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Rickets is a paediatric bone disorder characterised by defective mineralisation of bony matrix due to abnormalities in calcium and phosphate metabolism. Despite being a common disease globally, literature on the anaesthetic concerns in rickets are scant. Herein, we describe the management of a 12-year-old child with symptomatic vitamin D deficiency rickets with secondary hyperparathyroidism, undergoing general anaesthesia for an urgent orthopaedic procedure. There are numerous risks involved in such a case, such as hypocalcemia, hypophosphatemia, chest and vertebral deformities, restrictive lung disease, difficult intubation and weaning, difficult regional anaesthesia, chronic bone pain, infectious complications and postoperative decreased renal function, all of which require careful preoperative assessment and risk stratification. In elective surgeries, it is important to optimise the metabolic parameters before taking up the case. However, in urgent and emergent procedures like ours, it is imperative to take up the case after informing the parents of the risks involved., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome is seen in association with the overproduction of fibroblast growth factor-23 (FGF-23) by certain mesenchymal tumors in adults. In children, these phosphaturic mesenchymal tumors produce features of rickets similar to TIO. This condition is characterized by elevated blood levels of FGF-23, low phosphate, low or normal active vitamin D, and high alkaline phosphatase. Though the removal of the tumor is curative; in cases where surgical resection is not possible, medical treatment is successful with phosphate and active vitamin D in the improvement of symptoms. The case of a child with features of rickets is presented here to illustrate the importance of identifying this rare condition and instituting appropriate intervention., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Vitamin D 3 deficiency and insufficiency are becoming a common global issue for us, especially in the most industrially developed countries. The only acknowledged activity of vitamin D 3 in vertebrates is to promote the absorption of calcium and, therefore, allow for the mineralization of bones. Accordingly, its deficiency is associated with diseases such as rickets. Other numerous vital functions associated with vitamin D 3 are yet to be considered, and the function of vitamin D 2 in plants is unknown. Thus, 100 years after its discovery, the importance of vitamin D still seems to be unacknowledged (except for rickets), with little attention given to its decrease throughout the world. In this review, I suggest that vitamin D deficiency and insufficiency may be linked to the westernized lifestyle in more developed countries. Furthermore, I suggest that, rather than the calcemic activity, the main function of vitamin D is, in general, that of strengthening living organisms. I conclude with the hypothesis that vitamin D deficiency may represent a marker for a greater risk of chronic inflammatory diseases and a shorter life expectancy.

Vitamin D is mainly produced in the skin (cholecalciferol) by sun exposure while a fraction of it is obtained from dietary sources (ergocalciferol). Vitamin D is further processed to 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D (calcitriol) in the liver and kidneys, respectively. Calcitriol is the active form which mediates the actions of vitamin D via vitamin D receptor (VDR) which is present ubiquitously. Defect at any level in this pathway leads to vitamin D deficient or resistant rickets. Nutritional vitamin D deficiency is the leading cause of rickets and osteomalacia worldwide and responds well to vitamin D supplementation. Inherited disorders of vitamin D metabolism (vitamin D-dependent rickets, VDDR) account for a small proportion of calcipenic rickets/osteomalacia. Defective 1α hydroxylation of vitamin D, 25 hydroxylation of vitamin D, and vitamin D receptor result in VDDR1A, VDDR1B and VDDR2A, respectively whereas defective binding of vitamin D to vitamin D response element due to overexpression of heterogeneous nuclear ribonucleoprotein and accelerated vitamin D metabolism cause VDDR2B and VDDR3, respectively. Impaired dietary calcium absorption and consequent calcium deficiency increases parathyroid hormone in these disorders resulting in phosphaturia and hypophosphatemia. Hypophosphatemia is a common feature of all these disorders, though not a sine-qua-non and leads to hypomineralisation of the bone and myopathy. Improvement in hypophosphatemia is one of the earliest markers of response to vitamin D supplementation in nutritional rickets/osteomalacia and the lack of such a response should prompt evaluation for inherited forms of rickets/osteomalacia., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Historically vitamin D deficiency had devastating consequences for children causing rickets resulting in severe bone deformities often leading to death. The mystery of the cause of rickets finally came to light when it was observed that cod liver oil and sunlight could prevent and cure rickets. The first vitamin D to be discovered was vitamin D 2 from ergosterol in ultraviolet irradiated yeast. Vitamin D 3 was discovered from UV exposure to the skin. Investigations revealed the two major functions of vitamin D were to increase intestinal calcium and phosphate absorption and mobilize calcium from the skeleton to maintain calcium and phosphorus homeostasis. Later studies demonstrated that vitamin D does not have an active role in bone mineralization. Vitamin D deficiency results in secondary hyperparathyroidism increasing bone resorption. As a result, this decreases bone mineral content and compromises the architectural integrity increasing risk for fracture. Vitamin D deficiency has also been shown to enhance aging of the bone causing cracks and enhancing bone fractures. Vitamin D deficiency also causes osteomalacia. Therefore, vitamin D sufficiency is extremely important to maximize bone health throughout life. It helps to prevent bone loss, but it cannot restore bone loss due to increased bone resorption that can occur under a variety of circumstances including menopause. The Endocrine Society Guidelines recommends for all ages that adequate vitamin D obtained from the sun, foods and supplements is necessary in order to maintain a circulating concentration of 25-hydroxyvitamin D of at least 30 ng/mL for maximum bone health., (Copyright © 2024. Published by Elsevier Inc.)

Nutritional rickets is a global health problem reflecting both historical and contemporary health disparities arising from racial, ethnic, environmental, and geopolitical circumstances. It primarily affects marginalized populations and can contribute to long-term morbidity. Deficits in bone health in childhood may also contribute to osteomalacia/osteoporosis. Solutions require a global public health approach., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: Nutritional rickets is the failure of normal bone formation in children, caused by vitamin D deficiency, low calcium intake, or a combination of both. In the United States, prolonged breastfeeding without vitamin D supplementation is a major risk factor. Increasing awareness of the rationale for and importance of vitamin D supplements for all breastfed infants and children should reduce the incidence of vitamin D deficiency rickets and prevent bone deformity., (Copyright © 2023 American Academy of Physician Associates.)

Introduction: Vitamin D deficiency affects from 10% to 50% in various pediatric population groups and causes life-threatening hypocalcemia in infants, crippling rickets in infants and children, and increased risk of subsequent adult metabolic and neurologic problems., Areas Covered: An English language literature search of PubMed was performed since 1940 as were the authors' personal literature collections. References identified in the reviewed literature are considered., Diagnosis: The diagnosis of vitamin D deficiency is based on serum 25-hydroxyvitamin D levels. Clinical features of rickets include bone deformities and elevated alkaline phosphatase. Most children and adolescents who are biochemically vitamin D deficient do not have specific symptoms or signs of deficiency., Prevention: Prevention of vitamin D deficiency is via exposure to sunshine, food and beverage fortification, and dietary supplementation., Treatment: Effective treatment of vitamin D deficiency is via oral or injectable administration of vitamin D. Dosing and duration of vitamin D therapy have been described for healthy children and for children with underlying medical conditions, but recommendations vary., Expert Opinion: Further investigation is needed to determine long-term non-skeletal effects of childhood vitamin D deficiency, benefits of supplementation in asymptomatic individuals with biochemical vitamin D deficiency, and appropriate screening for vitamin D deficiency in asymptomatic children and adolescents.

Vitamin D deficiency is prevalent among various groups in the UK, and can result from insufficient sunlight exposure and dietary intake. There is a population-wide recommendation of 10 micrograms (400 international units) of vitamin D per day, with a daily supplement advised. However, supplement use is often suboptimal, compounding the risk of deficiency. Long-term vitamin D deficiency can cause rickets in children and osteomalacia or osteoporosis in adults. Therefore, it is important that nurses recognise which groups are at increased risk of vitamin D deficiency and understand how to assess people's vitamin D status. Nurses also need to be able to support the prevention and treatment of low vitamin D levels, which typically involves supplementation and lifestyle changes., Competing Interests: None declared, (© 2023 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.)

Vitamin D plays a vital role in regulating calcium and phosphate metabolism and maintaining bone health. A state of prolonged or profound vitamin D deficiency (VDD) can result in rickets in children and osteomalacia in children and adults. Recent studies have demonstrated the pleiotropic action of vitamin D and identified its effects on multiple biological processes in addition to bone health. VDD is more prevalent in chronic childhood conditions such as long-standing systemic illnesses affecting the renal, liver, gastrointestinal, skin, neurologic and musculoskeletal systems. VDD superimposed on the underlying disease process and treatments that can adversely affect bone turnover can all add to the disease burden in these groups of children. The current review outlines the causes and mechanisms underlying poor bone health in certain groups of children and young people with chronic diseases with an emphasis on the proactive screening and treatment of VDD.

Nutritional rickets, caused by vitamin D and/or calcium deficiency is by far the most common cause of rickets. In resource-limited settings, it is therefore not uncommon to treat rickets with vitamin D and calcium. If rickets fails to heal and/or if there is a family history of rickets, then refractory rickets should be considered as a differential diagnosis. Chronic low serum phosphate is the pathological hallmark of all forms of rickets as its low concentration in extracellular space leads to the failure of apoptosis of hypertrophic chondrocytes leading to defective mineralisation of the growth plate. Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) control serum phosphate concentration by facilitating the excretion of phosphate in the urine through their action on the proximal renal tubules. An increase in PTH, as seen in nutritional rickets and genetic disorders of vitamin D-dependent rickets (VDDRs), leads to chronic low serum phosphate, causing rickets. Genetic conditions leading to an increase in FGF23 concentration cause chronic low serum phosphate concentration and rickets. Genetic conditions and syndromes associated with proximal renal tubulopathies can also lead to chronic low serum phosphate concentration by excess phosphate leak in urine, causing rickets.In this review, authors discuss an approach to the differential diagnosis and management of refractory rickets., (© 2023. The Author(s).)

Background: A multivariable logistic regression model resulting from a case-control study of nutritional rickets in Nigerian children suggested that higher levels of serum 25(OH)D may be required to prevent nutritional rickets in populations with low-calcium intakes., Objectives: This current study evaluates if adding serum 1,25-dihydroxyvitamin D [1,25(OH) 2 D] to that model shows that increased levels of serum 1,25(OH) 2 D are independently associated with risk of children on low-calcium diets having nutritional rickets., Methods: Multivariable logistic regression analysis was used to model the association between serum 1,25(OH) 2 D and risk of having nutritional rickets in cases (n = 108) and controls (n = 115) after adjusting for age, sex, weight-for age z-score, religion, phosphorus intake and age began walking and the interaction between serum 25(OH)D and dietary calcium intake (Full Model)., Results: Serum 1,25(OH) 2 D levels were significantly higher (320 pmol/L vs. 280 pmol/L) (P = 0.002), and 25(OH)D levels were lower (33 nmol/L vs. 52 nmol/L) (P < 0.0001) in children with rickets than in control children. Serum calcium levels were lower in children with rickets (1.9 mmol/L) than in control children (2.2 mmol/L) (P < 0.001). Dietary calcium intakes were similarly low in both groups (212 mg/d) (P = 0.973). In the multivariable logistic model, 1,25(OH) 2 D was independently associated with risk of having rickets [coefficient = 0.007 (95% confidence limits: 0.002-0.011)] after adjusting for all variables in the Full Model., Conclusions: Results confirmed theoretical models that in children with low dietary calcium intake, 1,25(OH) 2 D serum concentrations are higher in children with rickets than in children without rickets. The difference in 1,25(OH) 2 D levels is consistent with the hypothesis that children with rickets have lower serum calcium concentrations which prompt the elevation of PTH levels resulting in an elevation of 1,25(OH) 2 D levels. These results support the need for additional studies to identify dietary and environmental risks for nutritional rickets., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Rickets is the disease of a growing skeleton and results from impaired apoptosis of hypertrophic chondrocytes and mineralization of the growth plate. Nutritionally induced rickets, secondary to vitamin D and/or calcium deficiency, remains a major global problem. In this review, we discuss pathogenesis, clinical signs, investigation and management of nutritional rickets., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

For more than two centuries, lack of sunlight has been understood to cause vitamin D deficiency and documented as a primary cause of rickets. As such, evidence of rickets in the archeological record has been used as a proxy for vitamin D status in past individuals and populations. In the last decade, a clinical global consensus has emerged wherein it is recognized that dietary calcium deficiency also plays a role in the manifestation of rickets and classic skeletal deformities may not form if dietary calcium is normal even if vitamin D is deficient. This disease is now clinically called "nutritional rickets" to reflect the fact that rickets can take calcium deficiency-predominant or vitamin D deficiency-predominant forms. However, there are currently no paleopathological studies wherein dietary calcium deficiency is critically considered a primary etiology of the disease. We review here the interplay of calcium, vitamin D, and phosphorous in bone homeostasis, examine the role of dietary calcium in human health, and critically explore the clinical literature on calcium deficiency-predominant rickets. Finally, we report a case of rickets from the late Formative Period (~2500-1500 years ago) of the Atacama Desert and argue the disease in this infant is likely an example of calcium deficiency-predominant rickets. We conclude that most archeological cases of rickets are the result of multiple micronutrient deficiencies that compound to manifest in macroscopic skeletal lesions. For clinicians, these factors are important for implementing best treatment practice, and for paleopathologists they are necessary for appropriate interpretation of health in past communities., (© 2022 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Background: Vitamin D is one of the most important fat-soluble vitamins necessary for normal growth and development of the human body. According to a study done in Kabul shows that economic, racial, and social concerns are thought to be the main impediments to receiving appropriate amounts of this vitamin through dietary sources in countries like Afghanistan. Hypovitaminosis D, on the other hand, is now recognized as a pandemic in both industrialized and developing countries., Methods: To find out how common hypovitaminosis D is in children aged one month to eighteen years in afghan children Kabul, Afghanistan. Vitamin D deficiency and insufficiency are defined as serum levels of less than 20 ng/mL and 20 to 30 ng/mL, respectively. Children aged between 1 month to 18 years attending our hospital, AMC (Ariana Medical Complex) for health examination were checked for their 25-hydroxyvitamin D [25(OH)D]. Age, gender and address were recorded. 25(OH)D were determined using immunoassay auto analyzers. According to their serum 25(OH)D, the 25(OH)D were categorized into five categories: sufficiency: ≥ 30-100 ng/mL; insufficiency: ≥ 20-29 ng/mL; deficiency: < 20 ng/mL; severe deficiency: < 10 ng/mL; and intoxication: > 150 ng/mL. Participants who were intoxicated with vitamin D were excluded from the study., Results: A total of 4008 children aged 1 month to 18 years participated in this cross-sectional study. Hypovitaminosis D was found to be prevalent in 62.5 percent of the population. When compared to boys, female children were 1.2 times more likely to be vitamin D deficient. When compared to children of illiterate women, the odds of hypovitaminosis D were 1.4, 1.9, and 5.8 times lower in children with mothers educated up to primary school, graduation, and post-graduate. The average vitamin D level was 23 ng/mL, with a median of 15 ng/mL and maximum and minimum values of 135 ng/mL and 3 ng/mL, respectively. In all, 2500 (62.5%) of the children had low levels of vitamin D in their serum. Only 400 (16%) of the patients were sufficient, whereas 917 (36.7%) were severely deficient, 733 (29.3%) were deficient, and 450 (18%) were insufficient. With a female to male ratio of 1.2:1, the majority of those, 1335 (53.4%), were females and 1165 (46.6%) were males. Patients were 8.14 years old on average, with a median age of 7 years. The majority of the patients, 2152 (86.1%), were urban, while 348 (13.9%) were rural., Conclusion: The prevalence of hypovitaminosis D was very high in Afghan children. Female sex, higher socio economic status, higher educational status of the mother and living at urban areas were the factors with strong positive association with hypovitaminosis D., (© 2023. The Author(s).)

The discovery of a fat-soluble nutrient that had antirachitic activity and no vitamin A activity by McCollum has had far reaching health benefits for children and adults. He named this nutrient vitamin D. The goal of this review and personal experiences is to give the reader a broad perspective almost from the beginning of time for how vitamin D evolved to became intimately involved in the evolution of land vertebrates. It was the deficiency of sunlight causing the devastating skeletal disease known as English disease and rickets that provided the first insight as to the relationship of sunlight and the cutaneous production of vitamin D 3 . The initial appreciation that vitamin D could be obtained from ultraviolet exposure of ergosterol in yeast to produce vitamin D 2 resulted in the fortification of foods with vitamin D 2 and the eradication of rickets. Vitamin D 3 and vitamin D 2 (represented as D) are equally effective in humans. They undergo sequential metabolism to produce the active form of vitamin D, 1,25-dihydroxyvitamin D. It is now also recognized that essentially every tissue and cell in the body not only has a vitamin D receptor but can produce 1,25-dihydroxyvitamin D. This could explain why vitamin D deficiency has now been related to many acute and chronic illnesses, including COVID-19.

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D 3 , and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D 3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis., (© 2022. The Author(s).)

This open-label, block-randomized controlled trial compared the effect of 800 IU/day and 400 IU/day of oral vitamin D 3 supplementation in reducing vitamin D insufficiency (VDI) among healthy-term breastfed infants at 14 weeks of postnatal age. All eligible infants were randomized to receive either 800 or 400 IU/day of oral vitamin D 3 (starting within the first week until 14 weeks). The primary outcome was the proportion of infants with VDI (25-OH-D < 20 ng/ml) at 14 weeks. Secondary outcomes were vitamin D deficiency (VDD, < 12 ng/ml), severe VDD (< 5 ng/ml), anthropometry, biochemical or clinical rickets, and any adverse events related to vitamin D toxicity (VDT). Among 102 enrolled infants, the distribution of baseline variables (including cord 25-OH-D levels; 13.0 versus 14.2 ng/ml) was similar in both groups. On intention-to-treat analysis, the proportions of infants with VDI at 14 weeks were significantly lower in the 800 IU group compared to those in the 400 IU group [24% versus 55%; RR 0.44; 95% CI: 0.25-0.76]. The proportions of infants with elevated parathormone (6% versus 26.5%; p = 0.012) and severe VDD (0% versus 12.2%; p = 0.033) were significantly lower in the 800 IU group. Clinical rickets developed in three (6.2%) infants in the 400 IU group. No infant developed VDT.      Conclusions: Daily oral supplementation with 800 IU of vitamin D 3 resulted in an almost 50% reduction in the proportion of infants with VDI and prevented the occurrence of severe VDD at 14 weeks of age compared to 400 IU with no evidence of vitamin D toxicity.     Trial Registration: Clinical Trial Registry of India (CTRI/2019/02/017374). What is Known: • Breastfeeding is the ideal source of nutrition for healthy-term breastfed infants; however, vitamin D content of breastmilk is suboptimal. • AAP recommends daily oral supplementation of 400 IU of vitamin D to all healthy-term breastfed infants; however, trials from high-income countries support insufficiency of this dose in maintaining serum 25-OH-D levels >20 ng/ml with no such information from low-middle-income countries. What is New: • 800 IU/day of oral vitamin D3 supplementation among term breastfed infants significantly reduces vitamin D insufficiency at 14 weeks' age as compared to the recommended dose of 400 IU/day. • This higher supplemental dose is safe with no evidence of vitamin D toxicity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vitamin D deficiency has been considered to be the cause of nutritional rickets for most of the past century. During the past two decades, however, it has become clear that nutritional rickets may be caused by vitamin D deficiency or by dietary insufficiency of calcium. The combined deficiencies of calcium and vitamin D interact, and several other factors are also relevant in the pathogenesis of nutritional rickets., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Vitamin D is essential for the normal mineralization of bones during childhood. Although diet and adequate sun exposure should provide enough of this nutrient, there is a high prevalence of vitamin D deficiency rickets worldwide. Children with certain conditions that lead to decreased vitamin D production and/or absorption are at the greatest risk of nutritional rickets. In addition, several rare genetic alterations are also associated with severe forms of vitamin-D-resistant or -dependent rickets. Although vitamin D3 is the threshold nutrient for the vitamin D endocrine system (VDES), direct measurement of circulating vitamin D3 itself is not a good marker of the nutritional status of the system. Calcifediol (or 25(OH)D) serum levels are used to assess VDES status. While there is no clear consensus among the different scientific associations on calcifediol status, many clinical trials have demonstrated the benefit of ensuring normal 25(OH)D serum levels and calcium intake for the prevention or treatment of nutritional rickets in childhood. Therefore, during the first year of life, infants should receive vitamin D treatment with at least 400 IU/day. In addition, a diet should ensure a normal calcium intake. Healthy lifestyle habits to prevent vitamin D deficiency should be encouraged during childhood. In children who develop clinical signs of rickets, adequate treatment with vitamin D and calcium should be guaranteed. Children with additional risk factors for 25(OH)D deficiency and nutritional rickets should be assessed periodically and treated promptly to prevent further bone damage.

Objective: Rickets is considered an indicator of vitamin D deficiency in palaeopathology, but a strand of biomedical thought maintains that dietary calcium deficiency may sometimes play a part in its causation. Our aim is to evaluate the extent to which low calcium intake should be considered as a factor in biocultural interpretations of rickets., Methods: We assess published modern epidemiological studies that provide primary data to support claims for a role for dietary calcium deficiency in rickets. We also consider how we might identify, via indicators of calcium intake, populations at risk of calcium deficiency in the past., Results: Support for dietary calcium deficiency as a cause of rickets is equivocal. Direct measurement of dietary calcium in the past is not possible, but exposure to risk factors for low calcium intake can to some extent be identified., Conclusion: Whilst there is little evidence to alter the view that rickets is essentially an indicator of a population's vitamin D status, occasionally, in very low calcium intake groups, dietary calcium deficiency may play a synergistic role by accentuating the need for vitamin D., Significance: The notion that dietary calcium deficiency may be a cause of rickets appears to be gaining currency in bioarchaeological studies. This paper shows that it is unusual for this to be the case, and even then the role of vitamin D remains crucial., Limitations: This paper attempts to summarise the current state of biomedical study in an area that is subject to continuing investigation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Here, we review the most up-to-date understanding of the pathogenesis, prevention and treatment of vitamin D deficient rickets in children. This will include recent advances in the genetic determinants of abnormal vitamin D metabolism, with the intention of aiding clinicians with establishing the diagnosis and implementing treatment plans for children presenting with vitamin D deficiency rickets., Recent Findings: Vitamin D deficiency rickets is a frequently encountered, but entirely preventable, disorder of bone mineral metabolism. Risk factors for developing vitamin D deficiency rickets include inadequate exposure to sunlight, exclusive breast feeding without vitamin D supplementation and inadequate intake of vitamin D, calcium or phosphorus. Other factors that may influence the development of vitamin D deficiency and/or rickets include genetic alterations or medications that alter vitamin D metabolism., Summary: Vitamin D levels in individuals are influenced by environmental factors, as well as genetic factors. A thorough understanding of these factors is critical for the evaluation and treatment of a child presenting with rickets. There remains a great need for additional research to determine ideal vitamin D status across diverse populations, and to better understand how vitamin D status affects overall health., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Vitamin D-resistant rickets shows the resistance to vitamin D (Vit-D) therapy, which traditionally works well in cases with deficiency rickets. The signs start appearing as early as in the first month of life and are characterised by the defective mineralisation at the ends of cartilage and bones despite having normal Vit-D levels in the serum. This case report highlights the dental and maxillofacial manifestations in a 3-year-old girl diagnosed with pseudo-Vit-D deficiency rickets. The report also highlights the variations in the dental manifestations of the condition reported in the literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

BACKGROUND Rickets is the deficiency in mineralization of the bone associated with lack of sunlight exposure and inadequate dietary calcium and/or vitamin D in children. Important efforts to eradicate rickets include appropriate sunlight exposure advice and fortification of food and milk with vitamin D. However, there is a growing concern that the current Coronavirus Disease 2019 (COVID-19) pandemic will increase the incidence of rickets due to inadequate sunlight exposure resulting from movement restriction measures imposed by governments across the world. CASE REPORT A 22-month-old girl presented to our primary care clinic in Selangor, Malaysia with abnormal gait and bowing of the legs during the COVID-19 pandemic. She had a history of inadequate sun exposure as she lived in an apartment and there was a Movement Control Order in place because of the pandemic. Calcium intake was also poor as she could not tolerate formula milk and did not consume any other dairy products. Investigations revealed severe hypocalcemia and low vitamin D level. She was diagnosed with nutritional rickets and was referred for admission to correct the hypocalcemia. She was subsequently discharged with oral calcium and vitamin D supplementation. Her calcium and vitamin D levels improved and at her 6-month review, her bilateral bowed legs had improved significantly. CONCLUSIONS This case highlights the importance of having a high degree of suspicion for vitamin D deficiency and rickets in young children growing up during the COVID-19 pandemic. Public health messages on preventing the spread of COVID-19 should also be interlaced with messages addressing the possible effects of our new norms such as inadequate sunlight exposure.

We looked at existing recommendations and supporting evidence on the effectiveness of vitamin D supplementation in infancy for reducing vitamin D deficiency and for preventing rickets and infections. We also looked at optimal dose of vitamin D and the age until which vitamin D supplementation is beneficial.We conducted a literature search up to the 17th of July 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.A daily dose of 400 international units of vitamin D in infants has shown to be effective for improving bone health and preventing rickets. Evidence is more robust in groups of infants and children at risk. Vitamin D supplementation is well tolerated, and not associated with toxicity. Higher doses have not shown to add benefit while it could potentially cause toxic blood levels and hypercalcemia. Adequate levels of vitamin D might not be achieved with lower daily doses. Universal vitamin D supplementation starting shortly after birth, regardless of the mode of feeding and until 12 months of age, is strongly recommended. Beyond 12 months of age vitamin D supplementation is recommended only in groups of children at risk., (© 2021. The Author(s).)

Cholecalciferol (vitamin D 3 ) is essentially known for its role in the phosphocalcic metabolism and its associated pathologies, such as rickets. In Switzerland, 35 to 50% of children are vitamin D deficient. Due to skin colour, poor nutrition, living conditions and cultural practices, migrant population is particularly at risk. Our aim is to attest the prevalence of hypovitaminosis D in children arriving in Switzerland. We retrospectively assessed 528 children's vitamin D status and parathyroid hormone, phosphate and calcium levels between 2015 and 2018 by electrochemiluminescence and spectrophotometry. Cholecalciferol was considered insufficient under 50 nmol/L and severely deficient below 25 nmol/L. Seventy-three percent of children showed hypovitaminosis D and 28% had a severe deficiency. Highest prevalence of deficiency was found in children from Eastern Mediterranean (80%) and African regions (75%). Severe deficiency was more prevalent in the South East Asian (39%) and Eastern Mediterranean regions (33%) and more frequent in females. Deficiency was more frequent and more severe in winter. Hypovitaminosis D increased with age. Two children presented with all three biological manifestations associated to severe hypovitaminosis D (hyperparathyroidism, hypocalcaemia and hypophosphatemia).Conclusion: A majority of migrant children presented with hypovitaminosis D. They should be supplemented to prevent complications. A strategy could be to supplement all children at arrival and during wintertime without regular vitamin D level checks. What is Known: Hypovitaminosis D is frequent in children and can lead to bone-related complications. Migrant children are particularly at risk of deficiency. What is New: Three-quarters of migrant children evaluated at our migrant clinic in Geneva's children hospital are deficient in vitamin D, one third severely. A strategy to correct the deficiency would be to supplement all migrant children at arrival and in winter., (© 2021. The Author(s).)

Atypical coeliac disease in young children is frequently missed when it presents atypically as non-gastrointestinal presentations to different specialties. There was a greater delay (54 months) in establishing the diagnosis in those with atypical coeliac disease (p < 0.001). No difference was observed in the mode of delivery or duration of breast feeding, but significant difference was observed between gestational age at birth (p < 0.001). Most cases showed stunted growth and underweight. Irritability, anaemia, rickets, dermatitis herpetiformis, alopecia and intussusception were other common predictors of atypical coeliac disease. Because of a myriad spectrum of non-gastrointestinal symptoms, at any age with diverse presentation, a high index of suspicion is therefore required.

Introduction: Rickets is not an unusual diagnosis for pediatricians even currently in developed countries. Children typically present with leg bowing, enlargement of wrists, rachitic rosary (swelling of costochondral junctions) and/or waddling gait. But not every child with growth delay and enlarged metaphyses is diagnosed with rickets. Metaphyseal anadysplasia (MAD) is a disorder of variable severity with metaphyseal flaring and irregularities, without vertebral abnormalities. MAD is characterized by an early onset and a regressive course in late childhood without treatment, despite persistent short stature. Autosomal dominant or recessive variants in the matrix metalloproteinase 13 gene (MMP13) are responsible for these transient metaphyseal changes., Case Presentation: We report a new pathogenic heterozygous variant in MMP13 (NM&#95;002427.4: c.216G>C, p.Gln72His) in a toddler, initially thought to have rickets, and his father, with MAD phenotypes. Additionally, we review the seven reported MMP13 variants., Conclusion: One should keep a wide differential diagnosis in cases of suspected rickets, including skeletal dysplasias which might have a regressive course.

Objective: Studies have detected differences in various measures of bone health between individuals with autism spectrum disorder (ASD) and their peers. However, these measures do not amount to direct clinical evidence of increased orthopedic pathology in this population. Some of the most compelling evidence to this effect comes from case reports of nutritional rickets in children with ASD. We report on 1 such case that, to our knowledge, is the first report of nutritional rickets in ASD necessitating corrective surgery., Methods: Case report, review of relevant literature, and implications for further research., Results: An 11-year-old girl with ASD was admitted for postoperative medical comanagement after successful repair of bilateral genu valgum (knock knees). On admission, the patient's mother reported that the patient was a "picky eater." No cause had been determined preoperatively, although the deformity had developed at 10 years of age, thereby qualifying as pathologic. The medical team considered rickets because of the patient's limited diet. Subsequent laboratory work demonstrated hypocalcemia, vitamin D deficiency, and secondary hyperparathyroidism. The patient was diagnosed with nutritional rickets due to inadequate vitamin D intake, a consequence of severe food selectivity associated with ASD., Conclusion: This case exemplifies the extreme orthopedic and metabolic complications that can result from food selectivity in children with ASD, pointing to the need for further research into the prevalence and causes of orthopedic pathology and nutritional rickets in this population. The case also underscores the need for evidence-based guidelines to prevent orthopedic pathology in children with ASD., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The review provides a historical perspective on the convergence of our understanding of the physiology and pathophysiology of bone, calcium, phosphorus, vitamin D, parathyroid hormone, and FGF-23 their impact on rickets.

Background: Rickets is a common disease worldwide. In the developed world, its prevalence dramatically decreased but still diagnosed in at-risk populations. The skin plays a critical role in vitamin D synthesis. Therefore, several skin diseases, especially keratinization disorders, could lead to impaired vitamin D metabolism and vitamin D deficient rickets., Objective: The article aimed to summarize the current knowledge of skin diseases and conditions associated with rickets., Methods: To examine the association between rickets and skin diseases, we performed a systematic review of the literature using PubMed database. The search included studies published from the database inception to August 2019., Results: A total number of 75 articles were included. Identified conditions associated with rickets were ichthyosis being a more common skin diseases, alopecia, epidermal and melanocytic nevi, xeroderma pigmentosum, mastocytosis, psoriasis, and atopic dermatitis. Three types of rickets were identified: vitamin D-dependent rickets, hypocalcemic vitamin D-dependent rickets type 2, and hypophosphatemic rickets. Cutaneous skeletal hypophosphatemia syndrome is a newly described and under-recognized condition. It is defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of fibroblast growth factor 23. Rickets in patients with ichthyosis was mainly due to impaired ability of ichthyotic skin to synthesize vitamin D, poor UV penetration of the skin caused by keratinocyte proliferation, and dark phototype. The latter may be considered a risk factor for rickets in patients with ichthyosis., Conclusion: Despite its rarity, these associations should be properly recognized by dermatologists. Early diagnosis of rickets is important to prevent growth retardation and skeletal deformities., (© 2020 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Objectives: A high prevalence of rickets of unknown aetiology has been reported in Chakaria, Bangladesh. Classically, rickets is caused by vitamin D deficiency but increasing evidence from Africa and Asia points towards other nutritional deficiencies or excessive exposure to some metals. The aim of this study was to investigate the aetiology of rickets in rural Bangladeshi children., Methods: 64 cases with rickets-like deformities were recruited at first presentation together with age-sex-village matched controls. Data and sample acquisition included anthropometry, radiographs, fasted plasma and urinary samples, 24 h weighed dietary intake together with a 24 h urine collection, and 13 C-breath tests to detect Helicobacter (H.) pylori infection., Results: One child had active rickets and frank hypovitaminosis D (F, n = 1) and one had deformities with radiological features of Blount disease (M, n = 1). The remaining cases were grouped into those with active rickets, defined as a radiographic Thacher score ≥1.5 (Group A, n = 24, 12M, 12F) and rickets-like bone deformities but not active rickets (Group B, n = 38, 28M, 10F). All children had a low dietary calcium intake, but this was lower in Group A than their controls (mean (SD): 156 (80) versus 323 (249) mg/day, p = 0.005). Plasma 25-hydroxyvitamin D (25OHD) was lower in Group A compared to controls; 63% of Group A and 8% of controls had a concentration <25 nmol/L (p ≤ 0.0001). There was, however, no evidence of differences in skin sunshine exposure. Group A had lower plasma calcium and phosphate and higher 1,25-dihydroxyvitamin D (1,25(OH) 2 D) and parathyroid hormone (PTH). 88% of Group A and 0% of controls had undetectable plasma intact fibroblast growth factor (iFGF23), with c-terminal FGF23 (cFGF23) concentrations in the normal range. Urinary phosphate and daily outputs of environmental metals relative to creatinine were higher and tubular maximal phosphate reabsorption per unit glomerular filtration rate (TmP/GFR) was lower in Group A compared to controls. Although less pronounced than Group A, Group B had higher alkaline phosphatase, 1,25(OH) 2 D and PTH concentrations than controls but similar calcium intake, TmP/GFR, iFGF23 and cFGF23 concentrations. Mean 25OHD concentrations were also similar to controls and there was no significant difference in the percentage <25 nmol/L (Group B: 13%, controls: 5%, p = 0.2) No group differences were seen in prevalence of anaemia, iron deficiency or H. pylori infection., Conclusion: Nutritional rickets in this region is likely to be predominantly due to low calcium intake in the context of poor vitamin D status and exposure to environmental metals, but not H. pylori infection, anaemia or iron deficiency., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Context: Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3., Objective: A large kindred with 5 HR patients was recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in HR patients., Design: Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes., Results: PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion., Conclusions: The c.979-96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We report the case of a 13-month-old infant who was referred to the pediatric emergency department because of psychomotor regression with four bone fractures due to nutritional rickets. The reason was prolonged breastfeeding from a vegetarian mother followed by a vegan diet for the infant after weaning. Rickets is one of the many nutritional deficiencies that could affect infants fed vegan or vegetarian diets. These diets are a public health concern requiring adapted information that suggests alternative formulas made from rice or soy proteins and adapted supplementation after weaning., (Copyright © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)

Background: Nutritional rickets is a disease which affects children, especially in low- and middle-income countries. It causes problems such as skeletal deformities and impaired growth. The most common cause of nutritional rickets is vitamin D deficiency. Vitamin D administered with or without calcium is commonly regarded as the mainstay of treatment. In some sunny countries, however, where children are believed to have adequate vitamin D production from exposure to ultraviolet light, but who are deficient in calcium due to low dietary intake, calcium alone has also been used in the treatment of nutritional rickets. Therefore, it is important to compare the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children living in different settings., Objectives: To assess the effects of vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children., Search Methods: We searched CENTRAL, MEDLINE, LILACS, WHO ICTRP Search Portal and ClinicalTrials.gov. The date of the last search of all databases was 25 July 2019. We applied no language restrictions., Selection Criteria: We included randomised controlled trials (RCT) involving children aged 0 to 18 years with nutritional rickets which compared treatment with vitamin D, calcium or a combination of vitamin D and calcium., Data Collection and Analysis: Two review authors independently screened the title and abstracts of all studies, extracted data and assessed the risk of bias of included studies. We resolved any disagreements by consensus or recourse to a third review author. We conducted meta-analyses for the outcomes reported by study authors. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI) and, for continuous outcomes, we calculated mean differences (MD) with 95% CIs. We assessed the certainty of the evidence of the included studies using GRADE., Main Results: We identified 4562 studies; of these, we included four RCTs with 286 participants. The studies compared two or more of the following: vitamin D, calcium or vitamin D plus calcium. The number of participants randomised to receive vitamin D was 64, calcium was 102 and vitamin D plus calcium was 120. Two studies were conducted in India and two were conducted in Nigeria. None of the included studies had a low risk of bias in all domains. Three studies had a high risk of bias in at least one domain. The age of the participants ranged between six months and 14 years. The duration of follow-up ranged between 12 weeks and 24 weeks. Two studies compared vitamin D to calcium. There is low-certainty evidence that, at 24 weeks' follow-up, calcium alone improved the healing of rickets compared to vitamin D alone (RR 3.26, 95% CI 1.59 to 6.69; P = 0.001; 1 study, 71 participants). Comparing vitamin D to calcium showed no firm evidence of an advantage or disadvantage in reducing morbidity (fractures) (RR 0.27, 95% CI 0.03 to 2.32; P = 0.23; 1 study, 71 participants; very low-certainty evidence). Adverse events were not reported. Two studies compared vitamin D plus calcium to vitamin D at 12 or 24 weeks. Vitamin D plus calcium improved healing of rickets compared to vitamin D alone at 24 weeks' follow-up (RR 3.06, 95% CI 1.49 to 6.29; P = 0.002; 1 study, 75 participants; low-certainty evidence). There is no conclusive evidence in favour of either intervention for reducing morbidity (fractures) (RR 0.24, 95% CI 0.03 to 2.08; P = 0.20; 1 study, 71 participants; very low-certainty evidence) or adverse events (RR 4.76, 95% CI 0.24 to 93.19; P = 0.30; 1 study, 39 participants; very low-certainty evidence). All four included studies compared vitamin D plus calcium to calcium at different follow-up times. There is no conclusive evidence on whether vitamin D plus calcium in comparison to calcium alone improved healing of rickets at 24 weeks' follow-up (RR 1.17, 95% CI 0.72 to 1.90; P = 0.53; 2 studies, 140 participants; very low-certainty evidence). Evidence is also inconclusive for morbidity (fractures) (RR 0.89, 95% CI 0.06 to 13.76; P = 0.94; 1 study, 72 participants; very low-certainty evidence) and adverse events (RR 4.29, 0.22 to 83.57; P = 0.34; 1 study, 37 participants; very low-certainty evidence). Most of the evidence in the review is low or very low certainty due to risk of bias, imprecision or both. None of the included studies assessed all-cause mortality, health-related quality of life or socioeconomic effects. One study assessed growth pattern but this was not measured at the time-point stipulated in the protocol of our review (one or more years after commencement of therapy)., Authors' Conclusions: This review provides low-certainty evidence that vitamin D plus calcium or calcium alone improve healing in children with nutritional rickets compared to vitamin D alone. We are unable to make conclusions on the effects of the interventions on adverse events or morbidity (fractures)., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Fortification of food products with vitamin D was central to the eradication of rickets in the early parts of the 20th century in the United States. In the subsequent almost 100 years since, accumulating evidence has linked vitamin D deficiency to a variety of outcomes, and this has paralleled greater public interest and awareness of the health benefits of vitamin D. Supplements containing vitamin D are now widely available in both industrialized and developing countries, and many are in the form of unregulated formulations sold to the public with little guidance for safe administration. Together, this has contributed to a transition whereby a dramatic global increase in cases of vitamin D toxicity has been reported. Clinicians are now faced with the challenge of managing this condition that can present on a spectrum from asymptomatic to acute life-threatening complications. This article considers contemporary data on vitamin D toxicity, and diagnostic and management strategies relevant to clinical practice.

Rickets was first described in great detail in the mid 17th century and was affecting a great number of children in major European cities. The disease, however, existed already in the Roman times. The etiology of this disease remained enigmatic until the 1920s when two different mechanisms, lack of exposure to sunlight and lack of a dietary factor were finally solved by the discovery of vitamin D and its dual origin. Soon thereafter, the implementation of vitamin D supplementation for all infants and small children largely eliminated nutritional rickets in Europe and North America. It took nearly a century to elucidate the complex chemistry, metabolism, mode and spectrum of activity of the vitamin D endocrine system. Nutritional rickets, whether due to simple vitamin D or calcium deficiency or both, remains widely ravaging many infants and children around the world. Asian countries and the Middle East are mainly confronted with vitamin D deficiency whereas many African and some Asian countries face calcium deficiency rickets. Immigrants and refugees or in general people with a darker skin living in moderate climate zone are also confronted with this disease. There is great consensus how this disease could be prevented or cured. In collaboration with most international professional societies, we prepare a memorandum, in line with the successful battle against iodine deficiency disorders, to convince the World Health Organization and its member states to start an implementation program to eradicate nutritional rickets by 2030., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The purpose of this review is the study of literature for the current data on the metabolism of vitamin D and its role in development of bone tissue in children. The role of the main marker enabling assessing 25(OH)D concentration in the body the reference values has been analyzed. Summarizing the literature data, we may say that vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a mayor impact on health of infants, children and adolescents.