Pathological fracture of the femur in Alagille syndrome that was treated with low-intensity pulsed ultrasound stimulation and an Ilizarov ring fixator: a case report
© Nozaka et al.; licensee BioMed Central Ltd. 2014
Received: 22 February 2014
Accepted: 4 July 2014
Published: 8 July 2014
Alagille syndrome is a multisystem disorder, which is characterized by hypoplasia of the intrahepatic bile ducts, malformations of the cardiovascular system, eyes, and vertebral column, and abnormal facies. Several of the characteristics of Alagille syndrome may result in an especially high risk of fracture. The majority of patients suffer from chronic cholestasis, which can have a variety of adverse effects on bone metabolism. In Alagille syndrome, fractures primarily occur in the lower limb long bones in the absence of significant trauma.
A 9-year-old Japanese girl with Alagille syndrome was admitted to our institution with marked hyperbilirubinemia and a pathological fracture of the femur. She had been diagnosed with biliary atresia at the age of 1 month and treated with surgical bile duct reconstruction, vitamins D and K, and ursodeoxycholic acid. However, her liver dysfunction and hyperbilirubinemia worsened. The pathological fracture of the femur was treated with low-intensity pulsed ultrasound stimulation (LIPUS) and an Ilizarov ring fixator. Seventy-four days after surgery, the patient had anatomically and functionally recovered. There was no leg-length discrepancy and no angular malalignment of the lower extremities as measured clinically and radiographically. The range of motion of the hip, knee, and ankle of the patient’s operative leg matched the range of motion in the nonoperative leg.
To the best of our knowledge, there are no reports on use of the Ilizarov frame and LIPUS in diaphyseal femoral fractures in Alagille syndrome. This case report provides evidence that this procedure is successful for managing such diaphyseal fractures in Alagille syndrome.
KeywordsAlagille syndrome Low-intensity pulsed ultrasound stimulation (LIPUS) Ilizarov ring fixator
Alagille syndrome is a multisystem disorder, which is characterized by hypoplasia of the intrahepatic bile ducts, malformations of the cardiovascular system, eyes, and vertebral column, and abnormal facies . Major clinical features of this syndrome include jaundice, cholestasis, and congenital heart disease with peripheral pulmonary artery stenosis. Alagille syndrome is caused by mutations in the JAGGED1 gene in the overwhelming majority of cases, and by mutations in the NOTCH2 gene in 1–2% of cases [2–4]. A genetic test was not performed in our case because the diagnosis of Alagille syndrome was already established based on the presence of distinct clinical features.
Several of the characteristics of Alagille syndrome may result in patients having an especially high risk of fracture. The majority of patients suffer from chronic cholestasis , which can have a variety of adverse effects on bone metabolism. Hyperbilirubinemia inhibits osteoblast proliferation and induces osteoporosis. Most importantly, cholestasis leads to a deficiency of intestinal bile acids. This deficiency ultimately interferes with the absorption of vitamins and minerals that are critical to bone development, including calcium, vitamin D, and vitamin K. Management of a pathological lower extremity fracture in a child with Alagille syndrome can sometimes be a challenging problem in the orthopedic field. There are few reports of pathological fractures of the femur in Alagille syndrome. Case studies have documented multiple recurrent fractures in some patients  and poor healing and/or marked post-fractural deformities in others [7, 8]. We report a case of a 9-year-old girl with marked hyperbilirubinemia from birth who presented with a pathological fracture of the femoral shaft.
Alagille syndrome is rare, occurring in 1 in 70,000 births, and affects both sexes equally . Alagille syndrome is autosomally dominant with a low penetrance and highly variable expression. The Alagille gene has been identified in the 20pl2 region. This syndrome manifests as a multisystem disorder involving the liver, heart, eyes, face, and skeleton [1, 8]. One of the manifestations of Alagille syndrome is hyperbilirubinemia caused by cholestasis secondary to a paucity of interlobular bile ducts. Patients with chronic liver disease have an increased prevalence of osteoporosis because of calcium malabsorption caused by low levels of 25-hydroxy vitamin D3 and hyperbilirubinemia. Nonetheless, the underlying mechanism causing osteoporosis secondary to hyperbilirubinemia remains unclear. Patients with primary biliary cirrhosis and osteoporosis have higher serum bilirubin levels than those without osteoporosis. A high serum bilirubin level is independently associated with increased bone loss at the femur in patients with chronic liver disease. Exposure to excessive levels of bilirubin inhibits the proliferation of osteoblasts in cell cultures. Despite these findings, studies investigating the association between bilirubin levels and osteoclast function are lacking . In the present patient, long-term hyperbilirubinemia was associated with systemic osteoporosis.
Lin et al.  reported that, in patients with Alagille syndrome, fracture lesions deteriorated despite treatment, and all of the patients eventually succumbed. Many previous reports have described the management of diaphyseal femoral fractures in normal children. However, no clear consensus has been reached on the best way to treat diaphyseal femoral fractures in normal children [10–12]. Kapukaya et al.  reported that external fixation in closed femoral shaft fractures in children could be a rational alternative mode of therapy because it has some advantages and can be easily removed without undergoing a second round of anesthesia. The rationale for this technique is immediate weight-bearing.
Many studies regarding the effects of LIPUS on bone have been reported, including an acceleration of endchondral ossification of the callus at the fracture site , an increase in aggrecan messenger RNA levels and proteoglycan synthesis in chondrocyte cultures , and modulation of transforming growth factor formation and adenylate cyclase production in osteoblasts . In addition, an increase in insulin-like growth factor in bone marrow-derived stromal cells  and an increase in prostaglandin E2 production in osteoblasts have been observed . Recently, LIPUS was used for treatment of Charcot joint and leg lengthening [19–21]. In Alagille syndrome, deficiency of intestinal bile acids ultimately interferes with the absorption of vitamin D, and failure of endochondral ossification is generally associated with the disturbance of absorption of vitamin D. However, the underlying mechanism causing delayed union in Alagille syndrome remains unclear. Therefore, we consider that LIPUS might promote enhancement of endochondral ossification in femoral shaft fracture healing in Alagille syndrome. The good clinical healing in the present case indicates that these mechanisms are induced by LIPUS, and that its effects are sufficient for healing of fractures associated with this condition.
To the best of our knowledge, no studies have reported use of the Ilizarov frame and LIPUS in diaphyseal femoral fractures in Alagille syndrome. The rationale for this technique is immediate weight-bearing, good knee and ankle motion, and a high rate of a successful union. Furthermore, the reported average time that fixators are removed is approximately 55 (range, 38–79) days . Following the original principles of the Ilizarov technique, the closed indirect reduction technique was used under image guidance, first using ligamentotaxis to compress the fracture ends . Obtaining perfect reduction and absolute compression of the fracture ends were not difficult. Fracture healing occurred by secondary intention and callus formation. We did not experience wire cut through, especially in the presence of pin-tract infection. The early union in this case, despite having Alagille syndrome, might be attributed to the initial closed reduction. Early ambulation and immediate weight-bearing may improve limb circulation and enhance the healing process, based on the fact that the speed of fracture healing is usually proportional to the amount of available circulation to and between the fragments . One of the most important advantages of using this technique is the excellent recorded knee and ankle range of motion within a short time from frame removal. Active and passive movements of both joints were allowed and encouraged along the entire course of treatment immediately after application of the frame. Additionally, no physiotherapy sessions were needed to regain normal full activity. The main disadvantages of this procedure are that it is technically demanding, the need for imaging, its relatively high expense, depression may occur in some patients, and the absolute necessity of adequate care of the frame. From our point of view, immediate weight-bearing and the fact that the patient could go back to school were adequate justification for this procedure. Furthermore, a reduction in hospital stay and time needed for physiotherapy are also important considerations.
This case report provides satisfactory evidence that LIPUS and an Ilizarov ring fixator are successful for managing diaphyseal fractures in Alagille syndrome. Some reports have described that although internal fixation is better tolerated by patients with lower morbidity and better (although delayed) mobility, it is associated with some complications, such as delayed weight-bearing, implant failure, need for further surgery, and less mobility in the knee and ankle. Although technically demanding, the procedure reported here is a reliable and efficient method of treating simple femoral shaft fractures in Alagille syndrome because it resulted in adequate healing time, immediate ambulation and weight-bearing, excellent ankle and knee motion, and no complications. Based on the final clinical and radiographic outcomes, this technique proved to be adequate for managing a simple diaphyseal femoral fracture in Alagille syndrome. LIPUS treatment is an effective, non-invasive adjuvant method to enhance callus maturation in fracture healing. Using this treatment, the healing time and duration of external fixation can be reliably shortened.
Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
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