Nutritional rickets in African American breast-fed infants

Kreiter, Shelley; Schwartz, Robert P.; Kirkman, Henry N.; Charlton, Philippa A.; Çalıkoğlu, Ali S.; Davenport, Marsha L.

doi:10.1067/mpd.2000.109009

Cited by 322 publications

(247 citation statements)

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“…Dr Hollis, as the principal investigator (PI) of the project, worked with Dr Wagner in the conception of the project, study design, implementation of the study, laboratory analyses, data analyses, and writing of the manuscript; Dr, Wagner as clinical PI of the study, worked with Drs Hollis and Howard, site PI at the University of Rochester (U of R), and all other coinvestigators in the conception of the project, study design, implementation of the study, review of clinical and laboratory data, subject safety, data analyses, and writing of the manuscript; Dr Howard as clinical site PI at the U of R worked directly with Dr Wagner; she was involved in the conception of the project, study design, implementation of the study, laboratory analyses, data analyses, and writing of the manuscript; Ms Ebeling, as Data Manager and part of the biostatistics team, was involved in all aspects of study design, data analyses, and interpretation of the data, writing of the manuscript; Ms Shary, as project manager, was involved in study design, data collection, and data analyses, as well as interpretation of the data and writing of the manuscript; 4 Vitamin D activity in "normal" lactating women's milk is known to be in the range of 5 to 80 IU/L depending on the method of assay 1,5,6 ; however, the vitamin D content of human milk can be greatly increased by maternal oral vitamin D supplementation and/or increasing solar exposure of the mother. [7][8][9] Infants solely breastfed by women with vitamin D intakes of 400 IU/day typically attain a circulating 25(OH)D concentration in the marginally sufficient to severely deficient (,12.5 nmol/L) range.…”

Section: What This Study Addsmentioning

confidence: 99%

Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial

et al. 2015

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OBJECTIVE: Compare effectiveness of maternal vitamin D 3 supplementation with 6400 IU per day alone to maternal and infant supplementation with 400 IU per day.METHODS: Exclusively lactating women living in Charleston, SC, or Rochester, NY, at 4 to 6 weeks postpartum were randomized to either 400, 2400, or 6400 IU vitamin D 3 /day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitamin D 3 /day; infants in 2400 and 6400 IU groups received 0 IU/day (placebo). Vitamin D deficiency was defined as 25-hydroxy-vitamin D (25(OH)D) ,50 nmol/L. 2400 IU group ended in 2009 as greater infant deficiency occurred. Maternal serum vitamin D, 25(OH)D, calcium, and phosphorus concentrations and urinary calcium/creatinine ratios were measured at baseline then monthly, and infant blood parameters were measured at baseline and months 4 and 7.RESULTS: Of the 334 mother-infant pairs in 400 IU and 6400 IU groups at enrollment, 216 (64.7%) were still breastfeeding at visit 1; 148 (44.3%) continued full breastfeeding to 4 months and 95 (28.4%) to 7 months. Vitamin D deficiency in breastfeeding infants was greatly affected by race. Compared with 400 IU vitamin D 3 per day, 6400 IU/day safely and significantly increased maternal vitamin D and 25(OH)D from baseline (P , .0001). Compared with breastfeeding infant 25(OH)D in the 400 IU group receiving supplement, infants in the 6400 IU group whose mothers only received supplement did not differ. CONCLUSIONS:Maternal vitamin D supplementation with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy her nursing infant's requirement and offers an alternate strategy to direct infant supplementation. WHAT'S KNOWN ON THIS SUBJECT:The vitamin D concentration in breast milk of women taking 400 IU vitamin D per day is relatively low, leading to vitamin D deficiency in breastfeeding infants. As a result, the American Academy of Pediatrics recommends breastfeeding infant vitamin D supplementation within days after birth. WHAT THIS STUDY ADDS:Maternal vitamin D supplementation alone with 6400 IU/day safely supplies breast milk with adequate vitamin D to satisfy the requirement of her nursing infant and offers an alternate strategy to direct infant supplementation. Dr Hollis, as the principal investigator (PI) of the project, worked with Dr Wagner in the conception of the project, study design, implementation of the study, laboratory analyses, data analyses, and writing of the manuscript; Dr, Wagner as clinical PI of the study, worked with Drs Hollis and Howard, site PI at the University of Rochester (U of R), and all other coinvestigators in the conception of the project, study design, implementation of the study, review of clinical and laboratory data, subject safety, data analyses, and writing of the manuscript; Dr Howard as clinical site PI at the U of R worked directly with Dr Wagner; she was involved in the conception of the project, study design, implementation of the study, laboratory analyses, data analyses, and writing of the manuscript; M...

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Section: What This Study Addsmentioning

confidence: 99%

Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial

et al. 2015

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“…1 Of the 166 cases, 50 occurred in southern states. [1][2][3][4][5] In the southern states, all cases involved African-American infants diagnosed at 8-25 months of age. 1 Recognition of the persistence of rickets in the United States and Canada has sparked reinforcement of guidelines for vitamin D intake and investigation of the risk factors leading to the development of vitamin D-deficient rickets.…”

Section: Introductionmentioning

confidence: 99%

Neonatal vitamin D status at birth at latitude 32°72′: evidence of deficiency

et al. 2007

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Objective: With vitamin D deficiency as a serious public health problem, vitamin D status at birth was measured in neonates at latitude 32172 0 (southeastern United States).Study Design: In umbilical cord blood, vitamin D status, demonstrated by circulating 25-hydroxyvitamin D, was measured and related to race and season of birth.Result: The mean±standard deviation of 25-hydroxyvitamin D in 100 cord blood samples was 13.5±8.3 ng/ml for the cohort. African-American infants, with a mean±standard deviation of 10.5±6.0 ng/ml, demonstrated significantly lower vitamin D status than Caucasian infants, with a mean±standard deviation of 19.5±9.6 ng/ml (P<0.0001). By season, the mean 25-hydroxyvitamin D level at birth in NovemberMarch compared to April-October was 11.3 ng/ml lower in Caucasian infants (from 29.0 to 17.7 ng/ml) and 3 ng/ml lower in African-American infants (from 13.1 to 10.1 ng/ml).

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“…Along these lines, it is of possible significance that the vitamin D 25-hydroxylase-deficient subject identified here was Nigerian. Individuals with dark skin require exposure to sunlight for longer periods of time to generate requisite levels of vitamin D 3 as compared with those with less skin pigmentation and may be more sensitive to impaired synthesis of the vitamin (43)(44)(45)(46). Furthermore, we sequenced exon 2 of the CYP2R1 gene in 50 control subjects from Nigeria (22), and identified one individual who was heterozygous for the L99P mutation.…”

Section: -40)mentioning

confidence: 99%

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

Cheng

Levine

Bell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

652

399

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The synthesis of bioactive vitamin D requires hydroxylation at the 1␣ and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1␣-hydroxylation in the kidney but the identity of the hepatic 25-hydroxylase has remained unclear for >30 years. We previously identified the microsomal CYP2R1 protein as a potential candidate for the liver vitamin D 25-hydroxylase based on the enzyme's biochemical properties, conservation, and expression pattern. Here, we report a molecular analysis of a patient with low circulating levels of 25-hydroxyvitamin D and classic symptoms of vitamin D deficiency. This individual was found to be homozygous for a transition mutation in exon 2 of the CYP2R1 gene on chromosome 11p15.2. The inherited mutation caused the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and eliminated vitamin D 25-hydroxylase enzyme activity. These data identify CYP2R1 as a biologically relevant vitamin D 25-hydroxylase and reveal the molecular basis of a human genetic disease, selective 25-hydroxyvitamin D deficiency.T he metabolic pathway leading to the synthesis of active vitamin D involves three reactions that occur in different tissues (1). The pathway is initiated in the skin with the UV light-mediated cleavage of 5,7,-cholestadien-3␤-ol to produce the secosteroid (3␤,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol (vitamin D 3 ). The second step occurs in the liver and is catalyzed by a cytochrome P450 (CYP) enzyme that hydroxylates carbon 25, producing the intermediate 25-hydroxyvitamin D 3 , which is the major circulatory form of the vitamin. The third and final step takes place in the kidney and involves 1␣-hydroxylation by another CYP, producing 1␣,25-dihydroxyvitamin D 3 . This product is a potent ligand of the vitamin D receptor (VDR) and mediates most of the physiological actions of the vitamin (1).Although the chemical and enzymatic steps in the vitamin D 3 biosynthetic pathway have been known for 30 years (1), the enzyme catalyzing the 25-hydroxylation step in the liver has never been identified. At least six CYPs can catalyze this reaction in vitro, including CYP2C11, CYP2D25, CYP3A4, CYP2J1, CYP27A1, and CYP2R1 (2-4). Of these CYPs, the two most viable candidates for the vitamin D 25-hydroxylase are CYP27A1 and CYP2R1 (2). Both enzymes are expressed in the liver and are conserved among species known to have an active vitamin D signaling pathway. However, mutations in the human and mouse genes encoding the mitochondrial CYP27A1 protein impair bile acid synthesis, but have no consequences for vitamin D metabolism (5-9). It is thus not clear whether the two vitamin D 3 25-hydroxylases represent an example of biological redundancy in an important biosynthetic pathway or whether CYP2R1 alone or some unidentified enzyme fulfills this essential role.In contrast to the uncertainty surrounding vitamin D 3 25-hydroxylase, the renal enzyme responsible for 1␣-hydroxylation of the vitamin...

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Nutritional rickets in African American breast-fed infants

Cited by 322 publications

References 16 publications

Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial

Maternal Versus Infant Vitamin D Supplementation During Lactation: A Randomized Controlled Trial

Neonatal vitamin D status at birth at latitude 32°72′: evidence of deficiency

Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

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