Abstract
Summary
X-linked hypophosphatemic rickets (XLH), the most prevalent form of inherited hypophosphatemic rickets, is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX). This case series presents 14 cases of XLH from Gulf Cooperation Council (GCC) countries. The patients’ medical history, biochemical and radiological investigative findings, as well as treatment responses and side effects from both conventional and burosumab therapy, are described. Cases were aged 2–40 years at diagnosis. There were two male cases and 12 female cases. All cases were treated with conventional therapy which resulted in a lack of improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients’ quality of life and adherence to treatment. In the 10 patients treated with burosumab, there was a marked improvement in the biochemical markers of rickets, with a mean increase in serum phosphate of +0.56 mmol/L and tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) of +0.39 mmol/L at 12 months compared to baseline. Furthermore, a mean decrease in serum alkaline phosphatase (ALP) of −80.80 IU/L and parathyroid hormone (PTH) of −63.61 pmol/L at 12 months compared to baseline was observed in these patients. Additionally, patients treated with burosumab reported reduced pain, muscle weakness, and fatigue as well as the ability to lead more physically active lives with no significant side effects of treatment.
Learning points
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Conventional therapy resulted in a suboptimal response, with a lack of improvement of clinical signs and symptoms.
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Side effects of conventional therapy included nausea, diarrhea, abdominal pain, nephrocalcinosis, and hyperparathyroidism, which affected the patients’ quality of life and adherence to treatment.
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Burosumab demonstrated marked improvements in the biochemical markers of rickets, in addition to reducing pain, muscle weakness, and fatigue.
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There were no significant side effects associated with burosumab therapy.
Background
X-linked hypophosphatemic rickets (XLH) is the most common form of inherited hypophosphatemic rickets (1). Based on a study in the United Kingdom, the prevalence of the disease has been estimated at 14.0 per million, 17.0 per million in the pediatric population, and 13.3 per million in the adult population (2). Furthermore, a Japanese study reported an incidence of XLH of 1 in 20 000 (3). XLH is caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homolog, X-linked (PHEX), which is expressed in osteoblasts and plays a role in the suppression of serum fibroblast growth factor 23 (FGF-23) (4, 5). Excess serum FGF-23 leads to decreased renal phosphate reabsorption and limits phosphate absorption from the gut (5). Hypophosphatemia leads to rickets and osteomalacia, which often manifest as growth failure, deformities of the lower limbs (bowing of the legs), bone pain, fractures, spontaneous dental abscesses, hearing problems, arthritis, and muscular dysfunction (2, 5, 6). Patients generally show symptoms within the first few years of life, which might also include delayed walking or a waddling gait (7, 8).
XLH poses a significant burden on patients’ lives, with lower levels of health-related quality of life, as well as social and physical functioning reported in XLH patients compared to the general population (7). According to the Rare and Undiagnosed Diseases Study, 25% of XLH patients experienced extreme or severe problems with pain, and approximately 20% had excessive or severe problems with mobility (9). A European qualitative study also reported fatigue, pain, and stiffness in XLH patients, which adversely impacted their daily activities and physical functioning (10).
A diagnosis of XLH is considered when there are clinical or radiological signs of rickets and growth impairment in children, a history of lower-limb deformities and clinical or radiological signs of osteomalacia in adults, and low serum phosphate levels associated with renal phosphate wasting in the presence of normal or slightly elevated parathyroid hormone (PTH) levels (7). A recent consensus statement on the diagnosis and management of XLH in children and adolescents in the GCC has highlighted the importance of timely and correct diagnosis of patients to enable appropriate and prompt treatment with either conventional therapy or burosumab (11).
Since the 1980s, XLH has been treated with daily oral phosphate and active vitamin D analog (alfacalcidol or calcitriol) supplementation, known as conventional therapy (7). This type of therapy, however, does not treat the underlying cause of the disease but serves only to alleviate symptoms (4). Complete healing of rickets and osteomalacia is difficult to achieve in patients treated with conventional therapy since frequent doses and the unpleasant taste of oral phosphate supplements can affect adherence. Furthermore, due to excess phosphate and calcitriol, conventional therapy can also result in hyperparathyroidism, hypercalciuria, nephrocalcinosis, and renal insufficiency.
There is a lack of consensus regarding the treatment of XLH in adults. However, conventional treatment is usually restarted or maintained to manage pain and joint stiffness, coupled with rehabilitation to provide optimal care and minimize pain for the patient (4). Surgery may also be used to treat residual leg bowing at the end of growth. Adult patients may also experience complications such as osteoarthritis, enthesopathies, and pseudo-fractures that can adversely affect their quality of life (7).
Recently, burosumab, a novel, fully human anti-FGF-23 immunoglobulin G1 monoclonal antibody that binds and inhibits FGF-23, has been approved for XLH treatment in both adult and pediatric patients (aged 6 months and older) (6, 12). Burosumab has been shown to increase renal tubular reabsorption of phosphate in children, ameliorate rickets, and limit early growth reductions associated with the disease while also demonstrating increased renal tubular reabsorption of phosphate in adults (6, 13, 14, 15, 16).
Here, we present 14 cases of XLH from across the GCC region. The objectives of this case series are to describe these cases and their experiences with conventional therapy and burosumab for the treatment of XLH, including adverse events, biochemical parameters, and impact on patients’ quality of life.
Results
Patient characteristics
A total of 14 cases of XLH from across the GCC are described, six from the Kingdom of Saudi Arabia (KSA), three from the United Arab Emirates (UAE), and five from Kuwait. XLH patients’ phenotype and genotype are shown in Table 1. Of the 14 cases, all were treated with conventional therapy of phosphate supplementation and alfacalcidol, and 10 went on to be treated with burosumab. Radiographs are shown in Appendix 1 (see the section on supplementary materials given at the end of this article).
Patient phenotype and genotype of XLH cases.
| Case | Hospital | Age at diagnosis, years | Gender | PHEX gene mutation | Medical history | Conventional therapy | Burosumab |
|---|---|---|---|---|---|---|---|
| 1 | King Abdullah Specialist Children Hospital, Riyadh, KSA | 2 | Male | Hemizygous PHEX mutation c1077del; Heterozygous CYP2R1 mutation |
Radiological signs of rickets, bowing of both lower limbs, large head, short stature, wide wrists | Yes (duration 2.4 years) | Yes |
| 2 | King Abdullah Specialist Children Hospital, Riyadh, KSA | 11.5 | Female | Heterozygous PHEX mutation c.2070+5 G>A |
Radiological signs of rickets, bowing of both lower limbs, short stature, wide wrists. Family history |
Yes (duration 9 years) | Yes |
| 3* | King Abdullah Specialist Children Hospital, Riyadh, KSA | 4 | Female | Heterozygous PHEX mutation c.1682G>A |
Radiological signs of rickets, bowing of lower limb, short stature, wide wrists. Family history |
Yes (duration 1.6 years) | Yes |
| 4* | King Abdullah Specialist Children Hospital, Riyadh, KSA | 8 | Female | Heterozygous PHEX mutation c.1682G>A |
Radiological signs of rickets, bowing of lower limb, short stature, wide wrists. Family history |
Yes (duration 1.6 years) | Yes |
| 5 | Dubai Hospital, Dubai, UAE | 5 | Female | ChrX(GRCh37):g.22245660 _22245664dup |
Genu varum deformity of both lower extremities, tooth decay (started age 3 and diagnosed with vitamin D deficiency rickets), short stature (WHO z score of −2.63; <1st percentile) and consistently low serum phosphorus levels and high serum PTH and ALP levels | Yes | No |
| 6 | King Abdulaziz Medical City, Jeddah, KSA | 8 | Female | c.203delG, p.(Ser68IIefs*3) | Persistent rickets, worsening gait abnormalities, bone pain, genu valgum, dental caries, short stature (z = −2.53; treated with growth hormone), bilateral bowing of the femur, tibia and fibula with genu valgus appearance, and signs of osteomalacia of the long bones | Yes | Yes |
| 7 | American Hospital, Dubai, UAE | 17 | Female | N/S | Height growth impairment (from 9 years, treated with growth hormone 13.6 and 15 years), previous surgical correction of bilateral valgus deformity (16 years) | Yes (since 9 years old) | No |
| 8 | King Faisal Specialist Hospital & Research Centre, Riyadh, KSA | 4 | Male | Heterozygous loss of functional variant exon14:c.1536T>G:p.Y512X | Leg bowing (previously resolved with treatment), pain during walking (20 years) and history of short stature | Yes (since puberty) | No |
| 9 | Sheikh Khalifa Medical City, Abu Dhabi, UAE | 40 | Female | N/S | Gait abnormalities (aged 3), rickets (aged 10), tooth loss and short stature (age 32), genu varum and old fractures in left tibia and fibula (undergone surgical correction), history of low serum phosphorus and 25-OH vitamin D levels, multiple echogenic foci in kidney indicative of nephrocalcinosis | Yes | No |
| 10# | Al Jahra Hospital, Kuwait | 2 | Female | Heterogenous PHEX mutation c.1586+5G>A | Short stature, bone pain, positive family history | Yes (for 3 years) | Yes |
| 11# | Al Jahra Hospital, Kuwait | 4.5 | Female | Heterogenous PHEX mutation c.1586+5G>A | Short stature, bilateral genu varum, gait abnormality, persistent hypophosphatemia, positive family history, corrective osteotomy operation | Yes (for 7 years) | Yes |
| 12# | Al Jahra Hospital, Kuwait | 2 | Female | Heterogenous PHEX mutation c.1586+5G>A | Short stature, bilateral genu varum, gait abnormality, persistent hypophosphatemia, radiological signs of rickets, positive family history | Yes (for 12 years) | Yes |
| 13# | Al Jahra Hospital, Kuwait | 3 | Female | Heterogenous PHEX mutation c.1586+5G>A | Short stature, bilateral genu varum, gait abnormality, persistent hypophosphatemia, positive family history, corrective osteotomy operation | Yes (for 13 years) | Yes |
| 14# | Al Jahra Hospital, Kuwait | 5 | Female | Heterogenous PHEX mutation c.1586+5G>A | Short stature, bilateral genu varum, gait abnormality, persistent hypophosphatemia, positive family history, multiple corrective orthopedic surgeries | Yes (for 14 years) | Yes |
*,# Siblings.
Conventional therapy
During conventional therapy, cases 1–7 and 9 reported no improvement in or worsening of the clinical signs and symptoms of rickets or biochemical parameters. Furthermore, many patients reported unpleasant side effects of conventional therapy: cases 1–4 reported nausea, abdominal pain, diarrhea, and bad taste, case 7 reported severe diarrhea which was treated with loperamide, and case 9 reported intermittent nausea. These side effects and the need for frequent dosing resulted in poor adherence in cases 1–4 and 7 and adversely affected the quality of life in cases 7 and 9.
Nephrocalcinosis was reported in two patients (cases 6 and 8). Hyperparathyroidism was reported in one patient (case 6), who was treated with cinacalcet but showed no improvement in symptoms (cinacalcet was subsequently stopped due to a hypocalcemia seizure). One patient developed a parathyroid adenoma (case 8).
Biochemical parameters measured during conventional therapy are shown in Fig. 1. Although the mean serum phosphate levels increased by +0.15 (s.d. 0.35, n = 5) at 6 months and +0.19 (s.d. 0.37, n = 5) at 12 months compared to baseline, two patients (cases 3 and 4) showed decreased phosphate levels over the 12-month time period (Fig. 1A). Mean alkaline phosphatase (ALP) levels decreased by −12.6 (s.d. 66.57, n = 5) at 6 months but increased by +21.8 (s.d. 98.44, n = 5) at 12 months compared to baseline (Fig. 1B). Mean PTH levels increased by +31.76 (s.d. 56.69, n = 5) at 6 months and by +121.77 (s.d. 234.14, n = 5) at 12 months compared to baseline (Fig. 1D).
Biochemical parameters measured during conventional and burosumab therapy. ALP, alkaline phosphatase; PTH, parathyroid hormone.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 2; 10.1530/EDM-23-0098
Recent biochemical parameters for cases who were not treated with burosumab are shown in Table 2. These cases had low phosphate and 25-hydroxy vitamin D, as well as high PTH and ALP levels, and may be considered for burosumab treatment in the future.
Biochemical testing for cases not treated with burosumab.
| Biochemical testing | Case 5 | Case 7 | Case 8 | Case 9 | |||
|---|---|---|---|---|---|---|---|
| Value | RR | Value | RR | Value | RR | ||
| Time period of testing | Recent | Recent | Recent | Recent | |||
| Age, years | 7 | 17 | 19 | 40 | |||
| Conventional therapy | On | On | Off | On | |||
| PO4, mmol/L | 0.5 | 0.74–1.19 | 0.61 | 1.1–2.0 | 0.75 | 0.54 | 0.8–1.45 |
| PTH, pmol/L | 2.59 | 1.06–5.83 | 11.9 | 0.13–4.1 | 58.3245 | 7.0 | 1.6–6.9 |
| ALP, IU/L | 393 | <300 | 235 | 50–117 | 556 | 97 | 50–150 |
| 25-OH vitamin D, nmol/L | NR | 28 | 75–250 | NR | 43.6 | 50–150 | |
ALP, alkaline phosphatase; NR, not reported; PTH, parathyroid hormone; RR, reference range.
Burosumab
In patients treated with burosumab, an increase in serum phosphate was observed (Fig. 1A). There was a mean increase of +0.33 mmol/L (s.d.0.13, n = 10) at 3 months (or 12 weeks), +0.43 mmol/L (s.d. 0.05, n = 5) at 6 months, and +0.56 mmol/L (s.d. 0.18, n = 5) at 12 months compared to baseline. Furthermore, decreased serum ALP levels were also reported in these patients (Fig. 1B). There was a mean decrease of −68.10 IU/L (s.d. 91.08, n = 10) at 3 months (or 12 weeks), −51.00 IU/L (s.d. 45.07, n = 5) at 6 months, and −80.80 IU/L (s.d. 23.61, n = 5) at 12 months compared to baseline. Improvement in the tubular maximum phosphate reabsorption (TmP) to glomerular filtration rate (GFR) ratio (TmP/GFR) was also observed (Fig. 1C), with a mean increase of +0.24 mmol/L (s.d. 0.21, n = 7) at 3 months (or 12 weeks), +0.40 mmol/L (SD 0.47, n = 9) at 6 months, and +0.39 mmol/L (s.d. 0.09, n = 2) at 12 months. Finally, a reduction in PTH levels was also reported (Fig. 1D), with a mean decrease of −36.22 pmol/L (s.d.71.94, n = 5) at 3 months, −50.26 pmol/L (s.d. 97.79, n = 5) at 6 months, and −63.61 pmol/L (s.d. 122.25, n = 5) at 12 months.
In terms of adverse events, one case (case 6) reported mild pain at the injection sites, which improved spontaneously. All other cases reported no treatment-related adverse events.
Cases 1–4 all experienced less pain and fatigue and were able to lead more physically active lives following burosumab therapy. Case 6 reported a significant reduction in bone pain, as well as an improvement in her muscle weakness and walking distance. After 6 months of burosumab treatment, cases 10–14 reported an improved overall quality of life with increased active mobility and reduced musculoskeletal pain without the need for daily pain management medication. Case 10 also reported healed rickets in the proximal tibia and lateral part of the distal femur.
Discussion
The 14 cases of XLH from the GCC region demonstrate the substantial burden of disease from childhood to adulthood, with symptoms such as bowing of the legs, dental caries, short stature, bone pain, and gait abnormalities affecting the patients’ quality of life. All of the patients had been treated with conventional therapy of daily oral phosphate supplements and active vitamin D analogs; however, they have reported unpleasant side effects such as nausea, diarrhea, and abdominal pain, and reported no improvement in rickets symptoms or even worsening of bone abnormalities. Such side effects as well as the unpleasant taste and frequent dosing of conventional therapy, have a negative impact on patient adherence and the quality of life. Nephrocalcinosis and parathyroid adenoma were also reported as side effects of conventional therapy among adult patients.
The side effects of conventional treatment have been widely reported in the literature (17). Such side effects may be controlled by continuous monitoring by multidisciplinary teams throughout treatment and adjustments in the doses of oral phosphate supplements or active vitamin D analogs as needed (18). Due to side effects, poor adherence to conventional treatment has been reported in the literature, with only 67% of children with XLH showing good levels of adherence in a study in Denmark (19). In a United States study, the mean compliance was between 77% and 96%, varying by gender and growth velocity (20). A survey-based study in the GCC region found that compliance to therapy was one of the challenges in XLH management and that conventional therapy was associated with compromised final adult height, inability to revert skeletal deformities, nephrocalcinosis, and tertiary hyperparathyroidism (21).
Ten of the fourteen cases initiated burosumab treatment. The treatment showed marked improvements in the biochemical markers of rickets, with increased serum phosphate levels, decreased serum ALP levels, improved TmP/GFR ratio, and improved PTH levels. Patients reported less pain, muscle weakness, and fatigue and led more physically active lives. No significant adverse effects were observed with burosumab therapy in these patients. An increase in PTH levels after burosumab therapy was observed in some patients with no clear explanation, but we believe that with the improvement of phosphate levels, the requirement for calcium will be greater to restore the depleted bones. Therefore, we recommend monitoring calcium and vitamin D levels and patients’ daily intake while on burosumab.
Clinical studies have demonstrated the efficacy and safety of burosumab for the treatment of XLH in children and adults (6, 13, 14, 15, 16, 22, 23, 24). The efficacy of burosumab in reducing the severity of rickets and improving biochemical markers and growth in children with XLH has been shown to be significantly greater than conventional therapy (22). Furthermore, patient-reported outcomes of pain, physical function, fatigue, physical health, and psychosocial health measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire as well as the SF-10 Health Survey for Children were improved in patients treated with burosumab (25). As such, expert recommendations, such as the British Paediatric and Adolescent Bone Group recommendations, support the use of burosumab for the treatment of XLH (26). The GCC guidelines for the diagnosis and management of XLH also recommend the use of burosumab for normalizing biochemical parameters as well as improving growth rate, quality of life, and muscular functional capacity (11).
The limitations of this study include the lack of formal assessment of quality of life during both conventional and burosumab therapy. Measures such as the 6-minute walk test and health-related quality of life could be used to better assess improvements in the quality of life of patients taking burosumab. Furthermore, the lack of standard rickets severity scores to assess for improvements in rickets is a further limitation to the study. Future research will focus on long-term monitoring of efficacy, safety, and quality of life of patients using burosumab in the region.
Conclusion
XLH poses a substantial burden on the lives of patients suffering from the condition, from childhood to adulthood. Conventional therapy remains challenging due to the persistence of symptoms and unpleasant side effects which can lead to poor adherence. Burosumab treatment improves bone health, patient symptoms, and quality of life.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EDM-23-0098.
Declaration of interest
Aljuraibah has received payment or honoraria for lectures and presentations from Kyowa Kirin. The other authors report no competing interests.
Funding
This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector. The treatment of the patients in this case series was not funded by an external source. Kyowa Kirin provided the publication fees and funded the medical writing support for the manuscript.
Patient consent
Written informed consent for publication of their clinical details and/or clinical images was obtained from either the patient or the parent of the patient.
Author contribution statement
All authors were involved in the diagnosis, treatment, and follow-up of their respective patients reported in this case series. All authors contributed toward the conception, development, data-analysis, drafting, revisions, and review and approval of the final version of the manuscript.
Acknowledgements
The authors thank Abigail Holland and Eric Mario, Connect Communications, Dubai, UAE, for their support in the preparation of the manuscript. The authors also thank the patients for their contributions.
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