Rheumatology Advance Access originally published online on January 10, 2007
Rheumatology 2007 46(4):716-717; doi:10.1093/rheumatology/kel416
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Progressive osseous heteroplasia: a rare case of late onset
Université Paris-Descartes, Faculté de Médecine, Assistance Publique-Hopitaux de Paris Hôpital Cochin- Service de rhumatologie A – 27 rue du Faubourg Saint Jacques – 75014, Paris, France
Correspondence to: Dr C. Job-Deslandre, Departement of Rheumatology A, Hôpital Cochin, 27 rue du Faubourg Saint Jacques–75014, Paris, France. E-mail: chantal.deslandre{at}cch.aphp.fr
SIR, Progressive osseous heteroplasia (POH) is a rare inherited ossifying disorder of infancy, characterized by diffuse cutaneous and deep connective tissue ossifications. We report a rare case of POH that appeared in adulthood.
In April 2001, a 52-yr-old woman, with no familial history of abnormal ossification, was admitted for pain and stiffness of the lower limbs. She first experienced symptoms in 1985, with knee, calf and ankle pains, and later suffered from lower limb stiffness.
Physical examination revealed subcutaneous ossifications of the lower limbs, hands and elbows, with impaired joint mobility, principally involving the left side. X-ray showed diffuse ossifications of all four limbs (Fig. 1A) and paravertebral muscles. Lower limbs computed tomography showed diffuse calcifications of the fascia, tendons, muscles and subcutaneous fat. Alkaline phosphatase and C-telopeptide of collagen 1 (CTX) levels were twice normal. Calcium, phosphate and parathyroid and thyroid hormones serum levels were normal. Bone scan showed multiple areas of enhanced isotope uptake (Fig. 1B). No dysmorphic or metabolic abnormalities were observed. POH was diagnosed on the basis of the patient's clinical and radiological profiles, despite the absence of the GNAS1 gene mutation. Etidronate (1g) was administered intravenously in January 2002, with no improvement.
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The patient was lost to follow-up until May 2005. Joint mobility had worsened, due to the progression of ossifications in areas of previous strong isotope uptake. Biological findings were similar to those obtained in 2001. Bone scan examination revealed persistent areas of technetium uptake. All these features were consistent with continuing active disease.
POH is the most recently described inherited ossifying disease with only a few reported cases [1–9]. POH was initially described in patients diagnosed with fibrodysplasia ossificans progressiva (FOP), but displaying atypical features [1].
FOP is characterized by diffuse progressive heterotopic ossifications, associated with big toe deformities. POH can be distinguished from FOP by the presence of cutaneous ossifications, the absence of congenital musculo-skeletal malformations or inflammatory tumour-like swellings and an asymmetric distribution of lesions. Furthermore, POH intramembranous ossification, i.e. ossification of connective tissues by differentiation of mesenchymal cells into osteogenic cells, results in progression of ossifications from skin and subcutaneous tissue into skeletal muscle. Whereas, predominance of endochondral ossification in FOP, i.e. conversion of cartilage into bone, results in a proximal to distal extension.
According to the 19 previous reported cases, POH was more frequent in females (17/19). Ossifications were mainly located on the limbs (18/19), or even axial (9/19), and often displayed hemimelic predominance (12/19), as in our case. Usually, first symptoms occur in childhood (birth to 3 yrs). We describe the first case with onset and persistent progression during the adulthood. Mild cases of late-recognition have been described in families of severely affected patients, but are characterized by non-extensive subcutaneous ossifications with slower progression [9]. In patients with early disease onset, progression generally ceases by adulthood [1]. Our patient might have developed mild ossifications in childhood. However, as she was of normal size, with no inequality in limb length, we presume that the disease was quiescent during growth.
We provided the first report of bone scan and CTX serum level in a patient with POH. Interestingly, ossifications progression predominated at sites of enhanced isotope uptake. Elevated alkaline phosphatases and CTX serum levels were also recorded, reflecting major bone turnover. Bone scans and bone-related biomarkers levels may be useful for evaluating disease extension and activity.
As no treatment is available and surgical removal is not recommended because of recurrence in most cases (5/6), therapeutic management of POH remains a dilemma. Our patient received intravenous etidronate, as used in FOP, but without improvement.
POH may be a sporadic or autosomal dominant disease associated with paternal inheritance of a GNAS1 mutation [9]. POH has to be distinguished from Albright hereditary osteodystrophy (AHO). Both are ossifying disease, share similar features and are associated with GNAS1-inactivating mutations. But, AHO is characterized by limited subcutaneous ossifications and by association with (pseudohypoparathyroidism) or without hormone resistance (pseudopseudohypoparathyroidism). The GNAS1 gene displays parental imprinting, with maternally inherited mutations resulting in AHO with pseudohypoparathyroidism, and paternally inherited mutations resulting in POH or AHO with pseudopseudohypoparathyroidism [9]. Our patient had no GNAS1 gene mutation, but only 13 of the 18 patients described by Shore and a few previous reported cases had GNAS1 mutations. The link between G-protein and ossification remains unclear. Decreases in expression of the 
-chain of G-protein were recently shown to be associated, in vitro, with the osteogenic differentiation of mesenchymal stem cells, and with changes in the expression of bone formation-related genes, such as Runx2/Cbfa1 [10].
Our patient seems to be the first case of POH to be detected in adulthood. As POH is rare and mostly affects children, it is probably best known to paediatricians. As a result, mild forms occurring in adults are probably underdiagnosed.
The authors have declared no conflicts of interest.
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