Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

Capelli, S.; Donghi, V.; Maruca, Katia; Vezzoli, Giuseppe; Corbetta, Sabrina; Brandi, Maria Luisa; Mora, Stefano; Weber, Giovanna

doi:10.1016/j.bone.2015.05.040

Cited by 45 publications

(40 citation statements)

References 27 publications

(40 reference statements)

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“…It would be reasonable to expect that patients with this condition who require surgery to be the most severely affected. In line with this, the mean final height of the entire cohort is −2.7 (± 1.7), less than the previously reported mean adult height in XLHR (10, 11, 20, 21, 22). Noteworthy, the mean age at diagnosis of this cohort is higher than what is usually reported in series of XLHR patients.…”

Section: Discussionsupporting

confidence: 76%

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

Gizard

Rothenbühler

Péjin

et al. 2017

Endocrine Connections

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BackgroundX-linked hypophosphatemic rickets (XLHR) is due to mutations in PHEX leading to unregulated production of FGF23 and hypophosphatemia. XLHR is characterized by leg bowing of variable severity. Phosphate supplements and oral vitamin analogs, partially or, in some cases, fully restore the limb straightness. Surgery is the alternative for severe or residual limb deformities.ObjectiveTo retrospectively assess the results of surgical limb correction in XLHR (osteotomies and bone alignment except for 3 transient hemiepiphysiodesis).MethodsWe analyzed the incidence of recurrence and post-surgical complications in 49 XLHR patients (29F, 20M) (mean age at diagnosis 6.0 years (± 7.1)).ResultsAt first surgery, the mean age was 13.4 years (± 5.0). Recurrence was observed in 14/49 (29%) patients. The number of additional operations significantly decreased with age (2.0 (± 0.9), 1.7 (± 1.0) and 1.2 (± 0.4) in children <11 years, between 11 and 15, and >15 years; P < 0.001). Incidence of recurrence seemed to be lower in patients with good metabolic control of the rickets (25% vs 33%). Complications were observed in 57% of patients.ConclusionWe report a large series of surgical procedures in XLHR. Our results confirm that phosphate supplements and vitamin D analog therapy is the first line of treatment to correct leg bowing. Surgery before puberty is associated with a high risk of recurrence of the limb deformity. Such procedures should only be recommended, following multidisciplinary discussions, in patients with severe distortion leading to mechanical joint and ligament complications, or for residual deformities once growth plates have fused.

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Section: Discussionsupporting

confidence: 76%

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

Gizard

Rothenbühler

Péjin

et al. 2017

Endocrine Connections

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“…Consequently, circulating levels of the phosphatonin fibroblast growth factor 23 (FGF23) increase and affected individuals manifest hypophosphatemia from renal wasting of inorganic phosphate (Pi), diminished kidney synthesis of 1,25‐dihydroxyvitamin D (1,25(OH) 2 D), and decreased intestinal absorption of calcium (Ca) and Pi . XLH accounts for >80% of heritable hypophosphatemic bone disease and occurs in ~1 per 20,000 births . Early in childhood, there is skeletal deformity (primarily lower extremity bowing), decreased growth velocity, and sometimes bone and joint pain, dental abscesses, and craniosynostosis .…”

Section: Introductionmentioning

confidence: 99%

“…XLH accounts for >80% of heritable hypophosphatemic bone disease and occurs in ~1 per 20,000 births . Early in childhood, there is skeletal deformity (primarily lower extremity bowing), decreased growth velocity, and sometimes bone and joint pain, dental abscesses, and craniosynostosis . During adult life, common complications of XLH include pseudofractures, osteoarthritis, vertebral ankylosis, and enthesopathy that can lead to spinal stenosis …”

Section: Introductionmentioning

confidence: 99%

“…PHEX has tissue‐specific expression with its mRNA present in healthy dento‐osseous lineage cells (osteoblasts, osteocytes, and odontoblasts) . Its 22 exons encode a 749–amino acid enzyme that, when compromised, increases circulating FGF23 thereby diminishing expression of two sodium‐Pi cotransporters in renal proximal tubule cells . Furthermore, FGF23 downregulates kidney 1α‐hydroxylase necessary to activate 25‐hydroxyvitamin D to 1,25(OH) 2 D .…”

Section: Introductionmentioning

confidence: 99%

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X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)

Smith

Gottesman

Zhang

et al. 2020

Journal of Bone and Mineral Research

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X-linked hypophosphatemia (XLH), the most prevalent heritable renal phosphate (Pi) wasting disorder, is caused by deactivating mutations of PHEX. Consequently, circulating phosphatonin FGF23 becomes elevated and hypophosphatemia in affected children leads to rickets with skeletal deformity and reduced linear growth while affected adults suffer from osteomalacia and forms of ectopic mineralization. In 2015, we reported uniquely mild XLH in six children and four of their mothers carrying the non-coding PHEX 3 0 -UTR mutation c.*231A>G. Herein, we characterize this mild XLH variant by comparing its features in 30 individuals to 30 age-and sexmatched patients with XLH but without the 3 0 -UTR mutation. The "UTR" and "XLH" groups, both comprising 17 children (2 to 17 years, 3 girls) and 13 adults (23 to 63 years, 10 women), had mean ages of 23 years. Only 43% of the UTR group versus 90% of the XLH group had received medical treatment for their disorder, including 0% versus 85% of the females, respectively (ps < .0001). The UTR group was taller: mean AE SD height Z-score (HZ) −1.0 AE 1.0 versus −2.0 AE 1.4 (p = .0034), with significantly greater height for females (−0.9 AE 0.7 versus −2.3 AE 1.4; p = .0050) but not males (−1.2 AE 1.1 versus −1.9 AE 1.5; p = .1541), respectively. Mean AE SD "arm span Z-score" (AZ) did not differ between the UTR −0.8 AE 1.3 versus XLH −1.3 AE 1.8 groups (p = .2269). Consequently, the UTR group was more proportionate with a mean ΔZ (AZ -HZ) of 0.1 AE 0.6 versus 0.7 AE 1.0 (p = .0158), respectively. Compared to the XLH group, the UTR group had significantly higher fasting serum Pi and renal tubular threshold maximum for phosphorus per glomerular filtration rate (TmP/GFR) (ps ≤ .0060), serum FGF23 concentrations within the reference range (p = .0068), and similar serum alkaline phosphatase levels (p = .6513). UTR lumbar spine bone mineral density Z-score was higher (p = .0343). Thus, the 3 0 -UTR variant of XLH is distinctly mild, especially in girls and women, posing challenges for its recognition and management.

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“…Additionally, this amount of heterogeneity in patients with HR emphasizes the role of other regulators in phosphate hemostasis. 13,56 In children, the goal of treatment is accurate tooth and bone mineralization and sufficient longitudinal growth whereas, in infant, immediate diagnosis of HR prevents the development of rickets. 70 In HHRH, phosphate supplementation alone can be beneficial for the amelioration of patient's condition, and there is no need for vitamin D add-on therapy.…”

Section: Molecular Testsmentioning

confidence: 99%

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

Manjili¹,

Aliabad²,

Kalantar³

et al. 2017

Int J Basic Sci Med

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Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

Cited by 45 publications

References 27 publications

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

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Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

Cited by 45 publications

References 27 publications

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

Outcomes of orthopedic surgery in a cohort of 49 patients with X-linked hypophosphatemic rickets (XLHR)

X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A&gt;G (A Retrospective Case–Control Study)

Molecular and Biochemical Aspects of Hypophosphatemic Rickets; an Updated Review

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X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)