Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans

Background. Little is known about diagnostic errors for a disease worldwide. Such errors could alter the disease’s natural history, especially if unwarranted interventions cause irreversible harm. Fibrodysplasia ossificans progressiva (FOP), a rare, autosomal dominant genetic disease characterized by episodes of permanent heterotopic ossification of soft tissues, occurs worldwide without racial, ethnic, or geographic predilection. There is no effective treatment, and soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, or mandibular blocks for dental procedures) and viral illnesses are likely to induce episodes of rapidly progressive heterotopic ossification, with resultant permanent loss of motion in the affected area. Accurate diagnoses can be made on the basis of the clinical findings of tumor-like swellings on the head, neck, back, or shoulders and characteristic short great toes with hallux valgus-like malformations and missing interphalangeal joints. On the basis of conversations with numerous individuals with FOP, we suspected that diagnostic errors with FOP are common and often associated with inappropriate and harmful diagnostic and therapeutic procedures. Objective. To document the frequency of diagnostic errors with FOP and complications resulting from misdiagnoses. Design. A questionnaire requesting detailed demographic, diagnostic, and treatment information was sent to all 269 patient-members of the International FOP Association; the sampling frame included >90% of all known FOP patients worldwide. We received 138 replies (51% response) from 25 countries. The age range was 2 to 71 years; there were 78 female subjects and 60 male subjects. In addition, to assess the availability and adequacy of information about FOP, we reviewed 184 English-language textbooks in relevant specialties published in the past 20 years. Results. Incorrect diagnoses were given initially to 87% of individuals with FOP. This astonishing rate of diagnostic errors occurred worldwide, regardless of ethnicity, geographic background, or misdiagnosing physician’s specialty. The most common incorrect diagnosis was cancer (32%). The mean period from the onset of symptoms to correct diagnosis was 4.1 years, and the median number of physicians consulted before the correct diagnosis of FOP was 6. For 67% of patients, unnecessary invasive procedures (biopsies) were performed; 68% received inappropriate therapies. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic ossification. Notably, only 8% of the 184 textbooks that were reviewed contained adequate descriptions of FOP, including the caution that trauma can accelerate the process of heterotopic ossification. Conclusions. Diagnostic errors and inappropriate medical procedures, which may lead to permanent harm, can alter the natural history of a disease. In FOP, the astonishing rates of diagnostic errors and inappropriate invasive medical procedures likely result from lack of physician awareness because of failure of information transfer. Pediatrics 2005;116:e654–e661. URL: www. pediatrics.org/cgi/doi/10.1542/peds.2005-0469; cancer, fibromatosis, heterotopic ossification, medical errors, myositis ossificans. ABBREVIATIONS. BMP4, bone morphogenetic protein 4; FOP, fibrodysplasia ossificans progressiva; IFOPA, International Fibrodysplasia Ossificans Progressiva Association; UCSF, University of California, San Francisco. The accurate diagnosis of disease has been a basic principle of medical care since antiquity. Mistaken or delayed diagnosis can lead to morbidity or death through use of inappropriate procedures or through withholding of necessary treatments. Rates of diagnostic errors for common diseases, such as acute cardiac ischemia, tend to be low,1,2 but relatively little is known about the unnatural history of rarer disorders in which iatrogenic harm resulting from misdiagnosis may be common. Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder with autosomal dominant inheritance3,4 and a point prevalence of 1 case per 2 million population worldwide.5 Almost all individuals with FOP have congenital malformations of the great toes that are recognizable at birth, consisting of a hypoplastic proximal phalanx with associated hallux valgus6 (Fig 1A). FOP is characterized postnatally by episodes of From the *Department of Pediatrics and Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; ‡International Fibrodysplasia Ossificans Progressiva Association, Winter Springs, Florida; §Department of Applied Science, Division of Biostatistics, University of California Davis, Davis, California; and Departments of Orthopedic Surgery and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Drs Kitterman and Kaplan conceived and designed the study. Dr Kitterman and Ms Kantanie participated in collection and compilation of the data. Drs Kitterman, Rocke, and Kaplan participated in analysis and interpretation of the data and in writing of the manuscript. All authors have seen and approved the final version. Accepted for publication Jun 28, 2005. doi:10.1542/peds.2005-0469 The questionnaire used in this study is available from the corresponding author. No conflict of interest declared. Reprint requests to (J.A.K.) Department of Pediatrics, Box 0734, University of California, San Francisco, San Francisco, CA 94143. E-mail: kittermj@ peds.ucsf.edu PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad-