Update on X-linked Hypophosphatemia

A special issue of Endocrines (ISSN 2673-396X). This special issue belongs to the section "Pediatric Endocrinology and Growth Disorders".

Deadline for manuscript submissions: closed (20 May 2022) | Viewed by 33313

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Guest Editor
Department of Endocrinology and Metabolism, Tokyo Metropolitan Children`s Medical Center, Tokyo, Japan
Interests: pediatric endocrinology; sex differentiation; growth; adrenal and gonad; bone and Ca/phosphate metabolism
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Guest Editor
Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
Interests: mineral & bone metabolism; metabolic bone diseases

Special Issue Information

Dear Colleagues,

X-linked hypophosphatemic rickets/osteomalacia is a clinical disease having seen great advancements, the key milestones being (1) the positional cloning of PHEX as a result of X-linked hypophosphatemic rickets/osteomalacia (1995), (2) the discovery of FGF23, a key molecule for phosphate regulation and the understanding of rickets/osteomalacia (2000 and 2001), and (3) the clinical application of the anti-FG23 antibody treatment (2018).

Rickets/osteomalacia is usually classified into two groups, (1) vitamin D-related and (2) hypophosphatemia-related, the latter further divided into (2-1) FGF23-related (e.g., XLH) and (2-2) defects in the renal tubules (e.g., Fanconi syndrome). This time, we would like to focus on hypophosphatemic rickets/osteomalacia, particularly on XLH, starting with a couple of general expert review articles, followed by ones on other specific items (related to XLH), such as the pathophysiology of XLH and the anti-FGF23 antibody treatment. The editors have considered balancing between basic and clinical medicine as planned below, hoping for the Special Issue regarding this field to be useful not only for learning in general, but also thinking (out of the box), having commenced asking experts to contribute. In addition, the editors would really like to invite physicians, hopefully challenging themselves to write new original articles, commentary/hypotheses, case reports on hypophosphatemic rickets/osteomalacia and related areas.

(1) General reviews

  • Bone mineralization;
  • Regulation of serum calcium and phosphate levels;
  • Pathology/clinical cause of rickets/osteomalacia.

(2) Specified reviews

  • XLH in children (Dx, Px, Tx);
  • XLH in adults;
  • Anti-FGF23 treatment in children;
  • Anti-FGF23 treatment in adults.

(3) Others

  • Commentary/hypothesis;
  • Original articles;
  • Case presentations;
  • Review articles (on issues other than described above).

Prof. Dr. Yukihiro Hasegawa
Prof. Dr. Seiji Fukumoto
Guest Editors

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Keywords

  • X-linked hypophosphatemic rickets/osteomalacia
  • FGF23
  • bone mineralization

Published Papers (13 papers)

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Editorial

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2 pages, 188 KiB  
Editorial
Special Issue: “X-Linked Hypophosphatemia”
by Seiji Fukumoto and Yukihiro Hasegawa
Endocrines 2023, 4(4), 720-721; https://doi.org/10.3390/endocrines4040052 - 16 Nov 2023
Viewed by 925
Abstract
Rickets and osteomalacia are associated with impaired mineralization in growth plate cartilage and the bone osteoid [...] Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)

Research

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9 pages, 1442 KiB  
Communication
Regulation of Phosphate Transporters and Novel Regulator of Phosphate Metabolism
by Megumi Koike, Minori Uga, Yuji Shiozaki, Ken-ichi Miyamoto and Hiroko Segawa
Endocrines 2023, 4(3), 607-615; https://doi.org/10.3390/endocrines4030043 - 21 Aug 2023
Cited by 1 | Viewed by 1702
Abstract
Phosphorus is essential for all living organisms. It plays an important role in maintaining biological functions, such as energy metabolism, cell membrane formation, and bone mineralization. Various factors in the intestine, kidneys, and bones regulate the homeostasis of the inorganic phosphate (Pi) concentration [...] Read more.
Phosphorus is essential for all living organisms. It plays an important role in maintaining biological functions, such as energy metabolism, cell membrane formation, and bone mineralization. Various factors in the intestine, kidneys, and bones regulate the homeostasis of the inorganic phosphate (Pi) concentration in the body. X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is characterized by an impaired mineralization of the bone matrix, hypertrophic chondrocytes with hypophosphatemia, and active vitamin D resistance in childhood. Phosphate-regulating gene with homologies to endopeptidases on the X chromosome was recognized as the responsible gene for XLH. XLH is classified as fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets. The enhanced FGF23 stimulates renal phosphate wasting by downregulating sodium-dependent Pi cotransporters, NaPi2a and NaPi2c proteins, in the proximal tubules. Recently, transmembrane protein (Tmem) 174 has been identified as a novel regulator of phosphate transporters. This review introduces the role of Tmem174 in the Pi homeostasis in the body. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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10 pages, 814 KiB  
Communication
Presentation and Diagnosis of Pediatric X-Linked Hypophosphatemia
by Kento Ikegawa and Yukihiro Hasegawa
Endocrines 2023, 4(1), 128-137; https://doi.org/10.3390/endocrines4010012 - 22 Feb 2023
Viewed by 1950
Abstract
X-linked hypophosphatemia (XLH) is a rare type of hereditary hypophosphatemic rickets. Patients with XLH have various symptoms that lower their QOL as defined by HAQ, RAPID3, SF36-PCS, and SF36-MCS in adult patients and SF-10 and PDCOI in pediatric patients. Early diagnosis and treatment [...] Read more.
X-linked hypophosphatemia (XLH) is a rare type of hereditary hypophosphatemic rickets. Patients with XLH have various symptoms that lower their QOL as defined by HAQ, RAPID3, SF36-PCS, and SF36-MCS in adult patients and SF-10 and PDCOI in pediatric patients. Early diagnosis and treatment are needed to reduce the burden, but the condition is often diagnosed late in childhood. The present review aims to summarize the symptoms, radiological and biological characteristics, and long-term prognosis of pediatric XLH. Typical symptoms of XLH are lower leg deformities (age six months or later), growth impairment (first year of life or later), and delayed gross motor development with progressive lower limb deformities (second year of life or later). Other symptoms include dental abscess, bone pain, hearing impairment, and Chiari type 1 malformation. Critical, radiological findings of rickets are metaphyseal widening, cupping, and fraying, which tend to occur in the load-bearing bones. The Rickets Severity Score, validated for XLH, is useful for assessing the severity of rickets. The biochemical features of XLH include elevated FGF23, hypophosphatemia, low 1,25(OH)2D, and elevated urine phosphate. Renal phosphate wasting can be assessed using the tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR), which yields low values in patients with XLH. XLH should be diagnosed early because the multisystem symptoms often worsen over time. The present review aims to help physicians diagnose XLH at an early stage. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)

Review

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16 pages, 7993 KiB  
Review
Histological Assessment of Endochondral Ossification and Bone Mineralization
by Tomoka Hasegawa, Hiromi Hongo, Tomomaya Yamamoto, Takafumi Muneyama, Yukina Miyamoto and Norio Amizuka
Endocrines 2023, 4(1), 66-81; https://doi.org/10.3390/endocrines4010006 - 2 Feb 2023
Cited by 1 | Viewed by 2349
Abstract
Finely tuned cartilage mineralization, endochondral ossification, and normal bone formation are necessary for normal bone growth. Hypertrophic chondrocytes in the epiphyseal cartilage secrete matrix vesicles, which are small extracellular vesicles initiating mineralization, into the intercolumnar septa but not the transverse partitions of the [...] Read more.
Finely tuned cartilage mineralization, endochondral ossification, and normal bone formation are necessary for normal bone growth. Hypertrophic chondrocytes in the epiphyseal cartilage secrete matrix vesicles, which are small extracellular vesicles initiating mineralization, into the intercolumnar septa but not the transverse partitions of the cartilage columns. Bone-specific blood vessels invade the unmineralized transverse septum, exposing the mineralized cartilage cores. Many osteoblast precursors migrate to the cartilage cores, where they synthesize abundant bone matrices, and mineralize them in a process of matrix vesicle-mediated bone mineralization. Matrix vesicle-mediated mineralization concentrates calcium (Ca) and inorganic phosphates (Pi), which are converted into hydroxyapatite crystals. These crystals grow radially and are eventually get out of the vesicles to form spherical mineralized nodules, leading to collagen mineralization. The influx of Ca and Pi into the matrix vesicle is regulated by several enzymes and transporters such as TNAP, ENPP1, PiT1, PHOSPHO1, annexins, and others. Such matrix vesicle-mediated mineralization is regulated by osteoblastic activities, synchronizing the synthesis of organic bone material. However, osteocytes reportedly regulate peripheral mineralization, e.g., osteocytic osteolysis. The interplay between cartilage mineralization and vascular invasion during endochondral ossification, as well as that of osteoblasts and osteocytes for normal mineralization, appears to be crucial for normal bone growth. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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11 pages, 5734 KiB  
Review
Dental Manifestations and Oral Management of X-Linked Hypophosphatemia
by Rena Okawa and Kazuhiko Nakano
Endocrines 2022, 3(4), 654-664; https://doi.org/10.3390/endocrines3040056 - 21 Oct 2022
Viewed by 4344
Abstract
X-linked hypophosphatemia (XLH) is the most common genetic form of rickets and osteomalacia and is characterized by growth retardation, deformities of the lower limbs, and bone and muscular pain. Spontaneous dental abscesses caused by endodontic infections due to dentin dysplasia are well-known dental [...] Read more.
X-linked hypophosphatemia (XLH) is the most common genetic form of rickets and osteomalacia and is characterized by growth retardation, deformities of the lower limbs, and bone and muscular pain. Spontaneous dental abscesses caused by endodontic infections due to dentin dysplasia are well-known dental manifestations. When dentin affected by microcracks or attrition of the enamel is exposed to oral fluids, oral bacteria are able to invade the hypomineralized dentin and pulp space, leading to pulp necrosis, followed by the formation of a periapical gingival abscess. Without appropriate dental management, this dental manifestation results in early loss of teeth and deterioration in the patient’s quality of life. Early specific dental intervention and oral management in collaboration with medical personnel are strongly recommended for XLH patients. Importantly, dental manifestations sometimes appear before the diagnosis of XLH. Dentists should be alert for this first sign of XLH and refer affected children to a pediatrician for early diagnosis. A humanized monoclonal antibody for FGF23 (burosumab) is a promising new treatment for XLH; however, the effects on the dental manifestations remain to be elucidated. The establishment of fundamental dental therapy to solve dental problems is still underway and is eagerly anticipated. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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10 pages, 1085 KiB  
Review
Complications and Treatments in Adult X-Linked Hypophosphatemia
by Yasuo Imanishi, Tetsuo Shoji and Masanori Emoto
Endocrines 2022, 3(3), 560-569; https://doi.org/10.3390/endocrines3030047 - 8 Sep 2022
Cited by 2 | Viewed by 1908
Abstract
X-linked hypophosphatemia (XLH) is a rare inherited disorder involving elevated levels of fibroblast growth factor (FGF) 23, and is caused by loss-of-function mutations in the PHEX gene. FGF23 induces renal phosphate wasting and suppresses the activation of vitamin D, resulting in defective bone [...] Read more.
X-linked hypophosphatemia (XLH) is a rare inherited disorder involving elevated levels of fibroblast growth factor (FGF) 23, and is caused by loss-of-function mutations in the PHEX gene. FGF23 induces renal phosphate wasting and suppresses the activation of vitamin D, resulting in defective bone mineralization and rachitic changes in the growth plate and osteomalacia. Conventional treatment with combinations of oral inorganic phosphate and active vitamin D analogs enhances bone calcification, but the efficacy of conventional treatment is insufficient for adult XLH patients to achieve an acceptable quality of life. Burosumab, a fully human monoclonal anti-FGF23 antibody, binds and inhibits FGF23, correcting hypophosphatemia and hypovitaminosis D. This review describes a typical adult with XLH and summarizes the results of clinical trials of burosumab in adults with XLH. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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8 pages, 287 KiB  
Review
Treatment of X-Linked Hypophosphatemia in Children
by Toshihiro Tajima and Yukihiro Hasegawa
Endocrines 2022, 3(3), 522-529; https://doi.org/10.3390/endocrines3030042 - 11 Aug 2022
Cited by 1 | Viewed by 3582
Abstract
The conventional treatment for X-linked hypophosphatemia (XLH), consisting of phosphorus supplementation and a biologically active form of vitamin D (alfacalcidol or calcitriol), is used to treat rickets and leg deformities and promote growth. However, patients’ adult height often remains less than −2 SD. [...] Read more.
The conventional treatment for X-linked hypophosphatemia (XLH), consisting of phosphorus supplementation and a biologically active form of vitamin D (alfacalcidol or calcitriol), is used to treat rickets and leg deformities and promote growth. However, patients’ adult height often remains less than −2 SD. Moreover, adverse events, such as renal calcification and hyperparathyroidism, may occur. The main pathology in XLH is caused by excessive production of fibroblast growth factor 23 (FGF23). Several studies have demonstrated that treatment with burosumab, a blocking neutralizing antibody against FGF23, is better than conventional therapy for severe XLH and has no serious, short-term side effects. Thus, treatment with burosumab may be an option for severe XLH. The present article reviews the conventional and burosumab therapies. In addition to the fact that the long-term efficacy of antibody-based treatment has not been demonstrated, there are other, unresolved issues concerning the burosumab treatment of XLH. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
14 pages, 345 KiB  
Review
Pathogenic Variants of the PHEX Gene
by Yasuhisa Ohata and Yasuki Ishihara
Endocrines 2022, 3(3), 498-511; https://doi.org/10.3390/endocrines3030040 - 8 Aug 2022
Cited by 3 | Viewed by 2388
Abstract
Twenty-five years ago, a pathogenic variant of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene was identified as the cause of X-linked hypophosphatemic rickets (XLH). Subsequently, the overproduction of fibroblast growth factor 23 (FGF23) due to PHEX defects has been found to [...] Read more.
Twenty-five years ago, a pathogenic variant of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene was identified as the cause of X-linked hypophosphatemic rickets (XLH). Subsequently, the overproduction of fibroblast growth factor 23 (FGF23) due to PHEX defects has been found to be associated with XLH pathophysiology. However, the mechanism by which PHEX deficiency contributes to the upregulation of FGF23 and the function of PHEX itself remain unclear. To date, over 700 pathogenic variants have been identified in patients with XLH, and functional assays and genotype–phenotype correlation analyses based on pathogenic variant data derived from XLH patients have been reported. Genetic testing for XLH is useful for the diagnosis. Not only have single-nucleotide variants causing missense, nonsense, and splicing variants and small deletion/insertion variants causing frameshift/non-frameshift alterations been observed, but also gross deletion/duplication variants causing copy number variants have been reported as pathogenic variants in PHEX. With the development of new technologies including next generation sequencing, it is expected that an increasing number of pathogenic variants will be identified. This chapter aimed to summarize the genotype of PHEX and related analyses and discusses the pathophysiology of PHEX defects to seek clues on unsolved questions. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
10 pages, 7221 KiB  
Review
Orthopedic Complications and Management in Children with X-Linked Hypophosphatemia
by Chikahisa Higuchi
Endocrines 2022, 3(3), 488-497; https://doi.org/10.3390/endocrines3030039 - 3 Aug 2022
Cited by 1 | Viewed by 1959
Abstract
X-linked hypophosphatemia is an inheritable disease of renal phosphate wasting that results in clinically manifestations associated with rickets or osteomalacia. The various symptoms in the skeletal system are well recognized, such as short stature; lower limb deformities; and bone, joint, or muscle pain, [...] Read more.
X-linked hypophosphatemia is an inheritable disease of renal phosphate wasting that results in clinically manifestations associated with rickets or osteomalacia. The various symptoms in the skeletal system are well recognized, such as short stature; lower limb deformities; and bone, joint, or muscle pain, and it is often difficult to control these symptoms, despite the use of medication therapy in growing children. In addition, lower limb deformities can lead to degenerative osteoarthritis and dysfunction of lower limbs at the skeletal maturity. To prevent from future manifestation of those symptoms, orthopedic surgeries are applicable to growing patients with severe skeletal deformities or without response to conventional medication. Bone deformities are treated by acute or gradual corrective osteotomies and temporally hemiepiphysiodesis using guided growth method. The clinicians should choose the right procedure based on age, symptoms and state of deformities of the patient. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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8 pages, 272 KiB  
Review
X-Linked Hypophosphatemia Transition and Team Management
by Takuo Kubota
Endocrines 2022, 3(3), 411-418; https://doi.org/10.3390/endocrines3030032 - 5 Jul 2022
Cited by 2 | Viewed by 2090
Abstract
X-linked hypophosphatemia (XLH) is the most common form of inherited disorders that are characterized by renal phosphate wasting, but it is a rare chronic disease. XLH presents in multisystemic organs, not only in childhood, but also in adulthood. Multidisciplinary team management is necessary [...] Read more.
X-linked hypophosphatemia (XLH) is the most common form of inherited disorders that are characterized by renal phosphate wasting, but it is a rare chronic disease. XLH presents in multisystemic organs, not only in childhood, but also in adulthood. Multidisciplinary team management is necessary for the care of patients with XLH. Although XLH has often been perceived as a childhood disease, recent studies have demonstrated that it is a long-term and progressive disease throughout adulthood. In the past 20 years, the importance of the transition from pediatric care to adult care for patient outcomes in adulthood in many pediatric onset diseases has been increasingly recognized. This review describes transitional care and team management for patients with XLH. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
16 pages, 1201 KiB  
Review
Adult Presentation of X-Linked Hypophosphatemia
by Nobuaki Ito
Endocrines 2022, 3(3), 375-390; https://doi.org/10.3390/endocrines3030030 - 1 Jul 2022
Cited by 2 | Viewed by 3859
Abstract
Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of longitudinal ligaments (OPLL), osteophytes around large joints, and enthesopathy in the Achilles tendons), early osteoarthritis, the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT), and the subsequent progression of [...] Read more.
Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of longitudinal ligaments (OPLL), osteophytes around large joints, and enthesopathy in the Achilles tendons), early osteoarthritis, the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT), and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscesses. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets (ARHR1/2) due to mutations in PHEX, DMP1, and ENPP1 is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue, as many adult XLH patients suffer subsequent debilitating nervous symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of dosages by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, indications for this drug should be carefully considered, along with cost-effectiveness, guidelines or recommendations, and the health care system of each country. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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14 pages, 556 KiB  
Review
Pathogenesis of FGF23-Related Hypophosphatemic Diseases Including X-linked Hypophosphatemia
by Tatsuro Nakanishi and Toshimi Michigami
Endocrines 2022, 3(2), 303-316; https://doi.org/10.3390/endocrines3020025 - 2 Jun 2022
Cited by 1 | Viewed by 3425
Abstract
Since phosphate is indispensable for skeletal mineralization, chronic hypophosphatemia causes rickets and osteomalacia. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes in bone, functions as the central regulator of phosphate metabolism by increasing the renal excretion of phosphate and suppressing [...] Read more.
Since phosphate is indispensable for skeletal mineralization, chronic hypophosphatemia causes rickets and osteomalacia. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes in bone, functions as the central regulator of phosphate metabolism by increasing the renal excretion of phosphate and suppressing the production of 1,25-dihydroxyvitamin D. The excessive action of FGF23 results in hypophosphatemic diseases, which include a number of genetic disorders such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). Phosphate-regulating gene homologous to endopeptidase on the X chromosome (PHEX), dentin matrix protein 1 (DMP1), ectonucleotide pyrophosphatase phosphodiesterase-1, and family with sequence similarity 20c, the inactivating variants of which are responsible for FGF23-related hereditary rickets/osteomalacia, are highly expressed in osteocytes, similar to FGF23, suggesting that they are local negative regulators of FGF23. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by cleavage-resistant variants of FGF23, and iron deficiency increases serum levels of FGF23 and the manifestation of symptoms in ADHR. Enhanced FGF receptor (FGFR) signaling in osteocytes is suggested to be involved in the overproduction of FGF23 in XLH and autosomal recessive hypophosphatemic rickets type 1, which are caused by the inactivation of PHEX and DMP1, respectively. TIO is caused by the overproduction of FGF23 by phosphaturic tumors, which are often positive for FGFR. FGF23-related hypophosphatemia may also be associated with McCune-Albright syndrome, linear sebaceous nevus syndrome, and the intravenous administration of iron. This review summarizes current knowledge on the pathogenesis of FGF23-related hypophosphatemic diseases. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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Other

7 pages, 708 KiB  
Case Report
The Possible Outcomes of Poor Adherence to Conventional Treatment in Patients with X-Linked Hypophosphatemic Rickets/Osteomalacia
by Hiroaki Zukeran, Kento Ikegawa, Chikahiko Numakura and Yukihiro Hasegawa
Endocrines 2023, 4(1), 110-116; https://doi.org/10.3390/endocrines4010010 - 13 Feb 2023
Viewed by 1887
Abstract
X-linked hypophosphatemic rickets/osteomalacia is an inherited disease caused by the loss of function in PHEX. Elevated plasma FGF23 in patients with XLH leads to hypophosphatemia. The conventional treatment for XLH, consisting of oral phosphate and active vitamin D, is often poorly adhered [...] Read more.
X-linked hypophosphatemic rickets/osteomalacia is an inherited disease caused by the loss of function in PHEX. Elevated plasma FGF23 in patients with XLH leads to hypophosphatemia. The conventional treatment for XLH, consisting of oral phosphate and active vitamin D, is often poorly adhered to for various reasons, such as the requirement to take multiple daily doses of phosphate. Burosumab, an anti-FGF23 antibody, is a new drug that directly targets the mechanism underlying XLH. We report herein three adult patients with poor adherence to the conventional treatment. In Patient 1, adherence was poor throughout childhood and adolescence. The treatment of Patients 2 and 3 became insufficient after adolescence. All of the patients suffered from gait disturbance caused by pain, fractures, and lower extremity deformities early in life. We prescribed burosumab for the latter two patients, and their symptoms, which were unaffected by resuming conventional treatment, dramatically improved with burosumab. Maintaining adherence to the conventional treatment is crucial but challenging for patients with XLH. Starting burosumab therapy from childhood or adolescence in pediatric patients with poor adherence may help prevent the early onset of complications. Full article
(This article belongs to the Special Issue Update on X-linked Hypophosphatemia)
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