scholarly journals A PHEX Gene Mutation Is Responsible for Adult-Onset Vitamin D-Resistant Hypophosphatemic Osteomalacia: Evidence That the Disorder Is Not a Distinct Entity from X-Linked Hypophosphatemic Rickets1

1998 ◽  
Vol 83 (10) ◽  
pp. 3459-3462
Author(s):  
Michael J. Econs ◽  
Nancy E. Friedman ◽  
Peter S. N. Rowe ◽  
Marcy C. Speer ◽  
Fiona Francis ◽  
...  
Keyword(s):  
Vitamin D ◽  
Amino Acid Change ◽  
Hypophosphatemic Rickets ◽  
Adult Onset ◽  
Older Individuals ◽  
Distinct Entity ◽  
Radiographic Evidence ◽  
Dominant Form ◽  
Phex Gene ◽  
Hypophosphatemic Osteomalacia

Previous investigators described a kindred with an X-linked dominant form of phosphate wasting in which affected children did not have radiographic evidence of rickets, whereas older individuals were progressively disabled by severe bowing. They proposed that this kindred suffered from a distinct disorder that they referred to as adult-onset vitamin D-resistant hypophosphatemic osteomalacia (AVDRR). We recently identified a gene, PHEX, that is responsible for the disorder X-linked hypophosphatemic rickets. To determine whether AVDRR is a distinct form of phosphate wasting, we searched for PHEX mutations in affected members of the original AVDRR kindred. We found that affected individuals have a missense mutation in PHEX exon 16 that results in an amino acid change from leucine to proline in residue 555. Clinical evaluation of individuals from this family indicates that some of these individuals display classic features of X-linked hypophosphatemic rickets, and we were unable to verify progressive bowing in adults. In light of the variability in the clinical spectrum of X-linked hypophosphatemic rickets and the presence of a PHEX mutation in affected members of this kindred, we conclude that there is only one form of X-linked dominant phosphate wasting.

scholarly journals MON-373 Low Bone Mineral Density Does Not Equal Osteoporosis: The Finding of XLHR with a Novel Phex Mutation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Kelvin Tran ◽  
Michael Mortensen ◽  
Ghada Elshimy ◽  
Karyne Lima Vinales ◽  
Ricardo Rafael Correa
Keyword(s):  
Vitamin D ◽  
Genetic Testing ◽  
Hypophosphatemic Rickets ◽  
Mineral Density ◽  
Inherited Disorders ◽  
Femur Fractures ◽  
Vitamin D Levels ◽  
Phex Gene ◽  
History Of ◽  
Fgf 23

Abstract Introduction: X-linked Hypophosphatemic rickets (XLHR) is a rare form of rickets that mainly affects children but, in some cases, it can be missed and not diagnosed until later in life. We present a post-menopausal female that was misdiagnosed with osteoporosis for many years until complete work up was done, and she was found to have osteomalacia due to hypophosphatemia. Clinical case: A 59-year-old female was evaluated following admission to the hospital for a worsening femur fracture on imaging and had received ORIF. She was diagnosed with osteoporosis at the age of 45 and endorses a history of multiple femur fractures from low impact trauma. Despite previous bisphosphonate therapy, she continued to have recurrent fractures.[RC1] She reported no family history of early osteoporosis, but her mother was diagnosed with rickets as a child. Secondary workup for osteoporosis revealed normal 25OH vitamin D, SPEP, TSH, PTH and serum calcium, endomysial antibodies, and 24-hour urine calcium levels. However, the patient had persistently elevated alkaline phosphatase levels (150-200) and low phosphate levels (1.8-2.4). This raised the possibility of Paget’s disease, so a bone scan and lumbar X-ray were obtained which were normal. Given low phosphate levels, fibroblast growth factor (FGF)-23 was obtained and was elevated. This left the differential between tumor-induced osteomalacia (TIO) vs hypophosphatemic rickets. Ga-DOTATE scan and PET scan were negative, so the patient subsequently underwent genetic testing. She was found to have a phosphate regulating endopeptidase homologue (PHEX) gene mutation and was finally diagnosed with XLHR Her PHEX mutation was caused by a novel variant, c.1366 T>C or W456R, which has only been documented once in the literature. The patient was treated with 2 gm per day of phosphate supplementation in divided doses and calcitriol 0.25 mcg once daily which normalized her phosphate and 1,25 vitamin D levels. 1 month later after treatment, she reported significant improvements in bone pain, and her DEXA scans were stable for the following 4 years. Discussion: XLHR is a heterogeneous group of inherited disorders characterized by hypophosphatemia and impaired bone mineralization leading to rickets. It results from mutations affecting the PHEX gene of which more than 300 pathogenic variants have been described. The mutation causes excess FGF-23 which leads to osteomalacia and chronic hypophosphatemia. This condition can be difficult to distinguish from TIO as both present with low phosphate and elevated FGF-23 but can be differentiated with genetic testing. Recognition of the correct diagnosis is prudent to providing correct treatment. The current treatment for XLH is calcitriol and phosphorus replacement. Recently, burosumab was FDA approved in 2018 for treatment in adults.

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 <0.14), inappropriately normal FGF23 level (129 RU/ml) (N: >124 RU/mL). Genetic testing showed de novo mutation in PHEX gene (871C>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.

Adult-Onset Vitamin-D-Resistant Hypophosphatemic Osteomalacia

1969 ◽  
Vol 281 (14) ◽  
pp. 762-766 ◽  
Author(s):  
B. Lawrence Riggs ◽  
Randall G. Sprague ◽  
Jenifer Jowsey ◽  
Frank T. Maher
Keyword(s):  
Vitamin D ◽  
Adult Onset ◽  
Hypophosphatemic Osteomalacia

Deformity correction for vitamin D-resistant hypophosphatemic rickets of adults

2007 ◽  
Vol 128 (10) ◽  
pp. 1137-1143 ◽  
Author(s):  
Hidenori Matsubara ◽  
Hiroyuki Tsuchiya ◽  
Tamon Kabata ◽  
Keisuke Sakurakichi ◽  
Koji Watanabe ◽  
...  
Keyword(s):  
Vitamin D ◽  
Deformity Correction ◽  
Hypophosphatemic Rickets

Genotype and phenotypic spectrum of vitamin D dependent rickets type 1A: our experience and systematic review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Manjunath Havalappa Dodamani ◽  
Manjeetkaur Sehemby ◽  
Saba Samad Memon ◽  
Vijaya Sarathi ◽  
Anurag R. Lila ◽  
...  
Keyword(s):  
Systematic Review ◽  
Vitamin D ◽  
World Literature ◽  
Hot Spot ◽  
Severe Disease ◽  
Delayed Diagnosis ◽  
Hypophosphatemic Rickets ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Pathogenic Variants

Abstract Background Vitamin D dependent rickets type 1 (VDDR1) is a rare disease due to pathogenic variants in 1-α hydroxylase gene. We describe our experience with systematic review of world literature to describe phenotype and genotype. Methods Seven patients from six unrelated families with genetically proven VDDR1 from our cohort and 165 probands from systematic review were analyzed retrospectively. The clinical features, biochemistry, genetics, management, and long-term outcome were retrieved. Results In our cohort, the median age at presentation and diagnosis was 11(4–18) and 40(30–240) months. The delayed diagnoses were due to misdiagnoses as renal tubular acidosis and hypophosphatemic rickets. Four had hypocalcemic seizures in infancy whereas all had rickets by 2 years. All patients had biochemical response to calcitriol, however two patients diagnosed post-puberty had persistent deformity. Genetic analysis revealed two novel (p.Met260Arg, p.Arg453Leu) and a recurring variant (p.Phe443Profs*24). Systematic review showed that seizures as most common presentation in infancy, whereas delayed motor milestones and deformities after infancy. Diagnosis was delayed in 27 patients. Patients with unsatisfactory response despite compliance were >12 years at treatment initiation. Inappropriately normal 1,25(OH)2D may be present, however suppressed ratio of 1,25(OH)2 D/25(OH)D may provide a clue to diagnosis. Various region specific and hot-spot recurrent variants are described. Patients with truncating variants had higher daily calcitriol requirement and greatly suppressed ratio of 1,25(OH)2D/25(OH)D. Conclusion Delayed diagnosis may lead to permanent short stature and deformities. Truncating variants tend to have severe disease as compared to non-truncating variants. Diagnostic accuracy of 1,25(OH)2 D/25(OH)D ratio needs further validation.

METABOLIC AND ORTHOPEDIC ASPECT OF X-LINKED VITAMIN D-RESISTANT HYPOPHOSPHATEMIC RICKETS

2021 ◽  
pp. 42-43
Author(s):  
Rahul Kumar ◽  
Rajni Kumari ◽  
Shailesh Kumar ◽  
Santosh Kumar
Keyword(s):  
Vitamin D ◽  
Surgical Correction ◽  
Lower Limbs ◽  
Hypophosphatemic Rickets ◽  
Bone Lengthening ◽  
Normal Range ◽  
Bone Deformity ◽  
Bone Maturation ◽  
Leg Axis

INTRODUCTION: - The X-linked vitamin D-resistant hypophosphatemic rickets (VDXLR) is a metabolic disorder. Medication treatment consists of oral phosphate substitution and supplementation of active vitamin D compounds. Our study aimed to review our patients with VDXLR, focusing on those undergoing surgery, mainly lengthening procedures. The main parameters of interest were growth, height, the axis of the lower limbs, pain, and degenerative arthropathy. METHODS: - Twelve patients with VDXLR were followed at our institution. Eight patients underwent surgical correction, and three of them in combination with bone lengthening. The corrections were executed at the end of growth in the patients. Clinical end points were height, leg axis, and pain. RESULTS: - Single bilateral surgical correction was performed in six patients; one patient had three and ve corrections. Bone lengthening was performed in three patients. At the last follow-up, the height of seven operated patients was within normal range. In addition, the leg axis was normalized in six patients with mild genua vara in two. Bone healing was excellent, and no surgical complications. There was no one radiological evidence of degenerative arthropathy. CONCLUSIONS: - In case of bone deformity, surgery can safely be performed, independent of age or bone maturation. All patients were happy with the outcomes of axial corrective surgery and bone lengthening, and in the majority. Only one corrective intervention was needed.

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.

Sign in / Sign up

Export Citation Format

Share Document