FOP and Progressive Osseous Heteroplasia

Information on Progressive Osseous Heteroplasia

by 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 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. “What Is POH? A Guidebook for Families” (Kaplan, Wagman et al., 1997) is available through the POHA.

For more information, contact: 

Progressive Osseous Heteroplasia Association
1460 Bolingbrook Drive
Columbus, Ohio 43228

Phone: (614) 887-POHA [7642]

E-mail: Info@pohdisease.org

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