[Rare causes of Hypophosphatemia: diagnostic approach]. / Hypophosphatémies de causes rares : approche diagnostique.

Hypophosphatemia is common and may be overlooked due to its asymptomatic nature or non-specific symptoms. Two main mechanisms are at its origin: a shift towards the intracellular sector and an increase in urinary phosphate excretion. A measurement of the urinary phosphate reabsorption threshold allows a diagnostic orientation. Alongside common forms of parathyroid hormone-dependent hypophosphatemia, one should not ignore rare FGF23-mediated forms, in particular X-linked hypophosphatemic rickets. The treatment, above all etiological, also includes the administration of phosphate and, in the event of an excess of FGF23, supplementation with calcitriol. In cases of oncogenic osteomalacia and X-linked hypophosphatemic rickets, the use of burosumab, an anti-FGF23 antibody, must be considered.

L'hypophosphatémie est fréquente. Pourtant, elle peut parfois être méconnue de par son caractère asymptomatique ou ses symptômes non spécifiques. Deux grands mécanismes sont à son origine : un shift vers le secteur intracellulaire et une augmentation de l'excrétion urinaire de phosphate. Une mesure du seuil de réabsorption urinaire de phosphate permet une orientation diagnostique. À côté de formes communes d'hypophosphatémies parathormone-dépendantes, il ne faut pas méconnaître des formes rares FGF23 médiées, en particulier le rachitisme hypophosphatémique lié à l'X. Le traitement, avant tout étiologique comporte aussi l'administration de phosphate et lors d'un excès de FGF23, une supplémentation en calcitriol. En cas d'ostéomalacie oncogénique et de rachitisme hypophosphatémique lié à l'X, l'emploi de burosumab, anticorps anti-FGF23, doit être considéré.

Burden of disease of X-linked hypophosphatemia in Japanese and Korean patients: a cross-sectional survey.

The burden of disease of X-linked hypophosphatemia (XLH) in East Asia is poorly understood. This was a cross-sectional study using an online questionnaire to evaluate health-related quality of life (HRQOL) and disease complications in Japanese and Korean patients with XLH. Adults with XLH and the caregivers of children <18 years of age with XLH in Japan and Korea were surveyed. Respondents disclosed demographic data, family history, diagnostic history, medical history, surgical history, disease-specific clinical symptoms, treatment, medications, and use of ancillary equipment. Patient-reported outcomes (PROs; the Western Ontario and McMaster Universities Osteoarthritis Index, the brief pain inventory, and the 36-item short form health survey version 2) were used to assess pain, disability, and HRQOL in adults. Of those surveyed, all 14 children (100%) and 30/32 adults (93.8%) were receiving treatment for XLH. However, despite oral phosphate and active vitamin D use, short stature, gait abnormalities, dental conditions, and decreased physical function were reported. Stapling of the growth plates was reported in 14.3% of children but no adults. Adult patients reported high rates of bone pain (59.4%) and joint pain (65.6%). Caregivers of children with XLH also reported the occurrence of bone pain (35.7%) and joint pain (35.7%). Many adult patients had a history of impaired renal function (9.5%), nephrocalcinosis (15.6%), hyperparathyroidism (15.6%), and parathyroidectomy (6.3%), all of which are associated with conventional XLH treatments. These data show that patients (both pediatric and adult) continue to have symptoms such as pain, disability, and various complications despite receiving conventional therapies.

Twin girls with hypophosphataemic rickets and papilloedema.

A 7 year-old twin girl with hypophosphataemic rickets was evaluated for a recent onset of mild strabismus.She was a homozygous twin sister with hypophosphataemic rickets diagnosed at the age of 2 years, with a mutation in intron 21 of the PHEX gene, which was also present in her sister.The girls' clinical histories were remarkable for an important lower limb varus that progressively improved after starting phosphate supplementation with a galenical solution (Joulies solution 1 mmol phosphate/ml) and vitamin D 1,25 OH.During the examinations, both girls were in good general condition. Physical examinations were unremarkable, except for tibial varus, bilateral fifth finger clinodactyly and bilateral syndactyly of the third and fourth foot fingers. No major head shape abnormalities were noticeable except for a high forehead.One patient presented with a slight strabismus, normal isochoric isocyclic and reactive pupils, no signs of cranial nerve deficit, and no alterations in the rest of the neurological examination. An ophthalmological evaluation showed bilateral papilloedema. A cerebral MRI scan was then performed, suspecting elevated intracranial pressure (figure 1). The same examination was performed on the asymptomatic sister which also demonstrated papilloedema with similar findings on cranial MRI too.

X-linked hypophosphatemic rickets: Orthodontic considerations and management. A case report.

X-linked hypophosphatemic rickets (XLH) is a rare condition affecting bone metabolism. It has characteristic dental features such as poorly mineralised dentine, spontaneous abscess formation in the absence of caries and taurodontism. There are limited published data about patients with this condition undergoing orthodontic treatment, and there is no clear guideline on the suitability of orthodontic treatment in this cohort. We present a case report of a patient with XLH with a confirmed PHEX gene mutation undergoing orthodontic treatment and clinical recommendations to support treatment.

Burden of disease and clinical targets in adult patients with X-linked hypophosphatemia. A comprehensive review.

X-linked hypophosphataemia (XLH) is a lifelong condition. Despite the mounting clinical evidence highlighting the long-term multi-organ sequelae of chronic phosphate wasting and consequent hypophosphatemia over the lifetime and the morbidities associated with adult age, XLH is still perceived as a paediatric disease. INTRODUCTION: Children who have XLH need to transition from paediatric to adult healthcare as young adults. While there is general agreement that all affected children should be treated (if the administration and tolerability of therapy can be adequately monitored), there is a lack of consensus regarding therapy in adults. METHODS: To provide guidance in both diagnosis and treatment of adult XLH patients and promote better provision of care for this potentially underserved group of patients, we review the available clinical evidence and discuss the current challenges underlying the transition from childhood to adulthood care to develop appropriate management and follow-up patterns in adult XLH patients. RESULTS AND CONCLUSIONS: Such a multi-systemic lifelong disease would demand that the multidisciplinary approach, successfully experienced in children, could be transitioned to adulthood care with an integration of specialized sub-disciplines to efficiently control musculoskeletal symptoms while optimizing patients' QoL. Overall, it would be desirable that transition to adulthood care could be a responsibility shared by the paediatric and adult XLH teams. Pharmacological management should require an adequate balance between the benefits derived from the treatment itself with complicated and long-term monitoring and the potential risks, as they may differ across age strata.

A mosaic mutation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) in X-linked hypophosphatemic rickets with mild bone phenotypes.

X-linked hypophosphatemic rickets (XLH) is primarily characterized by renal phosphate wasting with hypophosphatemia, short stature, and bone deformity of the leg. Here we present a male case of XLH with relatively mild bone deformity caused by a mosaic mutation of the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX). Polymerase chain reaction (PCR) direct sequencing revealed a novel in-frame deletion, NM-000444.6:c.671-685del p.Gln224-Ser228del, at exon 6 in PHEX as a mosaic pattern. This mutation was not found in any database and may result in a significant change in higher-order protein structure and function. TA cloning of the PCR product and clone sequencing estimated the mutation allele frequency at 21%. Literature review of the previously reported three cases with novel mosaic mutations in PHEX, together with the present case, suggests that the rates of the mutation allele correlate with phenotype severity to some extent. We initially treated him with nutritional vitamin D supplements and phosphate salts. However, to avoid the development of secondary/tertiary hyperparathyroidism, we had switched nutritional to active vitamin D supplementation with reduced phosphorus salts. The present report contributes to understanding the relationship between the mosaic rate, in addition to the mutation locus, of the PHEX gene, and clinical features of XLH.

Presentation and non-surgical endodontic treatment of two patients with X-linked hypophosphatemia: a case report.

AIM: To describe two patients with X-linked hypophosphatemia presenting with spontaneous signs of pulpal necrosis in multiple intact teeth. The presentation and management are discussed, along with the diagnostic and endodontic treatment challenges. SUMMARY: Two young male patients with X-linked hypophosphatemia were referred to the Department of Restorative Dentistry at the Edinburgh Dental Institute, UK for management of dental infection. Both patients were referred due to their unusual clinical presentation and abnormal root canal morphology. They subsequently presented on multiple occasions with pain or sinus tracts over a 3- and 5-year period whilst under care. Clinical examination revealed intact teeth with buccal swellings, draining buccal sinuses and negative responses to pulp sensibility testing. Radiographic examination, generally consisting of periapical radiographs, revealed intact teeth with a range of unusual morphological features including large pulp chambers, wide canals, short roots and open apices, all with associated periapical radiolucencies. Due to the unusual morphology, some teeth required apexification with a mineral trioxide aggregate plug. Patient 1 underwent root canal treatment on teeth 21 and 43 over a 3-year period. Patient 2 underwent root canal treatment on 10 permanent teeth over a 5-year period. At follow-up, both patients were asymptomatic and clinically the teeth had no signs of infection or periapical inflammation. Radiographic examination confirmed complete resolution of the apical radiolucencies on 11 out of 12 teeth. Favourable outcomes have been demonstrated up to a follow-up of 4.5 years. KEY LEARNING POINTS: Patients with X-linked hypophosphatemia may present with 'spontaneous' signs of pulp necrosis in multiple teeth in the absence of caries and trauma posing a diagnostic challenge. Abnormal morphological features, including wide canals and open apices, may present challenges during root canal treatment. Outcomes demonstrate that an appropriate root canal treatment protocol, including the application of apexification procedures, may be implemented to successfully manage such cases.

Exploring the burden of X-linked hypophosphatemia: a European multi-country qualitative study.

INTRODUCTION: X-linked hypophosphatemia (XLH) is a rare, lifelong, progressive disease characterised by renal phosphate wasting and abnormal bone mineralisation. Symptoms begin in early childhood, with the development of rickets and related skeletal deformities and reduced growth, progressing to long-term complications, including pseudofractures and fractures, as well as pain, stiffness and fatigue. The present study was designed to explore the patient experience of pain, stiffness and fatigue and the psychosocial impact of XLH in detail. METHODS: A cross-sectional qualitative study was conducted in the United Kingdom (18), Finland (6), France (4), Germany (1) and Luxembourg (1) with XLH patients aged 26 and over. Interview discussion guides were developed in consultation with clinical experts and patient associations. Data were analysed thematically. RESULTS: Participants (N = 30) described pain, stiffness and fatigue as frequently experienced symptoms with a significant impact on physical functioning and activities of daily living (ADLs). Some also described the symptoms as impacting their mood/mental health, relationships, social life and leisure activities. Participants described how common symptoms could interact or aggravate other symptoms. Symptoms had often worsened over time, and for many, were associated with concern about the future. Most participants were worried or felt guilty about having children with XLH. The findings confirmed and extended the existing model of the burden of XLH. CONCLUSION: The present study is the first to provide an in-depth analysis of pain, stiffness and fatigue, their impact and the interrelatedness of these symptoms among adults with XLH. The study also described the psychosocial impact of XLH as a hereditary, lifelong progressive disease.

Multidisciplinary patient care in X-linked hypophosphatemic rickets: one challenge, many perspectives.

X­linked hypophosphatemic rickets (XLH, OMIM #307800) is a rare genetic metabolic disorder caused by dysregulation of fibroblast-like growth factor 23 (FGF23) leading to profound reduction in renal phosphate reabsorption. Impaired growth, severe rickets and complex skeletal deformities are direct consequences of hypophosphatemia representing major symptoms of XLH during childhood. In adults, secondary complications including early development of osteoarthritis substantially impair quality of life and cause significant clinical burden. With the global approval of the monoclonal FGF23 antibody burosumab, a targeted treatment with promising results in phase III studies is available for children with XLH. Nevertheless, complete phenotypic rescue is rarely achieved and remaining multisystemic symptoms demand multidisciplinary specialist care. Coordination of patient management within the major medical disciplines is a mainstay to optimize treatment and reduce disease burden. This review aims to depict different perspectives in XLH patient care in the setting of a multidisciplinary centre of expertise for rare bone diseases.

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.

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment.

Apart from the classic forms of rickets, there are rare genetic disorders from the group of vitamin D-resistant rickets where the clinical picture is very similar to the classic forms. Diagnosis of genetically conditioned rickets is often delayed. It is very important to know that a disorder of genetic background may be the cause of the failure of classic treatment in patients with rachitic symptoms. In the group of genetically conditioned rickets there are, among others, congenital hypophosphatemic rickets and vitamin D-dependent rickets type I and II. Congenital hypophosphatemic rickets is characterised by bone mineralisation disturbances related to hypophosphatemia secondary to renal loss of phosphates. The term "hypophosphatemic rickets" covers a group of diseases with similar phenotype but with different genotypes, inheritance models and etiopathogeneses. Mutation of at least 10 genes underlying this disease entity has been described. Vitamin D-dependent rickets are caused by defects of vitamin D metabolism. There are 4 forms described in literature that are distinguished by their genetic causes: type 1A (vitamin D-dependent rickets type IA), type 1B (vitamin D-dependent rickets type IB) and type 2A (vitamin D-dependent rickets type 2A), type 2B (vitamin D-dependent rickets type 2B). A detailed family history in combination with a physical examination, biochemistry and X-ray imaging helps in differential diagnostics of rare forms of rickets.

Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations.

X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia. This case-note review documents the clinical features and the complications of treatment in 59 adults (19 male, 40 female) with XLH. XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort, 14 of which have not been previously reported. Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years. Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common. The rarity of the disease and the large number of variants make it difficult to discern specific genotype-phenotype relationships. A new treatment, an anti-FGF23 antibody, that may affect the natural history of the disease is currently being investigated in clinical trials.

[Rickets/Osteomalacia. Anti-FGF23 antibody therapy in patients with FGF23-related hypophosphatemic rickets and osteomalacia.]

Fibroblast growth factor 23(FGF23)is a phosphaturic hormone, and its excess causes several kinds of congenital and acquired hypophosphatemic diseases. A combination of oral active vitamin D3 and phosphate salt is the current standard therapy for patients with FGF23-related hypophosphatemic rickets and osteomalacia. However, these medications may cause long-term complications, such as secondary hyperparathyroidism and chronic kidney disease. Therefore, an anti-FGF23 neutralizing antibody that blocks FGF23 activity has been produced. X-linked hypophosphatemic rickets(XLHR)is the most prevalent form of hereditary FGF23-related hypophosphatemia. The safety and efficacy of a human anti-FGF23 antibody, KRN23 or burosumab, has been confirmed in adults and children with XLHR. Moreover, Burosumab is being tested as a potential treatment for patients with tumor-induced osteomalacia(TIO), which is the most prevalent form of acquired FGF23-related hypophosphatemia.

[FGF23 related hypophosphatemic rickets:current therapy and unresolved issues].

FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment.

[Vitamin D dependency and its treatment].

Vitamin D dependency is classified to vitamin D-dependent rickets type 1 which shows defective 1,25(OH)(2)D production, and vitamin D-dependent rickets type 2 which shows end-organ unresponsiveness to 1,25(OH)(2)D. Recent advance in the molecular analysis of these diseases revealed variety in the presentation and in the inheritance patterns. Molecular diagnosis would be preferable for adequate therapy especially in type 2.

Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets.

X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible.

Review of the dental implications of X-linked hypophosphataemic rickets (XLHR).

OBJECTIVES: The aim of this article was to review the dental implications of X-linked hypophosphataemic rickets (XLHR) and to provide suggestions regarding the dental treatment of these patients. MATERIALS AND METHODS: The following search items "x-linked hypophosphataemia, hypophosphataemic rickets, vitamin D-resistant rickets" were used for literature search. Only full-text articles were analysed and summarized to get an overview of the different treatments and outcomes of hypophosphataemic patients. RESULTS: Radiographically, very large pulp chambers with an abnormally high pulp volume/tooth volume ratio, suggesting taurodontism, are often evident. The affected teeth are characterised by a thin enamel layer and dentinal defects. The gender distribution of hypophosphataemic patients is almost equal, but postpubertary males seem to show a trend to develop more severe dental symptoms of the disease. Abscesses without any signs of dental caries or trauma are frequent findings. The most often affected teeth are incisors followed by molars and premolars. CONCLUSIONS: Treatment options include frequent dental examination, application of topical fluoride varnish and sealing of pits and fissures to prevent microbial invasion that may result in pulpitis and further endodontic complications. CLINICAL RELEVANCE: X-linked hypophosphataemic rickets is associated with marked structural alterations of dental hard tissues and the development of multiple abscesses and sinus tracts of dental origin. Therefore, profound knowledge of the various dental implications of XLHR is required to provide these patients with the best possible treatment options.

Hypophosphatemic rickets: etiology, clinical features and treatment.

Hypophosphatemic rickets (HR) is a genetic disorder, which prevents sufficient reabsorption of phosphate in the proximal renal tubule, with increased phosphate excretion, resulting in rickets. The more common form of HR is an X-linked inherited trait, with a prevalence of 1/20,000. The defective gene is located on the X chromosome, but females may present with a wide variety of clinical manifestations. The less common form of HR is caused by autosomal-dominant transmission. Activating mutations of the fibroblast growth factor 23 (FGF-23) gene and inactivating mutations in the phosphate regulating gene (PHEX gene with homologies to endopeptidases on the X chromosome), involved in the regulation of FGF-23, have been identified and have been implicated in the pathogenesis of these disturbances. A review of etiopathogenesis and clinical, differential diagnostic and therapeutic aspects of HR, with a particular emphasis on bone impairment, is reported.

Anti-fibroblast growth factor 23 antibody therapy.

PURPOSE OF REVIEW: The review is intended to provide an update on the expanding knowledge regarding diseases caused by the excess actions of fibroblast growth factor 23 (FGF23) and also on the new therapeutic measures for these diseases, with an emphasis on the anti-FGF23 antibody. RECENT FINDINGS: FGF23 decreases serum phosphate and 1,25-dihydroxyvitamin D levels. After the cloning of FGF23, several hypophosphatemic diseases, including tumor-induced osteomalacia and X-linked hypophosphatemic rickets (XLHR), were shown to be caused by excess actions of FGF23. In addition, recent studies indicated that mutations in the family with sequence similarity 20, member C (FAM20C), HRAS and NRAS genes, also caused FGF23-related hypophosphatemic diseases. The inhibition of FGF23 production or activity is, theoretically, an ideal treatment for these hypophosphatemic diseases. The C-terminal fragment of FGF23, inhibitors of FGF receptor and extracellular signal-regulated kinase, and anti-FGF23 antibody were shown to inhibit FGF23 actions both in vitro and in vivo. A phase I clinical trial of anti-FGF23 antibody has shown that this antibody increases serum phosphate in patients with XLHR. SUMMARY: These recent findings confirm that FGF23 has a pivotal role in phosphate metabolism. The inhibition of FGF23 production or activity is promising as a new therapy for FGF23-related hypophosphatemic diseases. Further studies are clearly necessary to establish the clinical utility and long-term safety of these measures.

Unusually severe hypophosphatemic rickets caused by a novel and complex re-arrangement of the PHEX gene.

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX. Several other genetic forms of hypophosphatemia have also been described. These disorders share variable clinical presentation ranging from mild hypophosphatemia to severe lower extremity bowing. We report on a 43-year-old woman with short stature, painful leg deformities, and poor dentation. Her biochemical profile showed hypophosphatemia with renal phosphate wasting. Due to unusually severe clinical presentation and absence of mutations in Sanger sequencing of the PHEX gene, quantitative multiplex ligation-dependent probe amplification was performed. A large deletion within the PHEX gene encompassing exons 8 to 11 was identified. We generated a specific junction fragment using long-range PCR and sequenced the junction fragment to determine the exact deletion breakpoints. We found a heterozygous novel complex re-arrangement involving gross deletions, insertions, and inversion of PHEX (hg19:g.22,115,003_22,141,395del;g:22,145,536_22,150,789delinsCins22,114,640_22,114,698invinsA). Thus, the complex re-arrangement including a deletion of coding exons 8 to 11 of the PHEX can be regarded as the cause of XLH in the patient reported here. Phosphate and active vitamin D treatment was initiated with subsequent relief in bone pain and physical improvement. This report expands the spectrum of clinical severity underlying genetic defects in XLH and highlights the importance of conventional medical therapy even at adult age. Furthermore, our findings underscore the importance of search for gene deletions in patients with suspected XLH.