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Figure 1: Case 1. Lateral view of the dorsal spine of a 28-year-old woman with typical sandwich-structure, or Rugger-Jersey spine. Figure 2: Case 1. Radiograph of a 28-year-old woman with persisting Ehrlenmeyer flask apperance of her distal femur.
Osteopetrosis is a rare bone dysplasia, characterized by failure of bone resorption and persistence of calcified chondroid and primitive bone thought to be due to functional deficiency of osteoclasts.1,2 The effects of osteoclastic dysfunction may primarily or secondarily affect several organ systems, including skeletal, endocrine, neurologic, hematopoetic, renal, immunologic, ophthalmologic and otorhinolaringologic systems.3-6
In the skeletal system the pathologic process includes failure of normal skeletal growth and remodeling, failure of normal bone healing, failure of hematopoesis and abnormal development of cranial neural foramina with resultant cranial neuropathies.
This article presents a case of 4 relatives who presented with fractures and myelodysplastic anemia of varying severity.
A 28 year-old woman (II/9) was diagnosed with osteopetrosis at age 1 year after sustaining a forearm fracture.
Examination of the extended blood relatives revealed that one sister (II/3), one nephew (III/8), maternal grandmother (0/2), and one maternal uncle (I/3) also had osteopetrosis.
In 1996, the patient sustained a subtrochanteric fracture of the right femur after a fall. Examination revealed short stature, slight strabismus, and no splenomegaly. She had progressive optic nerve atrophy. Laboratory findings showed mild anemia (Hb 9.8g/dL, hematocrit 32%, white blood cell count 9500/mm3, and platelet count 280/mm3). Radiographs showed markedly increased bone density of the axial skeleton and long bones with a rugger-jersey appearance of the spine (Figure 1).
Growth defects were seen in the distal femora, with the Erlenmeyer flask deformity (Figure 2). Endobones were apparent in the metacarpal (Figure 3A) and tarsal bones (Figure 3B). Open reduction and fixation with a dynamic hip screw was performed. Her postoperative course was uneventful. The fracture healed 12 months postoperatively.
Figure 3: Case 1. Radiograph of a 28-year-old woman with “endobones” in metacarpal (A) and tarsal (B) bones.
Two years later, she sustained a subtrochanteric fracture of the left femur. The fracture was fixed with a dynamic hip screw. Drilling and reaming for the implant were difficult, with an operating time of 4 hours. The early postoperative course was uneventful.
Thirty-two months postoperatively, the patient developed a discharging sinus and reported intermittent pain in her left hip. Repeated smears from the sinus showed pus cells but no organisms, and cultures were repeatedly negative. Radiographs showed a periosteal reaction around the implant (Figure 4) and a healed fracture. Laboratory results revealed ESR 96/h, WBC 14,000/mm3, and CRP 45.
Figure 4: Case 1. Radiograph of the left hip 30 months after fixation of the subtrochanteric fracture with DHS, with apparent osteolysis around the implant. Figure 5: Case 1. Radiograph of the left hip 4 years after fixation shows a healed fracture after implant removal.
She was treated with antibiotics (cloxacillin and amoxicillin and potassium clavulanate). Thirty-seven months after the initial surgery the implant was removed and gentamycin beads inserted for persistent infection. The beads were removed after 1 month. The infection temporarily subsided, no discharge was observed, the patient was pain free, and the laboratory findings returned to normal values.
Eighteen months after implant removal, the patient reported left hip pain. Locally, no signs of infection or discharge were observed. Laboratory findings however, showed ESR 112/h, WBC 12000/mm3, and CRP 27. Technetium 99mdp and galium scan showed a focal uptake in the left femoral neck. Drilling, curretage and irrigation of the focus under fluoroscopic control was performed.
Cultures from drillings were negative. A follow-up bone scan and magnetic resonance imaging of the left hip showed no signs of infection. At 2-year follow-up, the patient had no clinical signs or laboratory evidence of persistent infection (Figure 5).
A 35-year-old woman (II/3), (the sister of the patient in Case 1) was diagnosed with osteopetrosis diagnosed in childhood. Examination revealed short stature, hepatomegaly (6 cm) and splenomegaly (5 cm) below the costal margin.
Her peripheral blood smear showed severe pancytopaenia (WBC 2.2/mm3, RBC Hb 3.5 g/dL, hematocrit 9.7%, and platelets 75/mm3). She has been blood transfusion dependent for several years requiring regular transfusions of 2-3 units every month. She also had chronic osteomyelitis of her mandible.
The patient gave birth to 5 children, of which the first two boys (III/1, III/2) died after delivery; none of her living children showed signs of osteopetrosis.
After a fall she sustained a right hip neck fracture, which was treated conservatively and resulted in fibrous union with varus deformity. The valgus deformity was left untreated (Figure 6) and she is ambulant with crutches.
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Figure 6: Case 2. Radiograph of the right hip of a 32 year-old woman with a femoral neck fracture, with typical transverse sharp fracture line and coxa vara. Figure 7: Case 3. Radiograph of a 6-month- old child with apparent increased radiodensity of the entire skeleton and typical “Ehrlenmeyer flask” deformity of the distal femora. Figure 8: Case 3. Radiograph of an 18-month-old child with a proximal femoral fracture, well-developed callus 8 weeks after the trauma.
Eight years later she sustained a left tibial fracture treated by calcaneal traction. One month later, she developed pin-track infection, the traction was removed, and a full cast was applied. Six month later there were no signs of healing. The patient was subsequently treated elsewhere with external fixator and bone grafting. She again developed pin track infection. The external fixator was removed after 9 months a full cast was applied. The fracture eventually healed 20 months after the injury without any signs of persisting infection.
An 18-month-old old boy (III/8) (the nephew of the patients in Case 1 and 2) was admitted after a fall, with pain and limited range of motion of his right hip. He had been diagnosed with osteopetrosis at age 4 months from the investigation of incidental findings of hepatosplenomegaly and pancytopaenia (Figure 7).
Clinically on admission he had hepatosplenomegaly 7 cm below the costal margin. Radiographs showed a transverse fracture of his right proximal femur and markedly increased density of the axial skeleton and the long bones. Laboratory findings revealed RBC 3.24 mm3 (normal 4.2-6.3 mm3), Hb 7.6 g/dL (normal 12.0-18.0 g/dL), HCT 23.6% (normal 37-51%), platelets 123 K/ul (normal 140-440), and RDW 23.3% (normal 1.5-14.5). His fracture, treated conservatively with an uneventful hospital course, healed with evident callus in 8 weeks (Figure 8).
The medical records of a 49-year-old man (the uncle of the patients in Case 1 and 2) (patient I/3) were reviewed. He had been diagnosed with osteopetrosis at age 4 years after sustaining a pathological tibial fracture that healed conservatively.
He had no splenomegaly and his laboratory findings were within normal limits. In 1993 he sustained a subtrochanteric fracture of his right hip that was treated with dynamic hip screw fixation. His postoperative course was uneventful and the fracture healed after 11 months.
Osteopetrosis is categorized as a disease spectrum with several variants defined by clinical and hereditary criteria.5
Fractures occur with increased frequency in patients with all forms of the disease. Because of excessive fragility of hard but brittle marble bones, a long bone fracture is the most common presenting feature. These fractures heal, but the time to union can be prolonged.2,7,8
The callus in osteopetrosis nearly is normal in the early stages of healing, with an abundant osteogenic cellular component and rich vascular network, later the callus is less vascular than in normal bone, with immature osteoid and fewer osteoclast-like cells. There is persistent primitive woven bone, with minimal signs of remodeling and failure to form Haversian lamellar structure.9 There is a particularly high incidence of proximal femoral fractures.5,6,10 These fractures can be fixed but the extreme hardness of the bone makes use of usual implants difficult.5,6,11,12
Osteopetrosis was originally described in a mild form with autosomal dominant inheritance and a malignant form with an autosomal recessive inheritance.6 In 1979 Beighton et al13 described intermediate forms of osteopetrosis. Sly et al4 and Whyte14 also reported patients with intermediate forms. In all forms the disease course is variable and the severity of hematologic, neurologic and skeletal manifestations may differ even between siblings.6,15
The incidence of autosomal recessive osteopetrosis is estimated to be 1:200 000. In some countries it is higher, due to a high degree of consanguinity.5 In Qatar, the incidence of consanguinous marriages is estimated to be 45%, (30% between first cousins).16 First cousins share an eighth of their genetic complement.17 Typically the child is underdeveloped, with hepatosplenomegaly, macrocephaly, frontal bossing and hepertelorism.6,15,18
Autosomal dominant osteopetrosis is sometimes either referred to as adult or benign. The form and shape of the long bones are often normal,19 patients have a normal life expectancy. Approximately half of the patients are asymptomatic2,5,6; autosomal dominant osteopetrosis originally was considered a heterogenous disease with various clinical manifestations.
Andersen and Bollerslev20 and Bollerslev and Mosekilde19 described two distinct forms. In Type I autosomal dominant osteopetrosis is present marked sclerosis of the cranial vault, sclerosis of the spine and pelvis. Fractures usually occur after substantial trauma and the fracture pattern is normal. In type II autosomal dominant osteopetrosis, the osteosclerosis is most pronounced in the base of the skull, a rugger-jersey appearance of the spine is observed, endobones are usually seen in the pelvis.19
Intermediate autosomal recessive osteopetrosis is rare. In a series of 79 patients, Armstrong6 reported only 3 cases of this form. Patients are usually diagnosed toward the end of the first decade of life.5 Pathologic fractures are frequently the presenting feature. These patients may have a disproportionaly short stature, dental abnormalities, recurrent mandibular osteomyelitis, macrocephaly and strabismus. Cranial nerve compression is present in >50 % of cases.6 The metaphyses are wider, failure of remodeling is seen especially in the distal femora as the Ehrlenmeyer flask deformity. In some patients the endobones can be seen. This is a core of primitive osseous tissue, mostly in the metacarpals, phalanges, tarsal bones, vertebral bodies and the pelvis. A subset of intermediate form of osteopetrosis is associated with renal tubular acidosis, intracerebral calcification and carbonic anhydrase II deficiency.4,14 In our cases the pattern of inheritance is consistent with an autosomal recessive disorder. The parents of the sisters were from one tribe but they were not close cousins. The parents of the child (II/15 and II/16) were second cousins. All four patients were diagnosed in the first year of life, pathologic fracture was the presenting feature in both sisters and their uncle, hepatosplenomegaly in their nephew. The clinical manifestations are consistent with the intermediate, autosomal recessive form, with persisting defects of skeletal modeling.
We believe that our case series is the first report of surgical fracture treatment in the rare intermediate form of osteopetrosis. Some previously reported cases may not have been accurately categorized.21 Hassenhutl22 reported a case categorized as autosomal dominant osteopetrosis, but stressed consanguinity of the parents. Two siblings of the patient were possibly also affected and died shortly after the birth. The patient is described as a lethargic child, with progressive anemia, blindness in the right eye, apparent modeling defects of the distal femora, and 33 fractures throughout his life with only minor trauma.
Benichou et al23 reported results of long-term follow-up of 42 patients with autosomal dominant osteopetrosis II, 78% of his patients suffered from recurrent fractures, 53% required an open procedure (open reduction and internal fixation, correction of deformity, and joint replacement). A high complication rate was noted (intraoperative fractures, infection, implant loosening, and nonunion). They referred to the previously used term benign osteopetrosis as a misnomer. Milgram and Jasty7 report that the manifestations of the two genetic types of osteopetrosis may overlap.
- Shapiro F, Glimcher MJ, Holtrop ME, Tashjian AH, Brickley-Parsons D, Kenzora JE. Human osteopetrosis: a histological, ultrastructural, and biochemical study. J Bone Joint Surg Am. 1980; 62:384-399.
- Tachdjian MO. Pediatric Orthopedics. Philadelphia, Pa: W.B. Saunders Co; 1990.
- Cameron HU, Dewar FP. Degenerative osteoarthritis associated with osteopetrosis. Clin Orthop Relat Res. 1977; 127:148-149.
- Sly WS, Whyte MP, Sundaram V, et al. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med. 1985; 313:139-145.
- Shapiro F. Osteopetrosis, current clinical considerations. Clin Orthop Relat Res. 1993; 294:34-44.
- Armstrong DG, Newfield JT, Gillespie R. Orthopedic management of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop. 1999; 19:122-132.
- Milgram JW, Jasty M. Osteopetrosis. A morphological study of twenty-one cases. J Bone Joint Surg Am. 1982; 64:912-929.
- Ashby ME. Total hip arthroplasty in osteopetrosis. A report of two cases. Clin Orthop Relat Res. 1992; 276:214-221.
- De Palma L, Tulli A, Maccauro G, Sabetta SP, del Torto M. Fracture callus in Osteopetrosis. Clin Orthop Relat Res. 1994; 308:85-89.
- Gupta R, Gupta N. Femoral fractures in osteopetrosis: case reports. J Trauma. 2001; 51:997-999.
- Greene WB, Torre BA. Femoral neck fracture in a child with autosomal dominant osteopetrosis. J Pediatr Orthop. 1985; 5:483-485.
- Casden AM, Jaffe FF, Kastenbaum DM, Bonar SF. Osteoarthritis associated with osteopetrosis treated by total knee arthroplasty. Report of a case. Clin Orthop Relat Res. 1989; 247:202-207.
- Beighton P, Hamersma H, Cremin BJ. Osteopetrosis in South Africa. The benign, lethal and intermediate forms. S Afr Med J. 1979; 55: 659-665.
- Whyte MP. Carbonic anhydrase II deficiency. Clin Orthop Relat Res. 1993; 294:52-63.
- Gerritsen EJ, Vossen JM, van Loo IH, et al. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 1994; 93:247-253.
- Teebi AS, Farag TI. Genetic Disorders Among Arab Populations. New York, NY: Oxford University Press Inc; 1996.
- Fitzsimmons JS. A Handbook of Clinical Genetics. London: William Heinemann Medical Books Ltd; 1980.
- Coccia PF, Krivit W, Cervenka J, et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med. 1980; 302: 701-708.
- Bollerslev J, Mosekilde L: Autosomal dominant osteopetrosis. Clin Orthop Relat Res. 1993; 294:45-51.
- Andersen PE Jr, Bollerslev J. Heterogeneity of autosomal dominant osteopetrosis. Radiology. 1987; 164:223-225.
- Osteopetrosis in the Fairbank Collection. J Bone Joint Surg Br. 1978; 60:53-55.
- Hasenhuttl K. Osteopetrosis, review of the literature and comparative studies on a case with a twenty four year follow up. J Bone Joint Surg Am. 1962; 44:359-370.
- Benichou OD, Laredo JD, de Vernejeoul MC. Type II autosomal dominant osteopetrosis (Albers-Schonberg disease): clinical and radiological manifestations in 42 patients. Bone. 2000; 26:87-93.
Drs Rysavy, Arun, and Wozniak are from the Deparment of Orthopedic Surgery, Hamad General Hospital, Doha, Qatar.
Correspondence should be addressed to: Martin Rysavy, MD, PhD, Dept of Orthopedic Surgery, Hamad General Hospital, PO Box 3050, Doha, Qatar.