Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare, progressive, and permanently disabling disorder of extraskeletal ossification, is characterized by episodic and painful flare-ups and irreversible heterotopic ossification in muscles, tendons, and ligaments. Prevalence estimates have been hindered by the rarity of FOP and the heterogeneity of disease presentation. This study aimed to provide a baseline prevalence of FOP in the United States, based on contact with one of 3 leading treatment centers for FOP (University of Pennsylvania, Mayo Clinic, or University of California San Francisco), the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) membership list, or the IFOPA FOP Registry through July 22, 2020. RESULTS: Patient records were reviewed, collected, and deduplicated using first and last name initials, sex, state, and year of birth. A Kaplan-Meier survival curve was applied to each individual patient to estimate the probability that he or she was still alive, and a probability-weighted net prevalence estimate was calculated. After deduplication, 373 unique patients were identified in the United States, 294 of whom who were not listed as deceased in any list. The average time since last contact for 284 patients was 1.5 years. Based on the application of the survival probability, it is estimated that 279 of these patients were alive on the prevalence date (22 July 2020). An adjusted prevalence of 0.88 per million US residents was calculated using either an average survival rate estimate of 98.4% or a conservative survival rate estimate of 92.3% (based on the Kaplan-Meier survival curve from a previous study) and the US Census 2020 estimate of 329,992,681 on prevalence day. CONCLUSIONS: This study suggests that the prevalence of FOP is higher than the often-cited value of 0.5 per million. Even so, because inclusion in this study was contingent upon treatment by the authors, IFOPA membership with confirmed clinical diagnosis, and the FOP Registry, the prevalence of FOP in the US may be higher than that identified here. Thus, it is imperative that efforts be made to identify and provide expert care for patients with this ultra-rare, significantly debilitating disease.

Self-reported baseline phenotypes from the International Fibrodysplasia Ossificans Progressiva (FOP) Association Global Registry.

A global, patient-reported registry has been established to characterize the course of disease and track clinical outcomes in patients with fibrodysplasia ossificans progressiva (FOP), an ultra-rare genetic condition of progressive heterotopic ossification (HO) that results in ankylosis of joints and renders most affected individuals immobile by the second decade of life. Here, we present baseline phenotypes on 299 patients (median age 21 years; range 0.1 to 78 years) from 54 countries based on aggregate data from the International FOP Association (IFOPA) Global Registry (the "FOP Registry"). The mean current age of the patients is 23.7 years (range, 0.1 to 78 years). Baseline characteristics are presented for FOP diagnosis, HO, flare-ups and precedent events, system-based prevalent symptomatology, encounters with medical and dental care providers, Patient Reported Outcomes Measurement Information System (PROMIS) Global Health Scale scores, physical function, as well as the use of aids, assistive devices, and adaptations. Correlations of PROMIS Global Health scores with HO burden and physical function are calculated. Associations of joint mobility with PROMIS Global Health scores, physical function, and use of aids, assistive devices, and adaptations are summarized. Overall, the FOP Registry database contains a broad sample of the global FOP patient population, providing a useful tool for expanding knowledge of FOP, designing clinical trials and facilitating evidence-based decisions about the optimal monitoring and management of affected individuals.

Co-morbidities Associated With Early Mortality in Adults With Spina Bifida.

OBJECTIVE: The aims of this quality improvement project were to identify secondary conditions and medical co-morbidities in adult patients with spina bifida and to determine which factors were associated with an earlier age of death. DESIGN: Retrospective chart review of 487 patients who attended the University of Pittsburgh Medical Center Adult Spina Bifida Clinic between August 1, 2005, and June 6, 2017, was conducted. RESULTS: Of 487 patients who had received care at the University of Pittsburgh Medical Center Adult Spina Bifida Clinic, 48 were deceased. The most commonly reported causes of death included infection, respiratory failure, renal failure, shunt malfunction, and metastatic cancer. Underlying co-morbidities and secondary conditions included hydrocephalus, Chiari II malformation, tethered cord, scoliosis, and abnormal renal function. In deceased patients, earlier age of death was significantly associated with myelomeningocele subtype and the presence of hydrocephalus and Chiari II malformation. CONCLUSIONS: Clinicians treating individuals with spina bifida should be aware of the potential for earlier mortality in individuals with myelomeningocele, hydrocephalus, and Chiari II malformation, especially with regard to infection, respiratory failure, renal failure, shunt malfunction, and cancer. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Discuss the importance of recognizing co-morbidities in adult individuals with spina bifida; (2) Describe secondary conditions and medical co-morbidities associated with spina bifida; and (3) Identify which conditions are associated with earlier age of death in adult individuals with spina bifida. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The FOP Connection Registry: Design of an international patient-sponsored registry for Fibrodysplasia Ossificans Progressiva.

The Fibrodysplasia Ossificans Progressiva (FOP) Connection Registry is an international, voluntary, observational study that directly captures demographic and disease information initially from patients with FOP (the patient portal) and in the near future from treating physicians (the physician portal) via a secure web-based tool. It was launched by the International FOP Association (IFOPA) with a guiding vision to develop and manage one unified, global, and coordinated Registry allowing the assembly of the most comprehensive data on FOP. This will ultimately facilitate greater access and sharing of patient data and enable better and faster development of therapies and tracking their long-term treatment effectiveness and safety. This report outlines the FOP Connection Registry's design and procedures for data collection and reporting, as well as the long-term sustainability of Registry. Patient-reported, aggregate data are summarized for the first 196 enrolled patients, representing participation from 42 countries and approximately 25% of the world's known FOP population. Fifty-seven percent of the current Registry participants are female with a mean age of 23.8years (median=21years, range=1, 76years). Among the Registry participants who provided their FOP type, 51% reported FOP Classic (R206H), 41% reported FOP Type Unknown, and 8% reported FOP Variant. Patients reported 5.4years (median=3.0years, range=0, 45.8years) as the mean age at which they noticed their first FOP symptoms and a mean age at final FOP diagnosis of 7.5years (median=5.0years, range=0.1, 48.4years). Information on the patients' diagnostic journeys in arriving at a correct diagnosis of FOP is also presented. These early patient-reported data suggest that the IFOPA's vision of one, unified, global, and coordinated approach to the FOP Connection Registry is well underway to being realized. In addition, the positive response from the FOP patient community to the initial launch of the Registry's patient portal has created a solid foundation upon which to build the largest international registry for monitoring the clinical progression of FOP among patients.

Metformin-diet benefits in women with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance.

We prospectively assessed whether metabolic and menstrual benefits of metformin-diet were equally realized in women with polycystic ovary syndrome (PCOS), categorized by pretreatment top (n = 32) and bottom (n = 35) quintile homeostasis model assessment insulin resistance (IR). Effects of metformin (2.55 g/d) and diet (6300-8400 J/d [1500-2000 cal/d], 26% protein, 44% carbohydrate) were prospectively assessed for 12 months. Pretreatment, the bottom and top insulin-resistant quintile groups differed by median weight (84 vs 121 kg), insulin (7.8 vs 40.5 I(1/4) U/mL), IR (1.62 vs 9.28), homeostasis model assessment insulin secretion (131 vs 416), glucose (82 vs 98 mg/dL), sex hormone-binding globulin (40 vs 15 nmol/L), (all P < .0001), free androgen index (2.76 vs 10.8) ( P < .001), triglyceride (92 vs 131 mg/dL), high-density lipoprotein (46 vs 39 mg/dL), systolic blood pressure (116 vs 128 mm Hg), and diastolic blood pressure (76 vs 84 mm Hg), (all P < .01). After 12 months on metformin-diet, weight fell by 7% in both insulin-resistant groups (P < .0001), insulin, IR, and insulin secretion fell in the top insulin-resistant group by 60%, 64%, and 39% (all P < .0001), with smaller reductions in the bottom insulin-resistant group of 18%, 13% (P > .05 for both), and 22% (P < .01), respectively. The free androgen index fell 39% (P > .01) in the top insulin-resistant group. The pretreatment percentage of expected menses in the top insulin-resistant quintile (26 +/- 39%) was 1.6 times less than in the bottom insulin-resistant quintile (41 +/- 38%) (P = .026). Over the 12-month treatment period, the percentage of spontaneous regular normal menses increased to 72 +/- 27% in the top insulin-resistant quintile group (P < .0001) and to 77 +/- 31% in the bottom quintile group (P < .0001), with no group difference (P = .33). Metformin-diet metabolic effects were much more marked in women in the top vs the bottom quintile for IR. Women with PCOS in the bottom insulin-resistant quintile, conventionally thought not to respond optimally to metformin-diet, nevertheless experience significant metabolic and menstrual benefits. Metformin-diet should benefit most women with PCOS, even those with normal serum insulin, without IR.