Do the Heterozygous Carriers of a CYP24A1 Mutation Display a Different Biochemical Phenotype than Wild Types?

2020 ◽  
Author(s):  
Alessandro Brancatella ◽  
Daniele Cappellani ◽  
Martin Kaufmann ◽  
Simona Borsari ◽  
Paolo Piaggi ◽  
...  
Keyword(s):  
Vitamin D ◽  
Fibroblast Growth Factor 23 ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Complete Analysis ◽  
Vitamin D Metabolites ◽  
Loss Of Function ◽  
Wild Type ◽  
Biochemical Phenotype ◽  
Heterozygous Carriers

Abstract Context Human cytochrome P450 24 subfamily A member 1 (CYP24A1) loss-of-function mutations result in impaired activity of the 24-hydroxylase involved in vitamin D catabolism, thus inducing a vitamin D-dependent hypercalcemia. Homozygotes often present an overt clinical phenotype named idiopathic infantile hypercalcemia (IIH), whereas it is debated whether heterozygotes display an abnormal phenotype. Objective To compare the clinical and biochemical features of heterozygous carriers of CYP24A1 variant and healthy wild-type controls sharing the same genetic and environmental exposure. Methods A large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites using mass spectroscopy including 1,24,25(OH)3D3. Subjects were divided into 2 groups according to their genotype: heterozygotes and wild-type for the CYP24A1 variant. Results The proband, a 40-year-old man, homozygous for p.Arg223* pathogenic variant, had a history of mild hypercalcemia with a seasonal trend, recurrent nephrolithiasis, and no episodes of acute hypercalcemia. He showed the highest serum levels of fibroblast growth factor 23, the highest 25(OH)D3/24,25(OH)2D3 ratio and undetectable levels of 1,24,25(OH)3D3, which represent indicators of a loss-of-function CYP24A1. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations (P = .017 and P = .025, respectively), without any difference in the other biochemical parameters and in the rate of nephrolithiasis. Conclusion Heterozygotes exhibit a biochemical phenotype different from that of wild-type subjects. In clinical practice, these individuals might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

scholarly journals Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Daniele Cappellani ◽  
Alessandro Brancatella ◽  
Martin Kaufmann ◽  
Angelo Minucci ◽  
Edda Vignali ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Mutations ◽  
High Serum ◽  
Pathogenic Variant ◽  
Vitamin D Metabolites ◽  
Loss Of Function ◽  
Life Threatening ◽  
History Of ◽  
Granulomatous Diseases ◽  
Serum Pth

Introduction. Loss of function mutations of CYP24A1 gene, which is involved in vitamin D catabolism, cause vitamin D-mediated PTH-independent hypercalcemia. The phenotype varies from life-threatening forms in the infancy to milder forms in the adulthood. Case Presentation. We report a case of a 17-year-old woman with a history of nephrolithiasis, mild PTH-independent hypercalcemia (10,5mg/dL), and high serum 1,25(OH)2D concentrations (107pg/mL). Other causes of hypercalcemia associated with the above biochemical signature were excluded. Family history revealed nephrolithiasis in the sister. Blood testing in first-degree relatives showed serum PTH in the low-normal range and 1,25(OH)2D at the upper normal limit or slightly elevated. The CYP24A1 gene analysis revealed a known homozygous loss-of-function pathogenic variant (c.428_430delAAG, rs777676129, p.Glu143del). The panel of vitamin D metabolites evaluated by liquid chromatography showed the typical profile of CYP24A1 mutations, namely, low 24,25(OH)2D3, elevated 25(OH)D3:24,25(OH)2D3 ratio, and undetectable 1,24,25(OH)3D3. The parents and both the siblings harbored the same variant in heterozygosis. We decided for a watchful waiting approach and the patient remained clinically and biochemically stable over a 24-month followup. Conclusion. CYP24A1 gene mutations should be considered in cases of PTH-independent hypercalcemia, once that more common causes (hypercalcemia of malignancy, granulomatous diseases, and vitamin D intoxication) have been ruled out.

scholarly journals The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 563
Author(s):  
Jon Vincze ◽  
Brian W. Skinner ◽  
Katherine A. Tucker ◽  
Kory A. Conaway ◽  
Jonathan W. Lowery ◽  
...  
Keyword(s):  
Vitamin D ◽  
Biological Effects ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Fractional Excretion ◽  
The United States ◽  
Vitamin D Supplementation ◽  
Loss Of Function ◽  
Case Presentation ◽  
Serum Inorganic Phosphate

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

scholarly journals Regulation of serum 1,25(OH)2Vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4

2011 ◽  
Vol 301 (2) ◽  
pp. F371-F377 ◽  
Author(s):  
Jyothsna Gattineni ◽  
Katherine Twombley ◽  
Regina Goetz ◽  
Moosa Mohammadi ◽  
Michel Baum
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Serum Levels ◽  
Phosphate Transport ◽  
Fibroblast Growth ◽  
Wild Type ◽  
Baseline Serum ◽  
Renal Phosphate Reabsorption

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. To determine the FGFRs regulating 1,25(OH)2Vitamin D3 levels, we studied FGFR3−/−FGFR4−/− mice as these mice have shortened life span and are growth retarded similar to FGF23−/− and Klotho−/− mice. Baseline serum 1,25(OH)2Vitamin D3 levels were elevated in the FGFR3−/−FGFR4−/− mice compared with wild-type mice (102.2 ± 14.8 vs. 266.0 ± 34.0 pmol/l; P = 0.001) as were the serum levels of FGF23. Administration of recombinant FGF23 had no effect on serum 1,25(OH)2Vitamin D3 in the FGFR3−/−FGFR4−/− mice (173.4 ± 32.7 vs. 219.7 ± 56.5 pmol/l; vehicle vs. FGF23) while it reduced serum 1,25(OH)2Vitamin D3 levels in wild-type mice. Administration of FGF23 to FGFR3−/−FGFR4−/− mice resulted in a decrease in serum parathyroid hormone (PTH) levels and an increase in serum phosphorus levels mediated by increased renal phosphate reabsorption. These data indicate that FGFR3 and 4 are the receptors that regulate serum 1,25(OH)2Vitamin D3 levels in response to FGF23. In addition, when 1,25(OH)2Vitamin D3 levels are not affected by FGF23, as in FGFR3−/−FGFR4−/− mice, a reduction in PTH can override the effects of FGF23 on renal phosphate transport.

scholarly journals Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Wo-Tu Tian ◽  
Fei-Xia Zhan ◽  
Qing Liu ◽  
Xing-Hua Luan ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Western Blotting ◽  
Age Of Onset ◽  
Neuropsychiatric Symptoms ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Brain Biopsy ◽  
Loss Of Function ◽  
Wild Type ◽  
Axonal Spheroids ◽  
Initial Symptoms

Abstract Background CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. Methods In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. Results Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. Conclusions Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. Trial registration ChiCTR, ChiCTR1800015295. Registered 21 March 2018.

scholarly journals CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2

2021 ◽  
Vol 22 (22) ◽  
pp. 12423
Author(s):  
Sara Morais ◽  
Mónica Pereira ◽  
Catarina Lau ◽  
Ana Gonçalves ◽  
Catarina Monteiro ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Pathogenic Variant ◽  
Nucleotide Exchange ◽  
Pathogenic Variants ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Heterozygous Carriers

RASGRP2 encodes the calcium and diacylglycerol (DAG)-regulated guanine nucleotide exchange factor I (CalDAG-GEFI) identified as a Rap1-activating molecule. Pathogenic variants previously identified in RASGRP2 allowed the characterization of CalDAG-GEFI deficiency as a non-syndromic, autosomal recessive platelet function disease. We report on the clinical manifestations and laboratory features of a Portuguese family with a likely pathogenic variant in RASGRP2 (c.999G>C leading to a p.Lys333Asn change in the CDC25 catalytic domain of CalDAG-GEFI) and discuss the contribution of this variant to the disease manifestations. Based on the study of this family with one homozygous patient and five heterozygous carriers and on a critical analysis of the literature, we challenge previous knowledge that CalDAG-GEFI deficiency only manifests in homozygous patients. Our data suggest that at least for the RASGRP2 variant reported herein, there is a phenotypic expression, albeit milder, in heterozygous carriers.

scholarly journals Coexistent CYP24A1 and PHEX Gene Mutations With Hypervitaminosis D Plus Hypercalcemia Treated With Fluconazole

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A188-A189
Author(s):  
David Bawden ◽  
William Fraser ◽  
Darrell Green ◽  
Shoib Ur Rehman
Keyword(s):  
Vitamin D ◽  
Gene Mutations ◽  
Pathogenic Variant ◽  
Full Blood Count ◽  
Vitamin D Metabolites ◽  
Dihydroxyvitamin D ◽  
Hypervitaminosis D ◽  
Vitamin D Levels ◽  
Phex Gene ◽  
25 Oh Vitamin D

Abstract Background: CYP24A1 and PHEX gene mutations are rare and can cause hypercalcemia, hypervitaminosis D and elevated FGF23 levels. Fluconazole, an antifungal medication, has shown therapeutic benefit in achieving normocalcemia plus normalisation of vitamin D levels in this case report. Clinical Case: A 42 year old man was referred to the endocrine clinic with a history of severe nephrocalcinosis and recurrent nephrolithiasis requiring surgical intervention and gradual decline in kidney function over 20 years. Biochemical investigations revealed hypercalcaemia with adjusted calcium levels of 2.83 mmol/L (R 2.2–2.6 nmol/L) and suppressed PTH 1.1 pmol/L(R 1.6–6.9 pmol/L). Twenty-four hour urine calcium/creatinine clearance ratio was above 0.0578 mmol/mmol indicating hypercalciuria. Vitamin D metabolites 25 OH Vitamin D was elevated at 201 nmol/L, (R 50–120 nmol/L) along with intermittently elevated 1,25 OH Vitamin D 147 pmol/L(R 55–139 pml/L). 24,25 Vitamin D was low at 2.0 nmol/L producing a 25:24,25 dihydroxyvitamin D ratio of 80 (n<25). This biochemical data was highly suggestive of a loss of function mutation in the CYP24A1 gene that codes for the enzyme 24-hydroxylase, which is responsible for conversion of 1,25 vitamin D to 24,25 vitamin D. A pathogenic variant (heterozygous c.756G>A) was confirmed on genetic testing. Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n<100 RU/mL) but a full body octreotide scan did not reveal malignancy or other paraneoplastic syndromes such as oncogenic osteomalacia. A pathogenic variant in his PHEX gene (homozygous c.1874A>T) was also identified that has been associated with increased levels of FGF23 plus hypophosphataemia. Fluconazole at 50 mg once daily was initiated. Azoles inhibit cytochrome P450 enzymes and have been used in sarcoidosis to block vitamin D-synthesizing enzymes such as 25-hydroxylases and 1-α-hydroxylase that are P450 dependent. Few cases of CYP24A1 gene defects have been treated with fluconazole, which has a favourable side effect profile and yields good results. Adjusted calcium reduced to 2.62 nmol/L, 25 OH Vitamin D normalised to 111 nmol/L and 24:24,25 dihydroxyvitamin D ratio is now 17. Patient’s liver functions and full blood count has been monitored regularly during the course of treatment and the drug was well tolerated. Conclusion: Genetic causes of hypercalcemia can be left undiagnosed for long periods and there is a lack of proven or definitive therapeutic agents for correction of elevated calcium. Here fluconazole has been shown to reduce the hypercalcaemic burden and effectively lowered the Vitamin D levels in this case of a CYP24A1 mutation. This study augments fluconazole use in these cases but further studies are needed to elucidate the long term safe usage.

scholarly journals Very Low Vitamin D in a Patient with a Novel Pathogenic Variant in the GC Gene that encodes Vitamin D-Binding Protein

2021 ◽  
Author(s):  
Ronadip R Banerjee ◽  
Tara Spence ◽  
Stuart J Frank ◽  
Raj Pandian ◽  
Andrew N Hoofnagle ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Deletion ◽  
Binding Protein ◽  
Pathogenic Variant ◽  
Plasma Vitamin ◽  
Vitamin D Metabolites ◽  
Vitamin D Binding Protein ◽  
Hydroxyvitamin D ◽  
Vitamin D Levels ◽  
Gc Gene

Abstract Circulating plasma vitamin D metabolites are highly bound to vitamin D-binding protein (DBP), also known as group-specific component or Gc-globulin. DBP, encoded by the GC gene, is a member of the albumin family of globular serum transport proteins. We previously described a homozygous GC gene deletion in a patient with apparent severe vitamin D deficiency, fragility fractures and ankylosing spondylitis. Here, we report an unrelated patient free of fractures or rheumatologic disease, but with very low 25-hydroxyvitamin D and 1,25-hydroxyvitamin D, as well as undetectable DBP measured by liquid chromatography-tandem mass spectrometry. A whole gene deletion was excluded by microarray, and Sanger sequencing of GC revealed a homozygous pathogenic variant affecting a canonical splice site (c.702-1G>A). These findings indicate that loss of function variants in GC that eliminate DBP, and severely reduced total circulating vitamin D levels, do not necessarily result in significant metabolic bone disease. Together with our previous report, these cases support the free-hormone hypothesis, and suggest free vitamin D metabolites may serve as preferable indicators of bone and mineral metabolism, particularly when clinical suspicion of DBP deficiency is high.

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