scholarly journals X-Linked Hypophosphatemic Rickets: Multisystemic Disorder in Children Requiring Multidisciplinary Management

2021 ◽  
Vol 12 ◽  
Author(s):  
Giampiero Igli Baroncelli ◽  
Stefano Mora
Keyword(s):  
Conventional Treatment ◽  
Fibroblast Growth Factor 23 ◽  
Serum Levels ◽  
Normal Serum ◽  
Tubular Reabsorption ◽  
Lower Limbs ◽  
Hypophosphatemic Rickets ◽  
Vitamin D Metabolites ◽  
Hydroxylase Activity ◽  
Phex Gene

X-linked hypophosphatemic rickets (XLH) is the commonest inherited form of rickets. It is caused by an impaired regulation of fibroblast growth factor 23 (FGF23) due to a PHEX gene mutation, which leads to reduced tubular reabsorption of phosphate and renal 1α-hydroxylase activity and increased renal 24-hydroxylase activity. Hypophosphatemia associated with renal phosphate wasting, normal serum levels of calcium, parathyroid hormone, and 25-hydroxyvitamin D represents the main biochemical sign in affected patients. Patients with XLH show rickets and osteomalacia, severe deformities of the lower limbs, bone and muscular pain, stunted growth, and reduced quality of life. However, XLH is a multisystemic disorder requiring multidisciplinary approaches in specialized subdisciplines. Severe complications may occur in patients with XLH including craniosynostosis, hearing loss, progressive bone deformities, dental and periodontal recurrent lesions, and psychosocial distress. Moreover, long-term conventional treatment with active vitamin D metabolites and oral inorganic phosphate salts may cause endocrinological complications such as secondary or tertiary hyperparathyroidism, and adverse events in kidney as hypercalciuria, nephrocalcinosis, and nephrolithiasis. However, conventional treatment does not improve phosphate metabolism and it shows poor and slow effects in improving rickets lesions and linear growth. Recently, some trials of treatment with recombinant human IgG1 monoclonal antibody that targets FGF23 (burosumab) showed significant improvement of serum phosphate concentration and renal tubular reabsorption of phosphate that were associated with a rapid healing of radiologic signs of rickets, reduced muscular and osteoarticular pain, and improved physical function, being more effective for the treatment of patients with XLH in comparison with conventional therapy. Therefore, a global management of patients with XLH is strongly recommended and patients should be seen regularly by a multidisciplinary team of experts.

Management of patients with X-linked hypophosphatemic rickets during Covid-19 pandemic lockdown

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Giampiero I. Baroncelli ◽  
Silvano Bertelloni ◽  
Mirna Cosci o Di Coscio ◽  
Nina Tyutyusheva ◽  
Sofia D’Elios ◽  
...  
Keyword(s):  
Conventional Treatment ◽  
Pediatric Patients ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Vitamin D Metabolites ◽  
Health Technologies ◽  
Phone Calls ◽  
High Doses ◽  
Phosphate Salts

Abstract Objectives To identify a safe pathway for management and treatment of patients with X-linked hypophosphatemic rickets (XLH) during Covid-19 pandemic lockdown. Methods Twenty-six patients with XLH (age 3.1–25.7 years) were enrolled in Pediatric Endocrine Unit; nine of them were receiving human monoclonal anti-fibroblast growth factor 23 antibody (burosumab) and 17 (pediatric patients, age 9.5–17.9 years, n=7; young-adult patients, age 20.1–25.7 years, n=10) received conventional treatment with inorganic oral phosphate salts and active vitamin D metabolites. A Covid-19 free pathway was addressed for XLH patients receiving burosumab treatment in hospital. XLH patients receiving conventional treatment were followed by phone calls, e-mails, or telemedicine. Results All XLH patients receiving burosumab continued the scheduled follow-up and treatment; none of them was infected by Covid-19. Seven XLH patients out of 17 (41%) receiving conventional treatment showed some complication related to the disease itself or its treatment: periapical abscess with gingival fistula was diagnosed in five patients (three children and two young-adults) and treated with antibiotics with complete resolution; one child showed abdominal pain due to the administration of high doses of inorganic oral phosphate salts solved by reducing the dosage, and one child had severe legs pain during deambulation after orthopedic surgery solved with common analgesics. Conclusions Covid-19 free pathway was safe and effective to manage XLH patients receiving burosumab. E-health technologies were useful methods to follow XLH patients receiving conventional treatment during Covid-19 pandemic lockdown.

scholarly journals X-linked hypophosphatemic rickets: Case report

2014 ◽  
Vol 142 (1-2) ◽  
pp. 75-78 ◽  
Author(s):  
Vladimir Radlovic ◽  
Zeljko Smoljanic ◽  
Nedeljko Radlovic ◽  
Zoran Lekovic ◽  
Dragana Ristic ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
De Novo ◽  
Serum Levels ◽  
High Serum ◽  
Hypophosphatemic Rickets ◽  
De Novo Mutation ◽  
Inherited Disease ◽  
X Ray ◽  
Phex Gene ◽  
Renal Tubular

Introduction. X-linked hypophosphatemic rickets (XLHR) is a dominant inherited disease caused by isolated renal phosphate wasting and impairment of vitamin D activation. We present a girl with X-linked hypophosphatemic rickets (XLHR) as a consequence of de novo mutation in the PHEX gene. Case Outline. A 2.2-year-old girl presented with prominent lower limb rachitic deformity, waddling gait and disproportionate short stature (79 cm, <P5; -1,85 SD). On the basis of hypophosphatemia, hyperphosphaturia, high serum level of alkaline phosphatase, normal calcemia, 25(OH)D and PTH, as well as characteristic clinical and X-ray findings, diagnosis of hypophosphatemic rickets (HR) was made. Normal calciuria and absence of other renal tubular disorders indicated HR as a consequence of isolated hyperphosphaturia. The treatment (phosphate 55 mg/kg and calcitriol 35 ng/kg per day), introduced 15 month ago, resulted in a stable normalization of alkaline phosphatase and phosphorus serum levels (with intact calcemia and calciuria), disappearance of X-ray signs of the active rickets and improvement of the child?s longitudinal growth (0.6 cm per month). Subsequently, by detection of already known mutation in the PHEX gene: c.1735G>A (p.G579R) (exon 17), XLHR was diagnosed. Analysis of the parental PHEX gene did not show the abnormality, which indicated that the child?s XLHR was caused by de novo mutation of this gene. Conclusion. Identification of genetic defects is exceptionally significant for diagnosis and differential diagnosis of hereditary HR.

scholarly journals Familial hypophosphatemic rickets caused by a large deletion in PHEX gene

2009 ◽  
Vol 161 (4) ◽  
pp. 647-651 ◽  
Author(s):  
Tasuku Saito ◽  
Yutaka Nishii ◽  
Toshiyuki Yasuda ◽  
Nobuaki Ito ◽  
Hisanori Suzuki ◽  
...  
Keyword(s):  
Clinical Features ◽  
Fibroblast Growth Factor 23 ◽  
Somatic Mosaicism ◽  
Underlying Mechanism ◽  
Large Deletion ◽  
Hypophosphatemic Rickets ◽  
Snp Analysis ◽  
Phex Gene ◽  
Dentin Matrix ◽  
Physical Findings

ContextX-linked hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant and recessive hypophosphatemic rickets/osteomalacia (ADHR and ARHR) share common clinical features including high fibroblast growth factor 23 (FGF23) levels. These diseases are caused by mutations in phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and dentin matrix acidic phosphoprotein 1 (DMP1) gene respectively. It remains unclear whether these diseases can be clinically discriminated.ObjectiveTo clarify the underlying mechanism of patients with hypophosphatemic rickets whose parents showed no physical findings suggesting rickets.Design and patientsThe proband is a 39-year-old woman. She and her 37-year-old brother show the same clinical features such as bowing of legs together with hypophosphatemia (sister: P 1.8 mg/dl, brother: P 1.6 mg/dl) and high FGF23 levels (sister: 542 pg/ml, brother: 96 pg/ml). Physical findings of their parents are normal and ARHR was suspected.ResultsSequencing of all coding exons and exon–intron junctions of DMP1 and FGF23 genes showed no mutation. Subsequent analysis revealed that there is a deletion of 52 143 bp including exons 1–3 in PHEX gene in the brother. His sister was found to be a heterozygote for the same deletion indicating that they are suffering from XLH. The same deletion was detected in the mother. However, the amount of the wild-type allele was more and that of the mutant one was less in genomic DNA from the mother compared with those from the sister. Single nucleotide polymorphism (SNP) analysis indicated that the mother has three kinds of PHEX alleles suggesting a somatic mosaicism.ConclusionCareful genetic analysis is mandatory for correct differential diagnosis of hypophosphatemic rickets with high FGF23 levels.

X-linked Hypophosphatemic Rickets: Awareness, Knowledge, and Practice of Pediatric Endocrinologists in Arab Countries

2020 ◽  
Author(s):  
Asma Deeb ◽  
Fahad Al Juraibah ◽  
Muhammad Al Dubayee ◽  
Abdelhadi Habeb
Keyword(s):  
Conventional Treatment ◽  
Fibroblast Growth Factor 23 ◽  
Multidisciplinary Care ◽  
Arab Countries ◽  
Hypophosphatemic Rickets ◽  
Pediatric Endocrinology ◽  
Online Questionnaire ◽  
Pathogenic Variants ◽  
Almost All ◽  
Fgf 23

AbstractX-linked hypophosphatemic rickets (XLHR) is a genetic disease caused by inactivating pathogenic variants in PHEX, which results in reduced mineralization of bone, teeth, and renal phosphate wasting. XLHR is traditionally treated by phosphate and vitamin D analogs. Recently, burosumab, a recombinant anti-fibroblast growth factor-23 (FGF-23) monoclonal antibody was approved as specific XLHR therapy. We aimed to assess the awareness, knowledge, and management of XLHR among members of the Arab Society for Pediatric Endocrinology and Diabetes (ASPED). Of the 97 physicians who answered the online questionnaire, 97% were aware of XLHR, and while 90% screen family members of the index case, only 29% manage children with XLHR. In children with rickets, 40% of participants measure serum/urine phosphate routinely, and 31% request serum FGF-23 in suspected XLHR cases. Almost all responders use conventional XLHR therapy, and 4% used Burosomab. Only 14% were satisfied with the conventional treatment, and 69% reported therapeutic complications in up to 25% of their patients. Multidisciplinary care for XLHR is practiced by 94%, but 82% of providers did not have transition clinics. Pediatric endocrinologists in ASPED countries are aware of XLHR but have variable practice and are unsatisfied with its conventional treatment. Raising awareness of the recognition and modern management of XLHR is needed.

scholarly journals Mineralizing Enthesopathy Is a Common Feature of Renal Phosphate-Wasting Disorders Attributed to FGF23 and Is Exacerbated by Standard Therapy in Hyp Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5906-5917 ◽  
Author(s):  
Andrew C. Karaplis ◽  
Xiuying Bai ◽  
Jean-Pierre Falet ◽  
Carolyn M. Macica
Keyword(s):  
Standard Therapy ◽  
Autosomal Recessive ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Phex Gene ◽  
Dentin Matrix ◽  
Insertion Sites ◽  
Autosomal Recessive Hypophosphatemic Rickets ◽  
The Impact ◽  
Inactivating Mutations

Abstract We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.

scholarly journals SAT-373 A Case of X Linked Hypophosphatemic Rickets Due to DE Novo Phex Gene Mutation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ahmed Badran ◽  
Renee Bargman
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Vitamin D Deficiency ◽  
Fibroblast Growth Factor ◽  
Gene Mutation ◽  
De Novo ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Fibroblast Growth ◽  
Phex Gene

Abstract Introduction Rickets is a condition that can affect bones of infants and children. It is characterized by growth plate demineralization and can occur secondary to, most commonly, vitamin D deficiency or various problems with vitamin D, Calcium or Phosphate metabolism. Hypophosphatemic rickets (HR) is a type of rickets that is inherited by X linked dominant pattern mainly however it can be also inherited by autosomal dominant and recessive patterns in rare cases. X linked dominant type (XLH) affects about 1 in 20,000 newborns. Each of the other hereditary forms of HR has been identified in only a few families. Clinical features of XLH is similar to other types of rickets including metaphyseal widening, palpable rachitic rosaries, frontal prominence, malformation of the horizontal depression along the lower border of the chest, insufficient weight gain and leg bowing. Case presentation: A 10-month-old infant presented to endocrinology with vitamin D deficiency, low serum phosphorus and hyperparathyroidism. Physical examination showed macrocephaly with frontal bossing, widening of the wrists and rachitic rosaries. His lab results showed low 25 OH vitamin D (11 ng/ml) (N:20-50 ng/ml), low phosphorus (PO4) (3.3 mg/dl) (N:4-6.5 mg/dl), high PTH (113 pg/ml) (N: 20-65pg/ml), high alkaline phosphatase (ALP) (836 IU/L) (N: 135-518 IU/L) and normal calcium (Ca2+) (9.6 mg/dl) (N:9-11 mg/dl). Vitamin D treatment was started however his follow up lab results showed persistent hypophosphatemia for age (2.8mg/dl) and elevated ALP (600IU/l) despite normalization of vitamin D (38 ng/ml). Additional lab tests were done showing high PO4 excretion (19.5 mg/dl)(N:1:3.5 mg/dl), Ca/Cr ratio 0.005 (N &lt;0.14), inappropriately normal FGF23 level (129 RU/ml) (N: &gt;124 RU/mL). Genetic testing showed de novo mutation in PHEX gene (871C&gt;T) which is consistent with XLH. PHEX gene mutation is the most common mutation associated with XLH. Normally this gene can directly or indirectly regulate a protein called fibroblast growth factor 23 (produced from FGF23 gene). This protein normally inhibits renal reabsorption of phosphate into the bloodstream. Gene mutations increase the production or reduce the breakdown of fibroblast growth factor 23 leading to an overactivation of this protein and reduction of phosphate reabsorption by the kidneys, resulting in hypophosphatemia. The patient was maintained on Burosomab (0.4 mg/kg biweekly); a recombinant human monoclonal antibody (IgG1) that binds to and inhibits the activity of fibroblast growth factor 23 (FGF23) and increases the phosphate reabsorption in the renal tubules. Conclusion: XLH due to PHEX gene mutation should be considered in rachitic children who have persistently low phosphate levels despite treating vitamin D deficiency.

scholarly journals Hypophosphatemic rickets and osteomalacia

2006 ◽  
Vol 50 (4) ◽  
pp. 802-813 ◽  
Author(s):  
Hamilton de Menezes Filho ◽  
Luiz Claudio G. de Castro ◽  
Durval Damiani
Keyword(s):  
Current Knowledge ◽  
Bone Mineralization ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Activating Mutations ◽  
Metabolism Regulation ◽  
Autosomal Dominant Hypophosphatemic Rickets ◽  
Phex Gene ◽  
Fgf 23 ◽  
Increased Activity

The hypophosphatemic conditions that interfere in bone mineralization comprise many hereditary or acquired diseases, all of them sharing the same pathophysiologic mechanism: reduction in the phosphate reabsorption by the renal tubuli. This process leads to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of calcitriol, causing osteomalacia or rickets in children and osteomalacia in adults. X-linked hypophosphatemic rickets, autosomal-dominant hypophosphatemic rickets, and tumor-induced osteomalacia are the main syndromes involved in the hypophosphatemic rickets. Although these conditions exhibit different etiologies, there is a common link among them: increased activity of a phosphaturic factor, being the fibroblast growth factor 23 (FGF-23) the most studied one and to which is attributed a central role in the pathophysiology of the hyperphosphaturic disturbances. Activating mutations of FGF-23 and inactivating mutations in the PHEX gene (a gene on the X chromosome that codes for a Zn-metaloendopeptidase proteolytic enzyme which regulates the phosphate) involved in the regulation of FGF-23 have been identified and have been implicated in the pathogenesis of these disturbances. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal metabolic axis, whose mechanisms of interaction have been poorly understood so far. This paper reviews the current knowledge status concerning the pathophysiology of phosphate metabolism regulation and the pathophysiologic basis of hypophosphatemic rickets. It also analyzes the clinical picture and the therapeutic aspects of these conditions as well.

scholarly journals Autosomal Dominant Hypophosphatemic Rickets Presenting in a Phenotypically Normal Adult Female

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Hala Mualla ◽  
Su Ah Bae ◽  
Abid Yaqub
Keyword(s):  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Missense Variant ◽  
Normal Serum ◽  
Hypophosphatemic Rickets ◽  
Pubic Bone ◽  
Hydroxyvitamin D ◽  
Autosomal Dominant Hypophosphatemic Rickets ◽  
Normal Serum Calcium ◽  
History Of

We describe a presentation of Autosomal Dominant Hypophosphatemic Rickets (ADHR) in a 22-year-old female with normal pubertal growth and development and a negative family history in first-degree relatives. The patient presented with a 2-year history of upper and lower extremity proximal muscle pain and weakness and bilateral femoral neck and pubic bone insufficiency fractures. She had a normal serum calcium but a low phosphate as well as 25-hydroxyvitamin D (25(OH)D) levels leading initially to a diagnosis of osteomalacia. Urine phosphate reabsorption was low confirming a phosphate wasting disorder. She had an elevated Fibroblast Growth Factor 23 (FGF23) level. After Tumor-Induced Osteomalacia was ruled out by extensive imaging, she was sent for genetic testing for hereditary rickets which showed a previously reported missense variant in FGF23. Subsequently, she found out that her father’s maternal aunt and grandfather had ‘bone disorder’ and were wheelchair-bound in adulthood. After replenishment of vitamin D, treatment with calcitriol and phosphate leads to complete resolution of patient’s symptoms and laboratory abnormalities.

scholarly journals Rare cause of pathological fracture in adults as hypophosphatemic rickets

2019 ◽  
Vol 6 (5) ◽  
pp. 1681
Author(s):  
Jeetendra Kumar J. M. ◽  
Mamatha T. R. ◽  
Divya Sharma K. R. ◽  
Gowtham S. Gowda
Keyword(s):  
Autosomal Recessive ◽  
Pathological Fracture ◽  
Autosomal Dominant ◽  
Fibroblast Growth Factor 23 ◽  
Normal Serum ◽  
Hypophosphatemic Rickets ◽  
Correct Identification ◽  
Recessive Type ◽  
Normal Serum Calcium ◽  
Defective Bone

Hypophosphatemic rickets is a disorder of defective bone minerlization due to defect in renal phosphate handling process. It is characterised by increased phosphate excretion accompanied by increased phosphatonins like fibroblast growth factor 23. It can be hereditary form of X linked, autosomal dominant, autosomal recessive type of hypophosphatemic rickets. It is associated with low serum phosphorus, normal serum calcium, inappropriately low to normal vitamin D level. Correct identification of these disorders is important for determining therapy. Early diagnosis and management prevent subsequent complication of the disease.

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