Burosumab treatment for FGF23-related hypophosphatemia in a two-year-old girl with McCune-Albright syndrome

Abstract

McCune-Albright syndrome (MAS) is a rare mosaic disorder caused by a gain-of-function pathogenic GNAS variant that triggers endocrine and skeletal manifestations, including fibrous dysplasia (FD) and FGF23-related hypophosphatemia. Conventional treatments (e.g., phosphate supplementation, vitamin D analogs) have shown limited efficacy against MAS. Burosumab, a monoclonal FGF23-targeting antibody, has recently been reported as a potential treatment. We report the case of a 2-yr-old girl with MAS complicated by hyperthyroidism, gonadotropin-independent precocious puberty, excess GH, Cushing syndrome, FD, and FGF23-related hypophosphatemia. Genetic testing confirmed a pathogenic GNAS variant (p.Arg201Cys). By the age of 16 mo, she experienced > 7 fractures. Burosumab (1.0 mg/kg bi-weekly) was administered at age 2 yr and 3 mo. Her serum phosphate levels normalized, tubular maximum reabsorption of phosphate-to-glomerular filtration rate ratio improved, bone pain resolved, and she experienced no further fractures since 2 yr and 7 mo, as of age 4 yr and 6 mo. To our knowledge, our patient is the youngest MAS patient treated with burosumab and the second reported case to receive burosumab among patients with genetically confirmed MAS. Burosumab improved biochemical abnormalities related to excess FGF23 and reduced fracture occurrence in our patient, supporting its efficacy in treating FGF23-related hypophosphatemia due to MAS.

Highlights

● MAS causes FGF23-related hypophosphatemia and fractures in some patients.

● Burosumab normalized phosphate and reduced fractures in our patient with MAS.

● Burosumab may improve the prognosis of patients with MAS and hypophosphatemia.

Introduction

McCune-Albright syndrome (MAS) is a rare mosaic disorder caused by a gain-of-function pathogenic variant of the GNAS gene. This gene encodes the Gαs protein, which mediates intracellular signaling for various hormone receptors. Gαs activation causes various clinical manifestations, including fibrous dysplasia (FD), café-au-lait macules, gonadotropin-independent precocious puberty, non-autoimmune hyperthyroidism, excess growth hormone (GH) levels, and Cushing syndrome. FD is a characteristic feature of MAS, and the skull, femur, and pelvis are commonly affected, resulting in recurrent fractures, pain, and progressive deformity (1). Excessive production of FGF23 has also been reported (2). Although the exact mechanism is unclear, FGF23 is considered to be produced by osteoblasts and osteocytes that have abnormally differentiated within FD lesions owing to the effect of Gαs activation (3, 4).

FGF23-related hypophosphatemia leads to rickets and decreased mechanical integrity, contributing to pathological fractures and skeletal deformities (5). Bone pain and fragility fractures caused by FD along with FGF23-related hypophosphatemia pose significant challenges to the management of MAS. However, no established treatment yet exists for this disorder, and conventional therapies such as phosphate supplementation, vitamin D analogs, and bisphosphonates have been used, with limited efficacy, to alleviate pain and reduce physical impairments in patients with MAS (6,7,8). Denosumab, a receptor activator of nuclear factor κB ligand (RANKL) inhibitor, has undergone clinical trials for FD and has been found to suppress lesion activity; however, in some patients, marked bone-turnover rebound with hypercalcemia has been reported (9).

Burosumab is a human monoclonal antibody that targets FGF23. To date, only five cases have been reported in the literature wherein burosumab was used to treat FGF23-related hypophosphatemia in patients with MAS, demonstrating significant improvements in terms of biochemical parameters, bone pain, and imaging findings (10,11,12,13,14).

Herein, we report the use of burosumab in a complex case of MAS involving hyperthyroidism, gonadotropin-independent precocious puberty, GH excess, and Cushing syndrome—all of which required multiple endocrine treatments. To our knowledge, this case represents that of the youngest patient with MAS and FGF23-related hypophosphatemia treated with burosumab that has been reported in the literature thus far and is the second reported case in which genetic testing confirmed the diagnosis of MAS. We report a case of the youngest patient with genetically confirmed MAS treated with burosumab, highlighting its potential to ameliorate refractory skeletal complications in early childhood.

Case Presentation

The patient was a girl born at 38 wk and 4 d of gestation, weighing 2116 g (–2.2 standard deviations [SD]) and measuring 45 cm in length (–1.7 SD). Café-au-lait macules were present across her body from birth. At 5 mo of age, she was referred to the Department of Endocrinology and Metabolism at Hyogo Prefectural Kobe Children’s Hospital because of hyperthyroidism. Genital bleeding and breast development were observed at 7 mo of age. Laboratory findings of LH < 0.07 mIU/mL, FSH 0.21 mIU/mL, and E₂ 242 pg/mL resulted in a diagnosis of gonadotropin-independent precocious puberty. Moreover, the absence of diurnal variations in cortisol levels, elevated 24-hour urinary free cortisol (74 μg/m²/d), and lack of suppression in a dexamethasone suppression test all suggested ACTH-independent hypercortisolism, thus leading to a diagnosis of Cushing syndrome. Oral metyrapone therapy was therefore initiated. At the age of 1 yr and 8 mo, genetic testing (15) using peripheral blood lymphocytes identified a previously reported pathogenic variant (c.601C>T, p.Arg201Cys) in the GNAS gene (NM_000516.7) at a low allele frequency (4.17%), confirming the diagnosis of MAS. Beginning at 1 yr and 8 mo of age, the patient’s IGF-1 levels exceeded +2 SD for her age. At 1 yr and 10 mo, paradoxical suppression on a bromocriptine loading test suggested excess GH levels. These findings prompted the initiation of oral bromocriptine therapy, which failed to decrease the patient’s IGF-1 levels. Her Cushing syndrome resolved at the age of 3 yr, at which point we discontinued metyrapone therapy. Subcutaneous octreotide injections were initiated at 3 yr and 6 mo of age to treat the patient’s excess GH; octreotide therapy successfully stabilized her IGF-1 levels to within the age-appropriate range. Oral letrozole and tamoxifen therapy were initiated at 3 yr and 8 mo of age, leading to cessation of the patient’s genital bleeding. Her growth curve is presented in Fig. 1.

Fig. 1.

Growth curves of our patient vs normal trajectories for her age range. Our patient exhibited a decline in growth rate during infancy; however, after the initiation of metyrapone therapy at 7 mo of age, her growth rate quickly improved. At 3 yr of age, her Cushing syndrome spontaneously resolved, so the metyrapone treatment was discontinued. Beginning at the age of 1 yr and 8 mo, her IGF-1 levels remained above +2 SD. After the initiation of octreotide therapy beginning at 3 yr and 6 mo of age, her IGF-1 levels returned to the normal range and her growth rate declined.

The patient’s FD- and FGF23-related hypop-hosphatemia courses proceeded as follows (Fig. 2): Her FD was initially severe and very extensive, involving the skull (sphenoid, parietal, occipital, and zygomatic bones) and long bones of the extremities (Figs. 3A–C). Her serum 25(OH) vitamin D levels were assessed regularly; however, no findings indicative of vitamin D deficiency were observed. She experienced multiple fractures: fractures of the bilateral femoral neck at 1 yr and 4 mo of age, proximal phalanx of the left index finger at 1 yr and 6 mo, left tibial shaft at 2 yr, and distal phalanx of the right index finger at 2 yr and 3 mo of age. She presented with a shepherd’s crook deformity of the femur caused by a femoral neck fracture. Bone fragility, deformities, and pain severely impaired her quality of life (QOL). At 2 yr of age, the patient was diagnosed with FGF23-related hypophosphatemia based on hypophosphatemia (3.2 mg/dL) and elevated FGF23 levels (133 pg/mL). Burosumab therapy (1.0 mg/kg every 2 wk) was initiated at 2 yr and 3 mo of age. The burosumab dose was planned according to the dosing for X-linked hypophosphatemia (XLH) (16) and the nearest dose was selected in 10-mg increments. Serum phosphate was assessed according to pre-burosumab values, and the target was at least the lower end of the normal reference range for age. One month after the initiation of burosumab, the patient’s serum phosphate level increased from 3.2 to 5.8 mg/dL, and her tubular maximum reabsorption of phosphate-to-glomerular filtration rate ratio increased from 2.49 to 4.59 mg/dL. Since the last bilateral femoral shaft fracture at 2 yr and 7 mo of age, no subsequent fracture was observed up to 4 yr and 6 mo of age, as of the time of writing this report. In addition, her bone pain, as assessed by both her parents and medical staff, was alleviated. Although she had previously been unable to stand due to the pain, she became able to stand with support following the initiation of burosumab therapy. However, serial radiographic evaluations showed no improvements in her FD lesions during the burosumab therapy (Fig. 3D). The patient continued burosumab therapy without any known adverse effects. The changes over time in her laboratory data are shown in Supplementary Table 1.

Fig. 2.

. Changes in the patient’s biochemical parameters and incidence rates of bone fractures before and after burosumab treatment. Following the initiation of burosumab therapy, the patient’s serum phosphorus levels and TmP/GFR ratio increased, and her incidence of bone fractures decreased. TmP, tubular maximum reabsorption of phosphate; GFR, glomerular filtration rate.

Fig. 3.

Representative imaging findings. A) Radiograph obtained when the patient was aged 2 yr shows extensive fibrous dysplasia in the femur, tibia, and fibula (yellow stars). Shepherd’s crook deformity was observed in the proximal femur (white arrows). B) Radiograph obtained when the patient was aged 2 yr shows a bone age of 4.2 yr according to the Tanner-Whitehouse 2-RUS (TW2-RUS) method. Ground-glass opacities were observed in all of the bones of her hand as well as in the radius and ulna (yellow stars). C) Computed tomography performed when the patient was aged 1 yr and 10 mo revealed extensive ground-glass opacities in the skull, indicating fibrous dysplasia (yellow stars). D) A radiograph taken when the patient was aged 4 yr and 5 mo shows no improvement of her FD lesions.

Discussion

This case represents a severe phenotypic manifestation of MAS with multiple complications that include hyperthyroidism, gonadotropin-independent precocious puberty, Cushing syndrome, excess GH levels, FD, and FGF23-related hypophosphatemia. To our knowledge, our patient is the youngest one reported in the literature that was treated with burosumab as well as the second reported patient with a genetically confirmed diagnosis of MAS to receive this treatment. Burosumab therapy demonstrated significant clinical efficacy in treating our patient, despite her persistent skeletal fragility secondary to FD and reduced QOL from residual bone deformities, as evidenced by significant improvements in her biochemical parameters and a notable reduction in bone fractures.

Various factors can affect bone health in patients with FD/MAS, including FGF23-related hypophosphatemia, Cushing syndrome, and excess GH levels. Chronic glucocorticoid excess in Cushing syndrome suppresses bone formation and subsequently increases long-term bone resorption, leading to glucocorticoid-induced osteoporosis (17). Excess GH is associated with a deterioration in FD involvement, particularly in the craniofacial bones. This can lead to significant morbidities such as optic neuropathy (and resulting visual impairment), sensorineural hearing loss, and progressive facial asymmetry (18). In the present case, appropriate medical management of both Cushing syndrome and excess GH may have contributed to the reduced fracture incidence that our patient experienced. However, even with optimal endocrine control, some degree of pathological fractures persisted.

FD and bone pain represent the two most common complications associated with MAS. FD is observed in 98% of the patients with MAS, with 80% of the adults and 50% of the children experiencing bone pain that tends to increase with age (19, 20). The incidence of limb fractures in patients with FD/MAS peaks between the ages of 6 and 10 and then declines (5). Excessive FGF23 production in patients with FD may be related to Gαs activation in abnormally differentiated osteoblasts and osteocytes (3, 4). FGF23 reduces serum phosphate levels by inhibiting phosphate reabsorption in the proximal tubules of the kidneys and reducing the production of active 1,25-dihydroxyvitamin D. Hypophosphatemia can worsen skeletal lesions in patients with MAS, contributing to early and frequent fractures, pain, rickets, and increased deformities (5). Chronic hypophosphatemia has been demonstrated to correlate with increased fracture risk and frequency of surgical interventions in patients with FD (21). FD lesions have insufficient mineralization compared to normal bone, potentially as a result of biochemical abnormalities such as hypophosphatemia, making them more fragile. Thus, the normalization of serum phosphate levels is important for preventing bone fragility in affected patients. Burosumab may, therefore, represent an attractive therapeutic option for the management of the FGF23-related hypophosphatemia associated with FD.

To date, five other cases of MAS that were treated with burosumab have been reported in the literature. A comparison of these cases is presented in Table 1. Gladding et al. reported that an 8-yr-old boy with MAS/FD showed improvements in hyperphosphatasemia, hypophosphatemia, fracture incidence, bone pain, and muscle weakness after burosumab treatment (13). Apperley et al. described the case of a 7-yr-old boy who showed improvements in hyperphosphatasemia, hypophosphatemia, and bone pain after this therapy (12). Sawamura et al. reported that an 11-yr-old girl experienced improvements in hyperphosphatasemia, bone pain, and FD findings after being started on burosumab (14). Sakka et al. reported improvement in hypophosphatemia and elevated alkaline phosphatase levels in an 8-yr-old girl (10). Barbato et al. reported improvement in hypophosphatemia and elevated alkaline phosphatase levels in an 8-yr-old boy with the same genetic variant as in the present case; however, no change was observed in the course of FD (11). These patients showed improvements in both their biochemical abnormalities and bone pain levels.

Table 1. Comparison of cases reported in the literature.

Our patient received oral metyrapone therapy for Cushing syndrome first, followed by bromocriptine therapy for GH excess, and finally burosumab for FGF23-related hypophosphatemia. Notably, a reduction in fracture incidence was documented following the initiation of burosumab therapy. The reduction in fracture frequency was observed at a younger age than that at which the peak incidence of fractures has been reported in this patient population, different from the natural course of FD/MAS (5). Although appropriate endocrine management likely contributed to partial skeletal stabilization, the rapid normalization of serum phosphate and concurrent decline in fracture incidence post-burosumab initiation suggest a therapeutic effect.

Despite insufficient evidence demonstrating that correcting hypophosphatemia reduces fracture incidence in patients with MAS/FD, we hypothesize that the normalization of serum phosphate levels achieved through burosumab results in improved bone mineralization, ultimately leading to enhanced skeletal integrity and subsequent clinical benefits. Despite the currently limited number of documented cases, accumulating clinical evidence suggests that the administration of burosumab in patients with MAS/FD effectively improves abnormal biochemical parameters and reduces the incidence of bone fractures. Further research is needed to clarify whether burosumab demonstrates therapeutic efficacy in patients with MAS/FD in the absence of hypophosphatemia or directly affects FD lesions. Rigorous long-term follow-up investigations are needed to establish the safety profile and sustain the clinical benefits of this therapeutic approach.

Conclusion

We report the case of a 2-yr-old girl with MAS in whom burosumab therapy demonstrated significant clinical efficacy, as evidenced by the normalization of biochemical parameters and significant reductions in fracture incidence and bone pain. These findings suggest that burosumab may be an effective therapeutic intervention even in young children with severe manifestations of MAS complicated by multiple endocrine disorders.

Conflict of interests

Keiichi Ozono received honoraria for writing promotional material for Kyowa Kirin; other authors have no conflict of interest.