The rarest of the rare

Posted by Karen - May 1st, 2016

I’ve talked many times on this blog about how my daughter Miranda’s disorder, fibrodysplasia ossificans progressiva, is super-duper rare. Only 1 in 2 million people, meaning that out of roughly 7 billion people worldwide, there are maybe 3,500 with FOP – and only 800 to 900 of those have been diagnosed. Yep, that’a a very, VERY uncommon disorder. Within this group, however, there is an even more rare sub-set…

All people with FOP have a mutation located on the second chromosome. The gene is referred to as ACVR1/ALK2, and in people with FOP, the gene builds a protein called ACVR1 – which it is supposed to do – but causes a substitution of one amino acid for another at a specific point in the protein. For about 95% of people with FOP, the switch is located at codon 206, and is for histidine instead of arginine.

An artist's conception of DNA

An artist’s conception of DNA


But – if 95% of people have the typical, or “classic” FOP mutation, this means of course that 5% do not. If we assume that about 850 people have been diagnosed with FOP, this means that around 43 people have a different mutation than the typical one. 43! This is a group so tiny it boggles the mind. Among these 43 or so people, the amino acid substitution point is somewhere else other than at codon 206 of the ACVR1 protein.

Even more interesting to science-geek types like me is that among the 43 or so people with a “variant mutation” (as scientists describe it), there’s not just one single different variant. In fact, there are a handful of them. I’m actually not sure how many variants there are, but my estimation is that it’s around 8 to 10. So, that means each variant itself is probably known by no more than 4 or 5 individuals, tops. Some – maybe even most – are known by just 1 person of each type. Wow. Just… wow.

What does this mean for the actual lived experience of FOP?  Well, it seems to matter where that tiny amino acid substitution occurs in the ACVR1 protein. Depending on whether the substitution is before or after the typical one at codon 206, people with FOP variants often have differences in two ways – (1) they have different skeletal abnormalities to than the classic FOP ones, and (2) they sometimes have different ages of onset of FOP extra-skeletal bone formation. Scientists describe this as saying that they have variable “phenotypes” (the phenotype is the presentation of the person’s physical characteristics).

The classic FOP phenotype starts with the toes. Here are a couple of sets of feet which you might see in young kids with the most common form of FOP…

Miranda's toes, circa age 7.


These are the toes of Erin McCloskey (the daughter of my co-blogger, Suzanne), circa age 3.

Among the variant phenotypes, some are what you would call a more “mild” version of FOP, and some are more “severe”. Among the milder ones, I understand that the toes often look normal or close to normal, rather than the angled-inward, bunion-y, and somewhat shrunken appearance of typical FOP toes. Additionally, the age of FOP ossification onset is delayed – among people with typical FOP, most are between age 2 and 5, with age 18 being usually the very latest age of onset, but among people with a “mild” FOP variant, ossification may not start until the late teens, twenties, or even much later in life. I recall reading once about a person with variant FOP who didn’t start to have FOP flare-ups until she was in her 50s! Associated with the late onset is also often a more sporadic, slower progression of the disease, such that disability is less extreme occurs later in life. I kind of wonder myself if there aren’t more of these mild variants in the general population which have just never been diagnosed.

Among the more “severe” FOP variants, my sense is that the major distinction to typical FOP is that the toes, and sometimes fingers, show more extreme differences. Some have shorter, stubbier toes and fingers than in typical FOP, and in a few instances, the great toes may be missing altogether. As for age of FOP onset and rate of disease progression – you might logically think that it would be earlier and more rapid than in classic FOP. However, this is hard to say. Classic FOP itself is pretty variable, with some people being severely disabled at a young age and others continuing to be pretty mobile well into their thirties. As such, my guess is that there are (a) too few “severe” cases and (b) too much variation even in typical FOP (with lots skewed to the earlier years) to draw any conclusions in this regard.

In the past, it probably didn’t mean much, practically speaking, to know that a person had typical FOP versus a variant form. With no treatment available for FOP, it was all academic as to which form of FOP a person was diagnosed with. Moving forward, though, there’s quite a bit of research being carried out right now into potential treatments for FOP. Will any given potential medication work for people with classic AND variant types of FOP? Maybe yes – but this can’t be predicted with any certainty. Also, I can imagine a scenario in which a particular medication works well for people with classic FOP and some variants, but less so or not at all for other variants. Therefore, knowing which type of FOP a person has is vitally important where drug testing is concerned.

So there you have it; my review of mega-ultra-rare FOP variants. If you find this to be an interesting topic, and don’t mind a fair bit of scientific terminology, I recommend the article at this link:


PS – For information about how people with FOP can contribute to FOP research, please go to the website of the International FOP Association at

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