X-linked Hypophosphatemic Rickets: Awareness, Knowledge, and Practice of Pediatric Endocrinologists in Arab Countries

Abstract

X-linked hypophosphatemic rickets (XLHR) is a genetic disease caused by inactivating pathogenic variants in PHEX , which results in reduced mineralization of bone, teeth, and renal phosphate wasting. XLHR is traditionally treated by phosphate and vitamin D analogs. Recently, burosumab, a recombinant anti-fibroblast growth factor-23 (FGF-23) monoclonal antibody was approved as specific XLHR therapy. We aimed to assess the awareness, knowledge, and management of XLHR among members of the Arab Society for Pediatric Endocrinology and Diabetes (ASPED). Of the 97 physicians who answered the online questionnaire, 97% were aware of XLHR, and while 90% screen family members of the index case, only 29% manage children with XLHR. In children with rickets, 40% of participants measure serum/urine phosphate routinely, and 31% request serum FGF-23 in suspected XLHR cases. Almost all responders use conventional XLHR therapy, and 4% used Burosomab. Only 14% were satisfied with the conventional treatment, and 69% reported therapeutic complications in up to 25% of their patients. Multidisciplinary care for XLHR is practiced by 94%, but 82% of providers did not have transition clinics. Pediatric endocrinologists in ASPED countries are aware of XLHR but have variable practice and are unsatisfied with its conventional treatment. Raising awareness of the recognition and modern management of XLHR is needed.

Introduction

X-linked hypophosphatemic rickets (XLHR) is a genetic disease caused by inactivating pathogenic variants in the PHEX gene. The mutations lead to increased synthesis and secretion of fibroblast growth factor-23 (FGF-23) which impairs the proximal renal phosphate reabsorption and decreases 1α-hydroxylation of 25-OH vitamin D. ¹ Most patients with XLHR present with rickets, lower limb deformities, and impaired growth. Other reported features include recurrent dental abscesses, craniosynostosis, osteoarthritis, enthesopathy, and spinal stenosis. ^{2 3} The biochemical picture includes hypophosphatemia, excessive renal phosphate wasting, high alkaline phosphatase (ALP), and a low 1,25(OH)2 vitamin D. ² The conventional XLHR therapy is a combination of oral phosphate salts and vitamin D analogs. ⁴ However, recently, a recombinant human immunoglobulin G1 monoclonal antibody targeting FGF-23, burosumab has been approved as a specific therapy for XLHR with promising short-term results. ⁵

In the Arab countries, nutritional rickets is still prevalent, ^{6 7 8} raising the possibility that rare forms of rickets, such as XLHR, may be misdiagnosed as nutritional rickets. This may lead to inappropriate treatment, which could aggravate skeletal deformities making it a challenge to rectify with late treatment. Given the high rate of consanguinity in the region, ^{9 10} nutritional and inherited forms of rickets may coexist. Indeed, there are reports from the region of patients with XLHR, and other forms of inherited rickets, misdiagnosed as nutritional rickets. ^{11 12 13} Recently, late diagnosis of XLHR was reported among three generations of the same family despite severe skeletal deformities since childhood. ¹⁴

This survey was conducted by the Arab Society for Pediatric Endocrinology and Diabetes (ASPED) to assess awareness, knowledge, and practice of its members on certain aspects of rickets with more focus on XLHR as an example of a genetic form of rickets that needs a specific treatment that is currently approved for its treatment.

Materials and Methods

Study Design

A cross-sectional electronic survey was conducted between September and December 2019 using commercial software (SurveyMonkey, United States). An invitation e-mail was sent to the members of the ASPED. The original e-mail was followed by two reminders, explaining the study rationale and method with a link to the questionnaire was sent to all ASPED members ( Appendix ). The voluntary nature of contribution, the unconditional right to decline participation and opting out from the database, and the strict confidentiality of participant details were all confirmed. Data were collected anonymously, and the questionnaire text was in English, as it is the scientific language used by ASPED members. Formal ethical approval was not deemed necessary for such a quality assurance type of survey.

The Survey

A comprehensive literature search on the study area was undertaken by coauthors. A survey is drawn based on the search and final version of questionnaire was approved by all coauthors and was peer reviewed for validation. Survey is uploaded in ASPED SurveyMonkey account and a survey link is created. The survey is structured under seven items. Each item has specific questions, mostly in the format of multiple choice but free text is offered for some open questions. The survey items were designed to cover participants' profile and various areas related to the awareness, knowledge, diagnosis, and management of rickets with more focus on XLHR ( Table 1 ).

Table 1. Summary of main XLHR survey categories.

Items of the survey
1.	Profile of participants (pediatrics or adults, years of experience, country of practice, and type of institution)
2.	Profile of rickets patients seen in participants' clinics (number of rickets patients, type of rickets, and patient presentation)
3.	Awareness of XLH and FGF-23-related diseases (multiple choice question on an XLH case scenario)
4.	Practice on rickets investigations
5.	Management of hypophosphatemic rickets (views on adequacy of conventional treatment of XLHR)
6.	Patient journey, follow-up, monitoring, and transition to adult care
7.	Physicians views on patients concern over their disease

Abbreviations: FGF, fibroblast growth factor; XLHR, X-linked hypophosphatemic rickets.

Results

Profile of Participants

An invitation e-mail for participation was sent to 340 members of the ASPED. In total, 97 physicians participated in the survey (80% practice in university teaching hospitals). Of those, 70% are based in the Gulf region and the rest practicing in North African (Egypt, Morocco, Libya, Algeria) or the Levant countries (Lebanon, Iraq, Jordan, Palestine). The majority (93%) were pediatric endocrinologists (78% consultant, 21% middle grade specialists, and an endocrine fellow), with 86% having more than 5 years' experience in pediatric endocrinology. Three participants declared that they manage both pediatric and adult patients, and four were adult endocrinologists.

Characterization of Patients Seen in Clinics

All respondents have patients with rickets in their clinics, and the number varied from 2 to more than 1,000 patients. Of the 97 physicians, 22% have more than 50 patients with rickets in their clinics; 13% of participants answered that around 84% of their patients have nutritional rickets. Delayed walking was the most common presentation of patients diagnosed with rickets followed by lower limb deformity and waddling gait.

Awareness of XLHR and FGF23-Mediated Rickets

Almost all (97%) participants indicated that they are familiar with XLHR, and 80% are aware of conditions mediated by excess FGF-23. However, only 29% of responders managed at least one case of XLHR, while four physicians had 10 to 35 XLHR patients in their clinics. These four physicians practice in large tertiary centers in the Kingdom of Saudi Arabia and Oman. Of the 68 participants who answered the case scenario quiz on a typical XLHR case, 87% suspected that the child has hypophosphatemic rickets. Of those, 40% selected the diagnosis of XLHR ( Fig. 1 ).

Fig. 1.

Answer of respondents on the classical XLHR case scenario quiz. The Y -axis shows the number of respondents. The X -axis shows the five options of answers to the case scenario. XLHR, X-linked hypophosphatemic rickets.

Practice Approach to Rickets Evaluation

When investigating a child with rickets, more than half of participants (57%) check serum calcium, ALP, phosphorus, 25(OH) vitamin D, and plasma parathyroid hormone (PTH). However, 60% of participants do not routinely check urine phosphate. When XLHR is suspected, majority check urinary phosphate creatinine ratio, 54% measure 1,25(OH)2D, and 31% request plasma FGF-23. Following the diagnosis of XLHR index case, 90% would screen family members for the condition.

Management of Hypophosphatemic Rickets

Most participants (72%) thought that more than 75% of their patients would respond to treatment with phosphate and active form of vitamin D. The reasons for lack of response were multiple with the highest choice related to poor compliance with medications. Other suggested reasons were incorrect diagnosis of rickets subtype, malabsorption, poor compliance, renal disease, and lack of access to regular treatment. More than half (56%) of participants would conduct further biochemical investigations if their patients were unresponsive to initial treatment. Others would refer patients to other specialties, explore family history, request further imaging, or reinvestigate compliance and 6% would request genetic testing. For XLHR treatment, four participants used burosumab, four used growth hormone, and five cinacalcet. One-third of participants indicated that they refer ∼25% of their patients on conventional treatment for surgery.

Views on Adequacy of Conventional Treatment for XLHR

When asked about adequacy of conventional treatment for XLHR, only 14% replied that conventional treatment is adequate, while 29% indicated that it is not adequate, and 57% thought it is adequate to some extent. The commonest suggested reasons for inadequacy of conventional treatment were: reduced final height, inability to revert skeletal deformities, poor compliance, and associated nephrocalcinosis. Other reasons were poor palatability of phosphate, ineffective bone mineralization, lack of accessibility to medications. Two-thirds of participants reported complications in their patients while on conventional treatment, with the most frequent complication being nephrocalcinosis followed by gastrointestinal side effects and hyperparathyroidism.

Patient Journey: Source of Referral, Team Management, Follow-up, Monitoring, and Transition

Multidisciplinary Management of XLHR and Source of Referral

The primary source of referral was orthopaedic surgeons in 40% of respondents, followed by direct self-/family referral, dentist, nephrologist, geneticist, neurosurgeon, and ophthalmologist ( Fig. 2 ). Multidisciplinary team approach is practiced by 94% of respondents. Various combinations of available team member specialties were chosen. These included orthopaedic surgeons, geneticists, dentists, nephrologists, neurosurgeons, ophthalmologists, physiotherapists, and audiologists with the top 2 specialties being orthopaedic surgeons and nephrologists.

Fig. 2.

Primary source of referral. The Y -axis shows the percentage of primary source of referral, while the X -axis shows the various options of referral source.

Monitoring, Follow-up, and Transition Care

Follow-up visit frequency varied from monthly to yearly with 88% of participants monitor their patients every 3 months. Choices of tests/assessment were given to rank in order of frequency of performance. Out of a list of quality of life, serum phosphate, calcium, ALP, PTH, 6-minute walk test, renal ultrasound, leg bowing, and dental assessment, 72% ranked PTH, quality of life, and serum phosphate as the top 3 frequent tests done for monitoring.

Transfer to Adult Care

Age of transfer to adult care varied from 13 to older than 18 years; however, 31% of participants would refer their patients to adult service at 16 years, while 82% managed the transition to adult care by direct referral and 12% had a system of joint pediatric and adult clinic resulting in planned transition, while 6% do not practice a specific model for transition.

Physicians' Views on Patients' Disease Concerns

The physicians' views on the patients' concern were particularly related to the short stature and skeletal deformities. These were expressed by 43% of participants. Other concerns were pain, social isolation and bullying, restricted mobility and physical function, fatigue, and poor muscle strength.

Discussion

In this study, we surveyed the awareness, knowledge, and practice of pediatric endocrinologists in Arab countries on some aspects of rickets with specific focus on XLHR. Most of our respondents were qualified pediatric endocrinologist practicing in more than 10 countries and thus providing a wide view from the region. A significant proportion of respondents have more than 50 patients of rickets in their clinics. This highlights the high prevalence of rickets in the region and supports previous reports which indicated that nutritional rickets is the most prevalent type of rickets. ^{6 15 16 17 18 19} However, due to the lack of disease registry, neither the diagnostic details of patients in this survey, we are unable to estimate the prevalence of different forms of rickets in the region. Differentiating nutritional rickets from XLHR has major clinical implications. For example, phosphate replacement is a cornerstone in the conventional management of XLHR. However, it is inappropriate choice for nutritional rickets and other types of calcipenic rickets ²⁰ as it may lead to acute hyperphosphatemia that chelates calcium and further worsens hypocalcemia and hyperparathyroidism. Furthermore, it might induce rapid skeletal mineralization and result in hungry bone syndrome which further worsens hypocalcemia. ²¹

XLHR is the commonest form of inherited rickets. ²² Although less than one-third of our responders have patients with the condition in their clinics, almost all of them are aware of XLHR, and it is reassuring that the majority of them suspected hypophosphatemic rickets as the likely diagnosis in the survey's case scenario. In this survey, most participants used the combination of serum phosphate, ALP, vitamin D [25(OH)D and 1,25(OH)2D], and PTH levels to confirm the diagnosis of XLHR. However, it is surprising that some of them do not measure urinary phosphate excretion even when hypophosphatemic rickets is suspected. Considering that majority of the participants are qualified endocrinologists, we assume the reasons could be related to lack of availability of the test or insurance restrictions. As the participants come from a wide geographical area, financial constrains can be obstacles in some countries compared with others.

It is important to alert physicians looking after children with rickets to the importance of calculating renal phosphate handling particularly in the presence of normal serum calcium or normal/low PTH levels. ²³ Despite the fact that 80% of responders are aware of skeletal conditions associated with high FGF-23, only 31% of them would request it in suspected XLHR. This is expected as FGF-23 assay is not readily available in all clinical facilities and being a specialized test, it requires knowledge of interpretation of its normal reference range. It is worth mentioning that a recent consensus guideline of XLHR management recommended the measurement of serum FGF-23 if genetic testing is not available or if there is no family history of the condition. ²³

Most respondents would treat XLHR with a combination of oral phosphate and active vitamin D supplements. In these patients, calcium intake from the diet should meet the daily requirement, and therefore, calcium supplement should not be prescribed as part of XLHR management. Calcium supplement in XLHR aggravates nephrocalcinosis which is a well-known complication of conventional XLHR therapy. However, these patients could have been treated with calcium by general pediatricians or primary health care physicians prior to the presentation to endocrinologists and confirming the diagnosis of XLHR.

Our respondents indicated that they see nephrocalcinosis in around 25% of patients. This percentage is lower than 52.2% reported by Colares Neto et al. ²⁴ Nevertheless, our data were obtained through a survey without a structured data collection and that nephrocalcinosis is often seen following long-term phosphate and vitamin D therapy, ²⁵ whereas the majority of our respondents were treating pediatric patients. Hyperparathyroidism is frequently seen with conventional therapy and PTH levels are known to fluctuate with the treatment. Interestingly, five responders reported using cinacalcet, which suggest that their patients had persistent hyperparathyroidism. Cinacalcet should be used with caution in pediatric age group since sudden death and prolonged QT interval have been reported. ²⁶ Growth hormone therapy has been used by four respondents but is not recommended in the recent clinical practice guideline of XLHR management. ²³

The majority of respondents believe that conventional therapy is not adequate for XLHR management. Reasons behind inadequacy of conventional treatment included poor compliance related to multiple doses, gastrointestinal side effects and unfavored palatability, reduced final height, persistence of skeletal deformities, and appearance of nephrocalcinosis as a complication.

The commonest suggested reasons for inadequacy of conventional treatment were: reduced final height, inability to revert skeletal deformities, poor compliance, and associated nephrocalcinosis. Other reasons were poor palatability of phosphate, ineffective bone mineralization, and lack of accessibility to medications. Two-thirds of participants reported complications in their patients while on conventional treatment, with the most frequent complication being nephrocalcinosis followed by gastrointestinal side effects and hyperparathyroidism.

Four respondents switched their patients to burosumab. Burosumab is a fully human monoclonal antibody recently approved for XLHR management by Food and Drug Administration and European Medicines Agency in children with promising short-term results. ^{5 27} Although burosumab provides better compliance as it is given twice a month and it may alter prognosis, its limited use by our responders may be related to the cost, availability, and lack of long-term experience and safety profile with such a new medication. Current recommendation supports the monitoring of XLHR patients every 3 months initially and then every 6 months, once the symptoms and signs of the patients are stable. ²³ Interestingly, most respondents would monitor phosphate regularly; however, during the conventional therapy, phosphate level should not be monitored and the phosphate dose should not be adjusted based on the phosphate level unless the patient is receiving burosumab. The dose of phosphate and active vitamin D should be adjusted according to the PTH and ALP levels. ^{2 23}

Orthopaedic surgeons and direct family physicians were the primary source of patient's referral followed by dentists, nephrologists, and geneticists. A multidisciplinary team approach is recommended in XLHR management ^{23 28} as the condition affects various systems and patients would benefit if other specialties were actively involved in their care. It is reassuring that the majority of the ASPED physicians practice this approach with good collaboration with orthopaedic surgeons, geneticists, dentist, nephrologist, audiologist, neurosurgeons, and ophthalmologist. There are limited data on the management of transition in XLHR and a general recommendation for the transition process has been published. ²⁹ Our survey showed lack of well-established transition care for children with XLHR in Arab countries as most of respondents managed the transition to adult care through direct referral. We noticed a variation in the age of transfer to adult service between different centers with some patients refereed as early as 13 years and others remained under pediatricians until 18 years of age. The early transition to adult service might result in underestimation of complications seen by pediatricians. The variation of the age of transition is expected in a survey of physicians practicing in countries with different policies on the cutoff age for pediatric age group. The transition of care from pediatric to adult care should be planned earlier, and for optimal care, patients should be seen in a combined pediatric and adult transition clinic. These clinics are joint clinics run simultaneously by pediatric and adult physicians and serve to gradually introduce the patient to the new team for smoother transfer. Almost half of our participants reported that the biggest concern for patients with XLHR is short stature and skeletal deformities; however, physicians' opinion can be subjective, thus patients' questionnaire including quality of life is needed to address this issue.

Our study has some limitations. First, it is a survey rather than real assessment of practice. Second, the number of responders is relatively small. We plan to include adult physicians in future work in XLHR considering the nature and chronicity of the disease. Involving adult physician will enhance current knowledge and practice in the management of patients with XLHR. Despite the limitations, the survey provides an overview of the awareness, recognition, and care of XLHR in the Arab region and highlights some gaps in the knowledge and management of this genetic condition which can be used in developing educational curriculum for physicians involved in XLHR care.

Conclusion

Pediatric endocrinologists in ASPED countries are aware of XLHR but have variable practice and are unsatisfied with its conventional treatment. Raising awareness of the recognition and modern management of XLHR is needed. Progress from survey to focus groups and culminating in consensus development are the two key steps needed to improve the current care of individuals with XLHR.