History. A 6-year-old girl presented with tender mass on the left side of her neck that had enlarged over the past week (Figure 1). Her primary care doctor initially prescribed amoxicillin/clavulanate for suspected bacterial lymphadenitis. The swelling progressed, and a CT scan was ordered. Results showed some inflammation of the neck muscles on the affected side. The child was referred to the inpatient pediatric service for further evaluation. On admission, intravenous clindamycin was started for suspected methicillin-resistant Staphylococcus aureus (MRSA) infection.
|Figure 1 – Young girl with firm, nodular, moderately tender swelling of greater than 8 cm in diameter on the lower left side of the posterior neck. Head is tilted slightly toward the swelling.|
No fever, trauma, prior swelling, night sweats, or weight loss reported. Child had frequent contact with a relative’s kitten and could recall being scratched on the neck. Medical history was uneventful.
Physical examination. Firm, nodular, moderately tender swelling of greater than 8 cm in diameter on the lower left side of the posterior neck, with mild overlying erythema, indistinct borders, and some induration that extended to the left suprascapular area. Head tilted slightly toward the swelling. Limited range of motion of the neck, particularly with rotation and extension. Decreased abduction of the left shoulder because of pain.
Laboratory results. Mildly low white blood cell count (3500/μL), with a normal differential. Other hematology parameters normal. C-reactive protein level, an extended chemistry panel, and levels of uric acid, lactate dehydrogenase, and creatine kinase also normal.
Hospital course. Over the next few days, the neck swelling continued to enlarge. Patient remained happy and afebrile. Her pain decreased significantly with ibuprofen; range of motion remained limited. An MRI scan of the neck and upper back showed inflammation, edema, and swelling of the posterior neck muscles, including the trapezius on the left, with no discernible cause. A muscle biopsy was scheduled.
In an effort to elucidate the cause of the muscle inflammation, an electronic literature search on the topic of “myositis and trapezius” was performed that revealed a number of interesting articles on fibrodysplasia ossificans progressiva (FOP). Among them was one with a Venn diagram of the key clinical diagnostic features of FOP—soft tissue tumorlike swellings and malformed great toes.1 Closer examination of the patient’s toes revealed characteristic bilateral hallus valgus deformities (Figure 2). On further review of the MRI scan, the radiologist confirmed that the muscle changes could be consistent with FOP.
|Figure 2 – Evaluation of patient's great toes revealed bilateral hallus valgus deformities, a characteristic clinical finding of fibrodysplasia ossificans progressiva.|
FIBRODYSPLASIA OSSIFICANS PROGRESSIVA: AN OVERVIEW
Incidence and etiology. FOP is a rare genetic disorder, with a prevalence of about 1 in 2 million persons. Although it can be inherited as an autosomal dominant trait, most cases are new mutations.2 The genetic mutation is a single nucleotide substitution for a bone morphogenetic protein (BMP) receptor.3 This mutation produces overactivity of the BMP receptor, which causes the metamorphosis of connective tissues (fascia, ligaments, tendons, and skeletal muscles) into actual bone.4 A “second skeleton” gradually forms that severely limits movement.
Clinical manifestations. Patients with FOP have normal development at birth, except for malformed great toes. During the first decade of life, painful, inflammatory soft tissue swellings develop. These usually begin in proximal axial muscles, as in this patient, and over time involve the distal/caudal muscles and connective tissues. For unclear reasons, the extra-ocular muscles, tongue, and diaphragm are spared. Repeated flare-ups followed by ossification lead to progressive disability and deformity.
In adulthood, many patients are unable to walk. Overall life expectancy is reduced because of thoracic insufficiency, which results when new bone formation impairs chest wall compliance.
Diagnosis. FOP can be diagnosed on the basis of characteristic clinical findings. Confirmation with genetic testing advisable. Misdiagnosis, which is common with this rare disorder, can lead to unnecessary invasive procedures (such as biopsy) that can trigger worse heterotopic bone formation.5
The differential diagnosis includes:
Lymphadenitis. This is the most common lateral neck mass in children. We considered staphylococcal lymphadenitis, particularly with MRSA, because of the lack of improvement after a week of amoxicillin/clavulanate treatment. However, we did have reservations about the mass being a suppurative lymphadenitis, because of the patient was afebrile, the WBC count and C-reactive protein level were normal, and the CT scan showed no obvious adenopathy or abscess.
Cat-scratch disease. Because of the child’s exposure to a kitten and her history of being scratched on the neck, serology testing for cat-scratch disease was performed. Results were nonreactive.
Tuberculosis. Although the patient had no history of tuberculosis exposure, we kept this infection, and atypical Mycobacteria infection, in the differential. Results of purified protein derivative (tuberculin) testing were nonreactive, and findings on a chest radiograph were normal, except for soft tissue swelling of the lower left side of the neck.
Branchial cleft cyst. A branchial cleft cyst seemed unlikely because the mass was located in the posterior triangle of the neck.
Cystic hygroma (lymphangiectasia). Although a cystic hygroma is typically soft and nontender, it can become large, firm, and tender when infected or when there is bleeding within the tumor. In this patient, ultrasonography showed no evidence of a cystic hygroma.
Malignancy. Malignancies that may affect the lower posterior neck include lymphoma and rhabdomyosarcoma.
Management. A number of different therapies have been postulated. The guidelines for medical management from the International Clinical Consortium on FOP recommend corticosteroid bursts immediately at the onset of flares and long-term use of NSAIDs and other anti-inflammatory medications.6 With the identification of the gene for FOP and elucidation of much of the complex pathophysiology of the illness, a new disease-altering treatment may be possible.
Flare-ups can be spontaneous or triggered by even minor physical trauma or by muscular inflammation from viral infection.7 Thus, it is important that patients minimize soft tissue trauma, limit surgical procedures, and receive influenza immunization.1,6 Routine health and dental care need to be carefully customized for all patients with FOP.
Outcome. We contacted Dr Frederick Kaplan1,2,4,5 at the University of Pennsylvania who recommended specific confirmatory genetic testing for FOP. Results were positive in this child. Following the guidelines from the International Clinical Consortium on FOP,6 we added high-dose methylprednisolone therapy (25 mg/kg/d IV every other day for 3 doses). At discharge, the patient had considerable decrease in pain but minimal change in the neck swelling or range of motion.
1. Kaplan FS, Xu M, Glaser DL, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008;121:e1295-e1300.
2. Kaplan FS, Shore EM, Connor JM. Fibrodysplasia ossificans progressiva. In: Royce PM, Steinmann B, eds. Connective Tissue and Its Heritable Disorders: Molecular, Genetic and Medical Aspects. 2nd ed. New York: Wiley-Liss; 2002:827-840.
3. Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006;38:525-527.
4. Kaplan FS, Shen Q, Lounev V, et al. Skeletal metamorphosis in fibrodysplasia ossificans progressiva (FOP). J Bone Miner Metab. 2008;26:521-530.
5. Kitterman JA, Kantanie S, Rocke DM, Kaplan FS. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva . Pediatrics. 2005;116:e654-e661.
6. The International Clinical Consortium on Fibrodysplasia Ossificans Progressiva. The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations. Philadelphia: The Center for Research in FOP and Related Disorders, The University of Pennsylvania School of Medicine; December 2008. Available at: http://www.ifopa.org.
7. Cohen RB, Hahn GV, Tabas JA, et al. The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients. J Bone Joint Surg Am. 1993;75:215-219.