Zaylie Olsen

Prof. Dan Carpenter

Biology 1010
29 October 2018
Fibrodysplasia Ossificans Progressiva
 Fibrodysplasia Ossificans Progressiva, better known as FOP means “A soft connective
tissue that progressively turns into bone” (3). FOP is a congenital skeletal malformation and is
linked to heterotopic ossification also known as HO (Kaplan, Frederick S, et al 4). This
autosomal dominant disorder is so rare, it has been reported to occur in 1 of every 2 million
people (Shore, Eileen M., and Frederick S. Kaplan 5).
The history of FOP began back in 1692, where a french physician named Guy Patin,
encountered a patient who suffered from FOP and mentioned the meeting in his journals (3). In
1736 John Freke, a british physician mentioned at length “an adolescent whose diagnosis
included swellings throughout his back” (3).
As of the 1900’s the disease got the name myositis ossificans progressiva which means
that muscle turns progressively into bone (3). In the early 1970’s the name officially changed to
fibrodysplasia ossificans progressiva by the deceased Dr. Victor McKusick from the John
Hopkins University School of Medicine (3). Dr. McKusick is known as the father of medical
genetics. They decided to change the name because it reflects the other soft tissue and muscle
that transforms into bone (3). The FOP Collaborative Research project was officialized in 1989
by Drs. Frederick Kaplan and Michael Zasloff at the University of Pennsylvania School of
Medicine (3). Just one year later in 1990, Drs. Kaplan and Zasloff conducted the first ever FOP
Natural History Study. In 1991 DR. Eileen M. Shore becomes the newest member of the
University of Pennsylvania research group (3). Through 1994 to 1997 Drs. Kaplan and Zasloff
were given many awards for their research such as; Isaac and Rose Nassau Professorship of
Orthopaedic Molecular Medicine at the University of Pennsylvania School of Medicine and the
NIH Research Grant, et cetera (3).
In 2000, the Human Genome was sequenced and in 2002 Dr. David Glaser joined the
FOP research team. The first phase of clinical trial for safety and efficiency of squalamine was
complex and thus, no patients enrolled in the trial. Squalamine is a form of a steroid compound
with broad antibiotic activities.
After fifteen arduous years of study and research, the FOP research team were finally
able to identify one specific gene mutation (3). The recurrent mutation was in the BMP (bone
morphogenetic protein) type 1 receptor AVCR1 which is what causes inherited and irregular
bone formation (3).
In 2009 Dr. Kaplan was elected to the Institute of Science. A survey of neurological
symptoms in FOP was done by Dr. Joseph Kitterman and in 2012 he got published in the Journal
of Neurology for his piece entitled Neurological Symptoms in Individuals with FOP (3).
This gene is one letter out of six billion that are located in the genome. Because it is so
rare this “finding is one of the most highly specific disease causing mutation in the genome”
(Kaplan, Frederick S, et al 4). AVCR1 is a strong applicant gene for FOP because the genetic
interlude that is contained in Activin A type I receptor gene. Which is a receptor for bone
morphogenetic protein or BMP (Cho, Tae-Joon, et al 1). AVCR1 is conveyed in many tissues
including the chondrocytes and skeletal muscle (Cho, Tae-Joon, et al 1). The hardwired
activation of AVCR1 causes alkaline phosphatase located in the C2C12 cells. It upregulates
BMP4, expands cartilage elements, starts ectopic chondrogenesis, and stimulates joint fusions
(Cho, Tae-Joon, et al 1). Researchers have concluded that constitutive activation of the receptor
causes what sufferers call flare-ups, which is when overgrowth of cartilage and bone causes
fusion of the joints (2). The mutation of the gene is an “identical heterozygous single nucleotide
change at nucleotide position 617 of the cDNA” (Shore, Eileen M., and Frederick S. Kaplan 5).
The amazing discovery in FOP led us to uncover a second genetic disorder, which has
been named POH or progressive osseous heteroplasia (Shore, Eileen M., and Frederick S.
Kaplan 5). While FOP and POH have many similarities such as; extensive bone formation in the
soft and connective tissues, POH and FOP also share many differences. One of these major
differences is how sufferers of POH tend to
develop ossification within the dermal layers
of the skin, which is unaffected in FOP
sufferers (Shore, Eileen M., and Frederick S.
Kaplan 5). Another difference between FOP
and POH is the heterotopic bone formation
that occurs in a mosaic type pattern and shows
a prevalence membranous rather than
endochondral bone formation (Shore, Eileen
M., and Frederick S. Kaplan 5). POH also
causes ulcers or open wounds from the area
that is being ossified from the condition, while
FOP does not cause any form of open wound
on the skin. The sufferer tends to simply feel
pain followed by inflammation which cause
the muscle and tissue to turn to bone.
Throughout the study of FOP another
interesting part is that FOP is genetic. More
and more families that had inherited FOP
came to light and a second genome-wide
linkage that used two out of the five families
that were identified with classic FOP
conducted a study which, resulted in finding a
specific link to the 2q23-24 region of
chromosome 2 (Shore, Eileen M., and Frederick S. Kaplan 5).
(The photo on the left is a skeleton of someone who suffered from FOP.)

Literature Cited

1) Cho, Tae-Joon, et al. “A Recurrent Mutation in the BMP Type I Receptor ACVR1 Causes
Inherited and Sporadic
 Fibrodysplasia Ossificans Progressiva.” Nature Publishing Group , 23 Apr. 2006.
2) “Fibrodysplasia Ossificans Progressiva - Genetics Home Reference - NIH.” U.S. National
Library of Medicine, National
Institutes of Health, 2007,
3) “History of FOP.” IFOPA - International Fibrodysplasia Ossificans Progressiva Association
4 )Kaplan, Frederick S, et al. “Fibrodysplasia Ossificans Progressiva.” Best Practice &
Research Clinical Rheumatology,
Baillière Tindall, 6 Mar. 2008,
5) Shore, Eileen M., and Frederick S. Kaplan. “Insights from a Rare Genetic Disorder of
Extra-Skeletal Bone Formation,
Fibrodysplasia Ossificans Progressiva (FOP).” Bone, U.S. National Library of Medicine,
Sept. 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC2601573/.