Raquitismo hipofosfatémico ligado al cromosoma X en Colombia: reporte de caso

X-linked hypophosphatemic rickets in Colombia: case report

Introducción. El raquitismo hipofosfatémico ligado al cromosoma X es una enfermedad rara (1.7-4.8 casos por cada 100 000 habitantes) caracterizada por una inadecuada mineralización ósea debido a una alteración genética del metabolismo del fósforo.

Presentación del caso. Niña de 2 años y 6 meses quien fue llevada al servicio de ortopedia de un hospital de cuarto nivel de atención en Bucaramanga (Colombia) por marcha inestable, cojera y dolor en el pie derecho. En el examen físico se documentó lo siguiente: genu varo bilateral de 10°, limitación para la abducción extrema de caderas, clinodactilia bilateral en quinto dedo de los pies, pie plano bilateral, peso de 11kg y talla de 79cm (menor al percentil 3 de las curvas de crecimiento del CDC). Los exámenes de laboratorio mostraron hipofosfatemia, fosfatasa alcalina elevada e hiperfosfaturia, por lo que se sospechó raquitismo hipofosfatémico. La paciente recibió tratamiento convencional con sales de ortofosfato y calcitriol, observándose fluctuaciones en su estado de salud con periodos de remisión de los síntomas y periodos de reagudización, así como aumento de la deformidad corporal. A los 5 años de edad, mediante análisis genético, se confirmó diagnóstico de raquitismo hipofosfatémico dominante ligado al cromosoma X, con variante patogénica c.1158G>A heterocigota en el gen PHEX. A los 9 años 8 meses de edad, se inició tratamiento con Burosumab, logrando una mejora de los síntomas y de la velocidad de crecimiento. La paciente continúa asistiendo a controles periódicos.

Conclusión. La experiencia del presente caso demuestra que la suplementación con calcitriol y sales de ortofosfato puede ser una opción de tratamiento adecuada de la XHL siempre que haya una buena adherencia. Sin embargo, el tratamiento con burosumab mostró una mayor efectividad, con una mejoría notable solo seis meses después de su implementación y con una apropiada adherencia.

Introduction: X-linked hypophosphatemic rickets is a rare disease (1.7-4.8 cases per 100 000 population) characterized by inadequate bone mineralization due to a genetic alteration of phosphorus metabolism.

Case presentation: A girl aged 2 years and 6 months was taken to the orthopedic service of a tertiary care hospital in Bucaramanga (Colombia) due to gait disturbances, limping, and pain in the right foot. Physical examination revealed bilateral genu varum of 10°, limitation of extreme hip abduction, bilateral clinodactyly in the fifth toe, bilateral flat feet, weight of 11 kg, and height of 79 cm (less than the percentile 3 in the CDC height-for-age growth charts). Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, and hyperphosphaturia, suggesting hypophosphatemic rickets. The patient received conventional treatment with orthophosphate salts and calcitriol, noting fluctuations in her condition with periods of symptom remission and periods of exacerbation, as well as increased body deformity. At 5 years of age, genetic analysis confirmed the diagnosis of X-linked dominant hypophosphatemic rickets, with pathogenic variant c.1158G>A heterozygous in the PHEX gene. At 9 years 8 months of age, treatment with burosumab was started, achieving an improvement of symptoms and growth velocity. The patient continues to attend periodic check-ups.

Conclusion: This case demonstrates that supplementation with calcitriol and orthophosphate salts can be a suitable treatment option for XHL provided there is good adherence. However, treatment with burosumab showed greater effectiveness, with remarkable improvement only six months after its implementation and with appropriate adherence.

case report

Víctor Mendoza-Rojas1 Andrea Paola Reyes-Mateus2 Sara Angarita-Diaz2

1 Universidad Industrial de Santander - Faculty of Health - School of Medicine - Department of Pediatrics - Bucaramanga - Colombia.

2 Universidad Industrial de Santander - Faculty of Health - School of Medicine - Medical Program - Bucaramanga - Colombia.

Open access

Received: 31/06/2025

Accepted: 25/11/2025

Corresponding author: Andrea Paola Reyes-Mateus. Programa de Medicina, Escuela de Medicina, Facultad de Salud, Universidad Industrial de Santander. Bucaramanga. Colombia. E-mail:
andrea2200062@correo.uis.edu.co.

Keywords: Familial Hypophosphatemic Rickets; Calcitriol; Fibroblast Growth Factors; PHEX Phosphate Regulating Neutral Endopeptidase; Case Reports (MeSH).

Palabras clave: Raquitismo Hipofosfatémico Familiar; Calcitriol; Factores de Crecimiento de Fibroblastos; Endopeptidasa Neutra Reguladora de Fosfato PHEX; Informes de Casos (DeCS).

How to cite: Mendoza-Rojas V, Reyes-Mateus AP, Angarita-Diaz S. X-linked hypophosphatemic rickets in Colombia: case report. Rev. Fac. Med. 2025;73:e119610. English. doi: https://doi.org/10.15446/revfacmed.v73.119610.

Cómo citar: Mendoza-Rojas V, Reyes-Mateus AP, Angarita-Diaz S. [Raquitismo hipofosfatémico ligado al cromosoma X en Colombia: reporte de caso]. Rev. Fac. Med. 2025;73:e119610. English. doi: https://doi.org/10.15446/revfacmed.v73.119610.

Copyright: ©2025 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, as long as the original author and source are credited.

Abstract

Resumen

Introduction

X-linked hypophosphatemic (XLH) rickets is a rare disease, with an incidence of 3.9 cases per 100 000 live births and a prevalence ranging from 1.7 to 4.8 cases per 100 000 people.1 XLH is the most common cause of hereditary phosphate loss1 and is caused by a mutation of the phosphate regulatory endopeptidase (PHEX) gene located at the Xp22.11 locus, which inhibits fibroblast growth factor (FGF23).2 This disease results in impaired apoptosis of hypertrophic chondrocytes and delayed mineralization of long bone growth plates.3

Hypophosphatemic rickets (HR) commonly occurs since early childhood.3,4 Children with this condition present stunted growth, skeletal alterations of the lower limbs,
increased joint volume, and craniofacial malformations. They may also have delayed motor development, gait disturbances, bone pain, myopathy, and hypotonia.3,4 Dental abscesses are also common in patients with XLH.3 In adults, chronic hypophosphatemia causes osteomalacia with musculoskeletal weakness and pain (mainly in the lower extremities). Bone pain may accompany insufficiency fractures or pseudofractures, and these patients may also suffer from fatigue, enthesopathy, osteoarthritis, and dental disease.3,4

According to clinical practice guidelines for the management of XLH, the diagnosis is based on the presence of clinical signs of rickets and/or osteomalacia, together with hypophosphatemia and renal phosphate loss when vitamin D or calcium are not deficient. Moreover, whenever possible, it is recommended to confirm the diagnosis by molecular genetic analysis or measurement of FGF23 levels.1,5,6

Conventional treatment for XLH includes phosphate supplementation (doses of 20-60 mg/kg elemental phosphorus 3-5 times per day, with most patients benefiting from supplementation with vitamin D analogues, e.g. calcitriol (doses of 0.02-0.03 μg/kg/day).5,6 Recently, the use of burosumab, a human monoclonal IgG antibody neutralizing FGF23, has demonstrated good results in adults and children (doses of 0.4-0.8 mg/kg every 2-4 weeks).7 Early initiation of treatment allows maintaining adequate linear growth in most patients, improving final height in adulthood, correcting lower limb deformities and, therefore, reducing the number of corrective surgeries required.6

The following is the case report of a 2-year-old girl who was diagnosed with XLH, which describes her clinical and therapeutic follow-up until the age of 10 years, in order to strengthen the evidence on the treatment of this rare condition in the country and the region.

Case presentation

A girl aged 2 years and 6 months was taken to the outpatient orthopedics department of a tertiary care hospital in Bucaramanga (Colombia) due to gait disturbance, limping, and pain in the right foot. The patient was born at 40 weeks gestation, with birth weight and height of 3 320 g and 50 cm, respectively, and hip dysplasia, which did not improve after completing treatment with a Milgram splint. Regarding family history, the following was reported: mean parental height of 168.6 cm (75-90th percentile of the CDC growth charts) and four relatives with musculoskeletal deformities (flat feet, genu valgum, and bilateral internal tibial torsion); there was no reported consanguinity, although the parents originated from the same geographic region.

The initial physical examination revealed bilateral genu varum of 10° (Figure 1) with full mobility of the knees; limitation of extreme abduction of the hips, without alteration of internal rotation; bilateral clinodactyly in the fifth toe; bilateral flat feet; weight of 11 kg (percentile 3 in the CDC weight-for-age growth charts), and height of 79 cm (less than percentile 3 in the CDC height-for-age growth charts). X-rays of the lower limbs and spine were requested, indicating bilateral coxa vara, bilateral genu varum, and postural lumbar scoliosis (Figure 2).

Figure 1. Photograph of the patient taken during the first assessment by the orthopedic service. Bilateral genu varum is observed, with an increase in the base of support.

Figure 2. X-ray of the right lower limb. Alteration of the usual morphology of the bone is observed due to metaphyseal splaying and cupping, bone demineralization, and champagne glass deformation of the femoral head epiphysis.

At 2 years and 11 months of age, in the presence of hypophosphatemia (2.2 mg/dL) without calcium deficiency or abnormal creatinine levels (Table 1), she was referred to the nephrology service, where further laboratory tests were requested. These tests were taken when the patient was 3 years and 1 month old, showing persistent hypophosphatemia, elevated alkaline phosphatase (ALP) (2364 U/L), vitamin D insufficiency (26.7 ng/mL), and hyperphosphaturia.

Considering the foregoing, a medical board for bone dysplasia was requested to evaluate the case, which took place when the patient was 3 years and 5 months old and included experts from the pediatric endocrinology, genetics, and radiology services. At that meeting, the patient was diagnosed with HR, and it was suggested that a molecular test should be performed to identify the subtype of the disease (which was authorized and performed 24 months later by the patient’s health insurance company). Additionally, it was indicated to start calcitriol (0.25 mcg/day).

Table 1. Laboratory tests performed while treating the patient.

Patient’s age	2y 11m*	3y 1m	3y 11m	4y 2m	5y 3m	5y 7m	7y 3m	9y 8m	10y 4m	10y 8m	Reference values
Serum inorganic phosphorus (mg/dL)	2.2	2.8	3.5	4.4	2.47	5.3	2.4	3.2	4.84	3.82	3m-5y: 4.5-6.5mg/dL 6a-12y: 3.6-6.8 mg/dL
Alkaline phosphatase (U/L)	-	2 364	1 446	1 554	-	-	-	1 243	674.6	-	<645 U/L
25-hydroxy vitamin D (ng/mL)	33.1	26.7	-	37.3	-	51.4	32.7	31.4	34.2	23.20	Insufficiency: 10-30 ng/mL. Sufficient: 30-100 ng/mL)
Serum calcium (mg/dL)	-	-	12.5	7.3	9.7	-	9.03	9.4	10.4	-	8.6-10.2 mg/dL
Ionized calcium (mmol/L)	1.15	-	-	-	-	-	-	-		1.35	1.10-1.30 mmol/L
Parathormone (pg/mL)	22.3	-	-	6.12	46.98	-	26.9	-	41	27.10	14.5-128 pg/mL
Serum creatinine (mg/dL) GFR (mL/min/1.73 m2) †	0.31 GFR: 114.57	0.36 GFR: 100.96	-	0.4 GFR: 103.25	-	-	-	-	0.4 GFR: 103.25	-	4-7 years: 0.3-0.5 mg/dL 8-10 years: 0.6-0.8 mg/dL
Calcium/creatinine ratio (mg/mg)	-	-	-	0.02	0.011	<0.1	-	-	<0.1	-	<0.2 mg/mg
Urine phosphorus level (mg/kg/24h)	-	72	-	38	12.06 139.26‡	-	62.1‡	-	23.4	71.92	12(±4.6) mg/kg/24h
Spot urine calcium level (mg/dL)	-	-	-	-	0.8	0.31	-	-	-	-	<0.35 mg/dL

y: years; m: months; GFR: glomerular filtration rate.

* First results of the diagnostic study.

† Calculated using the modified Schwartz formula (2009).

‡ In spot urine sample (mg/dL).

At 3 years and 8 months of age, the patient was evaluated by specialists from the pediatric endocrinology department, who reported the following findings: growth rate of
12.4 cm/year, height of 94 cm (10-25th percentile of the CDC height-for-age growth charts), weight of 16.3 kg (50-75th percentile of the CDC weight-for-age growth charts), wingspan of 100, cm, upper segment/lower segment ratio of 1.38 cm (Table 2), and persistence of bilateral genu varum. Normal dentition was also observed.

Table 2. Anthropometric data during patient treatment.

Patient’s age	2y 6m	3y 8m	3y 11m	4y 3m	4y 11m	5y 3m	5y 7m	8y 11m	10 y
Height (cm)	79	94	96	100	103	104	106	127	137
Growth rate (cm/year)	-	12.8	-	10.3	7	-	6	6.3	-
Weight (kg)	11	16.3	17.1	18.5	18.8	20.8	21	36.7	34.6
Head circumference (cm)	-	50	-	-	50.5	51	-	-	54
US/LS ratio (cm)	-	1.38	-	-	-	1.12	-	-	-
Wingspan (cm)	-	100	-	-	-	115	-	-	-

y: years; m: months; US/LS: upper segment/lower segment.

In this evaluation, it was indicated to continue treatment with calcitriol (0.25 mcg/day) and to initiate orthophosphate salts (40 mg/kg every 8 hours). However, it should be noted that the administration of calcitriol was delayed until 3 years and 6 months of age (one month after its initial formulation) and the administration of the salts was delayed until 4 years and 2 months of age due to difficulties with the delivery of these drugs by the health insurance company. The patient’s mother was instructed to continue taking her to periodic follow-ups (every 4 months) with the pediatric endocrinology service to evaluate adherence and response to treatment.

Follow-up at 3 years and 11 months of age showed improvement in height and weight (Figure 3) and a decrease in bilateral genu varum and coxa vara. Nevertheless, according to the mother, the child presented pain when walking. Moreover, although the ALP level decreased (1 446 U/L) compared to the levels found at 3 years and 1 month, it was still much higher than the reference value and even increased again at 4 years and 2 months (1 554 U/L) (Table 1). A similar behavior was observed in the serum inorganic phosphorus level, because even though it increased at 3 years 11 months with respect to the last
check-up, it was still below the reference value. However, unlike ALP, it increased at
4 years and 2 months of age to a level very close to the reference value and then showed a fluctuation between normal levels (5 years 7 months and 10 years) and low levels
(5 years 3 months and 7 years) (Table 1).

Regarding calcium levels, follow-up laboratory tests at 3 years and 11 months of age showed hypercalcemia, so the pediatric nephrology service discontinued calcitriol administration. In addition, based on the follow-up laboratory results at 4 years and 2 months (Table 2), administration of calcium carbonate (30 mg/kg every 8 hours) was started. Finally, at 4 years and 6 months, nephrocalcinosis was ruled out via renal ultrasound.

Figure 3. Growth chart while treating the patient.

At 4 years and 2 months of age, clinical improvement of coxa vara, genu varum (given by the observable decrease in the intermalleolar distance), and gait pattern was observed, as well as pain-free gait. A decrease in parathyroid hormone (PTH) levels (6.12 pg/mL) was also observed. Given the presence of associated hypocalcemia (7.3 mg/dL), calcium carbonate supplementation was maintained. Calcitriol administration (0.25 mcg/day) was also reinitiated at this follow-up appointment.

In turn, the pediatric nephrology service requested renal function tests, all with normal results: serum creatinine: 0.4 mg/dL, glomerular filtration rate: 103.25 mL/min/1.73m2, creatinine in spot urine: 105.95 mg/dL, urea nitrogen: 10 mg/dL, and calcium/creatinine ratio: 0.02. However, hyperphosphaturia was identified (38 mg/kg/24h), which persisted in follow-ups at 5, 7, and 10 years of age (Table 1).

At 5 years and 5 months of age, based on the results of molecular genetic analysis, she was diagnosed with X-linked dominant HR (MIM#307800), with pathogenic variant c.1158G>A (p.W386*) heterozygous in the PHEX gene. Given the persistence of hyperphosphaturia (tubular reabsorption of phosphate [TRP] rate: 77.3%), the case was taken to a new medical board one month after the diagnosis, where it was recommended to start treatment with burosumab. However, due to difficulties with the authorization of the drug by the health insurance company, this was only possible until the child was 9 years and 8 months old.

Since phosphaturia normalized (TRP: 86.3%), the girl was not taken for further endocrinology check-ups for a period of almost four years, but she continued to be followed up by the pediatric service. Then, at the age of 8 years and 6 months, she was taken by her mother to the orthopedic service of the hospital, stating that she presented pain when walking (mainly in the right foot and knee) and that the deformity in the lower limbs (genu varum in the right limb and valgus in the left limb) had worsened. The mother also reported interruptions in treatment with orthophosphates during this period due to administrative difficulties with her health care provider.

At 9 years and 8 months of age, after the discontinuation of calcitriol and orthophosphate salts one week earlier, treatment with burosumab (0.5 mg/kg/dose every 2 weeks) was initiated. Follow-up laboratory tests showed hypophosphatemia, elevated ALP, and persistent phosphaturia (Table 1).

Six months after initiating burosumab treatment, an improvement in serum phosphorus and ALP levels was observed, as well as a normal calcium/creatinine ratio and normal vitamin D levels. On physical examination, the following findings were documented:
no progression of lower limb deformity, decrease in pain, and improvement in height and weight; however, phosphaturia persisted (23.4 mg/kg/24h). The mother also reported that the child had undergone endodontic treatment.

At the last follow-up appointment, at the time of writing this case report (10 years
8 months), blood phosphorus, ionized calcium, and PTH levels were normal (Table 1), but the urine phosphorus level continued to increase (71.92 mg/kg/24h). Also, 25-hydroxy vitamin D deficiency was identified (23.20 ng/mL), so supplementation with calcitriol (0.25 mcg/day) was again indicated. The patient continues to attend periodic check-ups.

Discussion

The most common clinical manifestations and laboratory findings of XLH are hypophosphatemia, decreased in 1,25-dihydroxyvitamin D, cranial and limb (especially leg) deformities, pain on walking, abnormal gait pattern, disproportionately short stature for age, decreased growth velocity, and subsequent complications such as tooth abscesses.1,5 In the present case, during the first evaluation, the patient presented with gait disturbances, limping, pain on walking (mainly in the right foot), deformities (bilateral coxa vara with bilateral genu varum), very short stature (less than percentile 3 of the CDC growth charts), and hypophosphatemia, but no dental involvement was reported and vitamin D levels were normal. However, it should be noted that vitamin D deficiency was found at the age of 3 years and 1 month and it was only at the age of 10 years that she required endodontic treatment.

Being a rare disease, there are currently only three clinical practice guidelines for the diagnosis and treatment of XHL,1,8,9 two of which were published in 2025.1,8 In Colombia, the average time elapsed between the onset of symptoms and the confirmation of the diagnosis of XLH is 15 or more years.10 In the case reported here, the diagnosis was confirmed by genetic typing 2 years and 11 months after the initial assessment (at the age of 5 years and 5 months), a much shorter time than the national average and despite the administrative difficulties experienced.

Conventional treatment of XLH with phosphate supplementation and active vitamin D is effective in reducing bone pain, progressively correcting leg deformities, improving dental health, and stabilizing ALP levels.1,11 The effectiveness of this treatment was observed in the patient, since supplementation with calcitriol, calcium carbonate, and orthophosphate salts allowed normalizing inorganic phosphate levels, improving height, weight, and growth rate, and reducing lower limb deformities when adherence to treatment was adequate. When there were interruptions in this supplementation (from 7 years to 8 years and 4 months), the patient presented hypophosphatemia, increased deformity in the lower limbs, and pain when walking.

In any case, it should be considered that, despite medical therapy with vitamin D analogues and phosphate salts, the clinical manifestations of the disease may not be sufficiently controlled. This often results in growth delays, with a shorter final height, and deformities, such as alterations in the alignment of the extremities, relative shortening of the lower limbs, and widening of the bony metaphyses, which may require corrective surgery.12,13

Burosumab was approved in 2018 for the treatment of XLH by European and US health authorities.1,9 This drug inhibits FGF23 activity, increases tubular maximum reabsorption of phosphate (TmP) and, through the production of 1.25(OH)2-vitamin D, increases gastrointestinal absorption of phosphate and calcium, favoring bone mineralization.14,15 Regarding its effectiveness, burosumab treatment has been reported to stabilize rickets in children with XHL who had been on conventional treatment for several years.9,14,15 In the present case, treatment with burosumab (30 mg every 2 weeks) was started after 6 years of conventional treatment (both continuous and with interruptions), showing favorable results after 6 months, with pain reduction, absence of progression of lower limb deformity, improvement in height and weight, and stabilization of the parameters measured in the follow-up laboratory tests.

Imel et al.,16 in an international randomized clinical trial in 61 children between 1 and 12 years of age with XLH (32 assigned to continue with conventional therapy and 29 to burosumab therapy), reported that, compared to conventional therapy, the reduction in the Total Rickets Severity Score was almost 3 times greater in the burosumab group at week 40 after 40 weeks of treatment (least squares mean difference: −1.3, 95%CI: −1.7 - −0.9; p <0.0001) and that this improvement was maintained at week 64 (least squares mean difference: -1.2, 95%CI: −1.6 - −0.8; p<0.0001).

Likewise, Baroncelli et al.,17 in a case series in Pisa (Italy) involving 5 adolescents
(aged 13-17 years) with XLH in whom conventional treatment was switched to burosumab therapy, reported that serum phosphorus, 1.25(OH)2-vitamin D and TmP/GFR levels increased significantly with burosumab treatment. However, upon interruption of treatment, all these benefits were lost, with recurrence and progressive worsening of bone pain and difficulty in physical function within 2 to 3 months after discontinuation of burosumab. This highlights the importance of continued treatment and the need for more clinical trials with larger population samples to define therapeutic goals and prognosis in adult life for these patients.

In both therapeutic options, it is important to consider the safety profile of these drugs, balancing potential benefits and adverse effects such as pixeria, cough, arthralgia, vomiting, nasopharyngitis, pain in the extremities, headache, dental problems, among others, which occur more frequently with burosumab.16 In studies involving children aged 1-12 years treated with burosumab (0.2-0.8 mg/kg every 2 or 4 weeks), predominantly mild to moderate treatment-associated systemic adverse effects such as myalgia, headache, cough, and nasopharyngitis were reported.7,16,18,19

In the present case, calcitriol was temporarily suspended due to the risk of complications derived from hypercalcemia, but renal ultrasound was performed, ruling out the presence of nephrocalcinosis.

Finally, patients with XLH usually have normal or slightly elevated serum PTH concentrations.20 In this regard, although conventional treatment improves skeletal changes, it can generate nephrocalcinosis and secondary or tertiary hyperparathyroidism.21 On this subject, Baroncelli et al.20 suggest that the greater propensity to develop secondary or tertiary hyperparathyroidism in these patients may be related to a resistance to FGF23 at the parathyroid cell level. It is noteworthy that during the patient’s follow-up, PTH levels were within the reference range (14.5-128 pg/mL), except on one occasion (4 years and
2 months of age) when the value was low (6.12 pg/mL).

Conclusion

The experience of the present case demonstrates that supplementation with calcitriol and phosphate salts can be a suitable treatment option for XHL provided there is good adherence. However, treatment with burosumab showed greater effectiveness, with marked improvement only six months after implementation and with appropriate adherence.

In addition, it is recommended to perform HR genetic typing as soon as possible to confirm the diagnosis, expand therapeutic options in case of suboptimal response, estimate patient prognosis, and access family genetic counseling.

We hope that the present case report will contribute to increase the clinical evidence on the treatment of this rare condition in the country and the region.

Ethical considerations

For the preparation of this case report, informed consent was obtained from the patient’s mother, who, by signing it, authorized the use of the girl’s clinical data for academic purposes.

Conflicts of interest

None stated by the authors.

Funding

None stated by the authors.

Acknowledgments

None stated by the authors.

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