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Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cases with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.
Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
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Department of Clinical Biochemistry, SUHCG, GUH, Galway, Ireland
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Lambe Institute for Translational Research, School of Medicine, NUIG, Galway, Ireland
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Regenerative Medicine Institute at CÚRAM SFI Research Centre, School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland
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Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK
NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK
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Introduction
Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.
Methods
The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.
Results
The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up.
Conclusions
W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.
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Department of Medicine, University of Padova, Padova, Italy
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Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6–15% of osteoporosis and of 25–48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced insulin-like factor 3 and 25-OH vitamin D levels, and high follicle-stimulating hormone and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although dual-energy x-ray absorptiometry is recommended in the clinical workflow for patients with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score, high-resolution peripheral quantitative computed tomography and vertebral morphometry seem promising tools to better estimate the fracture risk of patients with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism.
CEB – Centro de Engenharia Biológica, Universidade do Minho, Braga, Portugal
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CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal
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Type 1 diabetes has an increasingly greater incidence and prevalence with no cure available. Vitamin D supplementation is well documented to reduce the risk of developing type 1 diabetes. Being involved in the modulation of cathelicidin expression, the question whether cathelicidin may be one of the underlying cause arises. Cathelicidin has been implicated in both the development and the protection against type 1 diabetes by mediating the interplay between the gut microbiome, the immune system and β cell function. While its potential on type 1 diabetes treatment seems high, the understanding of its effects is still limited. This review aims to contribute to a more comprehensive understanding of the potential of vitamin D and cathelicidin as adjuvants in type 1 diabetes therapy.
Department of Nutritional Sciences, University of Toronto, Toronto, Canada
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Department of Nutritional Sciences, University of Toronto, Toronto, Canada
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Molecular and Medical Genetics, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
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Department of Nutritional Sciences, University of Toronto, Toronto, Canada
Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, Canada
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Fetal growth restriction is linked to adverse health outcomes and is prevalent in low- and middle-income countries; however, determinants of fetal growth are still poorly understood. The objectives were to determine the effect of prenatal vitamin D supplementation on the insulin-like growth factor (IGF) axis at birth, to compare the concentrations of IGF-I in newborns in Bangladesh to a European reference population and to estimate the associations between IGF protein concentrations and birth size. In a randomized controlled trial in Dhaka, Bangladesh, pregnant women enrolled at 17–24 weeks of gestation were assigned to weekly oral vitamin D3 supplementation from enrolment to delivery at doses of 4200 IU/week, 16,800 IU/week, 28,000 IU/week or placebo. In this sub-study, 559 woman–infant pairs were included for analysis and cord blood IGF protein concentrations were quantified at birth. There were no significant effects of vitamin D supplementation on cord blood concentrations of IGF-I (P = 0.398), IGF-II (P = 0.525), binding proteins (BPs) IGFBP-1 (P = 0.170), IGFBP-3 (P = 0.203) or the molar ratio of IGF-I/IGFBP-3 (P = 0.941). In comparison to a European reference population, 6% of girls and 23% of boys had IGF-I concentrations below the 2.5th percentile of the reference population. IGF-I, IGF-II, IGFBP-3 and the IGF-I/IGFBP-3 ratio were positively associated with at least one anthropometric parameter, whereas IGFBP-1 was negatively associated with birth anthropometry. In conclusion, prenatal vitamin D supplementation does not alter or enhance fetal IGF pathways.
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Background
To investigate the relationship 25-hydroxy vitamin D (25OHD) level among children and in children with type 1 diabetes mellitus (T1DM).
Methods
A case–control study was conducted to compare the serum 25OHD levels between cases and controls. This study recruited 296 T1DM children (106 newly diagnosed T1DM patients and 190 established T1DM patients), and 295 age- and gender-matched healthy subjects as controls.
Results
The mean serum 25OHD in T1DM children was 48.69 ± 15.26 nmol/L and in the controls was 57.93 ± 19.03 nmol/L. The mean serum 25OHD in T1DM children was lower than that of controls (P < 0.01). The mean serum 25OHD level (50.42 ± 14.74 nmol/L) in the newly diagnosed T1DM children was higher than that (47.70 ± 15.50 nmol/L) in the established T1DM children but the difference was not statistically significant (P = 0.16). HbA1c values were associated with 25OHD levels in established T1DM children (r = 0.264, P < 0.01), and there was no association between 25OHD and HbA1c in newly diagnosed T1DM children (r = 0.164; P > 0.05).
Conclusion
Vitamin D deficiency is common in T1DM children, and it should be worthy of attention on the lack of vitamin D in established T1DM children.
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Objective
Chronic hypoparathyroidism (HP) is associated with acute and chronic complications, especially those related to hypocalcemia. We aimed to analyze details on hospital admissions and the reported deaths in affected patients.
Design and methods
In a retrospective analysis, we reviewed the medical history of 198 patients diagnosed with chronic HP over a continuous period of up to 17 years at the Medical University Graz.
Results
The mean age in our mostly female cohort (70.2%) was 62.6 ± 18.7 years. The etiology was predominantly postsurgical (84.8%). About 87.4% of patients received standard medication (oral calcium/vitamin D), 15 patients (7.6%) used rhPTH1–84/Natpar® and 10 patients (4.5%) had no/unknown medication. Two hundred and nineteen emergency room (ER) visits and 627 hospitalizations were documented among 149 patients, and 49 patients (24.7%) did not record any hospital admissions. According to symptoms and decreased serum calcium levels, 12% of ER (n = 26) visits and 7% of hospitalizations (n = 44) were likely attributable to HP. A subgroup of 13 patients (6.5%) received kidney transplants prior to the HP diagnosis. In eight of these patients, parathyroidectomy for tertiary renal hyperparathyroidism was the cause of permanent HP. The mortality was 7.8% (n = 12), and the causes of death appeared to be unrelated to HP. Although the awareness for HP was low, calcium levels were documented in 71% (n = 447) of hospitalizations.
Conclusions
Acute symptoms directly related to HP did not represent the primary cause of ER visits. However, comorbidities (e.g. renal/cardiovascular diseases) associated with HP played a key role in hospitalizations and deaths.
Significance statement
Hypoparathyroidism (HP) is the most common complication after anterior neck surgery. Yet, it remains underdiagnosed as well as undertreated, and the burden of disease and long-term complications are usually underestimated. There are few detailed data on emergency room (ER) visits hospitalizations and death in patients with chronic HP, although acute symptoms due to hypo-/hypercalcemia are easily detectable. We show that HP is not the primary cause for presentation but that hypocalcemia is a typical laboratory finding (when ordered) and thus may contribute to subjective symptoms. Patients often present with renal/cardiovascular/oncologic illness for which HP is known to be a contributing factor. A small but very special group (n = 13, 6.5%) are patients after kidney transplantations who showed a high ER hospitalization rate. Surprisingly, HP was never the cause for their frequent hospitalizations but rather the result of chronic kidney disease. The most frequent cause for HP in these patients was parathyroidectomy due to tertiary hyperparathyroidism. The causes of death in 12 patients appeared to be unrelated to HP, but we found a high prevalence of chronic organ damages/comorbidities related to it in this group. Less than 25% documented HP correctly in the discharge letters, which indicates a high potential for improvement.
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Department of Health Sciences, Department of Epidemiology and Biostatistics, Department of Public Health, Department of General Practice, Department of Internal Medicine and Cardiovascular Research Institute Maastricht, Department of Internal Medicine, Faculty of Earth and Life Sciences, EMGO Institute for Health and Care Research, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands
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Objective
A disturbed vitamin D–parathyroid hormone (PTH)–calcium axis may play a role in the pathogenesis of heart failure. Therefore, we investigated whether lower 25-hydroxyvitamin D (25(OH)D) and higher PTH are cross sectionally and after 8 years of follow-up associated with higher B-type natriuretic peptide (BNP) levels in older men and women.
Design and methods
We measured baseline 25(OH)D, PTH, and BNP in 502 subjects in 2000–2001 in the Hoorn Study, a population-based cohort. Follow-up BNP was available in 2007–2009 in 278 subjects. Subjects were categorized according to season- and sex-specific quartiles of 25(OH)D and PTH at baseline. We studied the association of 25(OH)D and PTH quartiles with BNP using linear regression analyses adjusting for confounders. Analyses were stratified by kidney function estimated glomerular filtration rate (eGFR; ≤60 ml/min per 1.73 m2) because of significant interaction.
Results
At baseline, subjects had a mean age of 69.9±6.6 years, mean 25(OH)D level was 52.2±19.5 nmol/l and mean PTH 6.1±2.4 pmol/l. Cross sectionally, 25(OH)D was associated with BNP in subjects with impaired kidney function (eGFR ≤60 ml/min) only. The association attenuated after adjustment for PTH. PTH was cross sectionally associated with BNP, also in subjects with impaired kidney function only: regression coefficient of highest quartile 9.9 pmol/l (95% confidence interval 2.5, 17.4) with a significant trend across quartiles. Neither 25(OH)D nor PTH was associated with BNP in longitudinal analyses.
Conclusion
This study showed overall no strong association between 25(OH)D and BNP. However, PTH was associated with BNP in subjects with impaired kidney function and may point to a potential role in myocardial function.
St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland
St Michael's Hospital, Metabolism Laboratory, School of Medicine and Medical Sciences, Dún Laoghaire, Dublin, Ireland
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Objective
The recommended daily intakes of vitamin D according to the recent Clinical Practice Guideline (CPG) of the Endocrine Society are three- to fivefold higher than the Institute of Medicine (IOM) report. We speculated that these differences could be explained by different mathematical approaches to the vitamin D dose response.
Methods
Studies were selected if the daily dose was ≤2000 IU/day, the duration exceeded 3 months, and 25-hydroxyvitamin D (25OHD) concentrations were measured at baseline and post-therapy. The rate constant was estimated according to the CPG approach. The achieved 25OHD result was estimated according to the following: i) the regression equation approach of the IOM; ii) the regression approach of the Vitamin D Supplementation in Older Subjects (ViDOS) study; and iii) the CPG approach using a rate constant of 2.5 (CPG2.5) and a rate constant of 5.0 (CPG5.0). The difference between the expected and the observed 25OHD result was expressed as a percentage of observed and analyzed for significance against a value of 0% for the four groups.
Results
Forty-one studies were analyzed. The mean (95% CI) rate constant was 5.3 (4.4–6.2) nmol/l per 100 IU per day, on average twofold higher than the CPG rate constant. The mean (95% CI) for the difference between the expected and observed expressed as a percentage of observed was as follows: i) IOM, −7 (−16,+2)% (t=1.64, P=0.110); ii) ViDOS, +2 (−8,+12)% (t=0.40, P=0.69); iii) CPG2.5, −21 (−27,−15)% (t=7.2, P<0.0001); and iv) CPG5.0+3 (−4,+10)% (t=0.91, P=0.366).
Conclusion
The CPG ‘rule of thumb’ should be doubled to 5.0 nmol/l (2.0 ng/ml) per 100 IU per day, adopting a more risk-averse position.
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Adequate vitamin D levels are particularly important in pregnant women for both maternal and neonatal health. Prior studies have shown a significantly high prevalence of vitamin D deficiency (VDD) among refugees. However, no study has addressed the prevalence of VDD in pregnant refugees and its effects on neonatal health. In this study, we examined the prevalence of VDD in refugee pregnant women living in Greece and compared our results with Greek pregnant inhabitants. VDD was frequent in both groups but was significantly more common in refugees (92.2 vs 67.3% of Greek women, P = 0.003) with 70.6% of refugees having severe hypovitaminosis D (<10 ng/mL). As a result, most newborns had VDD, which affected refugee newborns to a greater extent. Our results suggest a need to screen newcomer children and pregnant women for VDD in all host countries around the world. Such a screen will appropriately guide early and effective interventions with the goal to prevent adverse neonatal and maternal outcomes.
