We report the first known example of spontaneous, naturally occurring fibrodysplasia ossificans progressiva (FOP) in a mammal. The Southeast Asian mouse deer of the genus _Tragulus_ (Artiodactyla: Tragulidae) have an osseous sheath covering the lower back and upper thigh region consistent with the clinical definition of FOP. This heterotophic bone deposition is sex related apparently with a genetic basis - it only occurs in males and is lacking in females; it is present in all adults males, including both wild obtained and zoo bred animals. _Tragulus_ may offer the opportunity to examine many of the disease&#x27;s most significant attributes experimentally

Bruce Rothschild

Larry Martin

Robert Timm

English

Nature Precedings

23 Jan.′08 
A New Spontaneous Model of Fibrodysplasia Ossificans Progressiva 
 
Bruce D. Rothschild, M.D., Larry D. Martin M.S.,  Ph.D., and Robert M. Timm, M.S., Ph.D. 
 
Abstract:  We report the first known example of spontaneous, naturally occurring 
fibrodysplasia ossificans progressiva (FOP) in a non-human mammal.  The Southeast 
Asian mouse deer of the genus Tragulus (Artiodactyla: Tragulidae) have an osseous 
sheath covering the lower back and upper thigh region consistent with the clinical 
definition of FOP.  This heterotophic bone deposition is sex related apparently with a 
genetic basis—it only occurs in males and is lacking in females; it is present in all adults 
males, including both wild obtained and zoo bred animals.  Tragulus may offer the 
opportunity to examine many of the disease’s most significant attributes experimentally. 
~~~~~~~~~~~~~~ 
 The preparation of contemporary mammalian skeletal collections is focused on 
traditional structures and often does not include osteological features closely associated 
with the skin.  The result can be exquisite preparations, but sometimes at the expense of 
unique osseous structures.  A series of remarkable preparations at the University of 
Kansas Natural History Museum highlights the osseous sheath covering the lower back 
and upper thigh region of the genus Tragulus, the Southeast Asian mouse deer1.  The 
sabertoothed mouse deer or chevrotains of the genus Tragulus (Artiodactyla: Tragulidae) 
are among the smallest artiodactyls.  Some aspects of their ecology and distribution are 
fairly well understood as a few species are locally abundant; however, as nocturnal and 
solitary animals, most aspects of their biology are poorly known.  Two species, Tragulus 
javanicus and T. napu, generally are recognized in the literature; however, recent 
systematic reviews2,3 recognized six species—T. javanicus from Indonesia; T. kanchil 
from China south to Malaysia; T. napu from Indochina, Cambodia, and Indonesia; T. 
nigricans from the Philippines; T. veriscolor from Vietnam; and T. williamsoni from 
northern Thailand. 
A remarkable skeletal sexual dimorphism is present in apparently all species of the 
genus—an osseous sheath covering the lower back and upper thigh region in males, but 
lacking in females (Figs. 1, 2).  It is believed to function as a pelvic shield in males, which 
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are aggressive, solitary, and engage in combat with large, saber-like canines.  Perhaps 
because of the lack of specimens, and especially the lack of material prepared 
specifically to elucidate this ossified sheath, little work has been done on the ossifiations.  
The pelvic region and sheath was described4 and figured5, albeit few details are visible.  
It was described as “Unique to tragulids is an ossified plate, derived from an aponeurosis 
(a membranous sheet of tendon) to which the sacral vertebrae attach6. 
 The osseous sheath is interesting as a unique anatomical feature for artiodactyls, as 
well as all mammals, but it may also have important medical ramifications as a potential 
model for the devastating human disease, fibrodysplasia ossificans progressiva (FOP).  
FOP, first described by Guy Paten in 1692, is a genetic disorder characterized by 
progressive ossification of tendons, ligaments, fascia, and striated muscle7,8,9,10.  As 
opposed to simple calcification or deposition of calcium in crystalline form, these 
structures are actually composed of bone.  The relentlessly progressive and seemingly 
uncontrollable nature of FOP results in immobilization and wheel chair confinement by 
age 30 in humans10,11. 
 Heterotopic bone in FOP forms rigid synostoses with the normal skeleton.  
Heterotopic refers to occurrence in an unusual part of the body.  It shares with normal 
bone the similar histologic appearance of mature cortical and trabecular organization. 
 There is no established treatment for FOP9 and prophylactic efforts have had only 
limited effect12,13.  Its rarity in humans precludes any scientific assessment of therapeutic 
efficacy or even natural history of the disease.  A natural animal model would allow 
clarification of its pathophysiology, natural history, and allow meaningful assessment of 
therapeutic intervention14. 
 Tragulus provides a useful model for FOP, given its reproducibility and its apparent 
genetic basis.  It only occurs in males and was present in all the adults suitable for 
observation, including both wild obtained and zoo bred animals.  This contrasts with a 
more sporadic occurrence in cats and pigs of a condition that resembles aspects of 
FOP14.  Kaplan et al. (14, p. 229) noted that “no known living animals have been available 
for further study.”  However a recent paper15 may provide a mouse model that along with 
Tragulus could establish the experimental basis for a controlled study of the cause(s) and 
treatment of FOP. 
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 The ossifications observed in Tragulus mirror that seen in human FOP, especially that 
illustrated by the skeleton of Harry Eastlack and as illustrated in a recent cat scan16,17.  
Mr. Eastlack donated his skeleton, which now resides in the Mütter Museum of The 
College of Physicians of Philadelphia, and provides the classic standard for recognition of 
FOP.  The pathology described in previous spontaneous animal models appears to be 
somewhat different.  In cats, muscle masses and calcification in or around muscles has 
been described, but documentation of full heterotopic ossification seems lacking in most 
reports.  Valentine et al.18 reported firm enlargement of caudal thigh and gastrocnemius 
muscles, with ‘defined areas of mineralization.  Individual muscle fibers (not muscles) 
were surrounded by abnormal calcium deposits; however, there was no heterotopic bone 
formation.  In contrast, they describe proliferative tissue with many hard, gritty or bony 
foci 0.1–4 cm in diameter19.  Norris et al.20 reported widespread fibrosis and ossification 
of skeletal muscles, primarily as spicules.  However, ossification adjacent to the femur 
was noted, producing the appearance of a second “femur”, complete with a fatty marrow 
cavity.  Most of the observed pathology in this cat was due to calcification, not 
ossification.  ‘Mineralized’ connective tissue was present as spicules in abdominal 
musculature and as plaques in the small intestine.  Waldron et al.21 did note flat plates or 
cylindrical bone masses in the sporadic feline case they reported. 
Similar osteological reactions have not been reported in other animals.  The 
spontaneous occurrence of lesions in a boar (and 34 of the 115 pigs it sired) is described 
as parosteal fibrosis and osseous metaplasia with joint fusion, but not as heterotopic 
bone18,22.  Multiple firm enlargements on necrospsy were found to be large, irregular 
masses of cancellous (with pseudomarrow of fatty or fibrous tissue) extracortical bone, 
often continuous with adjacent skeletal bone.  Seibod and Davis22 reported showing a 
section at a 1944 Armed Forces Institute of Pathology conference (AFIP accession 
104031) for which the consensus diagnosis was progressive myositis ossificans.  Minority 
diagnoses included osteoma (excluded because of lesional atrophic fibrosed muscle 
tissue), osteosarcoma (excluded because microscopic appearances were ‘generally 
benign’), osteitis fibrosia (excluded because underlying bones ‘were not sufficiently 
affected’), and multiple hereditary cartilaginous exostoses (excluded because of lack of 
cartilaginous cap). 
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4
Rosenstirn’s23 citation of Lorge’s23 diagnosis of progressive ossifying myositis 
(multiple spicules) in a horse cannot be further assessed at this time.  Lorge24 described 
ossification of atrophied muscle that is more characteristic of myositis ossificans than of 
FOP25.  Thus, we have few earlier examples of this disease and most have serious 
problems in the details of their expression as models of FOP. 
Terminology is a challenge.  The term myositis ossificans has been used 
inappropriately19 because FOP ‘does not involve muscle, is multicentric, often 
symmetrical, and unrelated to trauma.  Myositis ossificans … is a peripheral zone of 
orderly maturation from fibrous to osseous tissue.  Definitions however, are open to 
question.  Whether these spontaneous models represent a different stage of FOP or 
entirely different diseases remains unclear.  The mouse embryonic stem cell chimeric c-
Fos model does have heterotopic ossification, but “lack the anatomic specificity seen in 
the human disease”15,16. 
Neither the cat model or Tragulus fully mirrors human FOP, in part because the latter 
is often associated with congenital malformations of distal limbs15,18.  Tragulus however, 
offers an opportunity to examine experimentally many of the disease’s most significant 
attributes in a mammal that can be bred in captivity, the ossifications occur 
spontaneously, and are sex related. 
 
Acknowledgments.  The following curators and collection staff graciously provided access 
to specimens under their care:  Darin Lunde, Nancy B. Simmons, Robert S. Voss, and 
Eileen Westwig (American Museum of Natural History); Suzanne B. McLaren (Carnegie 
Museum); Laura Abraczinskas and Barbara Lundrigan (Michigan State University).  We 
thank Heather A. York for assistance in creating the photographs used as Figs. 1 and 2. 
 
 
 
References 
 
1. Nowak, RM.  Walker’s Mammals of the World, 5th ed.  Baltimore:  Johns Hopkins 
University Press, 1991. 
 
2 Meijaard, E, Groves, CP.  A taxonomic revision of the Tragulus mouse-deer 
(Artiodactyla).  Zool J Linnean Soc 2004;140:63–102. 
 
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Rothschild et al. – 
 
5
3 Grubb, P.  Order Artiodactyla.  Pp. 637–722 in Wilson, DE, Reeder, DM. eds.  
Mammal species of the world: A taxonomic and geographic reference, 3nd ed. 
Washington: Smithsonian Institution Press, 2005. 
 
4 Lydekker, RL.  The Royal Natural History.  London: Frederick Warne and Co., 1922. 
 
5 Lekagul, B, McNeely, JA.  Mammals of Thailand.  Bangkok: Kurusapha Ladprao 
Press, 1977. 
 
6 Vaughan, TA, Ryan, JM, Czaplewski, NJ.  Mammalogy.  Fort Worth: Saunders 
College Publishing, 2000. 
 
7 Kaplan, FS, Strear, CM, Zasloff, JA.  Radiographic and scintigraphic features of 
modeling and remodeling in the heterotopic skeleton of patients who have 
fibrodysplasia ossification progressiva.  Clin Orthop Rel Res 1994;304:238–247. 
 
8 Kaplan, FS, Shore, EM, Zasloff, MA.  Fibrodysplasia ossoficans progressiva: 
Searching for a skeleton key.  Calcif Tissue Intl 1996;59:75–78. 
 
9 Mahboubi, S, Glaser, DL, Shore, EM, Kaplan, FS.  Fibrodysplasia ossificans 
progressiva.  Pediatr Radiol 2001;31:307–314. 
 
10 Rocke, DM, Zasloff, M, Peeper, J.  Age-and-joint specific risk of initial heterotopic 
ossification in patients who have fibrodysplasia ossificans progressiva.  Clin Orthop 
Rel Res 1994;301:243–248. 
 
11 Cohen, RB, Hahn, GV, Tabas, JA.  The natural history of heterotopic ossification in 
patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients.  
J Bone Jt Surg 1993;75A:215–219. 
 
12 Brantus, JF, Meunier, PJ.  Effects of intravenous etidronate in acute episodes of 
fibrodysplasia ossificans progressiva. An open study.  Clin Orthop Rel Res 
1998;346:117–120. 
 
13 Zasloff, MA, Rocke, DM, Crofford, LJ.  Treatment of patients who have fibrodysplasia 
ossificans progressiva with isotretinoin.  Clin Orthop Rel Res 1998;346:121–129. 
 
14 Kaplan, FS, Shore, EM, Pignolo, RJ, Glaser, DL.  Animal models of fibrodysplasia 
ossificans progressive.  Clin Rev Bone Min Metab 2005;3(3–4):229–234. 
 
15 Kan, L, Hu, M., Gomes, WA, Kessler, JA.  Transgenic mice overexpressing BMP4 
develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype.  Am J Pathol 
2004;165:1107–1115. 
 
16 Kaplan, FS.  Fibrodysplasia ossificans progresiva:  An historical perspective.  Clin 
Rev Bone Min Metab 2005;3(3–4):179–181. 
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6
 
17 Tung, C-H, Lai, N-S.  Clinical image: Fibrodysplasia ossificans progressive seen on 
three-dimensional computed tomography.  Arthritis Rheum 2008;58:250. 
 
18 Valentine, BA, et al.  Fibrodysplasia ossificans progressivea in the cat. A case report.  
J Vet Intern Med 1992;6:335–340. 
 
19 Warren, HB, Carpenter, JL.  Fibrodysplasia ossificans in three cats.  Vet Pathol 
1984;21:495–499. 
 
20 Norris, AM, Pallett, L, Wilcock, B.  Generalized myositis ossificans in a cat.  J Am 
Animal Hosp Assoc 1980;16:659–663. 
 
21 Waldron, D, Pettigrew, V, Turk, M, Turk, J, Gibson, R.  Progressive ossifying myositis 
in a cat.  J Am Vet Med Assoc 1985;187:64–65. 
 
22 Siebold, HR, Davis, CL.  Generalized myositis ossificans (familial) in pigs.  Pathol Vet 
1967;4:79–88. 
 
23 Rosenstirn, J.  A contribution to the study of myositis ossificans progressive.  Ann 
Surg 1918;68:485–520, 591–637. 
 
24 Lorge, V.  Ossification du périmysium interne et atrophie consécutive des fibres 
musculaires.  Ann Méd Vét 1871;20:239–244. 
25 Resnick, D.  Diagnosis of bone and joint disorders.  Philadelphia: W. B. Saunders, 
2002. 
 
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7
Figure 1.  Dorsal and ventral view of the pelvic and abdominal region of an adult male 
Tragulus napu (KU 163,960).  Dermal ossifications extend from caudal-most ischiopubis 
to iliac crest and cephalidly from sacrum in a paraspinal distribution. 
 
Figure 2.  Dorsal view of 19th century preparation of an adult male Tragulus nigricans 
(KU 165,574).  Note residual heterotypic attached to sacrum.  When the preparation 
technique was to remove all material extraneous to the skeleton as has been traditionally 
done, one may see no, or only minimal evidence of the bone we herein call FOP.  This is 
exemplified in a dorsal view of wild caught specimen that was prepared in the early 
1900s. 
 
 
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A contribution to the study of myositis ossificans progressive.

A taxonomic revision of the Tragulus mouse-deer (Artiodactyla). Zool J Linnean Soc 2004;140:63–102. N a t u r e P r e c e d i n g s : h d l :

Age-and-joint specific risk of initial heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. Clin Orthop Rel Res 1994;301:243–248. 11

Animal models of fibrodysplasia ossificans progressive. Clin Rev Bone Min Metab

Diagnosis of bone and joint disorders.

Effects of intravenous etidronate in acute episodes of fibrodysplasia ossificans progressiva. An open study. Clin Orthop Rel Res

Fibrodysplasia ossificans in three cats. Vet Pathol 1984;21:495–499.

Fibrodysplasia ossificans progresiva: An historical perspective. Clin Rev Bone Min Metab 2005;3(3–4):179–181. N a t u r e P r e c e d i n g s : h d l : / n p r e .

Fibrodysplasia ossificans progressiva. Pediatr Radiol

Fibrodysplasia ossoficans progressiva: Searching for a skeleton key. Calcif Tissue Intl

Generalized myositis ossificans (familial) in pigs. Pathol Vet 1967;4:79–88.

Generalized myositis ossificans in a cat.

Intern Med

Jt Surg

Ossification du périmysium interne et atrophie consécutive des fibres musculaires. Ann Méd Vét 1871;20:239–244.

Progressive ossifying myositis in a cat.

Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossification progressiva. Clin Orthop Rel Res

The Royal Natural History. London: Frederick Warne and Co.,

Transgenic mice overexpressing BMP4 develop a fibrodysplasia ossificans progressiva (FOP)-like phenotype.

Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin. Clin Orthop Rel Res

New Spontaneous Model of Fibrodysplasia Ossificans Progressiva

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New Spontaneous Model of Fibrodysplasia Ossificans Progressiva

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