#ShareForRare: Fibrodysplasia ossificans progressiva (FOP)
This #RareDiseaseDay, we’re shedding light on FOP, an ultra-rare disease. Join us in raising awareness by exploring the intricacies of this condition, from its causes and early symptoms to treatment options.
What is FOP?
Fibrodysplasia Ossificans Progressiva (FOP) is an exceedingly rare genetic connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present, a phenomenon known as heterotopic ossification. This condition affects ligaments, tendons, and skeletal muscles, causing these tissues to undergo a metamorphosis, transforming into bone. This progressive process results in the locking of joints, making movement difficult or, in some cases, impossible. Patients with FOP commonly exhibit malformed big toes from birth (congenital), along with other skeletal malformations.
FOP is often referred to as one of the rarest diseases, with an estimated incidence of about 1 in 2 million people worldwide. However, up to this day, there is no evidence of any ethnic, racial, gender, or geographic predilection to FOP.
Although most cases of FOP are sporadic, a small number of inherited FOP cases show germline transmission. FOP is caused by an autosomal dominant allele in the ACVR1 (also known as activin-like kinase 2 (ALK2)), located on chromosome 2q23–24. The allele has variable expressivity, but complete penetrance.
Molecular aspects of FOP
At the molecular level, FOP is associated with a specific mutation in the ACVR1 gene (OMIM 102576), located on chromosome 2q23–24. This gene is a part of the bone morphogenetic protein (BMP) pathway, crucial for embryonic skeleton formation and postnatal skeletal repair.
The ACVR1 gene is responsible for encoding the activin receptor type-1 transmembrane kinase that binds to BMP receptors (Type I BMPR and Type II BMPR) for chondrogenesis signaling. Normally, the binding of ACVR1 protein to BMP receptors starts a signaling cascade that is crucial for inducing endochondral bone formation during development, as well as during physiological skeletal and tissue homeostasis processes.
Specifically, the most common causal variant of FOP is a substitution of codon 206 from arginine to histidine in the ACVR1 protein (ACVR1:c.617G>A) that triggers abnormal activation. This results in the transformation of connective and muscle tissue into a secondary skeleton, by inducing endothelial cells to transform into mesenchymal stem cells and subsequently into bone.
However, there are also Atypical FOP patients who present other heterozygous ACVR1 missense mutations in conserved amino acids. According to Franklin, there are at least 14 pathogenic variants reported in this gene as of February 2024. All of them have a missense effect, and most of them were reported de novo.
Clinical features and diagnosis of FOP
People with FOP typically exhibit normal appearances at birth, except for abnormalities in their great toes, characterized by hallux valgus, malformed first metatarsal, or monophalangism. Then, typically starting in early childhood, the ossification process unfolds progressively throughout their lives, in inevitable and unpredictable episodes, with the mean age of onset being 5 years old. By the third decade of life, the majority of individuals with FOP find themselves dependent on wheelchairs, necessitating lifelong care.
These episodic flare-ups, characterized by painful inflammatory soft tissue swellings, are often precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls, or fatigue. The ossification usually becomes evident 2–8 months following the swelling. The abnormal development of bone at multiple soft tissue sites leads to stiffness, limited movement, and eventual fusion (ankylosis) of affected joints, often following a specific pattern (neck, back, shoulders, elbows, hips, knees, wrists, ankles, jaw).
In addition to Classic FOP, atypical forms of FOP have been documented. Patients with Atypical FOP either have one or more features in addition to characteristic FOP, such as intercurrent aplastic anemia, craniopharyngioma, childhood glaucoma, or growth retardation (FOP Plus); or present major variations in one or both of the two classic defining features of FOP, like normal great toes or severe reduction deficits of digits (FOP Variants).
Diagnosing FOP involves recognizing congenital malformations, progressive heterotopic ossification, and characteristic flare-ups. Radiological imaging and genetic testing targeting the ACVR1 gene are essential for accurate diagnosis.
Treatments and clinical trials
At present, there is no definitive cure or treatment for FOP. The management of FOP remains challenging, focusing on preventative care based on prophylactic measures against falls (e.g. improvement in household safety, use of protective headgear) and viral infections to minimize trauma and flare-ups. Surgical interventions and intramuscular injections are generally avoided due to the risk of exacerbating abnormal bone growth.
For the episodes, it is usually recommended to administrate a brief 4-day course of high-dose corticosteroids, started within the first 24 hours of a flare-up, which may help reduce the intense inflammation and tissue edema seen in the early stages of the disease.
As of February 2024, 7 clinical trials related to Fibrodysplasia Ossificans Progressiva are actively recruiting or announced but not yet recruiting on ClinicalTrials.gov. While most of these trials explore novel approaches and therapies, there is also an actively recruiting study for the FOP Connection Registry. This is a patient and physician-driven database of clinical and medical information about FOP, initiated by the International Fibrodysplasia Ossificans Progressiva Association (IFOPA). With this initiative, they aim to help grow the knowledge about FOP, contribute to finding effective treatments and possibly a cure, aid doctors in better understanding FOP, and improve patient care.
Resources and initiatives
There are interesting resources for patients and caregivers, such as the NIH’s Genomic and Rare Disease (GARD) and MedlinePlus. Furthermore, the Focus on FOP website offers a free reference guide called Let’s Talk FOP with educational materials for families and individuals.
For doctors and other help professionals, the website Orphanet, OMIM, and the NIH’s Genetic Testing Registry offer information to help with diagnosis and testing.
Regarding advocacy, several NGOs are especially dedicated to connecting families affected by the disease, such as the ones leading the Patient Registry initiative, IFOPA. In addition, the NORD (National Organization for Rare Disorders) offers education programs, advocacy, research, and patient services for many rare diseases, and has resources for patients, caregivers, clinicians, and researchers.
What’s #ShareForRare?
In line with Franklin’s commitment to advancing the field of rare disease diagnosis and treatment, this initiative aims to raise awareness of uncommon disorders in the Franklin Community and encourage collaboration among community members.
Our team of clinical curators has prepared a monthly spotlight on different genetic diseases to help educate and connect professionals from around the world who are working on similar conditions. Take a look at the whole collection here.
If you’d like us to focus on a particular disease you’ve been working on, make your suggestion here!
