1 Department of Pediatric Orthopaedics, Orthopaedic Hospital Speising, Vienna, Austria 2 Vienna Bone and Growth Center, Vienna, Austria 3 Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Medical University of Vienna, Vienna, Austria 4 Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
X-linked hypophosphatemia is a rare disorder of bone metabolism caused by inactivating mutations in the
PHEX. Conservative therapies such as treatment with phosphate salts or FGF23-inhibiting antibodies can
improve symptoms, the latter being superior to the healing of rickets. Recent studies show a high burden
of disease of children and adults with XLH. Orthopedic surgeons should be aware that lower limb deformity
in early childhood can present as the first symptom of XLH and should prompt further diagnostics and
treatment. Treatment needs to be coordinated with pediatric endocrinologists. The optimal and adequate
planning of orthopedic interventions seem to be key factors which may lead to a satisfactory result.
Hipofosfatemia sprzężona z chromosomem X (XLH) jest rzadkim zaburzeniem metabolizmu kości powodowanym
przez mutacje inaktywujące gen PHEX. Leczenie zachowawcze, np. leczenie solami fosforanowymi
lub przeciwciałami hamującymi FGF23, może złagodzić objawy, przy czym te ostatnie są lepsze pod
kątem leczenia krzywicy. Ostatnie badania wskazują na duże obciążenie chorobą dzieci i dorosłych z XLH.
Chirurdzy ortopedzi powinni być świadomi, że deformacja kończyn dolnych we wczesnym dzieciństwie
może być pierwszym objawem XLH i powinna skłaniać do dalszej diagnostyki i leczenia. Leczenie musi
być prowadzone we współpracy z endokrynologami dziecięcymi. Optymalne i adekwatne zaplanowanie
interwencji ortopedycznych wydaje się stanowić kluczowy czynnik, który może prowadzić do osiągnięcia
X-linked hypophosphatemia (XLH, OMIM # 307800) is a rare disorder of the bone metabolism caused by inactivating mutations in PHEX (phosphate-regulating endopeptidase homolog, X-linked). A dysregulation of the main regulator of phosphate homeostasis, fibroblast growth factor 23 (FGF23), leads to chronic renal phosphate loss and, thus, to associated skeletal changes: rickets, osteomalacia, short stature and complex leg deformities account for the most prevalent orthopedic manifestations of this disease, which should be managed in a multidisciplinary setting [1,2].
Conservative therapies, such as treatment with phosphate salts or FGF23-inhibiting antibodies, can improve the symptoms, the latter being superior to the healing of rickets [3,4].
Recent studies show a high burden of disease of children and adults with XLH [5,6]. Pain was the predominantly reported complaint affecting 80% of children and 97% of adults., 38% of children and 91% of adults reported gait abnormalities, such as a restricted range of motion, with lower limb deformity being a main factor of decreased quality of life . Therefore, physiological lower limb alignment needs to be the main treatment focus for orthopedic surgeons.
This rare bone disease gained a lot of scientific interest since the implementation of new therapeutic options a few years ago. Besides the importance of a multidisciplinary treatment setting and the need for further research, orthopedic aspects of diagnostics and treatment are described in this article.
Orthopedic aspects of XLH
Orthopedic surgeons should be aware that lower limb deformity in early childhood can present as the first symptom of XLH and should prompt further investigations.
Treatment of lower limb deformity in XLH had previously been reported , however, disease specific deformities were analyzed in detail only recently.
Various types of deformities can occur on different anatomic levels of lower limbs. Varus deformities of the hip as well as reduced femoral antetorsion were described in children with XLH [8,9]. Acetabular malorientation was recently observed in children  and adults with XLH . Additionally, varus or valgus knee deformities, reduced external tibial (and fibular) torsion as well as ankle varus deformities are frequently occurring skeletal changes [8,9]. Furthermore, femoral and tibial procurvatum deformities of different degrees exist in children and adults with XLH [8,12].
Gait deviations such as increased lateral trunk lean (“waddling gait”) have been identified as disease specific in children and adults [8,12] (Fig. 1). Gait quality is decreased in children with higher BMI and/or with lower limb deformity [8,12]. Decreased standing height may be caused by decreased growth but can also occur due to severe lower limb deformities.
In adolescence and adulthood further disease specific symptoms with a profound impairment of quality of life can occur, including gait deviations, a limited joint range of motion, multilevel enthesopathies, pseudofractures and early osteoarthritis [8,12,13]. In a recent study we observed that lower limb deformity, increased BMI and enthesopathies significantly reduce the quality of gait in adolescents and adults with XLH .
Pseudofractures are frequently seen in adults with XLH and necessitate regular radiographic follow up examinations in adulthood . The pathomechanism of these chronic changes has not been identified thus far.
In a recent survey by Javaid et al.  43 to 47% of adults with XLH reported a history of fractures. However, current research lacks differentiation between fractures and pseudofractures.
Enthesopathies have been identified as an important disease specific skeletal symptom  – up to 39% of adults with XLH reported such symptoms .
Additionally spinal deformities, such as spinal stenosis as early as young adulthood can occur . Less research is available for upper limb pathologies .
Muscle weakness and fatigue are frequently reported by patients with XLH . Even though muscle size is like healthy control groups, patients with XLH exhibit lower muscle density, lower peak muscle power and force [15,16].
Recent research describes the variety of orthopedic problems in children and adults with XLH relating to lower limb deformities and gait deviations [8-10,12] and therefore, explains the observed subjective loss of quality of life in children and adults with XLH [5,6].
Orthopedic management needs to be coordinated with pediatric endocrinologists. Regular clinical and radiological follow up examinations during the entire growth period are recommended. Furthermore, monitoring radiographic signs of enthesopathies and pseudofractures after the end of growth is advisable.
The use of long leg braces for potential guidance of growth in children with XLH lacks scientific evidence  and is not recommended anymore .
While guided growth procedures are not able to correct all deformities occurring in children with XLH, they are a potent and minimal invasive option especially for knee varus and valgus correction. However, multiple difficulties have to be faced using this method in children with XLH: the deformity recurrence rate is higher (Fig. 2), due to decreased growth potential, initial surgery has to be considered at an earlier age and the correction rate might not only be influenced by the patient’s age but also by medical treatment schemes . The first cases of children who underwent guided growth during burosumab therapy showed a relatively fast correction rate . In guided growth – from a pediatric orthopedic view – persistent rachitic changes are no contraindication for these procedures. However, the optimization of metabolic values is an important aspect of multidisciplinary treatment to obtain a successful surgical outcome with minimal complications (e.g., deformity recurrence) (Fig. 2).
Correction of maltorsion and/or deformities after the end of growth requires more invasive methods including osteotomies and several types of osteosynthesis. Acute correction can be fixed using k-wires or plates in small children, while nails are the preferred implant in adults. Gradual correction with external fixators enables a multilevel and multidimensional correction and, therefore, should be considered an adequate surgical option, specifically for XLH deformity correction (Fig. 3). Whenever osteotomies are considered treatment options, metabolic optimization should be obtained prior to surgery in an interdisciplinary preoperative setting.
Spinal deformity, such as spinal stenosis, can occur in patients with XLH. Although incidence rates are comparable to healthy control groups, these deformities present clinically at a much younger age, even as young as 18. Surgical intervention includes spinal decompression or fusion .
Enthesopathies are a burdensome skeletal symptom in patients with XLH. The pathomechanism is not well defined and surgical methods may not be the primary solution leading to desired pain reduction and the improvement of range of motion.
Another topic lacking specific definition is the treatment of pseudofractures in patients with XLH. While orthopedic management with intramedullary stabilization (Fig. 4) was the main option thus far, newer therapeutic approaches (burosumab) are promising .
Adequate limb alignment may not only reduce the patients’ reported burden of disease, but it is also crucial for successful joint replacement surgery in adults with osteoarthritis of the knee or hip. The implant survival of total knee replacement is reduced due to severe varus or valgus deformities, which also result in a higher complication rate. In severe cases, the alignment of bone deformity should be addressed prior to joint replacement to obtain a higher success rate .
Non-Orthopedic aspects / Multidisciplinary care
Patients with XLH not only present with skeletal symptoms, as this disease is also associated with whole body involvement . However, orthopedic issues primarily influence a patients’ perception of quality of life as well as gait.
A multidisciplinary treatment setting should include a neurosurgical team even though the occurrence of neurocranial symptoms is rare, they are highly relevant clinical complications in XLH. Craniosynostosis, syringomyelia and Chiari 1 malformation have been described in children with XLH. The protrusion of cerebellar tonsils was found in 25% of children with XLH .
Dental problems frequently affect young children, consisting of excessive cavities and even leading to complications requiring oral and maxillofacial surgery such as abscesses, dental root complications and implant failures .
Hearing loss, mainly sensorineural, and tinnitus may be complications associated with XLH, thus audiometric monitoring should be performed in children as well as adults [5,22].
Orthopedic management highly depends on other disciplines, mainly pediatric and adult endocrinologists/nephrologists The optimization of metabolic laboratory values as well as a preoperative reduction of BMI not only highly influence surgical outcome parameters, such as guided growth, and the management of complications, but also may influence the occurrence of pseudofractures and enthesopathies.
To improve surgical and patient related outcomes, postoperative rehabilitation is advised . Furthermore, at our center, pediatric XLH rehabilitation groups with specific multidisciplinary settings including physiotherapy, occupational therapy, underwater therapy, as well as informational sessions for parents have been implemented as standard operative procedures of XLH care for children with XLH with and without surgical intervention.
Early diagnosis, adequate medical therapy and monitoring, frequent orthopedic assessments during the entire growth period and optimal planning of orthopedic interventions seem to be key factors requiring a multidisciplinary setting. Disease specific rehabilitation programs and a well-organized transition to adult care may positively influence the lives of patients with XLH in the future. Further research on the pathomechanism of the development of lower limb deformities in XLH seems necessary.
Progressing improvements in medical treatment and gaining scientific knowledge are promising aspects in the treatment of this rare disease. The advancement of orthopedic surgical methods may lead to preventive and minimally invasive approaches in the treatment of XLH in the future. However, presently, this disease, with its severe deformities and multiple disease specific skeletal symptoms, demands a full range of orthopedic treatment including comprehensive lower limb deformity correction methods.
1. Raimann A, Mindler GT, Kocijan R, Bekes K, Zwerina J, Haeusler G, et al.: Multidisciplinary patient care in X-linked hypophosphatemic rickets: one challenge, many perspectives. Wien Med Wochenschr 1946. 2020 Apr;170(5–6):116–23.
2. Haffner D, Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, Wicart P, Bockenhauer D, Santos F, Levtchenko E, Harvengt P, Kirchhoff M, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenicky P, Rejnmark L, Linglart A: Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Consens Statement. Nat. Rev. Nephrol. 15 (2019)435–455:21.
3. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O et al.: Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. The Lancet. 2019 Jun;393(10189):2416–27.
4. Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM et al.: Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2022 Feb 17;107(3):813–24.
5. Skrinar A, Dvorak-Ewell M, Evins A, Macica C, Linglart A, Imel EA et al.: The Lifelong Impact of X-Linked Hypophosphatemia: Results From a Burden of Disease Survey. J Endocr Soc. 2019 Jul 1;3(7):1321–34.
6. Seefried L, Smyth M, Keen R, Harvengt P: Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review. Osteoporos Int. 2021 Jan;32(1):7–22.
7. Petje G, Meizer R, Radler C, Aigner N, Grill F: Deformity Correction in Children with Hereditary Hypophosphatemic Rickets. Clin Orthop. 2008;466(12):8.
8. Mindler GT, Kranzl A, Stauffer A, Haeusler G, Ganger R, Raimann A: Disease-specific gait deviations in pediatric patients with X-linked hypophosphatemia. Gait Posture. 2020 Sep;81:78–84.
9. Mindler GT, Stauffer A, Kranzl A, Penzkofer S, Ganger R, Radler C et al.: Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) – A Prospective Observational Study. Front Endocrinol. 2022 Mar 24;13:866170.
10. Bonnet-Lebrun A, Linglart A, De Tienda M, Ouchrif Y, Berkenou J, Assi A et al. : Quantitative analysis of lower limb and pelvic deformities in children with X-linked hypophosphatemic rickets. Orthop Traumatol Surg Res. 2021 Dec;103187.
11. Scorcelletti M, Kara S, Zange J, Jordan J, Semler O, Schönau E et al.: Lower limb bone geometry in adult individuals with X-linked hypophosphatemia: an observational study. Osteoporos Int [Internet]. 2022 Apr 18 [cited 2022 May 3]; Available from: https://link.springer.com/10.1007/s00198-022-06385-z
12. Mindler GT, Kranzl A, Stauffer A, Kocijan R, Ganger R, Radler C et al.: Lower Limb Deformity and Gait Deviations Among Adolescents and Adults With X-Linked Hypophosphatemia. Front Endocrinol. 2021 Sep 27;12:754084.
13. Steele A, Gonzalez R, Garbalosa JC, Steigbigel K, Grgurich T, Parisi EJ et al.: Osteoarthritis, Osteophytes, and Enthesophytes Affect Biomechanical Function in Adults With X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2020 Apr 1;105(4):e1798–814.
14. Javaid MK, Ward L, Pinedo-Villanueva R, Rylands AJ, Williams A, Insogna K et al.: Musculoskeletal Features in Adults With X-linked Hypophosphatemia: An Analysis of Clinical Trial and Survey Data. J Clin Endocrinol Metab. 2022 Feb 17;107(3):e1249–62.
15. Veilleux LN, Cheung M, Ben Amor M, Rauch F: Abnormalities in Muscle Density and Muscle Function in Hypophosphatemic Rickets. J Clin Endocrinol Metab. 2012 Aug;97(8):E1492–8.
16. Orlando G, Bubbear J, Clarke S, Keen R, Roy M, Anilkumar A et al.: Physical function and physical activity in adults with X-linked hypophosphatemia. Osteoporos Int [Internet]. 2022 Feb 5 [cited 2022 May 3]; Available from: https://link.springer.com/10.1007/s00198-022-06318-w
17. Novais E, Stevens PM: Hypophosphatemic Rickets: The Role of Hemiepiphysiodesis. J Pediatr Orthop. 2006;26(2):7.
18. Trombetti A, Al-Daghri N, Brandi ML, Cannata-Andía JB, Cavalier E, Chandran M et al.: Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia. Nat Rev Endocrinol [Internet]. 2022 Apr 28 [cited 2022 May 3]; Available from: https://www.nature.com/articles/s41574-022-00662-x
19. Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI, Cohen-Solal M et al.: Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period. Calcif Tissue Int. 2019 Sep;105(3):271–84.
20. Mills ES, Iorio L, Feinn RS, Duignan KM, Macica CM: Joint replacement in X-linked hypophosphatemia. J Orthop. 2018 Dec 21;16(1):55-60.
21. Rothenbuhler A, Fadel N, Debza Y, Bacchetta J, Diallo MT, Adamsbaum C et al.: High Incidence of Cranial Synostosis and Chiari I Malformation in Children With X‐Linked Hypophosphatemic Rickets (XLHR). J Bone Miner Res. 2019 Mar;34(3):490–6.
22. Fishman G, Miller-Hansen D, Jacobsen C, Singhal VirenderK, Alon Uri S: Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr [Internet]. 2004 Jul 28 [cited 2022 May 3]; Available from: http://link.springer.com/10.1007/s00431-004-1504-z
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