Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A

Abstract Context: Vitamin D 1α-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1α-hydroxylase (1α-hydroxylase, CYP27B1) gene. The human gene encoding the 1α-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns. We previously isolated the human 1α-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1α-hydroxylase deficiency. Objectives, Patients, and Methods: We analyzed the 1α-hydroxylase gene of 10 patients, five from Korea, two from the United States, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1,25-dihydroxyvitamin D3. Results: Direct sequencing identified the responsible 1α-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included a nonsense mutation in exon 6, substitution of adenine for guanine (2561G→A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C→T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G→A) causing a frameshift. Conclusions: Mutations in the 1α-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1α-hydroxylase mutations and the clinical findings of 1α-hydroxylase deficiency.

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Disorders of bone mineralization—osteomalacia

10.1093/med/9780199642489.003.0146 ◽

2013 ◽

Author(s):

Deepak R. Jadon ◽

Tehseen Ahmed ◽

Ashok K. Bhalla

Keyword(s):

Vitamin D ◽

Bone Mineralization ◽

Bone Biopsy ◽

Gene Mutations ◽

Sun Exposure ◽

Phosphate Deficiency ◽

Skeletal Deformity ◽

Bone Scans ◽

Metabolizing Enzyme ◽

Biochemical Assessment

Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.

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Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0169 ◽

2020 ◽

Vol 33 (10) ◽

pp. 1353-1358

Author(s):

Ayla Güven ◽

Martin Konrad ◽

Karl P. Schlingmann

Keyword(s):

Vitamin D ◽

Stop Codon ◽

Gene Mutations ◽

Splice Site Mutation ◽

Heterozygous Mutation ◽

High Dose ◽

Loss Of Function ◽

Site Mutation ◽

Medullary Nephrocalcinosis ◽

Idiopathic Infantile Hypercalcemia

AbstractObjectivesBoth CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today.Case presentationHypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis.ConclusionsA biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

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Disorders of bone mineralization—osteomalacia

Oxford Textbook of Rheumatology ◽

10.1093/med/9780199642489.003.0146_update_002 ◽

2013 ◽

pp. 1252-1258

Author(s):

Deepak R. Jadon ◽

Tehseen Ahmed ◽

Ashok K. Bhalla

Keyword(s):

Vitamin D ◽

Bone Mineralization ◽

Bone Biopsy ◽

Gene Mutations ◽

Sun Exposure ◽

Phosphate Deficiency ◽

Skeletal Deformity ◽

Bone Scans ◽

Metabolizing Enzyme ◽

Biochemical Assessment

Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.

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WES Reveals Novel Heterozygous NBAS Gene Mutations Associated with Fanconi Syndrome in a Patient with SOPH Syndrome: Case Report

10.36502/2021/asjpch.6162 ◽

2021 ◽

Vol 3 (1) ◽

pp. 1-10

Author(s):

Thong JY ◽

Li Z ◽

Halim A ◽

Wang X ◽

Halim M ◽

...

Keyword(s):

Vitamin D ◽

Case Report ◽

Early Detection ◽

Liver Failure ◽

Acute Liver Failure ◽

Optic Atrophy ◽

Fanconi Syndrome ◽

Clinical Laboratory ◽

Gene Mutations ◽

Whole Exome

Variations in the NBAS gene is known to cause a spectrum of phenotypes ranging from isolated recurrent acute liver failure (RALF) to a multisystemic presentation known as SOPH syndrome. Patients with SOPH present with optic atrophy, acute liver failure, short stature, and Pelger-Huet anomaly. We report the presence of a novel pair of biallelic heterozygous mutations c.5139-5T>G and c.2203-2A>G in the NBAS gene of a patient with SOPH syndrome. A 9-year-old patient was clinically diagnosed with SOPH following clinical laboratory analyses. Current interventions for managing the disease encompass IVIG, methylprednisolone, calcium, and vitamin D administration. Whole-exome sequencing (WES) results showed two mutations: c.2203-2A>G and c.5139-5T>G, in the NBAS gene, which had not been previously reported. Notably, we hypothesize that NBAS mutations could potentially contribute to the development of Fanconi syndrome, a clinical diagnosis reported in our patient. Our study also supports the renaming of SOPH to SOPHIA to allow early detection and effective treatment.

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

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.382 ◽

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.

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Identification of novel Vitamin D Receptor gene mutations in Chinese sporadic patients with Paget's disease of bone

Osteoporosis and Sarcopenia ◽

10.1016/j.afos.2017.08.039 ◽

2017 ◽

Vol 3 (3) ◽

pp. S21

Author(s):

Hua Yue ◽

Zhen-lin Zhang

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Receptor Gene ◽

Paget’S Disease ◽

Gene Mutations ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Vitamin D Receptor Gene ◽

Paget's Disease Of Bone

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Disorders of bone mineralization—osteomalacia

Oxford Textbook of Rheumatology ◽

10.1093/med/9780199642489.003.0146_update_003 ◽

2013 ◽

pp. 1252-1258

Author(s):

Deepak R. Jadon ◽

Tehseen Ahmed ◽

Ashok K. Bhalla

Keyword(s):

Vitamin D ◽

Bone Mineralization ◽

Bone Biopsy ◽

Gene Mutations ◽

Sun Exposure ◽

Phosphate Deficiency ◽

Skeletal Deformity ◽

Bone Scans ◽

Metabolizing Enzyme ◽

Biochemical Assessment

Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.

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Disorders of bone mineralization—osteomalacia

10.1093/med/9780199642489.003.0146_update_001 ◽

2015 ◽

Author(s):

Deepak R. Jadon ◽

Tehseen Ahmed ◽

Ashok K. Bhalla

Keyword(s):

Vitamin D ◽

Bone Mineralization ◽

Bone Biopsy ◽

Gene Mutations ◽

Sun Exposure ◽

Phosphate Deficiency ◽

Skeletal Deformity ◽

Bone Scans ◽

Metabolizing Enzyme ◽

Biochemical Assessment

Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.

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