Share this article on:

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets

Sharkey, Melinda S. MD; Grunseich, Karl BA; Carpenter, Thomas O. MD

JAAOS - Journal of the American Academy of Orthopaedic Surgeons: July 2015 - Volume 23 - Issue 7 - p 433–442
doi: 10.5435/JAAOS-D-14-00082
Review Article

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible.

From the Yale Department of Orthopaedics and Rehabilitation (Dr. Sharkey), the Yale School of Medicine (Mr. Grunseich), and the Yale Department of Pediatrics and Endocrinology (Dr. Carpenter), New Haven, CT.

Dr. Carpenter or an immediate family member has received royalties from Alfa Aesar; serves as a paid consultant to Alexion, Alfa Aesar, Merck, and UltraGenyx; and has received research or institutional support from Merck, and UltraGenyx. Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Sharkey and Mr. Grunseich.

X-linked hypophosphatemic rickets is the most common form of heritable rickets. Its incidence is estimated at 1 in 20,000 live births.1 X-linked hypophosphatemia (XLH) is inherited in an X-linked dominant fashion (Figure 1) and usually manifests in early childhood with prominent bowing of the legs, short stature, and medial tibial torsion. On radiographs, the distal femur and the proximal tibial physes are vertically widened and irregular, as is typical of rachitic bone disease (Figure 2). Progression of the disease may result in the development of progressive bone deformity, dental abscesses, enthesopathy, arthritis, and severe osteomalacia. Renal calcification may occur with therapy. Because of its presentation and relative rarity, XLH may be initially misdiagnosed as physiologic bowing or vitamin D–deficiency rickets. However, in a family with a short parent and other manifestations of the disease, XLH should be considered.

Figure 1

Figure 1

Figure 2

Figure 2

Back to Top | Article Outline

Etiology

XLH is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, which is expressed in osteocytes. Mutations in PHEX lead to an increase in the fibroblast growth factor 23 (FGF23) protein through a mechanism that is not well understood. At the kidney, FGF23 decreases the production of proteins involved in renal phosphate reabsorption and 1,25-OH vitamin D production. The increase in FGF23 leads to the phosphate-wasting characteristic of XLH. The aberration in phosphate availability to the skeleton contributes to a decrease in the mineralization of the long bones and teeth in patients with XLH. Early intervention with medical management improves outcomes but fails to completely heal the mineralization defect2-4 (Figure 2). Mutations in PHEX may also modify the regulation of mineralization at the osteocyte through a related family of proteins that may further contribute to the mineralization defect. Increased FGF23 is also tied to the related autosomal dominant and recessive forms of hypophosphatemic rickets and to tumor-induced osteomalacia.5

Back to Top | Article Outline

Laboratory Evaluation

XLH is primarily a disease of renal phosphate wasting. Initial laboratory studies typically include findings of hypophosphatemia and mildly elevated serum alkaline phosphatase activity, but levels of serum calcium and 25-OH vitamin D are normal.6 In this disease, the levels of 1,25-OH vitamin D are low or inappropriately normal given the degree of hypophosphatemia usually present. The parathyroid hormone level is usually normal at presentation when calcium levels are normal.

Back to Top | Article Outline

Clinical Evaluation

Children generally present with bowed legs, medial tibial torsion, and short stature. Radiographs of the knee should be obtained to determine the extent of initial bony pathology and to rule out other causes for short stature, such as skeletal dysplasias and physiologic bowing.7 With these findings, the diagnosis is usually confirmed by documenting excessive phosphaturia.7

Back to Top | Article Outline

Medical Treatment of the Child

Although newer treatment strategies for XLH that target either the deficiencies of PHEX or the aberrations in FGF23 are under development,8 the current mainstay of treatment relies on a balance of phosphate and vitamin D supplementation. Medical treatment should begin with diagnosis in childhood and continue through adolescence until growth has ceased. Except in the mildest cases, therapy is continued through adulthood. Adequate medical treatment has been shown to alleviate bowing, improve attained height, and reduce the need for corrective surgery.1,6,7,9 Linear growth response to medical therapy is variable, however, and some groups seem to respond better than others.1 Early diagnosis and medical intervention are associated with better outcomes.10 In 2011, Carpenter et al7 suggested starting at a 20- to 30-ng/kg dose of calcitriol split among two to three daily doses, as well as administration of 20 to 40 mg/kg of elemental phosphorus split among three to five daily doses. The use of multiple daily doses of medication is important because steady serum levels of phosphate and vitamin D are optimal for bone mineralization; this dosing schedule also reduces the gastrointestinal side effects of phosphate supplementation.

It should be emphasized that treatment should be adjusted based on therapeutic outcomes rather than the correction of serum phosphate levels. Records of height velocity, reduction of skeletal deformity, and evidence of physeal healing on radiographs should guide medical management, in conjunction with laboratory monitoring to avoid complications of treatment. A common complication of treatment is secondary hyperparathyroidism that may occur even when phosphate levels are in the normal range. Other complications include hypercalciuria, hypercalcemia, and nephrocalcinosis. Laboratory monitoring is recommended every 3 months; studies should include serum parathyroid hormone, phosphate, calcium, and creatinine levels, as well as urinary calcium and creatinine levels. Alkaline phosphatase levels (ie, either total serum or bone specific) can serve as a marker of skeletal response to treatment shown by a decrease in value; however, increases may occur acutely after the initial application of therapy. Aberrations in these values can be used in conjunction with the gauged response to adjust the dosage of therapy.

It is suggested that renal ultrasonography be conducted every 2 to 5 years to detect nephrocalcinosis. Radiographs of the knee are recommended at the initiation of therapy, followed by repeat radiographs after several months to gauge the response to treatment at the growth plate; radiographs should then be obtained every 1 to 2 years to evaluate any therapeutic change at the epiphyses or disease progression.

Back to Top | Article Outline

Medical Treatment of the Adult

When patients reach adulthood, treatment is strongly suggested in symptomatic patients who often have bone pain, insufficiency fractures, and poor bone healing. Outcomes should be measured by clinical response, and patients should be monitored to confirm appropriate dosing and to avoid toxicity. Medical treatment of adults undergoing orthopaedic surgery may reduce the time required for healing, as well as reduce the risk of prosthetic joint loosening.11 Suggested dosages in adults are 0.5 to 0.75 µg/d of calcitriol split into two doses and 750 to 1,000 mg/d of phosphorus split among three to four doses. Treatment of dental disease, enthesopathy, arthritis, and calcification of spinous ligaments is not effective with this therapy.

Back to Top | Article Outline

Micropathology and Macropathology of Bone Deformity in X-linked Hypophosphatemia

Histologic changes in the bone of persons with XLH rickets demonstrate abnormalities of endochondral ossification. This is particularly apparent at the physes at the zone of provisional calcification, where the cartilage matrix shows inadequate calcification. Uncalcified islands of cartilage are seen deep in the metaphysis. Throughout the skeleton, there is inadequate mineralization to appropriately serve as a scaffold for the deposition of osteoid, resulting in the accumulation of undermineralized bone matrix or osteomalacia.12

These histologic changes may manifest clinically as bone deformity of the lower extremities, including genu varum, genu valgum, and windswept deformities. XLH-associated bone deformities are often long, curved deformities that involve the entire bone. As described by Paley and Tetsworth,13 these deformities are multiapical, with multiple or even infinite apices of deformity or centers of rotation of angulation because the deformities occur through the bending and deformation of soft bone. Bone deformity in XLH may be considerable, consisting of large, decompensated deviations from the normal mechanical axis of the lower extremities in both the coronal and lateral planes (Figure 3). To treat these multiapical bone deformities, surgery generally involves multiple osteotomies to recreate a normal anatomic and mechanical axis.

Figure 3

Figure 3

Back to Top | Article Outline

History of the Surgical Treatment of Rickets

The history of the modern surgical treatment of rachitic bone manifests as a timeline of the evolution of surgery for bony deformity. In the late 1800s and early 1900s, surgeons promoted improved nutrition and sunlight, as well as bracing, for largely nutritional rachitic bone deformities.14-16 In more severe deformities, osteoclasis, or manually breaking the bone at the apex of the deformity, was used for correction of bone deformities in children.14-16 The broken bone was then casted in a more anatomic position until it healed.

In 1937, Albright et al17 first described vitamin D-resistant rickets, now known as X-linked hypophosphatemic rickets. Therapy consisted of massive, often toxic levels of vitamin D. In the 1950s and 1960s, several orthopaedic centers published their experiences in treating patients with X-linked hypophosphatemic rickets,12,18-20 and note was made of the variable severity of the disease. Bracing and high doses of vitamin D were used in an attempt to prevent and control bone deformity. When deformities were severe, osteotomies were performed and the bones were generally held in an improved position in plaster as they healed. Significant vitamin D toxicity with resulting hypercalcemia was noted in many patients, especially if the therapy was continued when the patients were immobilized in casts.

After the advent of antibiotics, fairly radical open surgical procedures increased in popularity. Although described and practiced by some clinicians before the widespread availability of antibiotics,14 in the 1950s, Sofield and Millar21 popularized extensive subperiosteal surgical exposures of deformed bones and performance of multiple osteotomies, followed by realignment of the bone pieces in a straightened configuration over a metal rod that was placed back within the metaphyses. In 1959, the clinicians published their 10-year experience with the technique, used largely for severe deformities related to osteogenesis imperfecta, but it was also used for pathologies, including resistant rickets.

A variety of techniques for treating complex bony deformities have since been advocated, including acute correction and fixation of osteotomies with Kirschner wires, plates, external fixators, and intramedullary nails. Additionally, use of the Ilizarov external fixator and, more recently, unilateral fixators and the Taylor Spatial Frame, have been advocated for gradual deformity correction after osteotomy, with or without concomitant bone lengthening.

Of particular importance, Paley and Tetsworth13 described a standardized method of evaluating complex multiapical deformities, as well as precise surgical planning of their correction. These methods have become the standard for how multiapical deformity correction is conceptualized and osteotomies are planned. Another important advancement has been the reintroduction and refinement of low-energy, percutaneous, tissue-respecting osteotomies.22,23

Back to Top | Article Outline

Natural History of Bone Deformity in X-linked Hypophosphatemia

Very little has been written on the natural history of bone deformity in XLH in the presence or absence of appropriate medical treatment. Large, controlled trials of adults with osteoarthritis have shown that varus or valgus alignment of the knee is a risk factor for the development and/or progression of osteoarthritis.24-30 The malalignment of the patients in the osteoarthritis studies is generally much less severe than that often seen in patients with XLH.

Some of the best information we have on the natural history of bone deformity in XLH comes from the case series presented in the 1950s and 1960s.12,19,20 Because these were uncontrolled studies, the patients likely represent the more severe phenotypes of XLH. Pedersen and McCarroll20 noted that adult patients were very short-statured and had severe waddling gaits caused by coxa vara. The adults often noted easy fatigability and frequently had pain in the lower back, hips, and knees. The authors also noted that bone deformity could progress or recur after skeletal maturity, and severe deformities were associated with ligamentous laxity at the knee and severe degenerative changes at the hip and knee.

The lack of knowledge regarding the natural history of bone deformity in XLH makes the treatment of young children particularly difficult. It is not known what degree of bony deformity at a given age may resolve with appropriate medical treatment. In 1988, Rubinovitch et al31 stated “mild deformities less than 15 degrees frequently correct spontaneously with good metabolic control.” However, we are not aware of any studies confirming this statement.

It is also unclear why some children demonstrate progressive bony deformity despite the use of appropriate medical therapy. Even siblings, who presumably possess the same genotype and have fairly similar medication compliance, can display widely varying phenotypes.

Back to Top | Article Outline

Surgical Treatment of Children with X-linked Hypophosphatemia

Perhaps because of the relative rarity of the disease, no standardized treatment protocols or agreed-upon surgical indications exist for children with XLH with bony deformity. Generally, XLH in children is treated primarily nonsurgically; surgery is considered only after nonsurgical medical management has been unsuccessful. Children with progressive bony deformities that result in significant gait disturbance, activity limitation, and pain are considered for surgical intervention. Long standing alignment radiographs in both AP (ie, patella facing forward and between the femoral condyles) and lateral planes are obtained to assess and plan for correction of bony deformity. To prevent vitamin D toxicity after surgery, we generally administer half doses of vitamin D and phosphate for 1 week and then increase to full dosing as long as the patient is able to mobilize.

In the surgical literature on the treatment of children with XLH, reports describe small groups of patients treated by a variety of different methods. Indications for surgery generally are not specifically described, and specific medication regimens are not noted. The follow-up has been relatively short, and assessment of the accuracy of deformity correction is often absent. Reported complications are variable in number and severity. However, most authors support the surgical treatment of significant bony deformities in children with XLH (Figure 4) because the presumed natural history of severe deformity is progressive gait disturbance, functional impairment, and severe arthritis.

Figure 4

Figure 4

In 1980, Evans et al32 reported on treating 10 affected children and adolescents with 33 surgical procedures. Of the 10 patients, the authors contrasted the 3 patients who were not properly diagnosed or not treated until later in life (ie, at ages 10, 17, and 19 years) with the 7 patients who were diagnosed and medically treated early in life. Of the 33 surgical procedures performed, 27 of them involved the three patients diagnosed late. The three patients had multiple complications, and their heights remained well below the third percentile, emphasizing the importance of timely medical treatment to decrease the need for surgical intervention and to maximize growth potential.

Rubinovitch et al31 further emphasized the importance of appropriate medical therapy for improved surgical outcomes. The authors reported on 10 skeletally immature patients with severe deformities who underwent 44 closing wedge osteotomies of the lower limb secured with staples and casting or plating and casting. They found a 27% rate of recurrence of deformity at a mean of 25 months after surgery and correlated these failures with the lack of medical control of the underlying bone disease.

In 1994, Stanitski33 first reported on the use of the Ilizarov technique for the treatment of deformities associated specifically with XLH. Treatment involved 18 limb segments in 8 patients with metabolic bone disease; 5 of the patients had XLH. Total time in the external fixator averaged just 12 weeks, and the only reported complications were pin tract infections and mild translational deformities in two patients. Emphasis was placed on the slow correction of deformity with incremental opening of osteotomies at a rate no faster than 0.5 mm daily; follow-up was only 1 year.

Kanel and Price34 reported on a series of nine children with XLH; most underwent low-energy, acute, corrective osteotomies and fixation, and all were treated with a unilateral external fixator. The only notable complication was the development of compartment syndrome in one patient, necessitating fasciotomy. The authors promoted this method because neither weight bearing nor motion needed to be restricted after surgery; thus, there was no need to interrupt medication treatment. Length of follow-up, accuracy of deformity correction, and functional results were not noted.

In 2002, Choi et al35 reported on using the Ilizarov technique for the treatment of 12 skeletally immature and 2 skeletally mature patients with XLH. Most of the treated bone segments underwent both deformity correction and lengthening. All but two of the patients maintained their alignment over time (ie, average follow-up was 5 years). Healing rates of the lengthened bone segments were correlated with serum phosphate levels. The authors found a significant relationship between bone regeneration healing rates and serum phosphate levels and concluded that lengthening should not be undertaken if serum phosphate levels were <2.5 mg/dL. However, there was no indication that the outcomes of lengthening in the patients with lower serum phosphate levels were inferior to the outcomes in those with higher serum phosphate levels.

Novais and Stevens36 and Stevens and Klatt37 promoted the use of the minimally invasive technique of guided growth for the treatment of bone deformity in patients younger than 10 years with XLH. The authors theorized that the early application of guided growth principles to correct the mechanical axis allows for more normal growth and functioning of the physes by shielding them from excessive concentrations of force seen in the presence of deformity. In a small series of patients with XLH, the authors reported that the physes can spontaneously improve in appearance as the mechanical axis normalizes. They also theorized that early correction and maintenance of a normal mechanical axis may prevent deformity at the diaphysis. Specific criteria for initiating guided growth treatment in this patient population have not been described and may be difficult to establish until the natural history of mild to moderate bony deformity early in childhood is better understood.

In 2008, Fucentese et al38 and Petje et al39 reported on 8 and 10 surgically treated children, respectively. Fucentese et al38 reported attainment of a normal mechanical axis in six of eight patients; the other two patients had mild varus alignment. Surgical techniques included osteotomies with Kirschner wire or plate fixation, as well as bone lengthening with deformity correction. Two patients required repeat corrective osteotomies. Petje et al39 used a variety of fixation devices for osteotomy stabilization, including Kirschner wires, external fixators, Ilizarov frames, Taylor Spatial Frames, and intramedullary nails. The authors performed a total of 98 osteotomies and found a deformity recurrence rate of 90% over a period of 5 to 12 months after the surgery. They also found that external fixator correction was associated with a uniform deformity recurrence at the metaphysis and diaphysis, and intramedullary nail fixation was associated with metaphyseal recurrence. Despite these findings, the authors still perform corrective procedures at an early stage of deformity but plan on two or three reoperations throughout growth.

In 2006, Song et al40 reported on surgeries in 18 bone segments in 9 children and 37 bone segments in 11 adults with XLH. Twenty-eight of the bone segments underwent deformity correction and lengthening and 27 of the bone segments underwent deformity correction alone. The clinicians used a wide variety of methods for both groups, including external fixation alone, external fixation followed by nailing, combined external fixation and nailing, as well as nailing alone. Some nails were solid, but most were flexible. Given the wide variety of methods, it is difficult to draw any firm conclusions about treatment superiority. In general, though, the group that underwent deformity correction and bone lengthening had many more major complications (ie, recurrent deformity and refracture) than did the group that underwent deformity correction alone. Even in children, the clinicians recommend intramedullary nailing in conjunction with or after treatment with an external fixator.

Back to Top | Article Outline

The Surgical Treatment of Adults With X-linked Hypophosphatemia

Similar to reports on children, reports of surgical treatment of bone deformity in skeletally mature adults with XLH include small numbers of patients with no control groups. Again, the importance of medical management with vitamin D and phosphate is stressed to optimize surgical outcomes and to prevent complications, such as nonunion and recurrent deformity. In general, the few articles specific to surgical treatment in adults with XLH promote intramedullary fixation after realignment osteotomies to span the entire bone; this method withstands long healing times and prevents recurrence of deformity in the long-term.40-43 Perioperative medication management is the same as that for children; the doses of vitamin D and phosphate are halved for 1 week and then increased to full dosing as long as the patient is able to mobilize. For surgical planning, preoperative assessment includes long standing lower extremity AP radiographs (ie, with the patella perfectly positioned between the femoral condyles) and lateral radiographs.

A fixator-assisted nailing technique (FAN) has been described and studied for skeletally mature patients with XLH.41,43,44 FAN for XLH is a tissue-respecting version of the Sofield osteotomy technique and is based on the described techniques of femoral and tibial deformity correction with intramedullary nails and femoral lengthening over an intramedullary nail.45 FAN is a technically demanding technique and has a steep learning curve. Careful preoperative planning and exacting intraoperative technique are important for successful realignment of the mechanical axis because, unlike the use of external fixators, no postoperative adjustments are possible.

In the operating room, percutaneous, low-energy osteotomies are made to anatomically realign the femoral and/or tibial intramedullary canal to allow for placement of an intramedullary nail. Prior to performing osteotomies, external fixator screws are placed proximal and distal to the osteotomy levels, parallel to the joint lines and out of the path of the intramedullary nail. After performing osteotomies, the anatomic axis is corrected and held in place by attaching the fixator pins to a bar. When intraoperative radiographs confirm correction of the mechanical axis of the bone, an intramedullary nail is introduced, often in combination with blocking screws, to narrow the intramedullary canal in the metaphyseal region and to prevent recurrence of deformity. An important point emphasized by Paley46 is that the intramedullary nail must start and end in the bone in the correct locations (ie, centrally) or the deformity will be either overcorrected or undercorrected. Once the nail is locked proximally and distally, the fixator is removed (Figures 5 and 6).

Figure 5

Figure 5

Figure 6

Figure 6

Eralp et al41 compared FAN with circular external fixator treatment of bone deformities. No difference was found in the accuracy of deformity correction. The authors felt that FAN was more acceptable to patients and that the retained intramedullary nail may protect against recurrent deformity.

Kocaoglu et al43 reported on 15 patients with XLH and 2 patients with renal osteodystrophy who underwent FAN. The study involved a total of 43 bone segments with a mean deformity of 28.7°. In six femurs, lengthening was performed along with deformity correction. Mean follow-up was 5 years. The authors reported very good accuracy in restoration of the mechanical axis and very good or good clinical and functional results according to the Paley classification system.45 The complication rate was low compared with prior studies, and no recurrence of deformity was reported.

Back to Top | Article Outline

Total Joint Arthroplasty in X-linked Hypophosphatemia

To our knowledge, only one article has been written on arthroplasty specifically in XLH patients. Larson et al47 reported on eight hip and six knee arthroplasties done between 1972 and 2006. Because of bone deformity, two patients who underwent hip arthroplasty required realignment osteotomy at the time of the arthroplasty, and one patient undergoing knee arthroplasty required postoperative osteotomies. Special implants were needed for three hips and one knee. At 7-year follow-up, hip and knee functional scores were improved.

Back to Top | Article Outline

Summary

X-linked hypophosphatemic rickets is the most common heritable form of rickets. The degree of bone deformity and related disability is quite variable between persons. Despite medical management, progressive bone deformities develop in some children. Surgical treatment of these deformities can be done before or after skeletal maturity, although growth plate–respecting surgery is necessary in the presence of open growth plates. In younger children, milder deformities may correct with guided-growth treatment. Skeletally mature persons may benefit from the placement of intramedullary rods for osteotomy fixation because the rods can span bone and provide long-term support.

Back to Top | Article Outline

References

Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 8 is a level I study. References 3-7, 11, 13, 24-26, 29, and 30 are level II studies. References 1, 2, 9, 10, 17, 22, 27, 28, 41, and 45 are level III studies. References 12, 15, 16, 18-21, 23, 31-40, 42-44, and 47 are level IV studies. Reference 14 is level V expert opinion.

References printed in bold type are those published within the past 5 years.

1. Petersen DJ, Boniface AM, Schranck FW, Rupich RC, Whyte MP: X-linked hypophosphatemic rickets: A study (with literature review) of linear growth response to calcitriol and phosphate therapy. J Bone Miner Res 1992;7(6):583–597.
2. Marie PJ, Glorieux FH: Bone histomorphometry in asymptomatic adults with hereditary hypophosphatemic vitamin D-resistant osteomalacia. Metab Bone Dis Relat Res 1982;4(4):249–253.
3. Marie PJ, Glorieux FH: Stimulation of cortical bone mineralization and remodeling by phosphate and 1,25-dihydroxyvitamin D in vitamin D-resistant rickets. Metab Bone Dis Relat Res 1981;3(3):159–164.
    4. Cheung M, Roschger P, Klaushofer K, et al.: Cortical and trabecular bone density in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2013;98(5):E954–E961.
      5. Carpenter TO: The expanding family of hypophosphatemic syndromes. J Bone Miner Metab 2012;30(1):1–9.
      6. Carpenter TO: New perspectives on the biology and treatment of X-linked hypophosphatemic rickets. Pediatr Clin North Am 1997;44(2):443–466.
      7. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL: A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 2011;26(7):1381–1388.
      8. Aono Y, Yamazaki Y, Yasutake J, et al.: Therapeutic effects of anti-FGF23 antibodies in hypophosphatemic rickets/osteomalacia. J Bone Miner Res 2009;24(11):1879–1888.
      9. Tsuru N, Chan JC, Chinchilli VM: Renal hypophosphatemic rickets: Growth and mineral metabolism after treatment with calcitriol (1,25-dihydroxyvitamin D3) and phosphate supplementation. Am J Dis Child 1987;141(1):108–110.
        10. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E: Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 2003;88(8):3591–3597.
        11. Sullivan W, Carpenter T, Glorieux F, Travers R, Insogna K: A prospective trial of phosphate and 1,25-dihydroxyvitamin D3 therapy in symptomatic adults with X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 1992;75(3):879–885.
        12. Pierce DS, Wallace WM, Herndon CH: Long-term treatment of vitamin-D resistant rickets. J Bone Joint Surg Am 1964;46:978–997.
        13. Paley D, Tetsworth K: Mechanical axis deviation of the lower limbs: Preoperative planning of multiapical frontal plane angular and bowing deformities of the femur and tibia. Clin Orthop Relat Res 1992;280:65–71.
        14. Giles RC: Rickets: The surgical treatment of the chronic deformities: With emphasis on bow-legs and knock-knees. J Natl Med Assoc 1922;14(1):9–11.
        15. Blanchard W: Osteoclasis and osteotomy: Annual Session of the American Medical Association, Section on Orthopedic Surgery. JAMA 1916;LXVII(7):504–508.
          16. Taylor HL: The Surgery of Rickets: Fifty-third Annual Meeting of the American Medical Association JAMA 1902;XXXIX(15):901–903.
            17. Albright FB, Butler AM, Bloomberg E: Rickets resistant to vitamin D therapy. Am J Dis Child 1937;54(3):529–547.
            18. Stickler GB, Hayles AB, Rosevear JW: Familial hypophosphatemic vitamin D resistant rickets: Effect of increased oral calcium and phosphorus intake without high doses of vitamin D. Am J Dis Child 1965;110(6):664–667.
              19. Tapia J, Stearns G, Ponseti IV: Vitamin-D resistant rickets: A long-term clinical study of 11 patients. J Bone Joint Surg Am 1964;46:935–958.
                20. Pedersen HE, McCarroll HR: Vitamin-resistant rickets. J Bone Joint Surg Am 1951;33(1):203–220.
                21. Sofield HA, Millar EA: Fragmentation, realignment, and intramedullary rod fixation of deformities of the long bones in children: A 10-year appraisal. J Bone Joint Surg Am 1959;41(8):1371–1391.
                22. Behrens FF, Sabharwal S: Deformity correction and reconstructive procedures using percutaneous techniques. Clin Orthop Relat Res 2000;375:133–139.
                23. Yasui N, Nakase T, Kawabata H, Shibata T, Helland P, Ochi T: A technique of percutaneous multidrilling osteotomy for limb lengthening and deformity correction. J Orthop Sci 2000;5(2):104–107.
                  24. Brouwer GM, van Tol AW, Bergink AP, et al.: Association between valgus and varus alignment and the development and progression of radiographic osteoarthritis of the knee. Arthritis Rheum 2007;56(4):1204–1211.
                  25. Cerejo R, Dunlop DD, Cahue S, Channin D, Song J, Sharma L: The influence of alignment on risk of knee osteoarthritis progression according to baseline stage of disease. Arthritis Rheum 2002;46(10):2632–2636.
                    26. Felson DT, Niu J, Gross KD, et al.: Valgus malalignment is a risk factor for lateral knee osteoarthritis incidence and progression: Findings from the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative. Arthritis Rheum 2013;65(2):355–362.
                      27. Khan FA, Koff MF, Noiseux NO, et al.: Effect of local alignment on compartmental patterns of knee osteoarthritis. J Bone Joint Surg Am 2008;90(9):1961–1969.
                        28. Sharma L: The role of varus and valgus alignment in knee osteoarthritis. Arthritis Rheum 2007;56(4):1044–1047.
                          29. Sharma L, Chmiel JS, Almagor O, et al.: The role of varus and valgus alignment in the initial development of knee cartilage damage by MRI: The MOST study. Ann Rheum Dis 2013;72(2):235–240.
                            30. Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD: The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286(2):188–195.
                              31. Rubinovitch M, Said SE, Glorieux FH, Cruess RL, Rogala E: Principles and results of corrective lower limb osteotomies for patients with vitamin D-resistant hypophosphatemic rickets. Clin Orthop Relat Res 1988;237:264–270.
                              32. Evans GA, Arulanantham K, Gage JR: Primary hypophosphatemic rickets: Effect of oral phosphate and vitamin D on growth and surgical treatment. J Bone Joint Surg Am 1980;62(7):1130–1138.
                              33. Stanitski DF: Treatment of deformity secondary to metabolic bone disease with the Ilizarov technique. Clin Orthop Relat Res 1994;301:38–41.
                              34. Kanel JS, Price CT: Unilateral external fixation for corrective osteotomies in patients with hypophosphatemic rickets. J Pediatr Orthop 1995;15(2):232–235.
                              35. Choi IH, Kim JK, Chung CY, et al.: Deformity correction of knee and leg lengthening by Ilizarov method in hypophosphatemic rickets: Outcomes and significance of serum phosphate level. J Pediatr Orthop 2002;22(5):626–631.
                              36. Novais E, Stevens PM: Hypophosphatemic rickets: The role of hemiepiphysiodesis. J Pediatr Orthop 2006;26(2):238–244.
                              37. Stevens PM, Klatt JB: Guided growth for pathological physes: Radiographic improvement during realignment. J Pediatr Orthop 2008;28(6):632–639.
                              38. Fucentese SF, Neuhaus TJ, Ramseier LE, Ulrich Exner G: Metabolic and orthopedic management of X-linked vitamin D-resistant hypophosphatemic rickets. J Child Orthop 2008;2(4):285–291.
                              39. Petje G, Meizer R, Radler C, Aigner N, Grill F: Deformity correction in children with hereditary hypophosphatemic rickets. Clin Orthop Relat Res 2008;466(12):3078–3085.
                              40. Song HR, Soma Raju VV, Kumar S, et al.: Deformity correction by external fixation and/or intramedullary nailing in hypophosphatemic rickets. Acta Orthop 2006;77(2):307–314.
                              41. Eralp L, Kocaoglu M, Toker B, Balcı HI, Awad A: Comparison of fixator-assisted nailing versus circular external fixator for bone realignment of lower extremity angular deformities in rickets disease. Arch Orthop Trauma Surg 2011;131(5):581–589.
                              42. Eyres KS, Brown J, Douglas DL: Osteotomy and intramedullary nailing for the correction of progressive deformity in vitamin D-resistant hypophosphataemic rickets. J R Coll Surg Edinb 1993;38(1):50–54.
                                43. Kocaoglu M, Bilen FE, Sen C, Eralp L, Balci HI: Combined technique for the correction of lower-limb deformities resulting from metabolic bone disease. J Bone Joint Surg Br 2011;93(1):52–56.
                                44. Kocaoglu M, Eralp L, Bilen FE, Balci HI: Fixator-assisted acute femoral deformity correction and consecutive lengthening over an intramedullary nail. J Bone Joint Surg Am 2009;91(1):152–159.
                                  45. Paley D, Herzenberg JE, Paremain G, Bhave A: Femoral lengthening over an intramedullary nail: A matched-case comparison with Ilizarov femoral lengthening. J Bone Joint Surg Am 1997;79(10):1464–1480.
                                  46. Paley D: Principles of Deformity Correction. Springer, 2005.
                                  47. Larson AN, Trousdale RT, Pagnano MW, Hanssen AD, Lewallen DG, Sanchez-Sotelo J: Hip and knee arthroplasty in hypophosphatemic rickets. J Arthroplasty 2010;25(7):1099–1103.
                                  © 2015 by American Academy of Orthopaedic Surgeons