title: Early diagnosis of fibrodysplasia ossificans progressiva.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Research in FOP and Related Disorders, and Department of Orthopaedic Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. frederick.kaplan@uphs.upenn.edu
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Meiqi
authors.initials: M
authors.lastname: Xu
authors.forename: David L
authors.initials: DL
authors.lastname: Glaser
authors.forename: Felicity
authors.initials: F
authors.lastname: Collins
authors.forename: Michael
authors.initials: M
authors.lastname: Connor
authors.forename: Joseph
authors.initials: J
authors.lastname: Kitterman
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: Vardit
authors.initials: V
authors.lastname: Ravitsky
authors.forename: Michael
authors.initials: M
authors.lastname: Zasloff
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
mesh_terms: D002648:Child; D002675:Child, Preschool; D042241:Early Diagnosis; D005260:Female; D006214:Hallux / Q000002:abnormalities; D006215:Hallux Valgus / Q000150:complications / Q000175:diagnosis; D006801:Humans; D007223:Infant; D008297:Male; D009221:Myositis Ossificans / Q000175:diagnosis*