Editorial

2 pages, 188 KiB

Open AccessEditorial

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

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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

Open AccessCommunication

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 1439

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

Open AccessCommunication

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

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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

Open AccessReview

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 - 02 Feb 2023

Cited by 1 | Viewed by 2111

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

Open AccessFeature PaperEditor’s ChoiceReview

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

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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

Open AccessReview

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 - 08 Sep 2022

Cited by 2 | Viewed by 1754

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

Open AccessFeature PaperReview

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 3388

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

Open AccessFeature PaperReview

Pathogenic Variants of the PHEX Gene

by Yasuhisa Ohata and Yasuki Ishihara

Endocrines 2022, 3(3), 498-511; https://doi.org/10.3390/endocrines3030040 - 08 Aug 2022

Cited by 2 | Viewed by 2242

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

Open AccessReview

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 - 03 Aug 2022

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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

Open AccessReview

X-Linked Hypophosphatemia Transition and Team Management

by Takuo Kubota

Endocrines 2022, 3(3), 411-418; https://doi.org/10.3390/endocrines3030032 - 05 Jul 2022

Cited by 2 | Viewed by 1935

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

Open AccessReview

Adult Presentation of X-Linked Hypophosphatemia

by Nobuaki Ito

Endocrines 2022, 3(3), 375-390; https://doi.org/10.3390/endocrines3030030 - 01 Jul 2022

Cited by 2 | Viewed by 3633

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

Open AccessFeature PaperReview

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 - 02 Jun 2022

Cited by 1 | Viewed by 3163

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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7 pages, 708 KiB

Open AccessCase 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

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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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