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Progressive osseous heteroplasia: A case report
Bone, vol . 15, lso. 5, pp. 471-475, 1994 Copyright s 1994 Elsevier Science Ltd Printed in the USA . All rights reserved
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8756-3282194 $6 .00 + .00
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CASE REPORT
Progressive Osseous Heteroplasia : A Case Report N . A . ATHANASOU, i M . K . D'A . BENSON ; D . P . BRENTON,3 and R . SMITH
2
Department of Pathology Department of Medicine and Surgery, Nu field Orthopaedic Centre . Oxford, UK
' Endocrine and Metabolic Unit, Middlesex Hospital, London, UK
Address for correspondence and reprints : Dr . N .
A.
Athanasou, Department of Pathology, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK .
Abstract
enlargement caused pain, and in some cases led to skin ulceration . In childhood, the provisional diagnosis was either FOP or "osteoma cutis" ; she had no other skeletal abnormalities, and measurements of serum calcium, phosphorus and alkaline phosphatase, and of urinary calcium and phosphate excretion were normal . Progressive ossification and repeated problems with skin ulceration led to a left through-knee amputation at the age of 5 years . Ossification, however, continued in the soft tissues of the thigh, groin, and left lower abdomen . By the age of 18 years, she was complaining of severe pain in this region . Overlying the insertion of the adductor longus in her left groin, there was ulceration of bone through the skin and a discharge of blood stained and chalk-white bony material . She had pain on micturition and urgency, but no urinary or fecal incontinence . Menstruation was normal . She also complained that her thigh muscles tended to go into spasm when she was in pain . Over the years she had received various treatments including prostaglandin E2 pads to groin and upper thigh when she was 1 l years old ; penicillamine when she was 12 years old ; and corticosteroids, several nonsteroidal anti-inflammatory agents, narcotic analgesics, as well as hypnotherapy at various periods during her childhood and adolescence . At presentation, she was on indomethacin, sodium diclofenac and pethidine hydrochloride . As the severity of her pain increased, an indwelling cannula was inserted to allow regular epidural anaesthesia . On examination, there was bony ankylosis of the left hip which was fixed in 45° flexion and 20° abduction . Bone was diffusely present and easily palpable in the subcutaneous tissues of the left thigh, groin, and lower abdomen, and there was marked tenderness about the groin and superior pubic ramus . There was a scanty discharge of blood-stained, white bony material from a wound in the left groin . Palpation of the abdomen revealed obvious discrete areas of ossification in superficial soft tissues on the left side . On vaginal and rectal examination, there was no evidence of ossification of the genitourinary organs or rectum . Clinical investigations were as follows ; hemoglobin, 13 g/dl ; white cell count, 6 .48 x 10'/1 ; platelets, 348 x 10'/1 ; ESR, 4 mm/hour ; calcium, 2 .4 mmol/l (normal range 2 .12-2 .62) ; phosphate, 1 .1 mmol/1 (normal range 0 .8-1 .45) ; albumin, 48 g/I (normal range 35-50) ; and alkaline phosphatase, 226 IU/I (normal range 80-250) . Both X-rays and MRI showed large areas of ossification with bone diffusely present throughout the superficial and deep soft tissues of the thigh, groin, and abdomen (Fig . 1) . To control her constant severe pain and to remove areas of infection, which had developed following recurrent skin ulceration by bone present in the subcutaneous tissues, she underwent
We report the case of a young female who, from infancy, suffered extensive, progressive, heterotopic ossification of her left lower limb . Hetertopic ossification, which was largely but not exclusively intramembranous in type, was most marked in subcutaneous fat but was also noted in muscle and deep connective tissue . The spectrum of changes noted suggests that this congenital disorder of soft tissues is similar to that recently described as progressive osseous beteroplasia . Key Words : Ectopic bone-Heteroplasia-AdipogenesisOssification-Fibrodysplasia-Ossificans progressivaMyositis ossificans .
Introduction Developmental disorders characterized by extensive primary heterotopic ossification in soft tissues are rare . The two major causes of primary soft tissue ossification are fibrodysplasia ossificans progressiva (FOP), an inherited disorder characterized by well-defined skeletal malformations and progressive muscle ossification, and Albright's hereditary osteodystrophy (AHO), characterized by multiple areas of subcutaneous or intracutaneous ossification and an association with the syndromes of pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism (Connor 1983) . Recently, a series of cases characterized by a similar pattern of extensive soft tissue ossification in muscle, superficial and deep subcutaneous tissue, and deep connective tissue has been described and separated from the above two conditions (Kaplan et al . 1994) . The distinct clinical and pathological features of this rare disorder of mesenchymal differentiation have been termed progressive osseous heteroplasia (POH) . The patient with severe heterotopic ossification presented in this report shows a number of similarities to POH, but exhibits some clinical and pathological features which have not previously been associated with this condition, Case Report An 18-year-old girl presented with long-standing ectopic bone formation affecting her left leg, thigh, and lower abdomen . She was first noted to have palpable bony lumps in soft tissues of the left leg and thigh at the age of 6 weeks, These lumps were present in muscle and subcutaneous tissues and their progressive 471
47 2 A
N . A . Athanasou et al . : Progressive osseous heteroplasia been ligated at previous surgery in childhood . Postoperatively, she was treated by radiotherapy and Indomethacin to minimize new bone formation . She developed an infected pelvic hematoma that was successfully treated with surgical drainage and antibiotics, but otherwise her recovery was unremarkable, Following amputation, the pain was dramatically relieved and within 2-3 weeks her analgesic medication almost stopped . There was no suggestion of causalgic pain . However, within 2 months of surgery pain similar in quality to that felt preoperatively recurred and proved, as before, unresponsive to opiate analgesics . Six months postoperatively, she underwent a partial cordotomy which effectively eliminated her pain, and she is currently walking satisfactorily with an orthosis . Immediate postoperative radiographs showed no evidence of bone in the soft tissues but subsequent CT and MRI scans show that bone had once again started to form diffusely about the groin within the rectus abdominis muscle and probably within the pelvis . Histopathology
Fig . 1 . (A) Pan of AP radiograph of left hip ; and (B) CT of right and left thighs showing extent of subcutaneous and intramuscular ossification in left thigh, groin, and pelvis. a left through-hip amputation . At surgery . and on gross pathological examination, abundant bony tissue was found within the thigh ; this was largely restricted to the medial aspect of the thigh where the subcutaneous fat and abductor muscles contained numerous areas of ossification ; dense bony adhesions had formed between the superior pubic ramus and the skin . Ossification extended into the hip joint capsule and superiorly involved subcutaneous fat and muscle of the lower anterior abdominal wall . The peritoneal cavity appeared uninvolved . The hip was firmly ankylosed by bone extending from the superior pubic ramus to the femur ; the iliacus muscle within the pelvis was atrophic and diffusely and heavily ossified . In the thigh, ossification was most prominent within subcutaneous fibrous tissue and fat, but numerous foci of ossification were also present in atrophic muscle and the deep fascia and intermuscular fibrous septae . Extensive bone formation was also noted around femoral vessels which had
Extensive ossification of soft tissues in both the thigh and pelvis was confirmed on histology . This involved the reticular denims, superficial and subcutaneous fat, and fat between atrophic muscle bundles, as well as tendons, fascia, and interstitial connective tissue between muscle bundles (Figs . 2-4) . Most of the woven bone appeared to be formed through intramembranous ossification by mesenchymal cells within interstitial connective tissue in muscle and fat (Fig . 4), although a single tiny focus of cartilage formation with subsequent endochondral ossification was found within fat (Fig . 5) . There was evidence of bone formation and resorption with osteoblasts and osteoclasts present on the surface of some woven bone trabeculae (Fig . 2) . Larger trabeculae of bone within muscle and subcutaneous fat showed partial or complete organization to lamellar bone ; these often contained prominent thick cement lines and were rimmed by flattened lining cells (Fig . 3) . In some areas, bone formation was extensive, essentially forming a complex bridging network of bars and trabeculae woven and lamellar bone of varying thickness between the reticular dermis, muscle, and deep connective tissue . Most of the bone lay within subcutaneous fat which was of normal appearance, but focally some mature fat contained areas of cellular fibrous tissue from which the bone appeared to form by intramembranous ossification (Fig . 4) . Mature fat but not hemopoietic tissue was seen in spaces enclosed by this eetopie bone . A bony network was often seen around skin adnexal structures such as sweat, apocrinc, and sebaceous glands as well as small nerve bundles and blood vessels within the skin (Fig . 2) . The overlying epidermis and papillary dermis was unaffected . Within atrophic muscle, bone formation was seen in fat, and connective tissue of the epimysium and perimysium . Bone formation was seen to lie intimately around individual muscle fibers and small groups of muscle fibers (Fig . 3), as well as in fat within and around atrophic muscle bundles . Bone formation was also seen in the epineurium and peiineurium of small, mediumsized, and large nerves with consequent disorganization of nerve bundles . Ectopic bone was also seen within and around walls of lymphatic vessels, small and large blood vessels (mostly veins as major arteries had atrophied), and in the fibrous capsule of inguinal lymph nodes (Fig . 4) . The femoral cortex was of variable thickness throughout its length and showed evidence of appositional woven bone formation on the surface . The distal end of femur was porotic with thin cortex and widely spaced, thin medullary bone trabeculae . Little hemopoietic tissue was present within the femoral medulla . Bi-
N . A. Athanasou et al . : Progressive osseous heteroplasia
47 3
Fig. 2 . (A) Heterotopic ossification in superficial tissues with woven bone formation in deep dermis adjacent to sweat glands (right) . Note osteoblasts (some arrowed) lining bone surface, osteocytes in lacunae and prominent cement lines within bone (H&E, X400) . (B) Same field as (A) showing irregular arrangement of collagenous matrix within woven bone . opsies taken of a deep iliac lymph node and retroperitoneal fat showed no evidence of ossification . Discussion The main clinical and pathological change noted in this case was that of a congenital, progressive, unilateral, heterotopic ossification affecting subcutaneous tissue, muscle, and deep connective tissue . Heterotopic ossification was almost exclusively intramembranous in type with only a single, tiny focus of endochondral ossification noted . Heterotopic ossification was primary and not associated with clinical or pathological evidence of abnormal calciumm metabolism, trauma, infection, or other causes of inflammation . The heterotopic ossification seen in this case is distinguished from FOP and AHO, the two major causes of primary ectopic
bone formation, by a number of clinical features . Unlike FOP, congenital malformation of the digits was not present, and rarer associations, such as failure of secondary sexual development, intellectual impairment, deafness, or baldness, were also absent (Connor 1983 ; Connor & Evans 1982 ; Smith et al . 1976) . Heterotopic ossification in this case was most extensive in superficial and deep subcutaneous fat and connective tissue ; although, in FOP, ectopic bone formation can rarely occur in connective tissue of ligaments, fasciae, aponeuroses, tendon, and joint capsules, ossification in muscle predominates (Connor 1983) . Unlike FOP, the axial musculature was not affected and episodes of ossification were not exacerbated by trauma . Alkaline phosphatase was also not found to be elevated, as may occur during new episodes of heterotopic ossification in FOP . Unlike AHO, lesions were not bilaterally distributed and widespread . In addition, heterotopic ossification was not restricted to the
Fig . 3. Heterotopic ossification in deeper tissues with : (A) lamellar bone within deep subcutaneous fat next to atrophic muscle (top left) (H&E, x 250) . (B) Same field as (A) viewed under polarized light showing ordered lamellar arrangement of collagenous matrix in mature bone (x 250) .
47 4
N.
Fig. 4 . Woven bone formation within deep fat containing areas of cellular fibrous tissue . There is maturation to lamellar bone, some of which partly surrounds dilated vascular channels (diamond) . Note also small focal areas of heterotopic ossification within fat (arrow) (H&E, x 1110). dermis and superficial subcutaneous tissues, but also involved muscle and deeper connective tissues . Brachydactyly, short stature, obesity, round facies, of mental impairment, as noted in AHO . were not seen in this case . There was no hypocalcemia or hyperphosphatemia and no other associated features of pseudohypoparathyroidism . Pathological features also distinguish the soft tissue bony lesions of this patient from those of FOP and AHO . In the present case, bone formation within soft tissues was almost entirely produced by noninflammatory intramembranous osseous heteroplasin with only a single area of endochondral ossification noted, Although fibroblast proliferation within fibrous septae of striated muscle can be seen in early FOP lesions, foci of endochondral ossification are also commonly found in both early and fully developed FOP lesions within muscles (Eaton et al . 1957 ; Frame et al . 1972 ; Kaplan et al . 1993 ; Smith et al . 1976) fully developed FOP lesions contain abundant cartilage and bone (both woven and lamellar) with the latter formed by endochondral ossification and little or no intramembranous bone formation present . Unlike AHO, areas of ossification were not solely intracutaneous or subcutaneous in distribution and amorphous calcium deposits were not seen (Lever & Schaumberg-Lever 1975) . Clinical and pathological changes similar to those noted in this patient have recently been noted in a series of cases reported by Kaplan et al . (1994) as examples of a distinct syndrome
A . Athanasou et al . : Progressive osseous heteroplasia
called progressive osseous heteroplasia (POH) . POH occurs exclusively in females and is characterized by heterotopic ossification of subcutaneous tissue, deep connective tissue, and muscle . Such heterotopic ossification showed a random, widespread anatomic distribution in several of these reported cases (and their relatives) ; but, in two cases, one of which had been reported previously (Gardner et al . 1988), ossification was progressive and restricted to a single lower limb in a manner similar to that of the present case . One of a pair of siblings included in the series of Gardner et al . (1988) and a previous report (Foster et al . 1986) also documented heterotopic ossification that was restricted to the left lower limb . Heterotopic ossification within discrete limb structures thus appears to be a prominent feature of POH, with the lower limb the most common site of singlelimb involvement . There was no family history of heterotopic ossification in the present case, indicating that the disease appears to have arisen as a result of a fresh mutation . Although Kaplan et al . (1994) report that two cases of POH had a family history of heterotopic ossification, the remainder appear to have arisen sporadically . Consequently, no known inheritance pattern has been established for POH . The heterotopic ossification of POH is associated with a spectrum of other clinical and pathological changes . Thus, an elevated alkaline phosphatase and pigmented skin lesions, which were absent in the present case, have been noted in some cases . In those cases where histological changes were described, heterotopic bone was formed almost exclusively by intramembranous ossification . Although intramembranous ossification was undoubtedly the main type of bone formation seen in our case, a single focus on endochondral ossification, with cartilage formation prior to ossification, was also noted . As no preceding cause for such ossification was evident, this would appear to confirm that primary endochondral ossification also occurs and makes a minor contribution to the heterotopic bone formation seen in POH . The pathogenesis of heterotopic ossification in POH is unknown . Although the precise mechanism of mesenchymal cell differentiation in extraosseous tissues is poorly understood, it is known that stromal stem cells within bone are capable of yielding more committed progenitors, each of which can give rise to a particular stromal cell line (e .g ., fibroblast, adipocytc, chondroeyte, osteocyte) (Owen 1985) . In POH, it is possible that pluripotent stromal stem cells or more committed osteogenic precursor cells are present in an extramedullary location in both fat and muscle, or that precursor cells committed to adipose and fibroblast differentiation are also able to proceed down the osteoblastic pathway of differentiation leading to osteoinduction . The variety of stromal cell elements found in the present case of POH would argue in favor of a degree of plasticity being present in differentiation from stromal cell precursors . Also, in view of the predominance of direct bone formation occurring in subcutaneous fat, it is of interest to note that there is some recent evidence which favors a close relationship between adipogenesis and osteogenesis (Beresford et al . 1992) .
References
e '
'IM i r
Fig . 5 . A single focus of heterotopic ossification within deep fat which showed cartilage formation (left) and endochondral ossification to bone (top right) containing osteocyte lacunae and cement lines (H&E, x400) .
Beresford, J . N . ; Bennett, J . H . ; Devlin . C . ; Leboy . P . S . ; Owen, M . E . Evidence for an inverse relationship between the differentiation of adipocytic and osleogenic cells in rat marrow stromal cell cultures . J. Cell Sei . 102 :341-355 ; 1992 . Connor, 1 . M . Soft hassle ossification . Berlin : Springer-Verlag; 1983 . Connor, J . M . ; Evans. D . A . P . Fibrodysplasiaossificans progressiva . The clinical features and natural history of 34 patients . J . Bone Joint Sure, 6411 :76-83 : 1982 .
Eaton,
W. L . :
Conking,
W. S . ::
Daeschner,
C. W.
Early myositis ossificans pro-
N . A . Athanasou et al . : Progressive osseous heteroplasia gressiva occurring in homozygotic twins . A clinical and pathological study . J . Pediarr . 50 :591-598; 1957 . Foster, C . M . ; Levin, S . ; Levine, M . ; Mukherjee, A . ; Coster, 1 . L . ; Eeries, E . P . ; Triche, T . ; Zasluff, M . Limited dermal ossification : clinical features and natural history . J . Pediar . 109 :71-76 ; 1986. Frame, B . ; Azad, N . ; Reynolds, W. A . ; Saeed, S . M . Polyostotic fibrous dysplasia and myositis ossificans progressive . A report of co-existence . Am . J . Dis . Childhood 124 :120-122;1972 . Gardner, R . 1 . M . ; Yon, K . ; Crow, S . M . Familial ectopic ossification . J . Med . Genet . 25 :113-117 ; 1988 . Kaplan, S . ; Craven, R . ; MacEwen, C . D . ; German, P . H . ; Finkel, G . ; Hahn, G . ; Tabas, J . ; McKinley Gardner, R . J . ; Zasloff, M . A. Progressive osseous beteroplasia : a distinct developmental disorder of heterotopic ossification . J . Bone Joint Surg . 76A:425-436; 1994 . Kaplan, F . S . ; Tabas, J . A . ; Gannon, F . N . ; Finkel, C . ; Hahn, G . V . ; Zasloff,
475 M . A. The histopathology of fibrodysplasia ossificans progressiva . J . Bone Joint Surg . 75A:220-230 ; 1993 . Lever, W . F. ; Schaumberg-Lever, G. Hisrnpathology of the skin . Philadelphia: 1 . B . Lippincott ; 1975 . Owen, M . Lineage of osteogenic cells and their relationship to the stromal system. Peck, W . A . ed . Bone and mineral research . Vol . 3 . Amsterdam : Elsevier; 1985; 1-23. Smith, R . ; Russell, R . G . G . ; Woods, C . G . Myositis ossificans progressive. Clinical features on eight patients and their response to treatment . J . Bone Joint Surg . 58B :48-57 ; 1976 .
Date Received: May 24, 1993 Date Revised: October 5, 1993 Dare Accepted: January 19, 1994
Pergamon
8756-3282194 $6 .00 + .00
8756-3282(94)EO013-0
CASE REPORT
Progressive Osseous Heteroplasia : A Case Report N . A . ATHANASOU, i M . K . D'A . BENSON ; D . P . BRENTON,3 and R . SMITH
2
Department of Pathology Department of Medicine and Surgery, Nu field Orthopaedic Centre . Oxford, UK
' Endocrine and Metabolic Unit, Middlesex Hospital, London, UK
Address for correspondence and reprints : Dr . N .
A.
Athanasou, Department of Pathology, Nuffield Orthopaedic Centre, Oxford OX3 7LD, UK .
Abstract
enlargement caused pain, and in some cases led to skin ulceration . In childhood, the provisional diagnosis was either FOP or "osteoma cutis" ; she had no other skeletal abnormalities, and measurements of serum calcium, phosphorus and alkaline phosphatase, and of urinary calcium and phosphate excretion were normal . Progressive ossification and repeated problems with skin ulceration led to a left through-knee amputation at the age of 5 years . Ossification, however, continued in the soft tissues of the thigh, groin, and left lower abdomen . By the age of 18 years, she was complaining of severe pain in this region . Overlying the insertion of the adductor longus in her left groin, there was ulceration of bone through the skin and a discharge of blood stained and chalk-white bony material . She had pain on micturition and urgency, but no urinary or fecal incontinence . Menstruation was normal . She also complained that her thigh muscles tended to go into spasm when she was in pain . Over the years she had received various treatments including prostaglandin E2 pads to groin and upper thigh when she was 1 l years old ; penicillamine when she was 12 years old ; and corticosteroids, several nonsteroidal anti-inflammatory agents, narcotic analgesics, as well as hypnotherapy at various periods during her childhood and adolescence . At presentation, she was on indomethacin, sodium diclofenac and pethidine hydrochloride . As the severity of her pain increased, an indwelling cannula was inserted to allow regular epidural anaesthesia . On examination, there was bony ankylosis of the left hip which was fixed in 45° flexion and 20° abduction . Bone was diffusely present and easily palpable in the subcutaneous tissues of the left thigh, groin, and lower abdomen, and there was marked tenderness about the groin and superior pubic ramus . There was a scanty discharge of blood-stained, white bony material from a wound in the left groin . Palpation of the abdomen revealed obvious discrete areas of ossification in superficial soft tissues on the left side . On vaginal and rectal examination, there was no evidence of ossification of the genitourinary organs or rectum . Clinical investigations were as follows ; hemoglobin, 13 g/dl ; white cell count, 6 .48 x 10'/1 ; platelets, 348 x 10'/1 ; ESR, 4 mm/hour ; calcium, 2 .4 mmol/l (normal range 2 .12-2 .62) ; phosphate, 1 .1 mmol/1 (normal range 0 .8-1 .45) ; albumin, 48 g/I (normal range 35-50) ; and alkaline phosphatase, 226 IU/I (normal range 80-250) . Both X-rays and MRI showed large areas of ossification with bone diffusely present throughout the superficial and deep soft tissues of the thigh, groin, and abdomen (Fig . 1) . To control her constant severe pain and to remove areas of infection, which had developed following recurrent skin ulceration by bone present in the subcutaneous tissues, she underwent
We report the case of a young female who, from infancy, suffered extensive, progressive, heterotopic ossification of her left lower limb . Hetertopic ossification, which was largely but not exclusively intramembranous in type, was most marked in subcutaneous fat but was also noted in muscle and deep connective tissue . The spectrum of changes noted suggests that this congenital disorder of soft tissues is similar to that recently described as progressive osseous beteroplasia . Key Words : Ectopic bone-Heteroplasia-AdipogenesisOssification-Fibrodysplasia-Ossificans progressivaMyositis ossificans .
Introduction Developmental disorders characterized by extensive primary heterotopic ossification in soft tissues are rare . The two major causes of primary soft tissue ossification are fibrodysplasia ossificans progressiva (FOP), an inherited disorder characterized by well-defined skeletal malformations and progressive muscle ossification, and Albright's hereditary osteodystrophy (AHO), characterized by multiple areas of subcutaneous or intracutaneous ossification and an association with the syndromes of pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism (Connor 1983) . Recently, a series of cases characterized by a similar pattern of extensive soft tissue ossification in muscle, superficial and deep subcutaneous tissue, and deep connective tissue has been described and separated from the above two conditions (Kaplan et al . 1994) . The distinct clinical and pathological features of this rare disorder of mesenchymal differentiation have been termed progressive osseous heteroplasia (POH) . The patient with severe heterotopic ossification presented in this report shows a number of similarities to POH, but exhibits some clinical and pathological features which have not previously been associated with this condition, Case Report An 18-year-old girl presented with long-standing ectopic bone formation affecting her left leg, thigh, and lower abdomen . She was first noted to have palpable bony lumps in soft tissues of the left leg and thigh at the age of 6 weeks, These lumps were present in muscle and subcutaneous tissues and their progressive 471
47 2 A
N . A . Athanasou et al . : Progressive osseous heteroplasia been ligated at previous surgery in childhood . Postoperatively, she was treated by radiotherapy and Indomethacin to minimize new bone formation . She developed an infected pelvic hematoma that was successfully treated with surgical drainage and antibiotics, but otherwise her recovery was unremarkable, Following amputation, the pain was dramatically relieved and within 2-3 weeks her analgesic medication almost stopped . There was no suggestion of causalgic pain . However, within 2 months of surgery pain similar in quality to that felt preoperatively recurred and proved, as before, unresponsive to opiate analgesics . Six months postoperatively, she underwent a partial cordotomy which effectively eliminated her pain, and she is currently walking satisfactorily with an orthosis . Immediate postoperative radiographs showed no evidence of bone in the soft tissues but subsequent CT and MRI scans show that bone had once again started to form diffusely about the groin within the rectus abdominis muscle and probably within the pelvis . Histopathology
Fig . 1 . (A) Pan of AP radiograph of left hip ; and (B) CT of right and left thighs showing extent of subcutaneous and intramuscular ossification in left thigh, groin, and pelvis. a left through-hip amputation . At surgery . and on gross pathological examination, abundant bony tissue was found within the thigh ; this was largely restricted to the medial aspect of the thigh where the subcutaneous fat and abductor muscles contained numerous areas of ossification ; dense bony adhesions had formed between the superior pubic ramus and the skin . Ossification extended into the hip joint capsule and superiorly involved subcutaneous fat and muscle of the lower anterior abdominal wall . The peritoneal cavity appeared uninvolved . The hip was firmly ankylosed by bone extending from the superior pubic ramus to the femur ; the iliacus muscle within the pelvis was atrophic and diffusely and heavily ossified . In the thigh, ossification was most prominent within subcutaneous fibrous tissue and fat, but numerous foci of ossification were also present in atrophic muscle and the deep fascia and intermuscular fibrous septae . Extensive bone formation was also noted around femoral vessels which had
Extensive ossification of soft tissues in both the thigh and pelvis was confirmed on histology . This involved the reticular denims, superficial and subcutaneous fat, and fat between atrophic muscle bundles, as well as tendons, fascia, and interstitial connective tissue between muscle bundles (Figs . 2-4) . Most of the woven bone appeared to be formed through intramembranous ossification by mesenchymal cells within interstitial connective tissue in muscle and fat (Fig . 4), although a single tiny focus of cartilage formation with subsequent endochondral ossification was found within fat (Fig . 5) . There was evidence of bone formation and resorption with osteoblasts and osteoclasts present on the surface of some woven bone trabeculae (Fig . 2) . Larger trabeculae of bone within muscle and subcutaneous fat showed partial or complete organization to lamellar bone ; these often contained prominent thick cement lines and were rimmed by flattened lining cells (Fig . 3) . In some areas, bone formation was extensive, essentially forming a complex bridging network of bars and trabeculae woven and lamellar bone of varying thickness between the reticular dermis, muscle, and deep connective tissue . Most of the bone lay within subcutaneous fat which was of normal appearance, but focally some mature fat contained areas of cellular fibrous tissue from which the bone appeared to form by intramembranous ossification (Fig . 4) . Mature fat but not hemopoietic tissue was seen in spaces enclosed by this eetopie bone . A bony network was often seen around skin adnexal structures such as sweat, apocrinc, and sebaceous glands as well as small nerve bundles and blood vessels within the skin (Fig . 2) . The overlying epidermis and papillary dermis was unaffected . Within atrophic muscle, bone formation was seen in fat, and connective tissue of the epimysium and perimysium . Bone formation was seen to lie intimately around individual muscle fibers and small groups of muscle fibers (Fig . 3), as well as in fat within and around atrophic muscle bundles . Bone formation was also seen in the epineurium and peiineurium of small, mediumsized, and large nerves with consequent disorganization of nerve bundles . Ectopic bone was also seen within and around walls of lymphatic vessels, small and large blood vessels (mostly veins as major arteries had atrophied), and in the fibrous capsule of inguinal lymph nodes (Fig . 4) . The femoral cortex was of variable thickness throughout its length and showed evidence of appositional woven bone formation on the surface . The distal end of femur was porotic with thin cortex and widely spaced, thin medullary bone trabeculae . Little hemopoietic tissue was present within the femoral medulla . Bi-
N . A. Athanasou et al . : Progressive osseous heteroplasia
47 3
Fig. 2 . (A) Heterotopic ossification in superficial tissues with woven bone formation in deep dermis adjacent to sweat glands (right) . Note osteoblasts (some arrowed) lining bone surface, osteocytes in lacunae and prominent cement lines within bone (H&E, X400) . (B) Same field as (A) showing irregular arrangement of collagenous matrix within woven bone . opsies taken of a deep iliac lymph node and retroperitoneal fat showed no evidence of ossification . Discussion The main clinical and pathological change noted in this case was that of a congenital, progressive, unilateral, heterotopic ossification affecting subcutaneous tissue, muscle, and deep connective tissue . Heterotopic ossification was almost exclusively intramembranous in type with only a single, tiny focus of endochondral ossification noted . Heterotopic ossification was primary and not associated with clinical or pathological evidence of abnormal calciumm metabolism, trauma, infection, or other causes of inflammation . The heterotopic ossification seen in this case is distinguished from FOP and AHO, the two major causes of primary ectopic
bone formation, by a number of clinical features . Unlike FOP, congenital malformation of the digits was not present, and rarer associations, such as failure of secondary sexual development, intellectual impairment, deafness, or baldness, were also absent (Connor 1983 ; Connor & Evans 1982 ; Smith et al . 1976) . Heterotopic ossification in this case was most extensive in superficial and deep subcutaneous fat and connective tissue ; although, in FOP, ectopic bone formation can rarely occur in connective tissue of ligaments, fasciae, aponeuroses, tendon, and joint capsules, ossification in muscle predominates (Connor 1983) . Unlike FOP, the axial musculature was not affected and episodes of ossification were not exacerbated by trauma . Alkaline phosphatase was also not found to be elevated, as may occur during new episodes of heterotopic ossification in FOP . Unlike AHO, lesions were not bilaterally distributed and widespread . In addition, heterotopic ossification was not restricted to the
Fig . 3. Heterotopic ossification in deeper tissues with : (A) lamellar bone within deep subcutaneous fat next to atrophic muscle (top left) (H&E, x 250) . (B) Same field as (A) viewed under polarized light showing ordered lamellar arrangement of collagenous matrix in mature bone (x 250) .
47 4
N.
Fig. 4 . Woven bone formation within deep fat containing areas of cellular fibrous tissue . There is maturation to lamellar bone, some of which partly surrounds dilated vascular channels (diamond) . Note also small focal areas of heterotopic ossification within fat (arrow) (H&E, x 1110). dermis and superficial subcutaneous tissues, but also involved muscle and deeper connective tissues . Brachydactyly, short stature, obesity, round facies, of mental impairment, as noted in AHO . were not seen in this case . There was no hypocalcemia or hyperphosphatemia and no other associated features of pseudohypoparathyroidism . Pathological features also distinguish the soft tissue bony lesions of this patient from those of FOP and AHO . In the present case, bone formation within soft tissues was almost entirely produced by noninflammatory intramembranous osseous heteroplasin with only a single area of endochondral ossification noted, Although fibroblast proliferation within fibrous septae of striated muscle can be seen in early FOP lesions, foci of endochondral ossification are also commonly found in both early and fully developed FOP lesions within muscles (Eaton et al . 1957 ; Frame et al . 1972 ; Kaplan et al . 1993 ; Smith et al . 1976) fully developed FOP lesions contain abundant cartilage and bone (both woven and lamellar) with the latter formed by endochondral ossification and little or no intramembranous bone formation present . Unlike AHO, areas of ossification were not solely intracutaneous or subcutaneous in distribution and amorphous calcium deposits were not seen (Lever & Schaumberg-Lever 1975) . Clinical and pathological changes similar to those noted in this patient have recently been noted in a series of cases reported by Kaplan et al . (1994) as examples of a distinct syndrome
A . Athanasou et al . : Progressive osseous heteroplasia
called progressive osseous heteroplasia (POH) . POH occurs exclusively in females and is characterized by heterotopic ossification of subcutaneous tissue, deep connective tissue, and muscle . Such heterotopic ossification showed a random, widespread anatomic distribution in several of these reported cases (and their relatives) ; but, in two cases, one of which had been reported previously (Gardner et al . 1988), ossification was progressive and restricted to a single lower limb in a manner similar to that of the present case . One of a pair of siblings included in the series of Gardner et al . (1988) and a previous report (Foster et al . 1986) also documented heterotopic ossification that was restricted to the left lower limb . Heterotopic ossification within discrete limb structures thus appears to be a prominent feature of POH, with the lower limb the most common site of singlelimb involvement . There was no family history of heterotopic ossification in the present case, indicating that the disease appears to have arisen as a result of a fresh mutation . Although Kaplan et al . (1994) report that two cases of POH had a family history of heterotopic ossification, the remainder appear to have arisen sporadically . Consequently, no known inheritance pattern has been established for POH . The heterotopic ossification of POH is associated with a spectrum of other clinical and pathological changes . Thus, an elevated alkaline phosphatase and pigmented skin lesions, which were absent in the present case, have been noted in some cases . In those cases where histological changes were described, heterotopic bone was formed almost exclusively by intramembranous ossification . Although intramembranous ossification was undoubtedly the main type of bone formation seen in our case, a single focus on endochondral ossification, with cartilage formation prior to ossification, was also noted . As no preceding cause for such ossification was evident, this would appear to confirm that primary endochondral ossification also occurs and makes a minor contribution to the heterotopic bone formation seen in POH . The pathogenesis of heterotopic ossification in POH is unknown . Although the precise mechanism of mesenchymal cell differentiation in extraosseous tissues is poorly understood, it is known that stromal stem cells within bone are capable of yielding more committed progenitors, each of which can give rise to a particular stromal cell line (e .g ., fibroblast, adipocytc, chondroeyte, osteocyte) (Owen 1985) . In POH, it is possible that pluripotent stromal stem cells or more committed osteogenic precursor cells are present in an extramedullary location in both fat and muscle, or that precursor cells committed to adipose and fibroblast differentiation are also able to proceed down the osteoblastic pathway of differentiation leading to osteoinduction . The variety of stromal cell elements found in the present case of POH would argue in favor of a degree of plasticity being present in differentiation from stromal cell precursors . Also, in view of the predominance of direct bone formation occurring in subcutaneous fat, it is of interest to note that there is some recent evidence which favors a close relationship between adipogenesis and osteogenesis (Beresford et al . 1992) .
References
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'IM i r
Fig . 5 . A single focus of heterotopic ossification within deep fat which showed cartilage formation (left) and endochondral ossification to bone (top right) containing osteocyte lacunae and cement lines (H&E, x400) .
Beresford, J . N . ; Bennett, J . H . ; Devlin . C . ; Leboy . P . S . ; Owen, M . E . Evidence for an inverse relationship between the differentiation of adipocytic and osleogenic cells in rat marrow stromal cell cultures . J. Cell Sei . 102 :341-355 ; 1992 . Connor, 1 . M . Soft hassle ossification . Berlin : Springer-Verlag; 1983 . Connor, J . M . ; Evans. D . A . P . Fibrodysplasiaossificans progressiva . The clinical features and natural history of 34 patients . J . Bone Joint Sure, 6411 :76-83 : 1982 .
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475 M . A. The histopathology of fibrodysplasia ossificans progressiva . J . Bone Joint Surg . 75A:220-230 ; 1993 . Lever, W . F. ; Schaumberg-Lever, G. Hisrnpathology of the skin . Philadelphia: 1 . B . Lippincott ; 1975 . Owen, M . Lineage of osteogenic cells and their relationship to the stromal system. Peck, W . A . ed . Bone and mineral research . Vol . 3 . Amsterdam : Elsevier; 1985; 1-23. Smith, R . ; Russell, R . G . G . ; Woods, C . G . Myositis ossificans progressive. Clinical features on eight patients and their response to treatment . J . Bone Joint Surg . 58B :48-57 ; 1976 .
Date Received: May 24, 1993 Date Revised: October 5, 1993 Dare Accepted: January 19, 1994