Published online May 1, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. e1295-e1300 (doi:10.1542/peds.2007-1980)

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ARTICLE

Early Diagnosis of Fibrodysplasia Ossificans Progressiva

Frederick S. Kaplan, MD^a,b,c, Meiqi Xu, BS^a,b, David L. Glaser, MD^a,b, Felicity Collins, MB, BS^d, Michael Connor, MD^e, Joseph Kitterman, MD^f, David Sillence, MD^g, Elaine Zackai, MD^h, Vardit Ravitsky, PhDⁱ, Michael Zasloff, MD^a,b,j, Arupa Ganguly, PhD^k and Eileen M. Shore, PhD^a,b,k

^a Center for Research in FOP and Related Disorders, and Departments of
^b Orthopaedic Surgery
^c Medicine
^k Genetics, University of Pennsylvania School of Medicine; Philadelphia, Pennsylvania
^d Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, New South Wales, Australia
^e Division of Developmental Medicine, Institute of Medical Genetics, University of Glasgow Medical School, Yorkhill Academic Campus, Glasgow, Scotland, United Kingdom
^f Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, California
^g Department of Genetic Medicine, University of Sydney, New South Wales, Australia
^h Department of Genetics; Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine; Philadelphia, Pennsylvania
ⁱ Center for Bioethics, University of Pennsylvania, Philadelphia, Pennsylvania
^j Departments Surgery and Pediatrics, Georgetown University School of Medicine; Washington, District of Columbia

BACKGROUND. Fibrodysplasia ossificans progressiva is a rare and disabling genetic condition characterized by congenital malformation of the great toes and by progressive heterotopic ossification in specific anatomic patterns. Most patients with fibrodysplasia ossificans progressiva are misdiagnosed early in life before the appearance of heterotopic ossification and undergo diagnostic procedures that can cause lifelong disability. Recently, the genetic cause of fibrodysplasia ossificans progressiva was identified, and definitive genetic testing for fibrodysplasia ossificans progressiva is now available before the appearance of heterotopic ossification.

METHODS. We recently evaluated 7 children for diagnosis of fibrodysplasia ossificans progressiva before the onset of heterotopic ossification. A medical history, physical examination, and skeletal survey were obtained on all of the patients, as well as clinical genetic testing for the canonical fibrodysplasia ossificans progressiva mutation.

RESULTS. All 7 of the children (4 girls and 3 boys; ages 3 months to 6 years) had congenital malformations of the great toes, but none had radiographic evidence of heterotopic ossification at the time of evaluation. Five of the 7 children had soft tissue lesions of the neck and back, suggestive of early fibrodysplasia ossificans progressiva flare-ups, 3 of whom had undergone invasive diagnostic procedures that exacerbated their condition. Two children had no history or signs of soft tissue swelling or flare-ups. DNA sequence analysis found that all 7 of the children had the recurrent fibrodysplasia ossificans progressiva missense mutation, a single nucleotide substitution (c.617G>A) at codon 206 in the glycine-serine activation domain of activin receptor IA, a bone morphogenetic protein type 1 receptor.

CONCLUSION. Clinical suspicion of fibrodysplasia ossificans progressiva early in life on the basis of malformed great toes can lead to early clinical diagnosis, confirmatory diagnostic genetic testing, and the avoidance of additional harmful diagnostic and treatment procedures. This is the first report of genetic confirmation of fibrodysplasia ossificans progressiva before the appearance of heterotopic ossification. Pediatricians should be aware of the early diagnostic features of fibrodysplasia ossificans progressiva, even before the appearance of heterotopic ossification. This awareness should prompt early genetic consultation and testing and the institution of assiduous precautions to prevent iatrogenic harm.

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Key Words: fibrodysplasia ossificans progressiva • heterotopic ossification • malformed great toes • bone morphogenetic protein • ACVR1

Abbreviations: FOP—fibrodysplasia ossificans progressiva • ACVR1—activin receptor IA • PCR—polymerase chain reaction

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Accepted Nov 1, 2007.

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