfan syndrome positioning and impaired development of the bony locus on 15q: results of an International Consortium study. components of that joint (Dunne and Clarren 1986; J Med Genet 1992; 29: 75–80 Bunch 1977; Baratta et al. 1988; Fidler and Jowett Schippers E, Dittler HJ. Multiple hollow organ dysplasia in 1976). However, normal growth of the osseous struc- Ehlers-Danlos syndrome. J Pediatr Surg 1989; 24: 1181–3 tures at a given joint depends not only on adequacy Schoonderwaldt HC, Boers GH, Cruysberg JR, Schulte BP, Slooff JL,Thijssen HO.Neurologic manifestations of homo- of the muscular forces applied, but also on proper cystinuria. Clin Neurol Neurosurg 1981; 83: 153–62 anatomical positioning and maintenance of the joint Sillence DO, Senn A, Danks DM. Genetic heterogeneity in activity; hence, absence or loss of one of these re- osteogenesis imperfecta. J Med Genet 1979; 16: 101–16 quirements affects bone growth, resulting in various Skovby F.Inborn errors of metabolism causing homocysteine- bone deformities. Deformed bones lead, in turn, to mia and related vascular involvement. Haemostasis 1989; 19: 4–9 anatomical incongruities at their articulation, fur- Smith SW. Roentgen findings in homocystinuria. Am J Roent- ther compromising correct bone positioning (Fer- genol Radium Ther Nucl Med 1967; 100: 147–54 rone 1976). An example of this complex interaction Stoltz MR, Dietrich SL, Marshall GJ. Osteogenesis imperfecta. of events is offered by hip subluxation/dislocation Perspectives. Clin Orthop 1989; 242: 120–36 occurring in association with neuromuscular disor- Svane S. Ehlers-Danlos syndrome. A case with some skeletal changes. Acta Orthop Scand 1966; 37: 49–57 ders, in which both absence of hip extensor and ab- Sykes B.Linkage analysis in dominantly inherited osteogenesis ductors – in the presence of functioning hip flexors imperfecta. Am J Med Genet 1993; 45: 212–6 and adductors – and valgus deformity of the femoral Tsipouras P, Del Mastro R, Sarfarazi M, Lee B, Vitale E, Child neck act in concert to facilitate lateral migration of AH, Godfrey M, Devereux RB, Hewett D, Steinmann B et al. Genetic linkage of the Marfan syndrome,ectopia lentis,and the femoral head (Goldman et al. 1988). Additional congenital contractural arachnodactyly to the fibrillin examples include glenoid dysplasia and shoulder in- 490 Chapter 8 · Joints

which joint laxity is prominent, such as the Ehlers- Danlos syndromes, Marfan syndrome, and spondy- loepimetaphyseal dysplasia with joint laxity (Giunta et al. 1999). In this section, some relevant instances of congen- ital single joint dislocation are presented, followed by examples of disorders that commonly manifest with multiple joint dislocations.

References

Akazawa H, Oda K, Mitani S, Yoshitaka T, Asaumi K, Inoue H. Surgical management of hip dislocation in children with arthrogryposis multiplex congenita. J Bone Joint Surg Br 1998; 80: 636–40 Baratta R, Solomonow M, Zhou BH, Letson D, Chuinard R, D’Ambrosia R. Muscular coactivation. The role of the an- tagonist musculature in maintaining knee stability. Am J Sports Med 1988; 16: 113–22 Bunch W. Origin and mechanism of postnatal deformities. Pediatr Clin North Am 1977; 24: 679–84 Dunne KB, Clarren SK. The origin of prenatal and postnatal Fig. 8.7. Rheumatoid arthritis in a 75-year-old woman. Multi- deformities. Pediatr Clin North Am 1986; 33: 1277–97 ple metacarpophalangeal joint subluxations with severe ulnar Ferrone JD. Congenital deformities about the knee. Orthop deviation of fingers. The simultaneous radial deviation at the Clin North Am 1976; 7: 323–30 radiocarpal joint of the wrist gives rise to the zigzag deformity Fidler MW, Jowett RL. Muscle imbalance in the aetiology of typical of the disease. Note osteoporosis and extensive carpal scoliosis. J Bone Joint Surg Br 1976; 58: 200–1 bone involvement, with progressive loss of articular space and Giunta C, Superti-Furga A, Spranger S, Cole WG, Steinmann B. sclerosis in all compartments (the widespread nature of wrist Ehlers-Danlos syndrome type VII: clinical features and involvement is characteristic of rheumatoid arthritis and al- molecular defects. J Bone Joint Surg Am 1999; 81: 225–38 lows differentiation from other disorders with selective com- Goldman AB, Valensin GL, Pamilla J. Orthopedic problems in partmental distribution) children caused by neuromuscular diseases. J Radiol 1988; 69: 721–30 Houston CS, Reed MH, Desautels JE. Separating Larsen syn- stability developing in patients with paralysis of the drome from the “arthrogryposis basket”. J Can Assoc Radi- upper arm caused by obstetric trauma to the brachial ol 1981; 32: 206–14 plexus or dislocation of an abnormally small patella, Sodergard J, Ryoppy S. The knee in arthrogryposis multiplex congenita. J Pediatr Orthop 1990; 10: 177–82 as seen in the nail-patella syndrome. In this context, it is not surprising that individuals who have suffered from intrauterine faulty positioning of the bone components in their joints, such as those with disor- Joint Subluxation and Dislocation ders loosely labeled arthrogryposis, can be affected by multiple joint subluxation or dislocations at birth ᭤ [Partial (subluxation) or complete (dislocation) (Akazawa et al. 1998; Sodergard and Ryoppy 1990; loss of contact between two osseous surfaces Houston et al. 1981). Similarly, it is not surprising that normally articulate] that patients with primary disorders of bone forma- tion and growth, such as those with dysostoses and Joint subluxation and dislocation can be present at skeletal dysplasias with prominent epiphyseal in- birth or occur later in life; can be inherited or ac- volvement, have an increased likelihood of develop- quired; can involve one joint or multiple joints; and ing joint dislocation at one or several anatomical can occur as an isolated anomaly or as part of a mal- sites. The arthrogrypotic syndromes have been dis- formation syndrome or bone dysplasia. cussed above in the section entitled “Joint Contrac- Congenital single joint dislocation or subluxation ture, Joint Stiffness.” The adverse effects of ligamen- occurs in a number of syndromic and nonsyndromic tous laxity on joint mechanics and stability have conditions and is therefore of little help in diagnosis. been discussed in the section headed “Joint Laxity, The subjects of patellar dislocation, atlantoaxial in- Joint hypermobility” along with the disorders in stability and dislocation, and developmental hip dys- Abnormalities of Joint Position 491

and short stature. Hip dysplasia and abnormalities of the distal radius are inconstant features (Beals 1967). A special type of congenital radial head dislocation, posterior (OMIM 179200) has been observed in sev- eral members of the same family (Cockshott and Omololu 1958; Abbott 1892).An association with an- tecubital pterygium has been recognized (Shun-Shin 1954). Recessive inheritance is likely, with instances of male-to-male transmission (Reichenbach et al. 1995). Rotation at the elbow is more compromised than extension. Congenital dislocation of the knee is a very rare anomaly accounting for approximately an estimated 1% of cases of congenital dislocation of the hip. Blacks are affected more frequently than whites, and females three times more frequently than males. Several causes have been proposed, including aberrant fetal position, breech delivery (Johnson et al. 1987), muscular imbalance (Jacobsen and Vopalecky 1985), and defective cruciate liga- ments (Katz et al. 1967), but none has been substanti- ated. Genetic factors are certainly important, as also demonstrated by the occurrence of familial cases Fig. 8.8. Congenital dislocation of the radial head in an adult (Callahan et al.1985; Collins et al.1995).The anomaly male patient. There is anterior radial head dislocation, and slight hypoplasia of distal ulna at the carpus. The anomaly was consists in partial or total anterior dislocation of the an isolated, unilateral finding tibia with respect to the femur, resulting in hyperex- tension with limited flexion capabilities of the knee, and valgus deformity. Shortening of the quadriceps plasia have been addressed in specific sections in this femoris tendon, a tight anterior articular capsule, book. Other single joint dislocations are briefly dis- and hypoplasia of the suprapatellar bursa take place cussed in this chapter. on a secondary basis (Ooishi et al.1993).Anterior tib- Congenital dislocation of the radial head is a well- ial bowing (genu recurvatum) and patellar hypo- recognized entity occurring either as an isolated plasia can also occur. Dislocation of the knee can be anomaly (uni- or bilateral) or in association with isolated or occur in association with other joint dis- other congenital abnormalities, particularly in the locations, spinal anomalies, and foot anomalies (Fer- hands (Kelly 1981; Campbell et al. 1992) (Fig. 8.8). nandez-Palazzi and Silva 1990). Congenital displace- Both anterior and posterior dislocation are possible, ment of a single vertebral body can also occur. Acute either resulting in decreased elbow motion (Agnew dislocation, often after a trivial trauma, is accompa- and Davis 1993). Hypoplasia of the proximal end nied by sudden onset of neurological deficits. In of the radius, a relatively short ulna, a defective other cases, neurological abnormalities appear grad- trochlea, and prominence of the ulnar epicondyle are ually and tend to worsen over time (Shapiro and Her- among the abnormalities that may be seen on radi- ring 1993). ograms. Dislocation of the radial head can occur as a Multiple congenital joint dislocations occur in a component of any of several syndromes, including selected group of systemic disorders and are there- nail-patella syndrome (OMIM 161200), oto-palato- fore of great diagnostic importance.The archetype of digital syndrome (OMIM 311300), Noonan syn- these disorders is Larsen syndrome (OMIM 150250, drome (OMIM 163950), tarsal/carpal coalition syn- 245600) (Larsen et al. 1950), a heterogeneous condi- drome (OMIM 186570), and ophthalmomandibu- tion with either an autosomal dominant or a reces- lomelic dysplasia (OMIM 164900) (McKusick). It can sive pattern of inheritance and possible instances of also occur as part of auriculo-osteodysplasia (OMIM parental germ-line mosaicism (Petrella et al. 1993; 109000), an autosomal dominant condition with Frints et al. 2000). Although this syndrome is dis- characteristic ear shape (abnormal attachment of an cussed in a separate section in this book, a few com- elongated lobe, accompanied by a small, slightly pos- ments are appropriate here. Features in this syn- terior lobule), dysplasia of the radiocapitellar joint, drome include a specific flat face with widely spaced 492 Chapter 8 · Joints

duction might be implicated (Pierquin et al. 1991). In the autosomal dominant Larsen syndrome, the gene maps to 3p21.1-p14.1, a locus which is close to, but distinct from, the COL7A1 locus (OMIM 120120) (Vujic et al. 1995). The fibrillar collagen genes COL1A1 (OMIM 120150), COL1A2 (OMIM 120160), COL3A1 (OMIM 120180), and COL5A2 (OMIM 120190), have been excluded as the site of the muta- tion in the recessive form of Larsen syndrome (Bonaventure et al. 1992). Furthermore, electro- phoretic analysis of collagens derived from fibroblast cultures have failed to show defective molecules. A lethal disorder closely resembling Larsen syndrome, Larsen-like syndrome, lethal type (OMIM 245650), is characterized by multiple joint dislocations (espe- cially anterior dislocation of both knees), flat face, cleft soft palate, rhizomelic shortening of upper limbs, hypoplastic fibula, laryngotracheomalacia, and pulmonary hypoplasia causing early death (Chen et al. 1982). Whether this disorder is produced by a mutation in a gene distinct from that of the re- cessive (OMIM 245600) or dominant (OMIM 150250) form of Larsen syndrome is not known (McKusick). Interestingly enough, abnormal collagen bundles in the derma, cartilage matrix, joint capsule, and tra- chea have been documented on electron microscopy Fig. 8.9. Larsen syndrome in a 3-month-old girl. Observe con- (Clayton-Smith et al. 1988). Desbuquois syndrome genital bilateral luxation of the elbows, knees and hips; equino- (OMIM 251450) is a constellation of severe rhizomel- varus deformity of the feet; relative shortening of the limbs; prominent abdomen; and flat face with hypertelorism and de- ic dwarfism manifesting in utero, narrow chest some- pressed nasal bridge. (From Weisenbach and Melegh 1996,) times causing respiratory distress,vertebral and meta- physeal abnormalities, and advanced carpotarsal os- sification (Desbuquois et al. 1966; Beemer et al. 1985; eyes and prominent forehead; bilateral anterior dis- Meinecke et al. 1989; Pazzaglia et al. 1988) (Fig. location of the tibia on the femur at the knees, club- 8.10a,b). Coronal cleft vertebrae may be observed in foot, and other joint dislocations, including the hips, infants. The proximal femurs are broad, with spur- the elbows, and the atlantoaxial joint (Fig. 8.9); and like projections of the lesser trochanters (‘monkey other skeletal anomalies, including accessory car- wrench’ appearance) (Shohat et al. 1994). Affected pals, short metacarpals and terminal phalanges, patients have glaucoma, mental retardation, and gen- cylindrically shaped fingers, a juxtacalcaneal acces- eralized joint laxity with dislocatable knees, hips, and sory bone – a feature that is possibly specific for this patellae. Although there are recognizable similarities disorder (Latta et al. 1971), – and cervical spinal ab- with the Larsen syndrome, the findings in the hands, normalities (Le Marec et al. 1994; Weisenbach and with supernumerary metacarpal ossification centers Melegh 1996). Complications secondary to disloca- causing deviation of the fingers, and the unique ap- tion of the cervical spine can be fatal (Laville 1994; pearance of the proximal femoral metaphyses un- Johnston et al. 1996). The phenotype of the dominant equivocally identify the Desbuquois syndrome (Le and recessive types is similar, with a less striking Merrer et al. 1991). Dislocation of multiple joints, to- ‘moon face’ and more frequent occurrence of syn- gether with progressive joint deformities, particular- dactyly, cleft palate, genital anomalies, severe short ly involving the knees, spine, and hips, are among the stature, and increased mortality from cardiac and cardinal features of spondyloepimetaphyseal dyspla- respiratory complications in the recessive form sia with multiple dislocations (OMIM 603546). De- (Strisciuglio et al. 1983). Joint hyperlaxity is charac- spite joint laxity, this disorder is distinctively differ- teristic of the disease (Rodriguez et al. 1994), raising ent from spondyloepimetaphyseal dysplasia with the possibility that a gene involved in collagen pro- joint laxity (OMIM 271640), being characterized by Abnormalities of Joint Position 493

Fig. 8.10 a,b. Desbuquois dys- plasia in a 37-week fetus a Postmortem full-body view. There are a relatively large cranium, flat face with mi- crognathia, small thorax, pro- minent abdomen, rhizomelic limb shortening and bowing, abnormal hands, and clubfeet. b Postmortem radiograph. The proximal femurs show a unique ‘monkey-wrench’ ap- pearance. The thorax is bell- shaped, and the ilia are nar- row. (From Hall 2001)

a b

unique changes in the epiphyses (smallness, flatten- Moreover, the genetics of the two disorders is differ- ing, irregularity, fragmentation); in the metaphyses ent.In a similar way to atelosteogenesis type 2 (OMIM (widening, irregularity, sclerosis); in the hands 256050) and achondrogenesis type 1B (OMIM (gracile metacarpals, long slender phalanges with 600972), diastrophic dysplasia results from a defect squared ends, prominent phalangeal tufts, small and in the sulfate transporter gene DTDST,which en- irregular carpal bones); and in the spine (posterior codes a sulfate transporter of the cell membrane scalloping of the lumbar vertebral bodies, end-plate (Hastbacka et al. 1994) and is a gene that is not in- irregularity, craniocaudal narrowing of the inter- volved in pseudodiastrophic dysplasia (Cetta et al. pediculate spaces) (Hall et al. 1998). On the other 1997). The RAPADILINO syndrome (OMIM 266280) hand, spondyloepimetaphyseal dysplasia with joint is an association of radial aplasia/hypoplasia (RA), laxity is associated with kyphoscoliosis at birth, tal- patella hypoplasia/aplasia and cleft/high-arched ipes equinovarus, cleft palate, congenital heart dis- palate (PA), diarrhea and dislocated joints (DI), small ease, and a specific facial dysmorphism. Multiple dis- size and limb malformations (LI), and long nose and locations also occur with pseudodiastrophic dyspla- normal intelligence (NO) (Kaariainen et al. 1989;Var- sia (OMIM 264180), a condition first described by gas et al. 1992). Longitudinal radial-ray deficiency Burgio et al.(1974).With few exceptions (Eteson et al. (radius and thumb) and patellar aplasia/hypoplasia 1986), this is an early lethal disorder that shares sim- are the main manifestations of the syndrome. Find- ilarities with, but is distinct from, diastrophic dyspla- ings in the face include elongated face, narrow palpe- sia (OMIM 222600). Rhizomelic shortening of the bral fissures, long slender nose, small chin, and un- limbs, severe clubfoot deformity, and atlantoaxial usual ears. Multiple joint dislocations may occur in instability are common to both conditions. Distinct association with stiff interphalangeal joints. Multiple features in pseudodiastrophic dysplasia include joint dislocations (hips, thumbs and great toes) are marked lumbar scoliosis, more severe platyspondyly, manifestations of cutis laxa, corneal clouding,and tongue-like deformities of the vertebral bodies in mental retardation (De Barsy syndrome, OMIM the lumbar spine, enlarged bitemporal diameter with 219150),a progeroid disorder with defective develop- midface hypoplasia, and a unique pattern in the ment (or synthesis?) of elastic fibers in the skin (de hands, with multiple interphalangeal and metacar- Barsy et al. 1968; Karnes et al. 1992).Affected patients pophalangeal joint dislocations and normal appear- show retarded psychomotor development, hypotonia ance of the 1st metacarpal, as opposed to the ovoid, and athetosis. The corneas are cloudy due to degen- hypermobile, abducted, proximally inserted (hitch- eration in the Bowman membrane. The skin is hiker) thumb of diastrophic dysplasia. Cartilage translucent, with unusually obvious superficial blood histology at the growth plate is also different in dias- vessels.A wrinkled face, inguinal hernia, and sclerot- trophic dysplasia and pseudodiastrophic dysplasia. ic foci in the skeleton are additional findings. 494 Chapter 8 · Joints

Reports of multiple dislocations in association • Coffin-Siris syndrome with metaphyseal dysplasia (Phaoke et al. 1993), • Cutis laxa ‘spondylo-acrodysplasia with severe combined im- • Cutis laxa/corneal clouding/mental retardation munodeficiency’ (Castriota-Scanderbeg et al. 1997), (De Barsy syndrome) and short stature and carpal coalition (Steel et al. • Dermo-chondro-corneal dystrophy of François 1993) have recently been reported. • Diastrophic dysplasia • Down syndrome Radiographic Synopsis • Dysautonomia (Riley-Day syndrome) 1. Hypoplastic proximal radius, with radial head • Dyschondrosteosis dislocation; short ulna; defective trochlea (isolat- • Ehlers-Danlos syndrome ed radial head dislocation) • Fanconi anemia 2. Dysplastic proximal radius, with radial head dis- • Fetal hydantoin syndrome location; short stature (auriculo-osteodysplasia) • Fetal trimethadione syndrome 3. Anterior dislocation of the tibia at the knee; genu • Freeman-Sheldon syndrome valgus; genu recurvatum; patellar hypoplasia • Frontometaphyseal dysplasia (isolated knee dislocation) • Hajdu-Cheney syndrome 4. Multiple congenital dislocations (knees, hips, el- • Humerospinal dysostosis bows); secondary epiphyseal deformities; abnor- • Keratoderma palmaris and plantaris familiaris mal spinal curvature; extracalcaneal ossification (tylosis) center (appearing after infancy); accessory • Larsen syndrome carpal bones (Larsen syndrome) • Lenz-Majewski syndrome 5. As Larsen syndrome plus: short humeri and fibu- • Marfan syndrome las; laryngotracheomalacia; pulmonary hypopla- • Melnick-Needles syndrome (osteodysplasty) sia (Larsen-like syndrome, lethal type) • Mesomelic dysplasia (Werner) 6. Severe rhizomelic dwarfism; narrow chest; monkey • Mucopolysaccharidoses wrench proximal femurs; accessory metacarpal • Multiple pterygium syndrome bones with digital clubbing; multiple joint disloca- (Escobar syndrome) tions (knees,hips,patellae) (Desbuquois syndrome) • Nager syndrome 7. Multiple joint dislocation; epiphyseal and meta- • Nail-patella syndrome physeal dysplasia; spinal changes (spondyloepi- • Neurofibromatosis metaphyseal dysplasia with multiple dislocations) • Oculo-dento-osseous syndrome 8. Rhizomelic limb shortening; clubfoot; atlantoax- • Osteogenesis imperfecta, type I ial instability; lumbar scoliosis; platyspondyly; • Oto-palato-digital syndrome, types I and II multiple interphalangeal and metacarpophalan- • Pallister-Hall syndrome geal joint dislocations; normal first metacarpal • Pallister-Killian syndrome (pseudodiastrophic dysplasia) • Potter syndrome 9. Radial and patellar hypoplasia/aplasia; short sta- • Robinow syndrome ture; multiple joint dislocations (RAPADILINO • Rubinstein-Taybi syndrome syndrome) • Schwartz-Jampel syndrome 10. Neonatal dwarfism; multiple joint dislocations; • Seckel syndrome sclerotic foci in the skeleton (De Barsy syndrome) • Smith-Lemli-Opitz syndrome • Spondyloepimetaphyseal dysplasia Associations with joint laxity • Aminopterin/methotrexate embryopathy • Spondyloepiphyseal dysplasia congenita • Amyoplasia congenita • Stickler syndrome • Arthritis (inflammatory, infectious) • TAR syndrome (hip, patella) • Arthrogryposis multiplex congenita • Thenevard syndrome • Atelosteogenesis, type I • Trauma • Auriculo-osteodysplasia syndrome (Beals) • Tricho-rhino-phalangeal dysplasia, type 2 • C syndrome (Opitz trigonocephaly syndrome) • Turner syndrome • Campomelic dysplasia • Cat’s eye syndrome • Chondrodysplasia punctata Abnormalities of Joint Position 495

References Hall BD. Lethality in Desbuquois dysplasia: three new cases. Pediatr Radiol 2001; 31: 43–7 Abbott FC. Congenital dislocations of radius. Lancet 1892; I: Hall CM, Elcioglu NH, Shaw DG. A distinct form of spondy- 800 loepimetaphyseal dysplasia with multiple dislocations. Agnew DK, Davis RJ. Congenital unilateral dislocation of the J Med Genet 1998; 35: 566–72 radial head. J Pediatr Orthop 1993; 13: 526–8 Hastbacka J, de la Chapelle A, Mahtani MM, Clines G, Reeve- Beals RK. Auriculo-osteodysplasia: a syndrome of multiple Daly MP, Daly M, Hamilton BA, Kusumi K, Trivedi B, osseous dysplasia, ear anomaly, and short stature. J Bone Weaver A, Coloma A, Lovett M, Buckler A, Kaitila I, Lander Joint Surg Am 1967; 49: 1541–50 ES. The diastrophic dysplasia gene encodes a novel sulfate Beemer FA, Kramer PPG, van der Harten HJ, Gerards LJ.A new transporter: positional cloning by fine-structure linkage syndrome of dwarfism, neonatal death, narrow chest, disequilibrium mapping. Cell 1994; 78: 1073–87 spondylometaphyseal abnormalities, and advanced bone Jacobsen K, Vopalecky F. Congenital dislocation of the knee. age. Am J Med Genet 1985; 20: 555–8 Acta Orthop Scand 1985; 56: 1–7 Bonaventure J, Lasselin C, Mellier J, Cohen-Solal L, Maroteaux Johnson E, Audell R, Oppenheim WL. Congenital dislocation P. Linkage studies of four fibrillar collagen genes in three of the knee. J Pediatr Orthop 1987; 7: 194–200 pedigrees with Larsen-like syndrome. J Med Genet 1992; Johnston CE, Birch JG, Daniels JL. Cervical kyphosis in pa- 29: 465–70 tients who have Larsen syndrome. J. Bone Joint Surg Am Burgio GR, Belloni C, Beluffi G. Nanisme pseudodias- 1996; 78: 538–45 trophique: étude de deux soeurs nouveau-nées.Arch Fr Pe- Kaariainen H, Ryoppy S, Norio R. RAPADILINO syndrome diatr 1974; 31: 681–96 with radial and patellar aplasia/hypoplasia as main mani- Callahan DJ, Chakraverty BP, Bream RC. Congenital disloca- festations. Am J Med Genet 1989; 33: 346–51 tion of the knees associated with a partial chromosome I Karnes PS, Shamban AT,Olsen DR, Fazio MJ, Falk RE. De Barsy deletion. J Pediatr Orthop 1985; 5: 593–6 syndrome: report of a case, literature review, and elastin Campbell CC, Waters PM, Emans JB. Excision of the radial gene expression studies of the skin. Am J Med Genet 1992; head for congenital dislocation. J Bone Joint Surg Am 1992; 42: 29–34 74: 726–33 Katz MP,Grogono BJ, Soper KC. The etiology and treatment of Castriota-Scanderbeg A, Mingarelli R, Caramia G, Osimani P, congenital dislocation of the knee. J Bone Joint Surg Br Lachman RS, Rimoin DL, Wilcox WR, Dallapiccola B. 1967; 49: 112–20 Spondylo-mesomelic-acrodysplasia with joint dislocations Kelly DW. Congenital dislocation of the radial head: spectrum and severe combined immunodeficiency: a newly recognised and natural history. J Pediatr Orthop 1981; 1: 295–8 immuno-osseous dysplasia. J Med Genet 1997; 34: 854–6 Larsen LJ, Schottstaedt ER, Bost FC. Multiple congenital dislo- Cetta G, Rossi A, Burgio GR, Beluffi G. Diastrophic dysplasia cations associated with characteristic facial abnormality. sulfate transporter (DTDST) gene is not involved in pseu- J Pediatr 1950; 37: 574–81 dodiastrophic dysplasia (letter). Am J Med Genet 1997; 73: Latta RJ, Graham CB, Aase JM, Scham SM, Smith DW. Larsen’s 493–4 syndrome: a skeletal dysplasia with multiple joint disloca- Chen H, Chang CH, Perrin E, Perrin J. A lethal, Larsen-like tions and unusual facies. J Pediatr 1971; 78: 291–8 multiple joint dislocation syndrome.Am J Med Genet 1982; Laville JM, Lakermance P, Limouzy F. Larsen’s syndrome: 13: 149–61 review of the literature and analysis of thirty-eight cases. Clayton-Smith J, Donnai D. A further patient with the lethal J Pediatr Orthop 1994; 14: 63–73 type of Larsen syndrome. J Med Genet 1988; 25: 499–500 Le Marec B, Chapuis M, Treguier C, Odent S, Bracq H.A case of Cockshott WP,Omololu A. Familial congenital posterior dislo- Larsen syndrome with severe cervical malformations. cation of both radial heads. J Bone Joint Surg Br 1958; 40: Genet Couns 1994; 5: 179–81 483–6 Le Merrer M, Young ID, Stanescu V, Maroteaux P. Desbuquois Collins AL, Dennis NR, Clarke N, Pope FM.A mother and three syndrome. Eur J Pediatr 1991; 150: 793–6 daughters with congenital dislocation of the hip and a McKusick VA. Online Mendelian inheritance in man.A catalog characteristic facial appearance: a new syndrome? Clin of human genes and genetic disorders. Dysmorphol 1995; 4: 277–82 www.ncbi.nlm.nih.gov De Barsy AM, Moens E, Dierckx L. Dwarfism, oligophrenia and Meinecke P, Spranger J, Schaefer E, Maroteaux P. Micromelic degeneration of the elastic tissue in skin and cornea.A new dwarfism with vertebral and metaphyseal abnormalities syndrome? Helv Paediatr Acta 1968; 23: 305–13 and advanced carpotarsal ossification: another observa- Desbuquois G, Grenier B, Michel J, Rossignol C. Nanisme tion. Am J Med Genet 1989; 32: 432–4 chondrodystrophique avec ossification anarchique et poly- Ooishi T, Sugioka Y, Matsumoto S, Fujii T. Congenital disloca- malformations chez deux soeurs. Arch Fr Pediatr 1966; 23: tion of the knee. Its pathologic features and treatment. Clin 573–87 Orthop 1993; 287: 187–92 Eteson DJ, Beluffi G, Burgio GR, Belloni C, Lachman RS, Ri- Pazzaglia UE, Pedrotti L, Beluffi G, Ceciliani L. Chondrodys- moin DL. Pseudodiastrophic dysplasia: a distinct newborn trophic dwarfism and multiple malformations in two sis- skeletal dysplasia. J Pediatr 1986; 109: 635–41 ters. Pediatr Radiol 1988; 19: 41–4 Fernandez-Palazzi F, Silva JR. Congenital dislocation of the Petrella R, Rabinowitz JG, Steinmann B, Hirschhorn K. Long- knee. Int Orthop 1990; 14: 17–9 term follow-up of two sibs with Larsen syndrome possibly Frints SG, de Smet L, Fabry G, Fryns JP. A young female with due to parental germ-line mosaicism. Am J Med Genet asymmetric manifestations of Larsen syndrome: another 1993; 47: 187–97 example of unilateral somatic cell-line mosaicism. Clin Phaoke SR, Sharma AK,Agarawal SS.A new syndrome of mul- Dysmorphol 2000; 9: 273–6 tiple joint dislocations with metaphyseal dysplasia. Clin Dysmorphol 1993; 2: 264–8 496 Chapter 8 · Joints

Pierquin G, van Regemorter N, Hayez-Delatte NI, Fourneau C, formerly classified as primary were instances of sec- Bormans J, Foerster M, Damis E, Cremer-Perlmutter N, ondary origin in which subtle underlying abnormal- Lapiere CM, Vamos E. Two unrelated children with partial ities had been overlooked.A more rational classifica- trisomy 1q and monosomy 6p, presenting with the pheno- type of the Larsen syndrome. Hum Genet 1991; 87: 587–91 tion system has identified two possible mechanisms Reichenbach H, Hormann D, Theile H. Hereditary congenital for the development of degenerative joint disease: (1) posterior dislocation of radial heads.Am J Med Genet 1995; altered biomechanics across the joint and (2) articu- 55: 101–4 lar or subchondral joint abnormalities in the pres- Rodriguez A, Asenjo B, Dominguez R, Lemaire R. Larsen syn- drome: multicenter study of 12 new cases. Diagnosis, plan- ence of normal biomechanics (Mitchell and Cruess ning and results of treatment. Acta Orthop Belg 1994; 60: 1977). Factors responsible for altered articular bio- 259–73 mechanics include congenital or acquired epiphyseal Shapiro J, Herring J. Congenital vertebral displacement. J Bone abnormalities, neuromuscular imbalance, leg-length Joint Surg Am 1993; 75: 656–62 discrepancy, congenital or acquired coxa valga and Shohat M, Lachman R, Gruber HE, Hsia YE, Golbus MS, Witt DR, Bodell A, Bryke CR, Hogge WA, Rimoin DL. Des- coxa vara, malunion of earlier fractures, ligamentous buquois syndrome: clinical, radiographic, and morpholog- abnormalities, and obesity. Causes of joint alteration ic characterization. Am J Med Genet 1994; 52: 9–18 include damage to the articular cartilage from tran- Shun-Shin M. Congenital web formation. J Bone Joint Surg Br schondral fractures, pre-existing arthritis, loose bod- 1954; 36: 268–71 ies, metabolic defects (gout, calcium pyrophosphate Steel HH, Piston RW,Clancy M, Betz RR. A syndrome of dislo- cated hips and radial heads, carpal coalition, and short dihydrate crystal deposition disease, acromegaly, stature in Puerto Rican children. J Bone Joint Surg Am alkaptonuria, mucopolysaccharidoses); and damage 1993; 75: 259–64 to the subchondral bone from osteonecrosis, osteo- Strisciuglio P, Sebastio G, Andria G, Maione S, Raia V. Severe porosis, osteomalacia, osteitis fibrosa cystica, neo- cardiac anomalies in sibs with Larsen syndrome. J Med plasms, osteopetrosis, and Paget disease (Resnick Genet 1983; 20: 422–4 Vargas FR, Cabral de Almeida JC, Llerena JC, Reis DF. RA- and Niwayama 1995; Mitchell and Cruess 1977). PADILINO syndrome. Am J Med Genet 1992; 44: 716–9 There are obviously situations in which both an ab- Vujic M,Hallstensson K,Wahlstrom J, Lundberg A, Langmaack normal concentration of force across the joint and C, Martinsson T.Localization of a gene for autosomal dom- joint abnormalities, involving either the articular inant Larsen syndrome to chromosome region 3p21.1–14.1 cartilage or the subchondral bone, act in concert. in the proximity of, but distinct from, the COL7A1 locus. Am J Hum Genet 1995; 57: 1104–13 In sharp contrast to the variety of its causative fac- Weisenbach J, Melegh B. Vertebral anomalies in Larsen’s syn- tors, osteoarthritis is characterized by a uniform pat- drome. Pediatr Radiol 1996; 26: 682–3 tern of radiological manifestations. This pattern con- sists in progressive loss of cartilage in the segment of the joint subject to pressure (or stressed), which ac- Premature Degenerative Joint Disease counts for localized diminution of the articular space, and osteophyte production in the segment of ᭤ [Early-onset osteoarthritis] the joint that is not subject to pressure (Resnick and Niwayama 1995). Loss of articular cartilage is cou- Degenerative joint disease is the most common joint pled with changes in the subchondral trabeculae, in- disease and its frequency is higher in older individu- cluding bony collapse, necrosis, cyst formation, and als.Yet this disease cannot be considered as an invari- eburnation (Havdrup et al. 1976; Crane and Scarano able consequence of aging (Alexander 1990; Oddis 1967). Because cartilage is not innervated, the pain 1996). This section summarizes the situations in experienced in osteoarthritis arises from secondary which degenerative osteoarthritis becomes clinically effects, such as joint capsule distension, stretching of evident in young adults well before the 5th and 6th periosteal nerve endings, and, possibly, synovial in- decades of life, after which an age-related predisposi- flammation.Although at some sites, such as the small tion to degenerative joint disease appears to increase joints in the hands and the sacroiliac joints, articular exponentially (Resnick and Niwayama 1995; Peyron space diminution may involve the entire articulation, 1984). Degenerative joint disease has been tradition- the focal nature of cartilage destruction remains an ally classified into a primary and a secondary type, important diagnostic criterion that can be applied to the former occurring in the absence of underlying differentiate degenerative osteoarthritis from other abnormalities and the latter being the result of alter- entities and from aging-related abnormalities. For ations caused by a pre-existing disease (Resnick and example, rheumatoid arthritis is characterized by Niwayama 1995). However, the improvement of diag- uniform joint space loss, joint effusion, osteoporosis, nostic capabilities has shown that a number of cases and inconspicuous bony eburnation and osteophyte Premature Degenerative Joint Disease 497 production. In the seronegative spondyloarthro- pathies (ankylosing spondylitis, psoriasis, and Reit- er’s syndrome) marginal erosions and intra-articular bone formation, sometimes resulting in joint ankylo- sis, are characteristic, while osteophytes and focal joint space loss are usually not observed. Radi- ographic changes in calcium pyrophosphate dihy- drate crystal deposition disease may closely resemble those of osteoarthritis, but the presence in the for- mer of intra- and extra-articular calcific deposits, in- volvement of unusual joints, and large subchondral cysts are valuable features in the differential diagno- sis. Gouty arthritis shows eccentric well-defined os- seous erosions without evidence of joint space loss. Fig. 8.11. Multiple epiphyseal dysplasia in a 16-year-old girl. The subchondral bone collapse in osteonecrosis, in Note marked deformation of the femoral heads with flattening the absence of joint space loss, is easily differentiated and subchondral sclerosis, most prominent on the left side. Joint space narrowing and marginal acetabular and femoral from eburnation of osteoarthritis until secondary osteophyte formation are consistent with degenerative os- degenerative changes become apparent. Neuropathic teoarthritis osteoarthropathy, a joint disease arising in the con- text of a neural disorder (syringomyelia, meningo- myelocele, multiple sclerosis, diabetes mellitus, indif- for osteoarthritis has been located at 11q (Chapman ference to pain, dysautonomia, and several others) et al.1999).(6) A mendelian recessive model has been and probably due to loss of proprioception and pain suggested for the common variety of osteoarthritis sensations, is characterized by severe fragmentation after a review of 337 families, each with two parents and collapse of the articular surfaces, extensive bony and at least one biological offspring (Felson et al. sclerosis, intra-articular osseous fragments, massive 1998). joint effusions, capsular rupture, subluxation, and The condition in which premature osteoarthritis dislocation. typically occurs as an effect of altered joint bio- Although the influence of hereditary factors in the mechanics is multiple epiphyseal dysplasia (OMIM development of degenerative osteoarthritis has not 132400). The universal epiphyseal dysplasia in this been completely elucidated, the following observa- disorder, with small epiphyses and epiphyseal frag- tions underscore the importance of genetics in at mentation and progressive flattening, results in loss least some forms of degenerative joint disease. (1) An of normal joint geometry, congruity, and alignment autosomal dominant trait in women and a recessive (Fig. 8.11). Genu varus or genu valgus and coxa vara, trait in men have been suggested for Heberden’s sometimes complicated by slipped capital femoral nodes, a designation for osteoarthritis of the distal epiphysis, further compromise joint congruity, there- interphalangeal joints (Stecher 1955; Lawrence et al. by contributing to the development of early-onset 1983). (2) A significant role has been suggested for osteoarthritis at the hip and knee levels (Treble et al. genetic factors in a generalized form of osteoarthritis 1990; Miura et al. 2000). Similar factors are at work in occurring in combination with Heberden’s nodes pseudoachondroplasia (OMIM 177170) (McKeand et and affecting preferentially the proximal interpha- al. 1996), the condition allelic to multiple epiphyseal langeal joints of the hand, the 1st carpometacarpal dysplasia; in the type II collagenopathies, including and tarsometatarsal joints, the knees, and the Stickler syndrome (OMIM 108300) (Rai et al. 1994), apophyseal joints of the spine (Kellgren et al. 1963). Kniest dysplasia (OMIM 156550), and spondyloepi- (3) A point mutation in the COL2A1 gene has been physeal dysplasia congenita (OMIM 183900); and al- found in four unrelated families with a distinctive so in other spondylo-epi-(meta)-physeal dysplasias, pattern of dominantly inherited generalized os- such as X-linked spondyloepiphyseal dysplasia tarda teoarthritis with mild chondrodysplasia (OMIM (OMIM 313400) (Whyte et al. 1999), spondylo-epi- 604864) (Vaisanen et al. 1987; Ala-Kokko et al. 1990; physeal dysplasia, Stanescu type, progressive pseudo- Winterpacht et al. 1994). (4) A specific COL2A1 hap- rheumatoid arthropathy (OMIM 208230), and Dyggve- lotype seems to predispose to sporadic generalized Melchior-Clausen dysplasia (OMIM 223800). How- osteoarthritis (OMIM 165720) (Meulenbelt et al. ever, in the ‘epiphyseal dysplasias,’ especially those 1999). (5) A female-sex-specific susceptibility gene with proven COL1A2 gene mutations, in addition to 498 Chapter 8 · Joints

the aforementioned mechanisms of altered bio- mechanics, abnormalities of the articular cartilage matrix may play a substantial role in the develop- ment of early osteoarthritis (Eyre et al. 1991). Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, also known as chondrocalcinosis or pseudogout, is a common articular disorder of the middle-aged and elderly characterized by the depo- sition of calcium-containing crystals in joint tissues (McCarty et al. 1983; Resnick et al. 1977). CPPD crys- tals are found in the joint fluid, synovium, cartilage, capsule, tendons, and ligaments. Both the fibrocarti- lage (of menisci, symphysis pubis, annulus fibrosus of the intervertebral disc, etc.) and the hyaline carti- lage are sites for CPPD crystal deposition (Fig. 8.12a,b). Cartilage fibrillation and disruption are fol- lowed by subchondral bone sclerosis and cystic de- generation, bone fragmentation and collapse, and in- tra-articular osseous bodies formation. In advanced stages, loss of joint function is common (Rosenthal 2001). Several clinical patterns are recognized, in- a cluding a pattern of acute self-limited attacks of arthritis lasting from days to weeks (pseudogout); a pattern of continuous acute attacks of arthritis last- ing from weeks to months (pseudorheumatoid arthritis); and a chronic-progressive course with or without superimposed acute inflammatory episodes (pseudo-osteoarthritis).The disease can occur in any of three forms: a sporadic (idiopathic) form, which is the common form in the elderly; a form associated with other disorders, such as hyperparathyroidism, hemochromatosis, hypothyroidism, and amyloido- sis; and a hereditary form (McCarty et al. 1983). One type of hereditary CPPD crystal deposition disease, chondrocalcinosis type 2 (CCAL2, OMIM 118600), is transmitted as an autosomal dominant trait. The gene causing the disease has been mapped to chro- mosome 5p (Hughes et al. 1995). Osteoarthritic joint b changes are absent or inconspicuous. In contrast, early-onset joint changes progressing to precocious Fig. 8.12 a,b. Calcium pyrophosphate dihydrate (CPPD) crys- osteoarthritis are typical manifestations of another a tal deposition disease in a 34-year-old man. Observe linear type of hereditary CPPD crystal deposition disease, deposits of CPPD crystals in the hyaline cartilage of femur and tibia. b Observe also chondrocalcinosis of the triangular fibro- referred to as chondrocalcinosis type 1 (CCAL1, cartilage of the wrist (arrow). The idiopathic form of the dis- OMIM 600668). In this form, which is also of autoso- ease is uncommon at this age. (From Hayashi et al. 2002) mal dominant inheritance, the defective gene maps to chromosome 8q (Baldwin et al. 1995). As in the sporadic form of the disease, CPPD crystal deposits build up within the joint, notably in the articular car- tilage, synovium, and capsule, and in the periarticu- lar soft tissues. Whether the disease is caused by the increased concentration of synovial fluid calcium hy- pophosphate crystals (caused by a defect in a CPPD gene), or by a primary defect of the articular carti- Premature Degenerative Joint Disease 499 lage (possibly related to mutation of an osteoarthritis • Hydroxyapatite deposition disease gene) that enhances accumulation of CPPD crystals, • Indifference to pain (congenital) is not known. In Wilson’s disease (hepatolenticular • Juvenile chronic arthritis degeneration, OMIM 277900), articular manifesta- • Lipoid dermatoarthritis tions, possibly due to copper deposition in the artic- • Macrodystrophia lipomatosa ular cartilage, are often part of the clinical picture. • Marfan syndrome Cartilage loss, subchondral cysts, and bone fragmen- • Mediterranean fever tation are common features. Although articular • Metaphyseal chondrodysplasia changes can mimic degenerative osteoarthritis, the • Multiple epiphyseal dysplasia (Fairbank) predilection for the small joints of the hands and • Neuropathic osteoarthropathy wrist and the extent of bone fragmentation clearly • Obesity, mechanical stress, malalignment identify Wilson’s disease. It may not be possible to • Osteoarthritis/chondrodysplasia differentiate between Wilson’s arthropathy and CP- • Osteoarthritis, primary PD crystal deposition disease or hemochromatotic • Osteochondritis dissecans arthropathy (Resnick 1995; Balint and Szebenyi • Osteogenesis imperfecta 2000). • Osteonecrosis • Polychondritis, relapsing Radiographic Synopsis • Rheumatoid arthritis 1. Focal loss of articular cartilage; osteophyte forma- • Scheuermann’s disease tion; subchondral bone changes (osteoarthritis) • Scleroderma 2. Diffuse loss of articular cartilage; joint effusion; • Scoliosis, idiopathic osteoporosis (rheumatoid arthritis) • Septic arthritis 3. Diffuse joint space narrowing; intra-articular • Slipped capital femoral epiphysis bone formation; marginal erosions; joint ankylo- • Spondyloepiphyseal dysplasias sis (seronegative spondyloarthropathies) • Spondyloepimetaphyseal dysplasias 4. Chondrocalcinosis; periarticular calcific deposits; • Spondylosis deformans large subchondral cysts (calcium pyrophosphate • Stickler syndrome dihydrate crystal deposition disease) • Surgery 5. Collapse/fragmentation of articular bone surface; • Thermal injury (burn, frostbite, electrical) intra-articular loose bodies; joint effusions; joint • Trauma subluxation/dislocation (neuropathic osteoarthro- • Wilson disease pathy)

Associations References • Acromegaly • Alkaptonuria Ala-Kokko L, Baldwin CT, Moskowitz RW, Prockop DJ. Single • Amyloidosis base mutation in the type II procollagen gene (COL2A1) • as a cause of primary osteoarthritis associated with a Calcium pyrophosphate dihydrate crystal mild chondrodysplasia. Proc Natl Acad Sci USA 1990; 87: deposition disease 6565–8 • Chondromalacia of patella Alexander CJ. Osteoarthritis: a review of old myths and cur- • Developmental hip dysplasia rent concepts. Skeletal Radiol 1990; 19; 327–33 • Diabetes mellitus Baldwin CT, Farrer LA, Adair R, Dharmavaram R, Jimenez S, • Anderson L. Linkage of early-onset osteoarthritis and Dysautonomia (Riley-Day syndrome) chondrocalcinosis to human chromosome 8q. Am J Hum • Dyschondrosteosis Genet 1995; 56: 692–7 • Dysplasia epiphysealis hemimelica Balint G, Szebenyi B. Hereditary disorders mimicking and/or • Ehlers-Danlos syndromes causing premature osteoarthritis. Baillieres Best Pract Res • Exostosis, multiple heritable Clin Rheumatol 2000; 14: 219–50 • Chapman K, Mustafa Z, Irven C, Carr AJ, Clipsham K, Smith A, Fibrogenesis imperfecta ossium Chitnavis J, Sinsheimer JS, Bloomfield VA, McCartney M, • Gaucher disease Cox O, Cardon LR, Sykes B, Loughlin J. Osteoarthritis-sus- • Gout ceptibility locus on chromosome 11q, detected by linkage. • Hemochromatosis Am J Hum Genet 1999; 65: 167–74 • Hemophilia Crane AR, Scarano JJ. Synovial cysts (ganglia) of bone. Report of two cases. J Bone Joint Surg Am 1967; 49: 355–61 • Homocystinuria 500 Chapter 8 · Joints

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