Misdiagnosis of FOP

FOP is one of the rarest diseases in the world. Few doctors encounter it in medical school. Its symptoms are baffling and it is no wonder it is so commonly misdiagnosed. Misdiagnosis rates for FOP have previously been reported to be in the range of 80% or greater. Dr. Joseph Kitterman, Professor of Pediatrics at UCSF, is presently evaluating the misdiagnosis rates in FOP as well as the most common causes for misdiagnosis. Suffice it to say, misdiagnosis of FOP has caused a great deal of pain and suffering for FOP patients and families worldwide.

Three of the most common misdiagnoses for FOP have been reported to be: cancer, aggressive juvenile fibromatosis, and progressive osseous heteroplasia (POH).

In the strict sense of the word, FOP lesions are “tumors” or “neoplasms” – new growths that should not be where they are. FOP lesions may appear suddenly and lead to severe swelling within hours. This is often a source of much consternation for cancer doctors who are often asked to see FOP patients. They are often baffled as to the sudden expansion and growth of such a tumor, and are at a loss to understand what type it might be. This often leads to the suggestion for a diagnostic biopsy. A biopsy of an early FOP lesion can be mistaken for several types of cancer depending upon the state of maturation of the lesion. The reason for this is that when a new bone forms through an endochondral process (as FOP bone does), it goes through various stages of massive cell proliferation including cells involved in connective tissue, cartilage, and bone. There are often many dividing cells which is a worrisome sign for cancer, but of course when a bone heals such as in a fracture, much new tissue has to be formed as well. In a sense, new FOP bone formation (whether it occurs in the muscle, tendon, ligament, or connective tissue) is essentially almost identical to the type of process seen in a healing facture. When someone breaks a bone, there is no question what the diagnosis is, and we rarely biopsy a fracture. But, if we did, and we looked under the microscope, we would see a process that could confuse us with cancer if we didn't know what we were looking at. The same is the case of FOP. Thus, it is the tumor-like lesions in FOP and the microscopic appearance of the biopsy specimens that often lead doctors to the erroneous and dangerous misdiagnosis of cancer rather than the correct diagnosis of FOP. It is easy to look back in retrospect and say if one only suspected FOP and looked at the toes, the correct diagnosis could have been made without a biopsy. Also, a careful history would have clearly revealed that the FOP lesions grew much more rapidly then any cancer could ever possibly grow.

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Another extremely common misdiagnosis for FOP is aggressive juvenile fibromatosis. This is a benign but highly aggressive condition where connective tissue cells called fibroblasts proliferate in various tissues including muscle, tendon, ligament, and fascia. These lesions can invade adjacent soft tissues and cause much pain and disability. They are often difficult to remove. They often grow slowly and are not associated with the type of swelling one sees with FOP lesions, but often the aggressive juvenile fibromatosis lesions do not come to the doctors attention until they are fairly large. Thus, many doctors who see a patient with FOP and see a soft tissue swelling might think that it looks like an aggressive juvenile fibromatosis lesion, especially since they arise from similar tissues.

Once again, if a biopsy is done, it might be mistaken for aggressive juvenile fibromatosis.

The reason is that the very early FOP lesions (which we call fibroproliferative lesions) look identical under the microscope to the fibroproliferative lesions of aggressive juvenile fibromatosis.

In aggressive fibromatosis, the lesions do not progress beyond the connective tissue growth phase, whereas in FOP, they mature through an endochondral process to form cartilage and bone. Once cartilage or bone cells are seen in a lesion, they can no longer be mistaken for aggressive juvenile fibromatosis. Also, patients with aggressive juvenile fibromatosis do not have malformed toes, so once again that is the key.

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A third condition that is often confused within FOP is fibrous dysplasia. Patients with FOP are rarely misdiagnosed as having fibrous dysplasia, but the word often appears on their diagnosis because it is a much more common condition than FOP, and it sounds very similar. Very often, patients with fibrous dysplasia will find the FOP website, and think that they have FOP. Fibrous dysplasia is a condition where primitive bone cells proliferate inside the bone, weakening its structure and causing pain and disability. Fibrous dysplasia can affect any bone in the body. Fibrous dysplasia is caused by an activating mutation of the same gene that actually causes POH. This is quite an interesting and fascinating coincidence. Patients with fibrous dysplasia often have severe problems with expansion of the bone in the skull or facial regions, areas commonly affected with condition, and rarely affected in FOP. It is very easy to distinguish between fibrous dysplasia and FOP, but the source of confusion often results from the similarity in the names.

In summary, there are many critical differences between FOP and the other conditions with which it is often mistaken such as cancer, aggressive juvenile fibromatosis, fibrous dysplasia, and POH. The key to diagnosing FOP is being aware of the condition, understanding the association with the malformed toe, and also being aware of the nature of how FOP progresses. An astute clinician knowledgeable about FOP can diagnosis the condition even before bone forms just from the presence of the malformed great toes and the rapidly appearing soft tissue swellings that form in characteristic anatomic locations.

One of the goals of the FOP community is to better educate physicians and healthcare workers around the world about the proper diagnosis of FOP so that dangerous misdiagnoses of FOP will not occur in the future.

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Information on Progressive Osseous Heteroplasia

Eileen M. Shore, PhD, and Frederick S. Kaplan, MD
From The Departments of Orthopaedic Surgery
The University of Pennsylvania School of Medicine
Philadelphia, PA

DEFINITION: Progressive osseous heteroplasia (POH) is a disabling autosomal dominant disorder characterized by dermal ossification during infancy and progressive heterotopic ossification of subcutaneous fat, skeletal muscle, and deep connective tissue.

DIFFERENTIAL DIAGNOSIS: Fibrodysplasia ossificans progressiva (FOP); Albright hereditary osteodystrophy (AHO).

SYMPTOMS AND SIGNS: The first sign occurs during infancy with the appearance of islands of heterotopic bone in the dermis. Over time, the islands of heterotopic bone coalesce into plaques with subsequent involvement of subcutaneous fat, skeletal muscle, and deep connective tissue. Extensive ossification of the deep connective tissues results in ankylosis of affected joints and focal growth retardation of involved limbs. Spicules of dermal bone may protrude through the epidermis, although bone formation does not originate in the epidermis.

ETIOLOGY/EPIDEMIOLOGY: The disorder may be sporadic or familial. Offspring of affected individuals inherit the disease in an autosomal dominant manner with widely variable expression. Males and females are affected equally. Occasional reports of mild heterotopic ossification in Albright hereditary osteodystrophy (AHO), and a recent report of two AHO patients with atypically extensive heterotopic ossification, suggested a common genetic basis for progressive osseous heteroplasia and Albright hereditary osteodystrophy. Albright hereditary osteodystrophy, a complex disorder characterized by developmental dysmorphologies and commonly associated with multiple hormone resistance, is caused by heterozygous inactivating mutations in the GNAS1 gene resulting in decreased expression or function of the alpha subunit of the stimulatory G protein (G s a ) of adenylyl cyclase. Paternally inherited heterozygous inactivating mutations of the GNAS1 gene have recently been reported as a cause of POH. These observations suggest that POH may lie at one end of a clinical spectrum of ossification disorders mediated by abnormalities in GNAS1 expression and impaired activation of adenylyl cyclase.

DIAGNOSIS: The disorder can be distinguished from FOP by the presence of cutaneous ossification, the absence of congenital malformations of the skeleton, the absence of inflammatory tumor-like swellings, the asymmetric mosaic distribution of lesions, the absence of predictable regional patterns of heterotopic ossification, and the predominance of intramembranous rather than endochondral ossification. It can be distinguished from AHO by the progression of heterotopic ossification from skin and subcutaneous tissue into skeletal muscle, the presence of normal endocrine function, and the absence of a distinctive habitus associated with AHO. The results of routine laboratory studies in POH are usually normal, although elevated levels of serum alkaline phosphatase have been observed. Typically, serum levels of calcium, inorganic phosphate, parathyroid hormone, and vitamin D metabolites are normal. Elevated serum levels of lactate dehydrogenase and creatine phosphokinase have been observed and may reflect bone deposition in skin and skeletal muscle.

TREATMENT

Standard Therapies: No effective treatments or preventions exist for POH. Areas of well-circumscribed heterotopic ossification may rarely be removed successfully; surgical removal of POH tissue has led to recurrence in most patients.

REFERENCES:

Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. J Bone Joint Surg. 1994;76-A:425-436.

Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Mineral Res. 2000;15:2084-2094.

Rosenfeld SR, Kaplan FS. Progressive osseous heteroplasia in male patients. Clin Ortho Rel Res . 1995;317:243-245.

Shore EM, Ahn J, Jan de Beur S, Li M, Xu M, Gardner RJM, Zasloff MA, Whyte MP, Levine MA, Kaplan FS. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Eng J Med. 2002;346:99-106.

Urtizberea JA, Testart H, Cartault F, Boccon-Gibod L, LeMerrer M, Kaplan FS. Progressive osseous heteroplasia. J Bone Joint Surg . 1998;80B:768-771.

Chapter: Dysmorphic Disorders

SUPPORT GROUPS:

The Progressive Osseous Heteroplasia Association (POHA) is a nonprofit organization that supports research and education on POH. The POHA has approximately 25 members. The POH Collaborative Research Project is an international group of physicians and scientists who work together on all clinical and basic aspects of the POH project. Currently, the POHA does not have its own newsletter but participates in The FOP Connection , published quarterly by the International FOP Association. “What Is POH? A Guidebook for Families” (Kaplan, Wagman et al., 1997) is available through the POHA.

The address of the POHA:

Fred Gardner
Executive Director
POHA
33 Stonehearth Square
Indian Head Park, Illinois 60525.
phone: 708-246-9410
email: info@pohdisease.org
Website: www.pohdisease.org

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FOP Contact:

Frederick S. Kaplan, M.D.
Isaac & Rose Nassau Professor of
Orthopaedic Molecular Medicine
and Chief, Division of Metabolic Bone Diseases
and Molecular Medicine
Department of Orthopaedic Surgery
Hospital of the University of Pennsylvania
3400 Spruce Street, 2 Silverstein
Philadelphia, PA 19104-4283
phone - 215-349-8727/8726, Fax:215-349-5928
email: Frederick.Kaplan@uphs.upenn.edu

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