DOI: 10.1148/radiol.2402031992
(Radiology 2006;240:607-610.)
© RSNA, 2006
Case 97: X-linked Hypophosphatemic Osteomalacia with Insufficiency Fracture1
Jon A. Jacobson, MD and
Monica Kalume-Brigido, MD
1 From the Department of Radiology, University of Michigan Medical Center, 1500 E Medical Center Dr, TC-2910G, Ann Arbor, MI 48109-0326. Received December 8, 2003; revision requested February 13, 2004; revision received April 6; accepted May 19; final version accepted June 17.
Correspondence: Address correspondence to J.A.J. (e-mail: jjacobsn{at}umich.edu).
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HISTORY
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A 48-year-old woman of short stature experienced diffuse and continuous pain of several years duration throughout her body. This pain was often more severe in the left lower extremity and was associated with limited range of motion. There was no history of trauma. Radiographs of the pelvis and left hip were obtained.
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IMAGING FINDINGS
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Pelvic and left hip radiographs demonstrate pronounced periarticular ossification about the acetabulae and proximal femora at tendon, ligament, and joint capsule attachments to bone (Fig 1). This enthesopathy is fairly well defined and symmetric. Additional sclerosis is seen about the sacroiliac joints and represents ligamentous calcification and ossification, without joint ankylosis or erosive changes. The left hip radiograph shows subtle bowing of the proximal femoral diaphysis (Fig 1b). A cortical lucency of the proximal medial femoral diaphysis with associated cortical thickening represents an insufficiency-type stress fracture.
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Figure 1a: (a) Anteroposterior pelvic and (b) anteroposterior and (c) frog-leg lateral left hip radiographs show pronounced enthesopathy (arrows) in a 48-year-old woman with X-linked hypophosphatemic osteomalacia. Note sacroiliac joint sclerosis (arrowheads in a) and insufficiency-type stress fracture (arrowheads in b and c) of the femur.
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Figure 1b: (a) Anteroposterior pelvic and (b) anteroposterior and (c) frog-leg lateral left hip radiographs show pronounced enthesopathy (arrows) in a 48-year-old woman with X-linked hypophosphatemic osteomalacia. Note sacroiliac joint sclerosis (arrowheads in a) and insufficiency-type stress fracture (arrowheads in b and c) of the femur.
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Figure 1c: (a) Anteroposterior pelvic and (b) anteroposterior and (c) frog-leg lateral left hip radiographs show pronounced enthesopathy (arrows) in a 48-year-old woman with X-linked hypophosphatemic osteomalacia. Note sacroiliac joint sclerosis (arrowheads in a) and insufficiency-type stress fracture (arrowheads in b and c) of the femur.
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DISCUSSION
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Findings of an insufficiency-type stress fracture and pronounced enthesopathy indicate X-linked hypophosphatemic osteomalacia is the correct diagnosis. Osteomalacia is defined as a disorder of bone tissue characterized by inadequate or delayed mineralization of osteoid in mature cortical and spongy bone (1). In children, this condition is associated with additional growth-plate abnormalities (ie, interruption of the normal development and mineralization of the growth plate) and is termed rickets (1). Thus, unlike in adults, both rickets and osteomalacia can coexist in affected children.
Common causes of osteomalacia can be generally divided into disorders characterized by a calcium deficiency, a vitamin D deficiency, or a phosphate deficiency. Conditions that produce hypophosphatemia should be considered separately from conditions that produce abnormally low calcium or vitamin D levels because of their differing effects on the parathyroid hormone. When calcium or vitamin D levels are low, parathyroid hormone levels are increased, which produces the characteristic features of bone resorption at imaging. In contrast, low phosphate levels do not cause an increase in parathyroid hormone levels, and the classic imaging features of hyperparathyroidism are typically absent (1).
The most common cause of hypophosphatemic osteomalacia is an inherited X-linked abnormality in which the renal tubules ineffectively reabsorb phosphate. Sporadic cases, which are likely due to mutation, occur in up to one-third of patients (1). In children, this condition has been referred to as "vitamin D–resistant rickets" or "refractory rickets" because of poor clinical response to vitamin D supplementation (2,3). Other causes of hypophosphatemic osteomalacia include Fanconi syndrome (a group of conditions characterized by renal tubular dysfunction and urinary loss of amino acids) and oncogenic hypophosphatemic osteomalacia (a tumor-associated cause) (1). In the latter condition, it is believed that an abnormal humoral substance (called phosphatonin) is produced by either a soft-tissue lesion or a bone lesion (benign or malignant) that inhibits the absorption of phosphate in the kidney and causes the excretion of phosphate (1,4). Magnetic resonance imaging has been used to identify the inciting lesion (5). Surgical removal of the lesion cures the disease or improves the patient's condition (4).
The clinical features of hypophosphatemic osteomalacia are variable and depend on the cause of the disease. With X-linked hypophosphatemic osteomalacia, the patient is typically of short stature, with possible bone deformities and limitations of movement; however, systemic findings, such as muscle weakness seen with other causes of osteomalacia, are typically absent (1,6,7). Pain may be due to complications of osteomalacia, such as an insufficiency fracture, and it may be the first symptom of the underlying condition. Patients may present with symptoms of hypophosphatemic osteomalacia at any age.
Radiographic manifestations of hypophosphatemic osteomalacia vary with the cause of the disease and the age at which symptoms develop. In adults with X-linked hypophosphatemic osteomalacia, diffuse bone sclerosis may be present, and well-defined enthesophytes may be visible (1). These findings are more pronounced in older patients (1). The degree of enthesopathy or entheses and joint capsule calcification can be extensive and a cause of joint dysfunction (7–9). Involvement of the sacroiliac joint and the acetabular, trochanteric, and iliolumbar ligaments (Fig 2a) can be seen in the pelvis (7). Spinal facet (Fig 2b) and sacroiliac joint fusion may occur, which may cause the radiographic appearance to resemble that of ankylosing spondylitis (8). Bone ossicles and calcific deposits in the carpal region have also been described (2,7,9). Bone mineralization is usually normal or increased, and bowing of long bones may be seen (9). Complications of osteomalacia, such as insufficiency fractures, are possible (9). Spinal canal stenosis may be seen due to short pedicles, and it may be compounded by apophyseal ligament calcification and ligamentum flavum ossification (10,11). In children, radiographic findings of X-linked hypophosphatemic osteomalacia are less severe when compared with findings of classic vitamin D–resistant rickets, as bowing of long bones is less pronounced and osteopenia is minimal (if present) (1). In addition, growth plate involvement is not uniform, is less severe, or is absent (Fig 3) (12).
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Figure 2a: Radiographs in a 62-year-old man with hypophosphatemic osteomalacia. (a) Anteroposterior pelvic image shows diffuse bone sclerosis, pronounced enthesopathy (arrows), sacroiliac joint sclerosis, and iliolumbar ligament calcification (arrowheads). (b) Lateral lumbar spine image shows apophyseal joint fusion (arrows) and enthesopathy (arrowhead) of the anterior vertebral bodies.
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Figure 2b: Radiographs in a 62-year-old man with hypophosphatemic osteomalacia. (a) Anteroposterior pelvic image shows diffuse bone sclerosis, pronounced enthesopathy (arrows), sacroiliac joint sclerosis, and iliolumbar ligament calcification (arrowheads). (b) Lateral lumbar spine image shows apophyseal joint fusion (arrows) and enthesopathy (arrowhead) of the anterior vertebral bodies.
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Figure 3: Anteroposterior radiograph of the knee in a 5-year-old girl with X-linked hypophosphatemic rickets shows partial fraying and irregularity of the distal femoral and proximal tibial growth plates (upper and lower arrows, respectively).
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Insufficiency fractures with osteomalacia have a characteristic radiographic appearance. They tend to occur at specific locations, typically the concave aspect of a bone, and they are often bilateral (9). Common sites for insufficiency fractures include the medial aspect of the proximal femur and proximal tibia, the pubic rami, the ribs, and the lateral aspect of the scapula (1). The fracture lines in the bone cortex are perpendicular to the bone surface and are associated with surrounding sclerosis, which is a characteristic finding in patients with osteomalacia. Other terms for osteomalacia-related insufficiency fractures include Looser zones or Milkman pseudofractures. These fractures should be regarded as true insufficiency fractures, as they represent the effects of normal stress on abnormal bone (1). The lucency of the insufficiency fracture persists, as the osteoid that is deposited in the fracture does not undergo mineralization.
There are various differential diagnoses, depending on which radiographic finding is considered. When a single insufficiency fracture is identified, the possibility of a fatigue-type stress fracture or traumatic fracture should be considered. However, the characteristic location of insufficiency fractures is helpful in this differentiation. When an additional insufficiency fracture is identified, especially one that is bilateral and symmetric, osteomalacia is likely present. The characteristic findings of osteosclerosis and diffuse pronounced enthesopathy in adults indicate X-linked hypophosphatemia is the cause of osteomalacia.
The differential diagnosis for generalized enthesopathy includes diffuse idiopathic skeletal hyperostosis, seronegative arthropathy, fluorosis, and retinoid-induced hyperostosis. The history of medication is helpful in the diagnosis or exclusion of retinoid-induced hyperostosis. The absence of erosion helps to exclude a diagnosis of inflammatory spondyloarthropathy. The absence of syndesmophytes also assists in the exclusion of ankylosing spondylitis (7,9). Although the enthesopathy in diffuse idiopathic skeletal hyperostosis may be extensive in some individuals, enthesopathy associated with hypophosphatemic osteomalacia may be quite pronounced, as in this patient (7). In addition, unlike diffuse idiopathic skeletal hyperostosis, diffuse involvement of the anterior longitudinal ligament of the thoracic and lumbar spine is rare in patients with hypophosphatemic osteomalacia (7). The presence of bone sclerosis with enthesopathy makes differentiation between hypophosphatemic osteomalacia and fluorosis difficult; however, the presence of an insufficiency fracture in association with short stature and absence of osteophytes suggests a diagnosis of hypophosphatemic osteomalacia.
In summary, the presence of a characteristic insufficiency fracture and coexisting pronounced enthesopathy indicates a diagnosis of X-linked hypophosphatemic osteomalacia.
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References
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- Pitt MJ. Rickets and osteomalacia. In: Resnick D, ed. Diagnosis of bone and joint disorders. 4th ed. Philadelphia, Pa: Saunders, 2002; 1901–1945.
- Steinbach HL, Kolb FO, Crane JT. Unusual roentgen manifestations of osteomalacia. Am J Roentgenol Radium Ther Nucl Med 1959;82:875–886.[Medline]
- Parfitt AM. Hypophosphatemic vitamin D refractory rickets and osteomalacia. Orthop Clin North Am 1972;3:653–680.[Medline]
- Sundaram M, McCarthy EF. Oncogenic osteomalacia. Skeletal Radiol 2000;29:117–124.[CrossRef][Medline]
- Avila NA, Skarulis M, Rubino DM, Doppman JL. Oncogenic osteomalacia: lesion detection by MR skeletal survey. AJR Am J Roentgenol 1996;167:343–345.[Free Full Text]
- Frymoyer JW, Hodgkin W. Adult-onset vitamin D-resistant hypophosphatemic osteomalacia. J Bone Joint Surg Am 1977;59:101–106.[Abstract/Free Full Text]
- Polisson RP, Martinez S, Khoury M, et al. Calcification of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med 1985;313:1–6.[Abstract]
- Burnstein MI, Lawson JP, Kottamasu SR, Ellis BI, Micho J. The enthesopathic changes of hypophosphatemic osteomalacia in adults: radiologic findings. AJR Am J Roentgenol 1989;153:785–790.[Abstract/Free Full Text]
- Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP. X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features. Radiology 1989;171:403–414.[Abstract/Free Full Text]
- Cartwright DW, Masel JP, Latham SC. The lumbar spine canal in hypophosphataemic vitamin-D resistant rickets. Aust N Z J Med 1981;11:154–157.[Medline]
- Adams JE, Davies M. Intra-spinal new bone formation and spinal cord compression in familial hypophosphataemic vitamin D resistant osteomalacia. Q J Med 1986;61:1117–1129.[Medline]
- Econs MJ, Feussner JR, Samsa GP, et al. X-linked hypophosphatemic rickets without "rickets." Skeletal Radiol 1991;20:109–114.[Medline]
Congratulations to the 78 individuals and two resident groups that submitted the most likely diagnosis (X-linked hypophosphatemic osteomalacia with insufficiency fracture) for Diagnosis Please, Case 97. Per the authors, credit was given only if hypophosphatemic osteomalacia or hypophosphatemia were mentioned. The names and locations of the individuals and resident groups, as submitted, are as follows:
Individual responses
- Jorge Ahualli, San Miguel de Tucumán, Tucumán, Argentina
- Alexandra Araújo, Lisbon, Portugal
- Lionel Arrivé, Paris, France
- Sebastian Bazzano, Rancagua, Chile
- Gustav Blomquist, Houston, Tex
- Jeff L. Boyd, Corvallis, Ore
- Eric L. Bressler, MD, Minnetonka, Minn
- Douglas C. Brown, MD, Virginia Beach, Va
- Paula Campos, MD, Cascais, Portugal
- Manuela Certo, Santo Tirso, Portugal
- Luisa F. Cervantes, Miami, Fla
- Neal R. Conti, MD, Seattle, Wash
- Peter C. De Baets, MD, Damme, Belgium
- Wagner Diniz de Paula, MD, Brasilia, Brazil
- Patrick Eiken, MD, Rochester, Minn
- Shella Farooki, MD, Dublin, Ohio
- Francis Flaherty, MD, Ridgefield, Conn
- Akira Fujikawa, Tokyo, Japan
- Ann S. Fulcher, MD, Richmond, Va
- Mark Goldshein, MD, Andover, Mass
- Alvaro Gomez Naar, Salta, Argentina
- Pramod Gupta, MD, Dallas, Tex
- Horacio Gutierrez, MD, Longmont, Colo
- Srinivasan Harish, Hamilton, Ontario, Canada
- Andreas Harzheim, MD, Cologne, Germany
- Alberto Iaia, MD, Wilmington, Del
- Rajapandian Ilangovan, MD, FRCR, London, United Kingdom
- Joao Rodrigues Inacio, Lisbon, Portugal
- Kiriakos Kalampoukas, MD, Athens, Greece
- Yasuhiro Kawahara, Omura, Japan
- Steven A. Klein, MD, Shrewsbury, Mass
- Yoshihisa Kurosaki, MD, Tokyo, Japan
- Mark Kutler, MD, Dallas, Tex
- Stefanos Lachanis, MD, Athens, Greece
- Mario Laguna, West Allis, Wis
- Dr Martin Lecompte, Ottawa, Ontario, Canada
- Julio L. Loureiro, MD, Buenos Aires, Argentina
- Patricia Lowry, MD, Richmond, Va
- Matthias Maier, MD, Basel, Switzerland
- Stephen Manghisi, MD, Closter, NJ
- N. B. S. Mani, MD, Nassau, Bahamas
- Michael B. Martin, MD, Austin, Tex
- Frank McKowne, MD, Vancouver, Wash
- Jonathan Meyer, MD, Chicago, Ill
- Manabu Minami, MD, Tsukuba, Ibaraki, Japan
- Sankar Ranjan Mondal, MD, Nassau, Bahamas
- Dr Thomas Moser, Strasbourg, France
- Bruno M. Moura de Sousa, Rio de Janeiro, Brazil
- Tammam Nehme, East Wenatchee, Wash
- Hiroshi Nobusawa, MD, Tokyo, Japan
- Marcos Nogueira Chagas, MD, Brasilia, Brazil
- Edward S. Oh, MD, Tucson, Ariz
- Michael T. O'Loughlin, MD, West Hartford, Conn
- Dr Klaus Orth, Aachen, Germany
- Carlos Ovejero Vela, MD, Barcelona, Spain
- Prakash Patel, MD, New City, NY
- Ivan Pilate, MD, Mechelen, Belgium
- Hilton Pittman, Pensacola, Fla
- Venkateswar Rao Surabhi, Herndon, Va
- Daniel Rappaport, MD, FRCPC, Toronto, Ontario, Canada
- Arthemizio Rocha, Brasilia, Brazil
- Matt Shapiro, MD, Charlottesville, Va
- Taro Shimono, MD, Osaka, Japan
- Grady Shue, Hickory, NC
- Ken Simmons, Sydney, Australia
- Alberto Simoncini, Buenos Aires, Argentina
- Stephen H. Slawson, RPh, MD, Joplin, Mo
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- Vinod Sukumaran, MD, Trivandrum, India
- Kazuhiro Suzuki, Tokyo, Japan
- Eliko Tanaka, Yokohama, Japan
- Douglas L. Teich, MD, Brookline, Mass
- Rogério Teles de Melo, Belo Horizonte, Brazil
- Rafael Valls, MD, St Quirze Valles, Spain
- Christopher Vittore, MD, Rockford, Ill
- S. R. Vydianath, MRCP, FRCR, Wolverhampton, United Kingdom
- Jimmy Wong, San Diego, Calif
- Joe Yut, Olathe, Kan
Resident group responses
- Hospital Italiano de Córdoba Radiology Residents, Córdoba, Argentina
- Hospital of the University of Pennsylvania Radiology Residents, Philadelphia, Pa
TOP
HISTORY
IMAGING FINDINGS
