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FOP diagnostic case series

When should we think FOP?

Delayed diagnosis and misdiagnosis are common in FOP, so establishing a prompt, correct diagnosis is key for avoiding inadvertent harm.

Click the buttons below to explore different case studies or review the key information about FOP

Case 1

Case 2

Case 3

Key information

These are hypothetical patient cases and do not constitute medical advice.
Clinicians are requested to exercise independent medical judgment.

DRSC-US-000457 | September 2024
FOP, fibrodysplasia ossificans progressiva.

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes.

Initial consultation with pediatrician

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes.

  • Physical examination revealed that as well as not walking, the child was ‘scooting’ instead of crawling
  • The pediatrician also notices the child is unable to turn his head to one side
  • Parents are advised that all children develop differently, but as a cautionary measure, would refer to a specialist

Who would you refer this patient to?

Click on the panels to discover why each of these specialists may be considered

NEUROLOGY

X

The inability of a two-year-old to walk and turn his head may be indicative of neurological issues, which a neurologist would be well placed to investigate further.1,2

ORTHOPEDICS

X

Orthopedics specialize in disorders affecting the musculoskeletal system — the limited range of motion in the neck and delayed ability to walk could be investigated further by an orthopedic specialist.1

RHEUMATOLOGY

X

Rheumatologists specialize in autoimmune and inflammatory disorders — often, these can present as joint/range of motion problems.1—3

Referral to specialist (pediatric neurologist)

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes.

  • In this case, the patient was referred to a neurologist
  • Physical examination excluded cervical dystonia
  • A swelling on the child’s back was noticed; it was hot to the touch and caused pain
    • Parents reported this appearing shortly after the child fell from a step
  • The clinician requested analgesics and a follow-up appointment

Referral to specialist (pediatric neurologist)

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes.

  • In this case, the patient was referred to a neurologist
  • Physical examination excluded cervical dystonia
  • A swelling on the child’s back was noticed; it was hot to the touch and caused pain
    • Parents reported this appearing shortly after the child fell from a step
  • The clinician requested analgesics and a follow-up appointment

6 months later

  • The child and his family did not attend the follow-up appointment due to a family bereavement
  • The child then developed a fever and was taken to the emergency department
    • A respiratory infection with pertussis was suspected, and the patient was prescribed antibiotics
    • A swelling on the shoulder was also noted during examination
  • Due to a history of previous swellings, the patient was referred to rheumatology

Referral to specialist (rheumatologist)

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes. It was also noted that the child was unable to turn his head to one side.

  • The child and his family did not attend the follow-up appointment due to a family bereavement
  • The child then developed a fever and was taken to the emergency department
    • A respiratory infection with pertussis was suspected, and the patient was prescribed antibiotics
    • A swelling on the shoulder was also noted during examination
  • Due to a history of previous swellings, the patient was referred to rheumatology

Which tests might you recommend?

Click on the panels to discover why each of these specialists may be considered

BIOPSY OF SWELLING

X

Swellings can be initially suspected as juvenile fibromatosis, lymphedema, or soft tissue sarcoma,1 in which case a biopsy would provide more information.*

Evaluation of inflammatory markers

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes. It was also noted that the child was unable to turn his head to one side.

After visiting a pediatric neurologist, the patient developed a fever and was taken to the emergency department. As a result, he was given antibiotics to treat a suspected infection. A swelling on the shoulder was also noted, resulting in a referral to a rheumatologist.

Inflammatory marker results:

  • Increased lymphocytes
  • Increased IL-3, IL-7 and GM-CSF
  • The increase in inflammatory markers and history of limited joint mobility prompted the rheumatologist to seek the advice of a multidisciplinary team
  • The team concluded that a gene panel for different skeletal dysplasia conditions should be carried out

GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin.

Evaluation of gene panel (skeletal dysplasia)

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes. It was also noted that the child was unable to turn his head to one side.

After visiting a pediatric neurologist, the patient developed a fever and was taken to the emergency department. As a result, he was given antibiotics to treat a suspected infection . A swelling on the shoulder was also noted, resulting in a referral to a rheumatologist .

Gene panel results:

  • Mutation in the ALK2/ ACVR1 gene
  • c.617G>A

Diagnosis of FOP

ACVR1, Activin A receptor type 1; ALK2, activin receptor-like kinase 2; FOP, fibrodysplasia ossificans progressiva.

Outcome

A two-year-old was taken to the clinic as his parents were concerned that he was not yet walking. He had no allergies or health conditions, but his clinical notes did mention that at birth, he had unusually shaped toes. It was also noted that the child was unable to turn his head to one side.

After visiting a pediatric neurologist, the patient developed a fever and was taken to the emergency department. As a result, he was given antibiotics to treat a suspected infection. 
A swelling on the shoulder was also noted, resulting in a referral to a rheumatologist. After consulting a multidisciplinary team, a gene panel was carried out, focusing on skeletal dysplasia.

Following a confirmed diagnosis of FOP, the patient’s family was given a list of recommendations to follow (to avoid triggering flare-ups) and genetic counselling.

What could have been done differently?

Missed sign

The most important symptoms that lead to a diagnosis of FOP are malformation of the great toes (present from birth) and soft tissue swellings.1

Missed sign

Stiffness of the neck is an early finding in most patients with FOP and may precede heterotopic ossification. This can prevent crawling and babies may scoot on their bottom instead.1,2

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. IFOPA website. FOP Symptoms. Available at: www.ifopa.org/symptoms.
Last Accessed July 2024.

Patient history

A five-year-old was taken to her primary care provider as she had multiple swellings on her head. Her parents stated that they had noticed neck swellings around two weeks ago, but these had disappeared. A physical examination revealed that the patient also had shortened big toes.

Click the buttons below to find out why

Referral to oncology

X

Swellings could be indicative of tumors.1

Oncologists would be best placed to identify whether the swelling is due to a tumor and which treatment would be most suitable.

Results from oncology referral

X

A biopsy and histological analysis of the swelling led the oncologist to diagnose the patient with aggressive juvenile fibromatosis.

Surgical removal of the swellings was planned.

Preparation for surgery

A five-year-old was taken to her primary care provider as she had multiple swellings on her head. Her parents stated that they had noticed neck swellings around two weeks ago, but these had disappeared. A physical examination revealed that the patient also had shortened big toes.

After a referral to oncology, she was diagnosed with aggressive juvenile fibromatosis, and surgical removal of the swellings was planned.

Click to discover what happened prior to undergoing surgery

Pre-surgery MRI

  • Revealed calcification within swellings
  • Oncology worked with an orthopedic surgeon for further consideration
Click to discover what happened at the orthopedist

Orthopedic surgeon

  • Based on calcified lesions and shortened big toes, genetic testing was requested
Click to discover the results of the genetic test

Genetic testing

  • Mutation within the ACVR1/ALK2 gene
  • Diagnosis of FOP confirmed

Outcome

A five-year-old was taken to her primary care provider as she had multiple swellings on her head. Her parents stated that they had noticed neck swellings around two weeks ago, but these had disappeared. A physical examination revealed that the patient also had shortened big toes. After a referral to oncology, she was diagnosed with aggressive juvenile fibromatosis, and surgical removal of the swellings was planned.

Prior to the surgery, an MRI scan revealed that the lesions were calcified, prompting a referral to an orthopedic specialist. Genetic testing revealed a mutation in the ACVR1/ALK2 gene, confirming the diagnosis of FOP.

What could have been done differently?

Missed sign

The most important symptoms that lead to a diagnosis of FOP are malformation of the great toes (present from birth) and soft tissue swellings.1

Harmful procedure

Biopsies should be avoided in people with FOP as the procedure can further exacerbate the disease.1

Non-invasive investigation

Radiography and bone scans can be used to identify heterotopic ossification in patients with suspected FOP.2

ACVR1, activin A receptor type 1; ALK2, activin receptor-like kinase 2; FOP, fibrodysplasia ossificans progressiva; MRI, magnetic resonance imaging.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448. 2. Kommana H, et al. Journal of Nuclear Medicine 2009;50:1050.

Patient history

An eight-year-old boy presented at the clinic with a severe mouth ulcer, for which he was given an antibiotic mouthwash. During his follow-up appointment, his clinician noticed that the patient’s jaw movement was slightly restricted.

Who would you refer this patient to?

Click on the panels to discover why each of these specialists may be considered

DENTIST

X

Dentists can investigate whether jaw pain and restricted movement is due to actions such as grinding of the teeth.1

PHYSIOTHERAPIST

X

Physiotherapists can massage the musculature around the joint and guide the patient through jaw-strengthening exercises.1*

MAXILLOFACIAL SURGEON

X

If the jaw is limited by congenital malformation of the joint, or other methods have failed to treat the issue successfully, a maxillofacial surgeon specializes in treating the jaw with more invasive procedures.1

Patient history

An eight-year-old boy presented at the clinic with a severe mouth ulcer, for which he was given an antibiotic mouthwash. During his follow-up appointment, his clinician noticed that the patient’s jaw movement was slightly restricted.

  • In this case, the patient was referred to a physiotherapist to stretch the jaw and recommend jaw-strengthening exercises
  • Six months later, the boy returned to the clinic with stiffness and pain in his back
  • The clinician was told that the boy had recently fallen over after playing with some friends in the park
  • Upon examination, small swellings in and around the neck and spine were observed

Patient history

An eight-year-old boy presented at the clinic with a severe mouth ulcer, for which he was given an antibiotic mouthwash. During his follow-up appointment, his clinician noticed that the patient’s jaw movement was slightly restricted. He referred the patient to a physiotherapist to stretch the jaw and recommend exercises to strengthen the jaw muscles.

Six months later, the patient returned to the clinic due to persistent stiffness and pain in the back following a fall. Upon examination, small swellings around the neck and spine were found.

Click to discover what happened after finding these swellings

Clinician referral

  • The clinician referred the patient to a pediatric orthopedist
Click to discover what happened at the orthopedist

Specialist review

  • After checking the swellings and medical history, the orthopedist checked the patient's feet
Click to discover what the feet revealed

Physical examination

  • He found that the two big toes were malformed
  • This prompted a genetic test for FOP, which was positive

Patient history

An eight-year-old boy presented at the clinic with a severe mouth ulcer, for which he was given an antibiotic mouthwash. During his follow-up appointment, his clinician noticed that the patient’s jaw movement was slightly restricted. He referred the patient to a physiotherapist to stretch the jaw and recommend exercises to strengthen the jaw muscles.

Six months later, the patient returned to the clinic due to persistent stiffness and pain in the back following a fall. Upon examination, small swellings around the neck and spine were found.

What could have been done differently?

Stretching of the jaw and muscular injury are both triggers

for heterotopic ossification and should be avoided if FOP is suspected.1

FOP, fibrodysplasia ossificans progressiva.

1. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127.

Physical features of FOP

Before heterotopic ossification becomes widespread, there are a number of physical signs that can suggest a person has FOP:1

Skeletal malformations

Restricted movement

Hearing
loss

Flare-ups

Skeletal malformations

X

  • The earliest sign of FOP is malformation of the big toes, which are present in almost all classical FOP cases1,2
  • Similar malformation of the thumbs has been frequently observed1
  • Spinal deformation with developmental abnormalities in the cervical spine can occur1

Restricted movement

X

Some babies with FOP have cervical malformations 
that prevent them from rotating their heads completely; they may not be able to turn their heads to one side. As a result, they may not be able to crawl and will scoot on their bottoms instead.1,2

Hearing loss

X

Conductive hearing loss may occur as a result of the middle ear bones becoming restricted.1,2

Flare-ups

X

  • Flare-ups are soft-tissue swellings which are warm and painful to the touch1
  • These flare-ups often result in the ossification of surrounding structures, but in some cases, they can spontaneously regress2
  • Heterotopic ossification from flare-ups occurs in anatomically distinct patterns:2
    • Typically, heterotopic ossification begins in the dorsal, axial, cranial, and proximal regions2
    • As FOP progresses, heterotopic ossification may be seen in the ventral, appendicular, caudal, and distal regions2

Diagnosing FOP

ACVR1

Ex1Ex2Ex3Ex4Ex5Ex6Ex7Ex8Ex91530 bp
   587T>C
605G>T
617G>A
619C>G		772A>G
774G>C		974G>A
982G>A
982G>T
983G>A		1067G>A
1124G>C		   

Figure adapted from Katagiri et al.1

  • FOP is caused by mutations in the ACVR1 gene, with the 617G>A substitution being the most common2
  • In cases where FOP is suspected, exon 4 of the ACVR1 gene is sequenced3
    • Changes in endonuclease restriction sites can be used as a secondary method when 617G>A is present4
  • If 617G>A is not found, whole exome sequencing/sequencing of the full ACVR1 gene can be carried out5,6

ACVR1, activin A receptor type 1; FOP, fibrodysplasia ossificans progressiva.

1. Katagiri T, et al. Endocrinol Metab 2018;33:331–338; 2. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127; 3. Ho NWT, et al. Pediatric Oncall J 2022;19:15–18;

4. Lee DY, et al. J Korean Med Sci 2009;24:433–437; 5. Ravazzolo R, et al. Biomedicines 2021;9:154; 6. Liu H, et al. Am J Med Genet A 2015;167:1337–1341.

Misdiagnosis of FOP

Figure adapted from Sherman et al.1

More than half of people with FOP have been misdiagnosed, with it taking an average of 1.5 years to reach a correct diagnosis.1

What are the consequences of misdiagnosis?

Click on the panels to discover what impact misdiagnosis of FOP can have on a patient

68%

X

of patients receive
inappropriate therapies2

67%

X

undergo unnecessary biopsies2

49%

X

report permanent loss of mobility following invasive interventions2

Misdiagnosis of FOP

The heterotopic ossification process in FOP is progressive and cumulative; timely diagnosis can ensure harmful procedures are avoided, and the patient/caregiver is educated on lifestyle changes to avoid flare-ups:

FOP, fibrodysplasia ossificans progressiva; TIS, thoracic insufficiency syndrome.

1. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127; 2. Baujat G, et al. Orphanet J Rare Dis 2017;12:123.

Preventing harm in FOP

The heterotopic ossification process in FOP is progressive and cumulative; timely diagnosis can ensure harmful procedures are avoided, and the patient/caregiver is educated on lifestyle changes that can be made to avoid flare-ups.1,2

Click on the buttons at the top to discover more about preventing harm in FOP

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. Pignolo RJ, et al. J Bone Miner Res 2016;31:650–656.

Preventing harm in FOP

Overexertion and fatigue can induce flare-ups, which later turn into areas of heterotopic ossification.1

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Orphanet J Rare Dis 2011;6:80.

Preventing harm in FOP

Surgical release of joints is not recommended, as it risks new heterotopic ossification from the trauma.1

If surgery is unavoidable, a multidisciplinary team with experience in managing someone with FOP is needed.2

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127.

Preventing harm in FOP

Dental procedures, such as blocking of the nerve or stretching of the jaw muscles are not recommended, as these can cause new flare-ups to occur.1,2

Preventative oral care is required in people with FOP to avoid them requiring invasive procedures later in life.2

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127.

Preventing harm in FOP

Biopsies are often taken if clinicians initially suspect cancer, but this can induce a flare-up and is therefore not recommended.1,2

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127.

Preventing harm in FOP

Intramuscular injections, including vaccines, are a risk factor for flare-ups and heterotopic ossification.1,2

They should be avoided wherever possible, with alternative routes of administration (sub-cutaneous, intra-cutaneous) explored, but no immunizations should be given if the patient is experiencing a flare-up.2

FOP, fibrodysplasia ossificans progressiva.

1. Pignolo RJ, et al. Pediatr Endocrinol Rev 2013;10:437–448; 2. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127.

Preventing harm in FOP

Stretching of the muscles, including passive stretching to the limit of range of motion, can cause flare-ups and should, therefore, be avoided.1

People with FOP should still try to maintain their physical health and function, so rehabilitation approaches such as aquatic therapy may be recommended.2

FOP, fibrodysplasia ossificans progressiva.

1. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127; 2. Levy CE, Clin Rev Bone and Min Metab 2005;3:251–256.

Preventing harm in FOP

Muscular injury can cause flare-ups and should, therefore, be avoided.1

While this means that contact sports should be avoided, people with FOP are still encouraged to exercise as much as their mobility allows, to maintain physical health (as this is often reduced in people with FOP).1–3

FOP, fibrodysplasia ossificans progressiva.

1. Kaplan FS, et al. Proc Intl Clin Council FOP 2022;2:1–127; 2. Smilde BJ, et al. Orthoped Res Rev 2022;14:113–120; 3. Ortiz-Agapito F, et al. J Child Orthop 2015;9:489–493.

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