I Med Genet 1993; 30: 687-689

A three generation family with fibrodysplasiaossificans progressiva

J M Connor, H Skirton, P W Lunt

AbstractA family with five persons affected withfibrodysplasia ossificans progressiva(myositis ossificans progressiva) in threegenerations is described. This is the firstwell documented three generation familywith this condition and provides furtherevidence for autosomal dominant in-heritance. A wide range of phenotypicseverity is apparent, from disabling ecto-pic bone formation and premature deathto an asymptomatic adult with charac-teristic big toe malformations.(J Med Genet 1993;30:687-9)

Fibrodysplasia ossificans progressiva (FOP,myositis ossificans progressiva, MIM 135100)is a rare disorder in which physical handicapowing to progressive soft tissue ossificationaccompanies characteristic skeletal malforma-tions.' Over 600 patients have been describedand attempted total ascertainment in the UKfound a minimum point prevalence of onepatient per 1-64 million of the population.2The sex ratio is equal and autosomal dominantinheritance is favoured on the basis of concor-dant monozygotic twins,34 a paternal age effectfor presumed new mutations,256 and severalinstances of parent to child transmission,including male to male transmission.78 Onlyone three generation family with FOP has beenpublished. Gaster9 in 1905 mentioned a familywith a grandfather, father, and three sonsaffected in a discussion at a medical meetingbut never published the family in further de-tail. We thus wish to describe a contemporarythree generation family with FOP.

after extraction of wisdom teeth. She had afurther operation at 23 years of age to replacethe right temporomandibular joint with aBowerman-Conroy titanium prosthesis butjaw fixation recurred one week afterwards. Sheis now 47 years of age and her only othersymptom has been gradually increasing backstiffness in recent years. On examination shehas limited neck mobility and jaw fixation butnormal mobility at other joints and clinicallynormal big toes. A radiograph of her cervicalspine showed anterior osteophytic bridging ofseveral vertebral bodies (fig 2) and a radio-graph of her feet showed symmetrical bonyspurs on the medial sides of the heads of thefirst metatarsals (fig 3).Her father (I.1, fig 1) had also been asymp-

tomatic until he developed back and neck

.~~~~~M

Duncan GuthrieInstitute of MedicalGenetics, Yorkhiil,Glasgow G3 8SJ, UK.J M Connor

Clinical GeneticsService, Taunton andSomerset Hospital,Taunton, Somerset,UK.H Skirton

Clinical GeneticsUnit, Institute ofChild Health, BristolRoyal Hospital forSick Children, Bristol,UK.P W Lunt

Correspondence toProfessor Connor.Received 16 February 1993.Accepted 26 March 1993.

Case reportThe family pedigree is shown in fig 1. Theproband (II.2) was asymptomatic until 22years of age when she developed jaw fixation

2I'

1 2Figure I Pedigree of the family.

Figure 2 Radiograph of the cervical spine of II.2.

Figure 3 Radiograph of both feet of II.2.

687

on February 26, 2020 by guest. P

rotected by copyright.http://jm

g.bmj.com

/J M

ed Genet: first published as 10.1136/jm

g.30.8.687 on 1 August 1993. D

ownloaded from

Connor, Skirton, Lunt

stiffness after trauma. His jaw also becamefixed after trauma and by his forties he haddeveloped a limp. He remained ambulant(with the use of a stick) until his early seventiesand died at 72 years of age from a myocardialinfarction. The diagnosis of FOP was con-firmed at the Royal National OrthopaedicHospital, London and some of his x rays arestill held in their radiological museum. Thesewere reviewed and showed normal hands, mal-formed big toes with superimposed ankylosis(similar to his granddaughter III.1), progres-sive ankylosis of the cervical spine, and multi-ple areas of soft tissue ossification.The proband's sister also had FOP. She was

well until 15 years of age when spontaneousswelling of the left leg occurred. A biopsy wasperformed and the family was told she had afibrosarcoma. The swelling subsequently sub-sided but she had limited left knee movementsthereafter. In her late teens she developedlimitation of movement at the right elbow aftertrauma. In her twenties she developed a suc-cession of painless lumps on her back. Afterthis she started to walk with a frame. Shegradually became more disabled and was bedbound for a year before her death from pneu-monia at 28 years of age. Her case records andradiographs are no longer available but herhospital diagnosis at the time of death wasmyositis ossificans.The proband's two daughters also have

FOP. The older (III.1) has had stiff big toesfor many years but is otherwise asymptomatic.Her examination at 24 years of age was normalexcept for no mobility at the interphalangealjoints of both big toes. Her radiographsshowed malformed halluces with bony spurson the medial sides of the heads of the firstmetatarsals and ankylosis of the hallucal inter-phalangeal joints (fig 4). Her radiograph of thecervical spine was normal (fig 5). The youngerdaughter was well until 13 years of age whenshe first noted painful lumps on her back.These appeared over several hours andresolved over several days. Subsequently shehas noted stiffness of her neck and lower back.For the past three years she has experiencedpainful limitation of movement of both hipsbut especially the right. She noted pain andclicking when she walks and this had beenassociated with occasional painful locking. Onexamination at 23 years of age she had palpable

Figure 4 Radiograph of both feet of III.1.

Figure 5 Radiograph of the cervical spine of III.I.

ectopic bone in the left lumbar region, limitedmobility of the neck and spine, and painfullimitation of all movements at both hips (rightmore than left), but clinically normal big toes.Her radiographs showed malformed big toeswith medial spurs on the heads of the firstmetatarsals (fig 6), an ectopic bony bar in theleft lumbar region (fig 7), a normal cervicalspine (fig 8), and abnormalities of bothhips with multiple osteochondromata anddeformed femoral heads (fig 9).

DiscussionThis family shows many typical features ofFOP but has two unusual features and one

Figure 6 Radiograph of both feet of III.2.

Figure 7 Radiograph of the upper lumbar spine ofIII.2.

688

on February 26, 2020 by guest. P

rotected by copyright.http://jm

g.bmj.com

/J M

ed Genet: first published as 10.1136/jm

g.30.8.687 on 1 August 1993. D

ownloaded from

A three generation family with fibrodysplasia ossificans progressiva

Figure 8 Radiograph of the cervical spine of III.2.

Figure 9 Radiograph of both hips of III.2.

atypical feature. Typical features include thebig toe malformations, the pattern of ectopicbone formation, the relationship of ectopicbone to trauma (including surgery), and themisdiagnosis of early ossifying lesions as a

fibrosarcoma. The unusual features are thenormal cervical spine radiographs in adult-hood in III.1 and 11I.2 and the mild disabilityin adulthood in 1.1, II.2, III.1, and III.2. Theatypical feature is the presence of symptomaticmultiple hip osteochondromata in III.2.

In the most common big toe malformationin FOP there is a single phalanx which resultsin a short big toe which often has valgusdeviation.'0 Less commonly other malforma-tions are found which include normal sized bigtoes which may later become stiff owing toankylosis.'0 Each member of this family (whereradiographs were available for study) showedthe same malformation of the first metatarsalwith superimposed ankylosis in I.1 and 11I.2.As in these patients, the malformations in FOPare characteristically symmetrical whereas theectopic bone formation is asymmetrical andunpredictable. Involvement of the paraspinalmuscles and extra-articular tissues of the jaw iscommon with resulting spinal stiffness and jawfixation.'0

Hall and Sutcliffe" described abnormal cer-vical vertebrae with small bodies, enlargedpedicles and short 'massive' spinous processesin eight children with FOP. Similar changeswere found in four of eight other children withFOP and in adult life variable fusion of thecervical vertebrae was a consistent feature.'2This fusion was first noted between adjacentneural arches in late childhood but alsoinvolved the vertebral bodies in some adultpatients. The normal cervical spines in adult-hood in patients III.1 and III.2 are thusunusual and probably reflect the generallybenign clinical course in these patients.

In general patients are severely handicappedowing to ectopic bone formation. Mostpatients have severe limitation of the spine andshoulders by 10 years of age, one or both hipsare involved by 20 years of age, and mostpatients are chair or bed bound by 30 years ofage.'0 The natural history in II.3 is thus fairlytypical whereas the four other affected subjectsin this family have had considerably milderclinical courses. This may reflect the nature ofthe underlying mutation or factors affectingvariable expression of this dominant trait. Asyet these factors are unknown and no medicaltreatment has been shown to influence the longterm prognosis.'

Multiple osteochondromata have not pre-viously been described in the hip joint in FOP.Usually these represent metaplastic cartilagi-nous nodules derived from the synovial mem-brane (synovial osteochondromatosis).13 Syno-vial osteochondromatosis most commonlyoccurs in young or middle aged adults and themost frequent areas of involvement are theknee joint, the hip, elbow, and shoulder.The genetic defect causing FOP and its

chromosomal regional localisation are cur-rently unknown and linkage studies in familiessuch as this will assist with exclusion mappingof possible candidate genes for this disorder.

We wish to thank Dr D J Stoker of the RoyalNational Orthopaedic Hospital Trust forkindly providing us with copies of radiographsof I.1.

1 Connor JM. Fibrodysplasia ossificans progressiva. In:Royce PM, Steinrann B. Connective tissue and its heri-table disorders. Molecular,genetic and medical aspects. NewYork: Wiley-Liss, 1992:603-11.

2 Connor JM, Evans DAP. Genetic aspects of fibrodysplasiaossificans progressiva. J Med Genet 1982;19:35-9.

3 Eaton WL, Conkling WS, Daeschner CW. Early myositisossificans progressiva occurring in homozygotic twins. Aclinical and pathologic study. J Pediatr 1957;50:591-8.

4 Vastine JH, Vastine MF, Arango 0. Myositis ossificansprogressiva in homozygotic twins. AJR 1948;59:204-12.

5 Tunte W, Becker PE, von Knorre GV. Zur Genetik derMyositis ossificans progressiva. Humangenetik1967;4:320-5 1.

6 Rogers JG, Chase GA. Patemal age effect in fibrodysplasiaossificans progressiva. J Med Genet 1979;16:147-8.

7 Burton-Fanning FW, Vaughan AL. A case of myositisossificans. Lancet 1901;ii:849-50.

8 Logacev KD. Progressive ossification of muscles. Klin Med(Mosk) 1964;42:106-10.

9 Gaster A. Discussion in meeting in West London Medico-Chirurgical Society, 7 October 1904. West London MedJ71905;10:37.

10 Connor JM, Evans DAP. Fibrodysplasia ossificans progres-siva. The clinical features and natural history of 34patients. J BoneJoint Surg (Br) 1982;64:76-83.

11 Hall CM, Sutcliffe J. Fibrodysplasia ossificans progressiva.Ann Radiol (Paris) 1979;22:119-23.

12 Connor JM, Smith R. The cervical spine in fibrodysplasiaossificans progressiva. Br I Radiol 1982;55:492-6.

13 Milgram JW. Synovial osteochondromatosis: a histopatho-logical study of 30 cases. J Bone joint Surg (Am)1977;59:792-801.

689

on February 26, 2020 by guest. P

rotected by copyright.http://jm

g.bmj.com

/J M

ed Genet: first published as 10.1136/jm

g.30.8.687 on 1 August 1993. D

ownloaded from