X-linked hypophosphatemia, obesity and arterial hypertension: data from the XLH21 study.

BACKGROUND: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved. METHODS: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)). RESULTS: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). CONCLUSION: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

Growth hormone treatment improves final height in children with X-linked hypophosphatemia.

BACKGROUND/AIM: Despite optimal conventional treatment (oral phosphate supplements and active vitamin D analogs), about 40-50% of children with well-controlled X-linked hypophosphatemia (XLH) show linear growth failure, making them less likely to achieve an acceptable final height. Here, we studied the hypothesis that rhGH treatment improves final height in children with XLH and growth failure. METHODS: Two cohorts of children with XLH were included in this retrospective longitudinal analysis: (1) a cohort treated with rhGH for short stature (n = 34) and (2) a cohort not treated with rhGH (n = 29). The mean duration of rhGH treatment was 4.4 ± 2.9 years. We collected the auxological parameters at various time points during follow-up until final height. RESULTS: In rhGH-treated children, 2 years of rhGH therapy was associated with a significant increase in height from - 2.4 ± 0.9 to - 1.5 ± 0.7 SDS (p < 0.001). Their mean height at rhGH discontinuation was - 1.2 ± 0.9 SDS and at final height was - 1.3 ± 0.9 SDS corresponding to 165.5 ± 6.4 cm in boys and 155.5 ± 6.3 cm in girls. Notably, the two groups had similar final heights; i.e., the final height in children not treated with rhGH being - 1.2 ± 1.1 SDS (165.4 ± 6.8 cm in boys and 153.7 ± 7.8 cm in girls), p = 0.7. CONCLUSION: Treatment with rhGH permits to improve final height in children with XLH and growth failure, despite optimal conventional treatment. We propose therefore that rhGH therapy could be considered as an option for short stature in the context of XLH.

Growth pattern in children with X-linked hypophosphatemia treated with burosumab and growth hormone.

BACKGROUND: X-linked hypophosphatemia (XLH) is characterized by increased serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphatemia and insufficient endogenous synthesis of calcitriol. Beside rickets, odonto- and osteomalacia, disproportionate short stature is seen in most affected individuals. Vitamin D analogs and phosphate supplements, i.e., conventional therapy, can improve growth especially when started early in life. Recombinant human growth hormone (rhGH) therapy in XLH children with short stature has positive effects, although few reports are available. Newly available treatment (burosumab) targeting increased FGF23 signaling leads to minimal improvement of growth in XLH children. So far, we lack data on the growth of XLH children treated with concomitant rhGH and burosumab therapies. RESULTS: Thirty-six patients received burosumab for at least 1 year after switching from conventional therapy. Of these, 23 received burosumab alone, while the others continued rhGH therapy after switching to burosumab. Children treated with burosumab alone showed a minimal change in height SDS after 1 year (mean ± SD 0.0 ± 0.3 prepubertal vs. 0.1 ± 0.3 pubertal participants). In contrast, rhGH clearly improved height during the first year of treatment before initiating burosumab (mean ± SD of height gain 1.0 ± 0.4); patients continued to gain height during the year of combined burosumab and rhGH therapies (mean ± SD height gain 0.2 ± 0.1). As expected, phosphate serum levels normalized upon burosumab therapy. No change in serum calcium levels, urinary calcium excretion, or 25-OHD levels was seen, though 1,25-(OH)2D increased dramatically under burosumab therapy. CONCLUSION: To our knowledge, this is the first study on growth under concomitant rhGH and burosumab treatments. We did not observe any safety issue in this cohort of patients which is one of the largest in Europe. Our data suggest that continuing treatment with rhGH after switching from conventional therapy to burosumab, if the height prognosis is compromised, might be beneficial for the final height.

Orthopedic and neurosurgical care of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is due to mutations in the PHEX gene leading to unregulated production of FGF23 and uncontrollable hypophosphatemia. XLH is characterized in children by rickets, short stature, waddling gait, and leg bowing of variable morphology and severity. Phosphate supplements and oral vitamin D analogs partially or, in some cases, fully restore the limb straightness. XLH patients may also be affected by premature, complete, or partial ossification of sutures between cranial bone, which could eventually result in cranial dysmorphia, decreased intracranial volume, and secondary abnormally high intracranial pressure with a cerebral compression. Our goal is to address the criteria and the management of the skeletal complications associated with XLH, mainly orthopedic and neurosurgical care, and reflect on decision-making and follow-up complexities.

X-linked hypophosphatemia and burosumab: Practical clinical points from the French experience.

Hereditary hypophosphatemia with increased FGF23 levels are rare inherited metabolic diseases characterized by low serum phosphate because of impaired renal tubular phosphate reabsorption. The most common form is X-linked hypophosphatemia (XLH), secondary to a mutation in the PHEX gene. In children, XLH is often manifested by rickets, delayed development of gait, lower limb deformities, growth retardation, craniosynostosis, and spontaneous dental abscesses. In adults, patients present diffuse musculoskeletal pain (bone and joints), early osteoarthritis, entesopathies, pseudo-fractures, muscular weakness, and severe dental damage. Conventional medical management is based on the combined administration of oral phosphate supplementation with active vitamin D analogs. Treatment with the recently approved anti-FGF23 burosumab is an alternative, especially in severe forms. Burosumab restores phosphate reabsorption in the proximal tubule and stimulates the endogenous synthesis of calcitriol. In Europe, burosumab has been approved for the treatment of XLH with radiographic evidence of bone disease in pediatric patients from one year of age and in adults. This manuscript will discuss the specific management of burosumab in children and adolescents in daily practice.

Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series.

AIM: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France. METHODS: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019. RESULTS: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography. CONCLUSION: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.

Diagnosis, treatment-monitoring and follow-up of children and adolescents with X-linked hypophosphatemia (XLH).

Early diagnosis, optimal therapeutic management and regular follow up of children with X-linked hypophosphatemia (XLH) determine their long term outcomes and future quality of life. Biochemical screening of potentially affected newborns in familial cases and improving physician's knowledge on clinical signs, symptoms and biochemical characteristics of XLH for de novo cases should lead to earlier diagnosis and treatment initiation. The follow-up of children with XLH includes clinical, biochemical and radiological monitoring of treatment (efficacy and complications) and screening for XLH-related dental, neurosurgical, rheumatological, cardiovascular, renal and ENT complications. In 2018, the European Union approved the use of burosumab, a humanized monoclonal anti-FGF23 antibody, as an alternative therapy to conventional therapy (active vitamin D analogues and phosphate supplements) in growing children with XLH and insufficiently controlled disease. Diagnostic criteria of XLH and the principles of disease management with conventional treatment or with burosumab are reviewed in this paper.

X-linked hypophosphatemia: Management and treatment prospects.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.

Lower incidence of fracture after IV bisphosphonates in girls with Rett syndrome and severe bone fragility.

BACKGROUND: Classic Rett Syndrome (RS) is a disabling condition mainly caused by MECP2 mutations. Girls with RS are at risk of developing bone fragility and fractures at a young age which results in pain and may seriously impair quality of life. OBJECTIVE: To retrospectively assess the safety and efficacy of IV bisphosphonates on fracture, bone mineral density (BMD) and bone markers in RS girls with bone fragility. METHODS: RS girls received either IV pamidronate (n = 19) or IV zoledronate (n = 1) for 2 years. RESULTS: Of 20 patients studied (age: 12.5 years [6; 39]), 14 were non-ambulatory. The incidence of fracture decreased from 37 fractures in 20 patients, to 1 fracture during or after treatment (follow-up: 3.1 years [1.5; 5]). The spine BMD Z-score improved from -3.2 [-5.6; -0.1] to -2.2 [-3.8; 0.0], p = 0.0006. Most parents reported decreases in chronic pain and 2 patients started to walk. Urinary calcium excretion decreased from 0.7 [0.18; 1.5] to 0.2 [0.03; 0.67] mM/mM of creatinine (p = 0.0001). Pamidronate was well tolerated. CONCLUSION: RS girls should be screened for impaired bone mineralization and preventive measures should be taken. In girls experiencing fractures, IV bisphosphonates constitute a beneficial adjuvant treatment to diminish the risk of fracture and restore bone density.

Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms.

OBJECTIVE: Adults with X-linked hypophosphatemia (XLH) may suffer from skeletal symptoms leading to functional disability. No data on their quality of life (QoL) have been reported so far. Our objectives were to evaluate the QoL and its determinants in XLH adults. PATIENTS AND METHODS: We conducted a prospective study in XLH adults, who consulted for musculoskeletal symptoms between 2013 and 2014. We assessed their QoL using HAQ, RAPID3 and SF36, and analysed the variables associated with low QoL. We compared their QoL to that of patients affected with axial spondyloarthritis (ax-SpA) (paired on age and gender), a rheumatologic disorder with a known low QoL. RESULTS: Fifty-two XLH adults (37 women (71.1%); mean age 41.8±13.3 years) were included; 44 (84.6%) patients had an altered QoL. Increased age and presence of structural lesions were significantly associated with worse QoL (HAQ, RAPID3) (P<0.05). Presence of enthesopathies was significantly associated with worse RAPID3 (OR=4.45 (1.09-18.29), P=0.038). Treatment with phosphate supplements and vitamin D in XLH adults were significantly associated with a better SF36-mental component score (OR=0.14 (0.03-0.57), P=0.007 and OR=0.26 (0.07-0.98), P=0.047 respectively). QoL was significantly worse in XLH than in ax-SpA adults (VAS pain, SF36-PCS, RAPID3) (P<0.05). CONCLUSION: Our study showed i) QoL of XLH adults is altered and significantly worse than that of ax-SpA patients (VAS pain, SF36-PCS and RAPID3), ii) structural lesions and especially enthesopathies are associated with a worse QoL and iii) treatment using phosphate supplements and/or vitamin D is associated with a better mental health score.

Therapeutic management of hypophosphatemic rickets from infancy to adulthood.

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

Endocrine manifestations of the rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor syndrome in childhood.

CONTEXT: Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor (ROHHADNET) is a newly described syndrome that can cause cardiorespiratory arrests and death. It mimics several endocrine disorders or genetic obesity syndromes during early childhood and is associated with various forms of hypothalamic-pituitary endocrine dysfunctions that have not yet been fully investigated. OBJECTIVE: The current report aspires to facilitate the earlier recognition and appropriate treatment of the ROHHADNET syndrome when children present with various endocrine manifestations, such as early obesity, growth failure, pseudo-Cushing's syndrome, glucocorticoid insufficiency, congenital hypopituitarism, or adrenal tumors. A more widespread knowledge of the syndrome will help characterize its molecular origin. DESIGN: Endocrine studies were performed in six patients admitted for seemingly common early-onset obesity associated with growth failure in five of them. The six patients later showed distinctive features of the ROHHADNET syndrome. RESULTS: Abnormalities of the pituitary adrenal axis ranged from a true Cushing-like profile (one of six), to glucocorticoid deficiency with normal ACTH (two of six). Complete GH deficiency with low IGF-I was observed in four of six, hypogonadotropic hypogonadism in four of six, hyperprolactinemia in six of six, and various degrees of TSH/T(4) abnormalities in five of five patients. All had increased natremia without diabetes insipidus. Five children had unilateral macroscopic adrenal ganglioneuroma. Two patients died at 8.5 and 12 yr of age. CONCLUSIONS: Various hypothalamic-pituitary endocrine dysfunctions are associated with ROHHADNET, carrying a risk of misdiagnosis until other elements of the syndrome make it more easily recognizable. Given its severity, ROHHADNET syndrome should be considered in all cases of isolated, rapid, and early obesity.