Early mortality and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva

Abstract

Background: Fibrodysplasia ossificans progressiva, a rare genetic disorder of progressive extraskeletal ossification, is the most disabling form of heterotopic ossification in humans. However, little is known about the lifespan or causes of mortality in these patients. We undertook this study to determine the lifespan and causes of mortality in individuals who had fibrodysplasia ossificans progressiva.

Methods: We reviewed comprehensive mortality reports from two large registries of patients with fibrodysplasia ossificans progressiva. Together, these registries comprise >90% of all known patients with this condition in the world. We noted the sex, dates of birth and death, and the cause of death for each individual. We verified the cause of death with extensive medical records, when available. We also collected date of birth, current age, and sex information for each living patient member of the International Fibrodysplasia Ossificans Progressiva Association.

Results: Sixty deaths (thirty male and thirty female patients) were reported in the fibrodysplasia ossificans progressiva community during a thirty-three-year-period. For all sixty patients, the median age at the time of death was forty years (range, three to seventy-seven years). Data were sufficient to establish the cause of death in forty-eight (80%) of the sixty individuals. The median age at the time of death for the forty-eight patients (twenty-four male and twenty-four female patients) with an established cause of death was also forty years. The median lifespan estimated from the 371 individuals in the international fibrodysplasia ossificans progressiva community who were alive and the sixty who had died was fifty-six years (95% confidence interval, fifty-one to sixty years). The most common causes of death in patients with fibrodysplasia ossificans progressiva were cardiorespiratory failure from thoracic insufficiency syndrome (54%; median age, forty-two years) and pneumonia (15%; median age, forty years).

Conclusions: Fibrodysplasia ossificans progressiva is not only an extremely disabling disease but also a condition of considerably shortened lifespan. The most common cause of death in patients with fibrodysplasia ossificans progressiva is cardiorespiratory failure from thoracic insufficiency syndrome.

Fig. 1

Age distribution (in years) at the time of death for sixty patients with fibrodysplasia ossificans progressiva (1973 to 2006).

Fig. 2

Kaplan-Meier survival curves for patients with fibrodysplasia ossificans progressiva (FOP) and for the 1980 U.S. population. The dotted lines are 95% confidence limits. The solid red line represents the actual survival data (average of male and female) for the U.S. population from the U.S. Census Bureau (1980). The Y axis is the percent survival ×10⁻², and the X axis is the age in years.

Fig. 3

Working model of the pathophysiology of thoracic insufficiency syndrome and cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva.