A De Novo Mosaic PHEX Variant Causing Sporadic X-Linked Hypophosphatemic Rickets in a 2-Year-Old Girl

2021 ◽  
Author(s):  
Kok-Siong Poon ◽  
Karen Mei-Ling Tan ◽  
Margaret Zacharin ◽  
Cindy Wei-Li Ho
Keyword(s):  
De Novo ◽  
Sporadic Case ◽  
Hypophosphatemic Rickets ◽  
Genu Varum ◽  
Splice Donor ◽  
Mosaic Pattern ◽  
Pathogenic Variants ◽  
Phex Gene ◽  
History Of ◽  
Generation Sequencing

AbstractPathogenic variants in the PHEX gene are causative of X-linked hypophosphatemic rickets (XLH). We present a case of a 2-year-old girl with hypophosphatemic rickets with genu varum and short stature without any family history of XLH. Next generation sequencing of the PHEX gene identified a splice donor variant, NM_000444.6:c.1173 + 5G > A in intron 10. This variant had a mosaic pattern with only 22% of the sequence reads showing the variant allele and was not present in the girl's parents, both of whom had a normal phenotype. This is a sporadic case of a de novo mosaic splice-site variant in the PHEX gene.

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 Eye Manifestations of Shprintzen–Goldberg Craniosynostosis Syndrome: A Case Report and Systematic Review

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Jamie H. Choi ◽  
Rachel Li ◽  
Rachel Gannaway ◽  
Tahnee N. Causey ◽  
Anna Harrison ◽  
...  
Keyword(s):  
Systematic Review ◽  
De Novo ◽  
Mitral Valve Insufficiency ◽  
Ocular Manifestations ◽  
Pathogenic Variants ◽  
Ophthalmic Manifestations ◽  
Valve Insufficiency ◽  
Aortic Root Dilatation ◽  
History Of ◽  
Tissue Abnormalities

Shprintzen–Goldberg craniosynostosis syndrome (SGS) is a rare autosomal dominant condition that was first documented in literature in 1982. The disorder is caused by pathogenic variants in the proto-oncogene SKI gene, a known suppressor of TGF-β activity, located on chromosome 1p36. There is considerable phenotypic overlap with Marfan and Loeys–Dietz syndromes. Common clinical features of SGS include craniosynostosis, marfanoid habitus, hypotonia, dysmorphic facies, cardiovascular anomalies, and other skeletal and connective tissue abnormalities. Ocular manifestations may include hypertelorism, downslanting palpebral fissures, proptosis, myopia, and ectopia lentis. We describe a 25-year-old male with the syndrome. Genetic analysis revealed a novel c.350G>A (p.Arg117His) de novo variant, which was predicted to be pathogenic by the CTGT laboratory. The patient presented with dysmorphic features, marfanoid habitus, severe joint contractures, mitral valve insufficiency, aortic root dilatation, and a history of seizures. His ocular manifestations included hypertelorism, downslanting palpebral fissures, bilateral ptosis, and high myopia. Ophthalmic manifestations are an integral component of the syndrome; however, they have not been well characterized in the literature. From a systematic review of previously published cases to date, we summarize the eye and ocular adnexa manifestations reported.

scholarly journals Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets

2016 ◽  
Vol 38 (6) ◽  
pp. 1703-1714 ◽  
Author(s):  
Shan-Shan Li ◽  
Jie-Mei Gu ◽  
Wei-Jia Yu ◽  
Jin-Wei He ◽  
Wen-Zhen Fu ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Hypophosphatemic Rickets ◽  
Phex Gene

scholarly journals DFNA20/26 and Other ACTG1-Associated Phenotypes: A Case Report and Review of the Literature

2021 ◽  
Vol 11 (4) ◽  
pp. 582-593
Author(s):  
Ugo Sorrentino ◽  
Chiara Piccolo ◽  
Chiara Rigon ◽  
Valeria Brasson ◽  
Eva Trevisson ◽  
...  
Keyword(s):  
Clinical History ◽  
Auditory Hair Cells ◽  
Pathogenic Variants ◽  
Normal Expression ◽  
Large Panel ◽  
History Of ◽  
Syndromic Hearing Loss ◽  
And Function ◽  
Actin Protein ◽  
Generation Sequencing

Since the early 2000s, an ever-increasing subset of missense pathogenic variants in the ACTG1 gene has been associated with an autosomal-dominant, progressive, typically post-lingual non-syndromic hearing loss (NSHL) condition designed as DFNA20/26. ACTG1 gene encodes gamma actin, the predominant actin protein in the cytoskeleton of auditory hair cells; its normal expression and function are essential for the stereocilia maintenance. Different gain-of-function pathogenic variants of ACTG1 have been associated with two major phenotypes: DFNA20/26 and Baraitser–Winter syndrome, a multiple congenital anomaly disorder. Here, we report a novel ACTG1 variant [c.625G>A (p. Val209Met)] in an adult patient with moderate-severe NSHL characterized by a downsloping audiogram. The patient, who had a clinical history of slowly progressive NSHL and tinnitus, was referred to our laboratory for the analysis of a large panel of NSHL-associated genes by next generation sequencing. An extensive review of previously reported ACTG1 variants and their associated phenotypes was also performed.

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&gt;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 Coffin-Lowry preprint 2018

2018 ◽  
Author(s):  
Paolo Moretti
Keyword(s):  
Family History ◽  
Clinical Features ◽  
De Novo ◽  
Severe Disease ◽  
Immunosuppressive Treatment ◽  
Pathogenic Variant ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

scholarly journals Mutational Analysis and Genotype-Phenotype Correlation of the PHEX Gene in X-Linked Hypophosphatemic Rickets

2001 ◽  
Vol 86 (8) ◽  
pp. 3889-3899 ◽  
Author(s):  
Ingrid A. Holm ◽  
Anne E. Nelson ◽  
Bruce G. Robinson ◽  
Rebecca S. Mason ◽  
Deborah J. Marsh ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Family Members ◽  
Hypophosphatemic Rickets ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Severity Of Disease ◽  
Skeletal Disease ◽  
Phenotype Analysis ◽  
Phex Gene ◽  
History Of

PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.

scholarly journals A unique case of two somatic APC mutations in an early onset cribriform-morular variant of papillary thyroid carcinoma and overview of the literature

2019 ◽  
Vol 19 (1) ◽  
pp. 15-21 ◽  
Author(s):  
M. D. Aydemirli ◽  
K. van der Tuin ◽  
F. J. Hes ◽  
A. M. W. van den Ouweland ◽  
T. van Wezel ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Somatic Mosaicism ◽  
Sporadic Case ◽  
Papillary Thyroid ◽  
Blood Leukocytes ◽  
Pathogenic Variants ◽  
History Of ◽  
Cribriform Morular Variant ◽  
Next Generation Sequencing Ngs

Abstract We report a case of a 22-year-old female patient who was diagnosed with a cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC). While at early ages this thyroid cancer variant is highly suggestive for familial adenomatous polyposis (FAP), there was no family history of FAP. In the tumor biallelic, inactivating APC variants were identified. The patient tested negative for germline variants based on analysis of genomic DNA from peripheral blood leukocytes. Somatic mosaicism was excluded by subsequent deep sequencing of leukocyte and normal thyroid DNA using next generation sequencing (NGS). This report presents a rare sporadic case of CMV-PTC, and to the best of our knowledge the first featuring two somatic APC mutations underlying the disease, with an overview of CMV-PTC cases with detected APC and CTNNB1 pathogenic variants from the literature.

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 ‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

2020 ◽  
Vol 182 (1) ◽  
pp. K1-K6 ◽  
Author(s):  
Yunting Lin ◽  
Yanna Cai ◽  
Jianan Xu ◽  
Chunhua Zeng ◽  
Huiying Sheng ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
De Novo ◽  
Hypophosphatemic Rickets ◽  
Dominant Inheritance ◽  
Germline Mosaicism ◽  
Pathogenic Variants ◽  
First Case ◽  
Heterozygous Variant ◽  
The Family ◽  
Normal Father

Objective X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR. Methods and results For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband. Conclusions This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

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