Burosumab for Pediatric X-Linked Hypophosphatemia

Purpose of Review X-Linked hypophosphatemia (XLH) is the most common genetic cause of rickets. This review describes advances in the management of XLH using burosumab which was FDA approved for treating children with XLH in 2018. Recent Findings Elevated FGF23 in XLH leads to systemic hypophosphatemia and several musculoskeletal manifestations, including rachitic bone deformities, impaired growth, dental abscesses, insufficiency fractures, osteoarthritis, and enthesopathy, with lifelong consequences for physical function and quality of life. Burosumab treatment has demonstrated clinical improvement of rickets and growth in children, including during a randomized controlled trial compared with conventional therapy. Burosumab also improved pseudofracture healing in adults. Summary Burosumab led to greater improvement in rickets and growth than conventional therapy. However, many questions remain regarding the impact of burosumab on several outcomes, including final height, nephrocalcinosis, dental disease, enthesopathy, and surgical interventions

Successful treatment of neonatal severe hyperparathyroidism with cinacalcet in two patients

Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11-12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders. LEARNING POINTS: NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels

FGF23 and Associated Disorders of Phosphate Wasting

Fibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option

Iron and fibroblast growth factor 23 in X-linked hypophosphatemia

Background Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls. Methods Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples. Results Intact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r= −0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00 ± 0.44) than controls (−0.28 ± 0.21, p<0.01), and correlated positively to serum iron (controls r= 0.276, p<0.001; XLH r= 0.428, p<0.05), with a steeper slope in XLH (p<0.01). Conclusion Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point

Infants With Congenital Adrenal Hyperplasia Are at Risk for Hypercalcemia, Hypercalciuria, and Nephrocalcinosis

In a retrospective study, most young children with CAH had at least one episode of hypercalcemia, whereas a smaller percentage was found to have hypercalciuria and/or nephrocalcinosis

The Case | Ectopic calcifications in a child

The case A nine year old boy, born of third degree consanguinity, presented with a hard left scapular swelling for 6 months. There was no history of fever, trauma or weight loss. There was no pain, redness or discharge. This mass was excised but recurred over the next 6 months (Left panel of Figure 1). A similar swelling had been excised from the left knee one year before presentation, but had recurred over 6 months. Family history was negative for similar lesions. Development was normal for age and he had no other medical problems. On examination, pulse was 84 per minute, blood pressure 96/68 mmHg, weight 22 kg and height 122 cm (both between 10th and 25th percentile). A 6 × 4 cm mass was noted in the right scapular region and a 3 × 3 cm mass at the lateral aspect of the left knee. Both of these masses were firm to hard, globular, nontender, and fixed to the bone. The overlying skin was without erythema or local warmth, though scars from the previous resections were noted. Lymphadenopathy was absent. The rest of the examination was unremarkable. Radiographs of the knee showed a lobular, inhomogenously but densely calcified lesion in the anterolateral region of the left knee (Right panel of Figure 1). Serum calcium was 9.

X-linked hypophosphatemia caused by the prevailing North American PHEX variant c.*231A\u3eG; exon 13–15 duplication is often misdiagnosed as ankylosing spondylitis and manifests in both men and women

Inactivating mutations of the gene coding for phosphate-regulating endopeptidase homolog X-linked (PHEX) cause X-linked hypophosphatemia (XLH). A nove

Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women

Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C-terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than ≥50mcg/dl. Longitudinal changes in iron predicted changes in C-terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C-terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women