Vitamin D-deficient rickets mimicking ankylosing spondylitis in an adolescent girl

Vitamin D-deficient rickets (VDDR) remains an important health problem especially in developing countries. Insufficient dietary intake of vitamin D and inadequate sun exposure increase the risk of vitamin D deficiency. Since their vitamin D requirement is increased, children and adolescents are potentially at higher risk for vitamin D deficiency. In adolescents, vitamin D deficiency causes osteomalacia, osteoporosis and muscle weakness. While osteoporosis is not associated with bone pain, osteomalacia has been associated with isolated or generalized bone pain. The present case suffered from generalized bone pain for three years. She was misdiagnosed as ankylosing spondylitis, which is a seronegative arthropathy, and was treated with corticosteroids and methotrexate, which have potential side effects. Hypocalcemia, hypophosphatemia, elevated alkaline phosphatase level, secondary hyperparathyroidism, and extremely low vitamin D level were consistent with the diagnosis of severe vitamin D deficiency. Complete clinical and biochemical resolution was achieved with vitamin D replacement.     

Nutritional and metabolic rickets

Nutritional rickets is casued by vitamin D deficiency due to lack of exposure to sunlight. Neonatal rickets occurs only in infants born to mothers with very severe osteomalacia. Calcium deficiency alone does not cause mineralisation defects. It only causes osteoporosis and secondary hyperparathyroidism with raised plasma, 1,25 (OH)₂D and osteocalcin. Low 25-OHD, increased IPTH, increased alkaline phosphatase in plasma and decreased calcium and increased hydroxyproline in urine are diagnostic of rickets. Low or undetectable plasma levels of 25-OHD, in presence of high plasma 1,25(OH)₂D and IPTH are often observed during treatment with vitamin D. Even the marginal intakes of fluoride (> 2.5 mg/day) cause rickets in calcium deficient children. Indian children often need high dose of vitamin D due to severely depleted D stores, high IPTH and severe bone disease (radiologic and histomorphometric) for treatment.     

Effects of early vitamin D deficiency rickets on bone and dental health,growth and immunity

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long‐term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25‐hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early‐life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long‐term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.     

Vitamin D deficiency causes rickets in an urban informal settlement in Kenya and is associated with malnutrition

The commonest cause of rickets worldwide is vitamin D deficiency, but studies from sub‐Saharan Africa describe an endemic vitamin D‐independent form that responds to dietary calcium enrichment. The extent to which calcium‐deficiency rickets is the dominant form across sub‐Saharan Africa and in other low‐latitude areas is unknown. We aimed to characterise the clinical and biochemical features of young children with rickets in a densely populated urban informal settlement in Kenya. Because malnutrition may mask the clinical features of rickets, we also looked for biochemical indices of risk in children with varying degrees of acute malnutrition. Twenty one children with rickets, aged 3 to 24 months, were identified on the basis of clinical and radiologic features, along with 22 community controls, and 41 children with either severe or moderate acute malnutrition. Most children with rickets had wrist widening (100%) and rachitic rosary (90%), as opposed to lower limb features (19%). Developmental delay (52%), acute malnutrition (71%), and stunting (62%) were common. Compared to controls, there were no differences in calcium intake, but most (71%) had serum 25‐hydroxyvitamin D levels below 30 nmol/L. These results suggest that rickets in young children in urban Kenya is usually driven by vitamin D deficiency, and vitamin D supplementation is likely to be required for full recovery. Wasting was associated with lower calcium (p = .001), phosphate (p < .001), 25‐hydroxyvitamin D (p = .049), and 1,25‐dihydroxyvitamin D (p = 0.022) levels, the clinical significance of which remain unclear.     

Deficiency rickets: the current situation in France and Algeria

Persisting vitamin D deficiency rickets in France results from the climatic, environmental and geographic situation of this country. Although systematic administration of vitamin D supplements to infants greatly reduced the prevalence of rickets among infants, clinical and/or biological signs of vitamin D deficiency are still found in children and adolescents, mainly during the winter and in populations vulnerable for economic, cultural or religious reasons. Signs of vitamin D deficiency are also found, during the winter-spring seasons, in pregnant women and their newborns living in urban areas. Such vitamin D deficiencies could be overcome by vitamin D supplementation to susceptible populations. In Algeria, vitamin D deficiency rickets present a continuing public health problem. The persisting high incidence of rickets among children appears to result mainly from economic and cultural factors. Vitamin D supplementation and health education are mandatory to reduce the prevalence of vitamin D deficiency among pregnant women and the occurrence of vitamin D deficiency rickets in infants, whether breast-fed or not.     

Vitamin D Deficiency and Acute Lower Respiratory Infections in Children Younger Than 5 Years: Identification and Treatment

IntroductionAcute lower respiratory infection (ALRI) is a leading cause of childhood mortality. Research suggests that vitamin D deficiency (VDD) puts children at risk for ALRI. The purpose of this review is to examine ALRI and VDD in children 5 years and younger. Common etiologies, diagnosis, prevention, treatment of ALRI, and recommendations for vitamin D supplementation are summarized.MethodDatabases were searched for studies investigating VDD and ALRI in children. Independent reviewers assessed the internal validity of the studies.ResultsOf 18 studies examined, VDD was found to be associated with increased risk or severity of ALRI in 13 studies; associations were not found in 4 studies. In one study it was found that high maternal vitamin D levels was associated with ALRI in infants.DiscussionVitamin D supplementation is a low-cost, low-risk intervention that providers should consider for children, especially those at high risk for ALRI. Practitioners should follow current recommendations when prescribing vitamin D supplementation for infants and children.     

Adolescent rickets in Saudi Arabia: a rich and sunny country

In this retrospective study from Saudi Arabia, which is a rich and sunny country, we report our experience with 34 adolescents (20 females, 10 males) with rickets. The commonest cause was vitamin D deficiency (58.8%) followed by rickets due to low calcium intake (11.8%) and genetic causes, including possible 25-hydroxylase deficiency (8.8%). The etiology of nutritional rickets is multifactorial, including lack of sun exposure and inadequate calcium intake. The clinical symptoms were nonspecific and therefore cases in this country are either underdiagnosed or missed. Vitamin D deficient patients needed an average of 19 months of treatment before recovery. High dose vitamin D plus calcium supplementation are recommended for treatment. Measures to prevent rickets in all age groups including adolescents are suggested. Further studies on nutritional and genetic forms of rickets are recommended.     

Vitamin D levels in children of asylum seekers in The Netherlands in relation to season and dietary intake

Low dietary intake and limited sun exposure during Dutch winters, in particular when combined with highly pigmented skin, could compromise the vitamin D status of asylum seekers’ children in The Netherlands. We determined the vitamin D status of children living in The Netherlands, but originating from Africa, Central Asia, or Eastern Europe. In a subgroup, we reassessed the vitamin D status after the summer, during which the children had been assigned at random to remain unsupplemented or to receive vitamin D supplementation. In total 112 children (median age 7.1 yr, range 2–12 yr) were assessed for serum concentrations of 25-Hydroxyvitamin D [25(OH)D], intact parathyroid hormone (I-PTH) and plasma alkaline phosphatase (ALP). Vitamin D deficiency (VDD) and hypovitaminosis D were defined as 25(OH)D below 30 or 50 nmol/L, respectively. Dietary intake of vitamin D and calcium was estimated using a 24 h recall interview. In mid-spring, 13% of the children had VDD, and 42% had hypovitaminosis D. I-PTH and ALP levels were significantly higher in children with VDD. The dietary intake of vitamin D was below 80% of the recommended daily allowances (RDA) in 94% of the children, but the dietary calcium intake was not significantly related to the s-25(OH)D levels found. After the summer, median s-25(OH)D increased with +35 nmol/L (+85%) and +19 nmol/L (+42%) in children with or without supplementation, respectively. The effect of supplementation was most prominent among African children. VDD and hypovitaminosis D are highly prevalent in mid-spring among asylum seekers’ children in The Netherlands. Although 25(OH)D levels increase in African children during Dutch summer months, this does not completely correct the compromised vitamin D status. Our data indicate that children from African origin would benefit from vitamin D supplementation.     

Persisting vitamin D deficiency in the Asian adolescent.

A study of 221 children admitted to hospital in the course of a year allowed establishment of a reference range for plasma 25-hydroxyvitamin D. None of these children had evidence of biochemical rickets. Most Asian children, however, were vitamin D deficient in comparison, and this deficiency was most noticeable in girls aged 13 to 15 years: biochemical rickets occurred in six per cent of these adolescent Asians. If vitamin D requirements are not met during the physiological growth spurt, permanent pelvic deformity may result. Vitamin D deficiency persisting into pregnancy will adversely affect the infant, producing an increased risk of hypocalcaemic fits, dental enamel hypoplasia, infantile rickets, and reduced postnatal growth. Our data support the need for vitamin D supplementation, and we suggest that annual oral vitamin D supplements in the autumn would alleviate the problem.     

Varying role of vitamin D deficiency in the etiology of rickets in young children vs. adolescents in northern India

The relative importance of calcium vs. vitamin D deficiency in the etiology of nutritional rickets in the tropics may be different in children compared with adolescents. We studied calcium intake, sun exposure, serum alkaline phosphatase, and 25 hydroxyvitamin D in 24 children and 16 adolescents with rickets/osteomalacia. The values were compared with those obtained in control subjects (34 children and 19 adolescents). We found that young children with rickets had lower calcium intake compared with controls (285 +/- 113 vs. 404 +/- 149 mg/day, p < 0.01), but similar sun exposure (55 +/- 28 vs. 56 +/- 23 min x m2/day) and 25 hydroxyvitamin D (49 +/- 38 vs. 61 +/- 36 nmol/l). Sixteen of 24 children with rickets had 25 hydroxyvitamin D above the rachitic range (> 25 nmol/l), in contrast to one of 16 adolescents. Adolescent patients had low calcium intake vs. controls (305 +/- 196 vs. 762 +/- 183 mg, p < 0.001), and lower sunshine exposure (16 +/- 15 vs. 27 +/- 17 min x m2/day, p < 0.01) and serum 25 hydroxyvitamin D (12.6 +/- 7.1 vs. 46 +/- 45.4 nmol/l, p < 0.001). The odds ratio for developing rickets with a daily calcium intake below 300 mg was 4.8 (95 per cent CI, 1.9 - 12.4, p = 0.001). Subjects with rickets were randomized to receive 1 g calcium daily, with or without vitamin D. Children showed complete healing in 3 months, whether they received calcium alone or with vitamin D. Adolescents showed no response to calcium alone, but had complete healing with calcium and vitamin D in 3-9 months (mean 5.3 months). Thus deficient calcium intake is universal among children and adolescents with rickets/osteomalacia. Inadequate sun exposure and vitamin D deficiency are important in the etiology of adolescent osteomalacia.     

Nutritional rickets around the world: causes and future directions

INTRODUCTION: Nutritional rickets has been described from at least 59 countries in the last 20 years. Its spectrum of causes differs in different regions of the world. METHODS: We conducted a systematic review of articles on nutritional rickets from various geographical regions published in the last 20 years. We extracted information about the prevalence and causes of rickets. RESULTS: Calcium deficiency is the major cause of rickets in Africa and some parts of tropical Asia, but is being recognised increasingly in other parts of the world. A resurgence of vitamin D deficiency has been observed in North America and Europe. Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas calcium deficiency typically presents after weaning and often after the 2nd year. Few studies of rickets in developing countries report values of 25(OH)D to permit distinguishing vitamin D from calcium deficiency. CONCLUSIONS: Rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Vitamin D supplementation alone might not prevent or treat rickets in populations with limited calcium intake.     

Global consensus on nutritional rickets: Implications for Australia

In 2016, a global consensus on the prevention, diagnosis and management of nutritional rickets was published. The bone and mineral working group of the Australasian Paediatric Endocrine Group provides a summary and highlights differences to previous Australian and New Zealand (ANZ) guidelines on vitamin D deficiency and their implications for clinicians. Key points are: (i) The International Consensus document is focused on nutritional rickets, whereas the ANZ guidelines were focused on vitamin D deficiency. (ii) Definitions for the interpretation of 25‐hydroxy vitamin D (25OHD) levels do not differ between statements. (iii) The global consensus recommends that routine 25OHD screening should not be performed in healthy children and recommendations for vitamin D supplementation are not based solely on 25OHD levels. The Australasian Paediatric Endocrine Group bone and mineral working group supports that screening for vitamin D deficiency should be restricted to populations at risk. (iv) Recommendations from the global consensus for vitamin D dosages for the therapy of nutritional rickets (diagnosed based on history, physical examination, biochemical testing and a confirmation by X‐rays) are higher than in ANZ publications. (v) The global consensus recommends the implementation of public health strategies such as universal supplementation with vitamin D from birth to 1 year of age and food fortification. We conclude that updated global recommendations for therapy of nutritional rickets complement previously published position statements for Australia and New Zealand. Screening, management and the implementation of public health strategies need to be further explored for Australia.     

Vitamin D deficiency in childhood — A review of current guidelines on diagnosis and management

Vitamin D deficiency has emerged as a significant public health problem throughout the world. Even in the Indian context,it has been reported to be present in majority of children in spite of wide availability of sunlight. Recent guidelines have defined vitamin D status as severe deficiency, deficiency, sufficiency and risk for toxicity as 25(OH)D levels <5, <15, >20 and >50ng/mL, respectively.The manifestations of deficiency may vary from hypocalcemic seizures, tetany in infancy and adolescence to florid rickets in toddlers. Treatment is necessary for all individuals with deficiency whether symptomatic or not and consists of vitamin D supplementation as Stoss therapy or daily or weekly oral regimens with equal efficacy and safety, combined with calcium supplements. Routine supplementation starting from newborn period is being increasingly endorsed by various international organizations. Prevention by sensible sunlight exposure, food fortification and routine supplementation are the currently available options for tackling this nutritional deficiency.     

Rickets

Worldwide, rickets is the most common form of metabolic bone disease in children. Despite the concept that it is a rare disease, it is on the increase in many regions, including Western Europe and the USA, and in many ethnic subgroups that have immigrated to temperate regions. Vitamin D deficiency is the main cause of rickets, though nutritional deficiency of calcium and phosphorous generates the same clinical picture. Rickets also occurs when the metabolites of vitamin D are deficient. This may be due to an inherited cause or secondary to disorders of the gut, pancreas, liver or kidney from disruption of vitamin D metabolism.     

Metabolic studies in congenital vitamin D deficiency rickets

Congenital rickets in 3 newborns of mothers with advanced nutritional osteomalacia, healed with maternal breast milk feeding when mothers alone were given calcium supplements and 7.5 mg of intravenous D₂ and the mother baby pair protected from sunlight. Maternal plasma biochemistry indicated more severe vitamin D deficiency compared to their newborns (intrauterine foetal priority). The first dose of 7.5 mg of vitamin D₃ and calcium supplements to mother healed osteomalacia but did not appear to heal the rickets of their breast fed infants (extrauterine maternal priority for vitamin D). A second dose given at 3 months interval healed the rickets in their infants and the biochemistry of the mother and baby returned towards normal. Congenital rickets developed when maternal bone mineral and vitamin D stores had been completely exhausted. Raised IPTH levels in the newborn suggested that foetal parathyroids were responsive to hypocalcaemic stimulus.     

Prevention and treatment of vitamin D and calcium deficiency in children and adolescents: Indian Academy of Pediatrics (IAP) guidelines

Justification

Vitamin D deficiency (VDD) is being increasingly reported from India from all age-groups. Reports suggest that VDD affects all age groups, from neonates to adolescents. Further, habitually low calcium intakes are also reported in Indian children. Given the multiple guidelines, peculiarities of Indian circumstances, changing lifestyles, and lack of fortification, the Indian Academy of Pediatrics (IAP) felt the need for a Practice Guideline for Pediatricians for the prevention and treatment of vitamin D and calcium deficiency in children and adolescents.

Process

The ‘Guideline for Vitamin D and Calcium in Children’ committee was formed by the IAP in September 2016. A consultative committee meeting was held in November 2016 in Mumbai. Evidence from Indian and international studies and other previous published recommendations, which were pertinent to the Indian circumstances, were collated for the preparation of these guidelines.

Objectives

To present a practice guideline for pediatricians for the prevention and treatment of deficiency of vitamin D and calcium in the Indian context.

Recommendations

For the prevention of rickets in premature infants, 400 IU of vitamin D and 150-220 mg/kg of calcium, and in neonates, 400 IU of vitamin D and 200 mg of calcium are recommended daily. For prevention of rickets and hypocalcemia in infants (after neonatal period) upto 1 year of age, and from 1-18 years, 400 IU and 600 IU vitamin D/day and 250-500 mg/day and 600-800 mg/day of calcium, respectively, are recommended. For treatment of rickets in premature neonates, infants upto 1 year and from 1-18 years, 1000 IU, 2000 IU and 3000-6000 IU of vitamin D daily, respectively, and elemental calcium of 70-80 mg/kg/day in premature neonates and 500-800 mg daily for all children over that age are recommended. Larger doses of vitamin D may be given from 3 months to 18 years of age as 60,000 IU/week for 6 weeks.

     

Case-control study of factors associated with nutritional rickets in Nigerian children

OBJECTIVE: Because the causes of nutritional rickets in tropical countries are poorly understood, we conducted a case-control study to determine factors associated with rickets in Nigerian children. STUDY DESIGN: We compared 123 Nigerian children who had rickets with matched control subjects. Dietary, demographic, anthropometric, and biochemical data were collected to assess factors related to calcium and vitamin D status, which might predispose children to rickets. RESULTS: Mean (+/- SD) daily dietary calcium intake was low in both children with rickets and control children (217 +/- 88 mg and 214 +/- 77 mg, respectively; P =.64). Children with rickets had a greater proportion of first-degree relatives with a history of rickets (14.6% vs 3.1%; P <.001), a shorter mean duration of breast-feeding (16.0 vs 17.3 months; P =.041), and a delayed age of walking (14 vs 12 months; P <.001). Among children with rickets, biochemical features suggestive of calcium deficiency included hypocalcemia, extremely low calcium excretion, and elevated 1, 25-dihydroxyvitamin D and parathyroid hormone values. Median 25-hydroxyvitamin D concentrations were 32 and 50 nmol/L (13 and 20 ng/mL) in children with rickets and control children, respectively (P <.0001). Only 46 subjects with rickets (37%) had 25-hydroxyvitamin D values <30 nmol/L (12 ng/mL). CONCLUSIONS: Vitamin D deficiency appears unlikely to be the primary etiologic factor of rickets in African children. Moreover, low dietary calcium intake alone does not account for rickets. Insufficient dietary calcium probably interacts with genetic, hormonal, and other nutritional factors to cause rickets in susceptible children.     

Nutritional rickets and z scores for height in the United Arab Emirates: To D or not to D?

Background: Vitamin D deficiency is still prevalent worldwide, including the Middle East. A cohort of patients with nutritional rickets was treated with vitamin D₂ (ergocalciferol) alone. After this intervention, patients were followed to document changes in z scores for height after treatment. The secondary aim was to determine the proportion of affected children who had vitamin D deficiency or calcium deficiency.
Methods: Z score for height was calculated as the difference between the observed value and the median value, divided by the SD of the population. Z scores were compared in patients before and after treatment.
Results: The improvement in z score after treatment was 0.86 ± 0.95. The 95% confidence interval for the mean difference was 1.32–0.40 ( t  = 3.95, P  < 0.001). With a diagnostic cut-off for 25 hydroxyvitamin D₃ (25D) deficiency of <25 nmol/L, only half were diagnosed with severe vitamin D deficiency. The remaining patients had presumable calcium deficiency. The alkaline phosphatase (ALP) was negatively correlated to z scores, implying that higher ALP concentrations predicted severe bone disease (lower z scores). The variables 25D and age were moderately and positively correlated (Pearson's r  = 0.59, 95%CI: 0.15–0.84; P  = 0.01), indicating that younger infants had the lowest 25D levels.
Conclusion: Vitamin D alone was efficient in resolving radiological and biochemical disturbances as well as improving z scores for height in a cohort of children with nutritional rickets, which included patients with 25D deficiency as well as calcium deficiency. The results support the hypothesis of the interplay and continuum of 25D deficiency and calcium deficiency in the pathogenesis of rickets.     

Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy.

An epidemiological study on vitamin D-dependent rickets was carried out in severely handicapped institutionalised children on long-term anticonvulsant therapy. Nine (10%) of 94 patients had overt rickets on the basis of roentgenological bone changes and biochemical indices, but 46 patients in hospital without medication, and 50 epileptic patients attending an outpatient clinic and taking anticonvulsants had no sign of rickets. Causative factors for the development of rickets were evaluated. Administration of anticonvulsive drugs depressed the serum 25-hydroxyvitamin D (25-OHD) level, but this was not the major factor in the development of rickets. Vitamin D intake seemed to be about average in these patients and its supplementation increased their serum 25-OHD level. This serum 25-OHD level was not maintained by supplemental vitamin D, unless the children were exposed to sunlight. These results indicate that although several factors--such as anticonvulsants, low vitamin D intake, and inactivity--are concerned in the development of rickets, the main cause is lack of sun in institutionalised handicapped children.