An Overview of Rickets in Children
2020; Elsevier BV; Volume: 5; Issue: 7 Linguagem: Inglês
10.1016/j.ekir.2020.03.025
ISSN2468-0249
AutoresRahul Chanchlani, Paul Nemer, Rajiv Sinha, Lena Nemer, Vinod Krishnappa, Etienne Sochett, Fayez Safadi, Rupesh Raina,
Tópico(s)Alkaline Phosphatase Research Studies
ResumoRickets is a common bone disease worldwide that is associated with disturbances in calcium and phosphate homeostasis and can lead to short stature and joint deformities. Rickets can be diagnosed based on history and physical examination, radiological features, and biochemical tests. It can be classified into 2 major groups based on phosphate or calcium levels: phosphopenic and calcipenic. Knowledge of categorization of the type of rickets is essential for prompt diagnosis and proper management. Nutritional rickets is a preventable disease through adequate intake of vitamin D through both dietary and sunlight exposure. There are other subtypes of rickets, such as vitamin D–dependent type 1 rickets and vitamin D–dependent type 2 rickets (due to defects in vitamin D metabolism), renal rickets (due to poor kidney function), and hypophosphatemic rickets (vitamin D–resistant rickets secondary to renal phosphate wasting wherein fibroblast growth factor-23 (FGF-23) often plays a major role), which requires closer monitoring and supplementation with activated vitamin D with or without phosphate supplements. An important development has been the introduction of burosumab, a human monoclonal antibody to FGF-23, which is approved for the treatment of X-linked hypophosphatemia among children 1 year and older. Rickets is a common bone disease worldwide that is associated with disturbances in calcium and phosphate homeostasis and can lead to short stature and joint deformities. Rickets can be diagnosed based on history and physical examination, radiological features, and biochemical tests. It can be classified into 2 major groups based on phosphate or calcium levels: phosphopenic and calcipenic. Knowledge of categorization of the type of rickets is essential for prompt diagnosis and proper management. Nutritional rickets is a preventable disease through adequate intake of vitamin D through both dietary and sunlight exposure. There are other subtypes of rickets, such as vitamin D–dependent type 1 rickets and vitamin D–dependent type 2 rickets (due to defects in vitamin D metabolism), renal rickets (due to poor kidney function), and hypophosphatemic rickets (vitamin D–resistant rickets secondary to renal phosphate wasting wherein fibroblast growth factor-23 (FGF-23) often plays a major role), which requires closer monitoring and supplementation with activated vitamin D with or without phosphate supplements. An important development has been the introduction of burosumab, a human monoclonal antibody to FGF-23, which is approved for the treatment of X-linked hypophosphatemia among children 1 year and older. Rickets, a common disease worldwide,1Craviari T. Pettifor J.M. Thacher T.D. et al.Rickets: an overview and future directions, with special reference to Bangladesh. A summary of the Rickets Convergence Group meeting, Dhaka, 26–27 January, 2006.J Health Popul Nutr. 2008; 26: 112-121PubMed Google Scholar,2Carpenter T.O. Shaw N.J. Portale A.A. et al.Rickets.Nat Rev Dis Primers. 2017; 3: 17101Crossref PubMed Scopus (57) Google Scholar substantially affects the health, growth, and development of children and adolescents. It results from abnormalities of the growth plate cartilage predominantly affecting longer bones and leads to poor bone growth, defective mineralization, and bony deformities, such as bow-legs and knock-knees.3Jagtap V.S. Sarathi V. Lila A.R. et al.Hypophosphatemic rickets.Indian J Endocrinol Metab. 2012; 16: 177-182Crossref PubMed Google Scholar This is usually secondary to deficiencies of calcium or phosphorus because they are essential for normal bone growth and mineralization.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,5Pitt M.J. Rickets and osteomalacia are still around.Radiol Clin North Am. 1991; 29: 97-118PubMed Google Scholar This review article delves and analyzes different types of rickets and their appropriate management plan. Bones consist of cells that have various specific roles during the bone formation process. Osteoblasts are bone-forming cells that secrete the extracellular matrix and mineralize the osteoid, whereas osteoclasts break down the bone matrix during the stage of remodeling, disease conditions, or aging. For bone maturation, the organic component of the bone matrix, the osteoid, must be mineralized by calcium salts. In rickets, this process is hampered and results in amassing of osteoid beneath the growth plate leading to softness in the bone over a gradual period of time.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar Rickets can be classified into 2 major groups: phosphopenic and calcipenic3Jagtap V.S. Sarathi V. Lila A.R. et al.Hypophosphatemic rickets.Indian J Endocrinol Metab. 2012; 16: 177-182Crossref PubMed Google Scholar,6Tiosano D. Hochberg Z. Hypophosphatemia:the common denominator of all rickets.J Bone Miner Metab. 2009; 27: 392-401Crossref PubMed Scopus (108) Google Scholar (Figure 1). Abundant in all tissues of the body, phosphorus is a vital structural component for mineralization of bone. Both calcium and phosphorus keep the bone in a healthy, functional state.7Goldsweig B.K. Carpenter T.O. Hypophosphatemic rickets: lessons from disrupted FGF23 control of phosphorus homeostasis.Curr Osteoporos Rep. 2015; 13: 88-97Crossref PubMed Scopus (34) Google Scholar In phosphopenic/hypophosphatemic rickets, the defect usually results from increased renal excretion of phosphate.3Jagtap V.S. Sarathi V. Lila A.R. et al.Hypophosphatemic rickets.Indian J Endocrinol Metab. 2012; 16: 177-182Crossref PubMed Google Scholar Urinary loss of phosphate can be either as a part of generalized tubular dysfunction as seen in Fanconi syndrome, or secondary to either increased synthesis/ reduced catabolism of the FGF-23, or inactivating mutations in genes encoding for sodium-dependent phosphate transporters in the proximal renal tubule (Figure 1).8Mughal M.Z. Rickets.Curr Osteoporos Rep. 2011; 9: 291-299Crossref PubMed Scopus (28) Google Scholar Calcipenic rickets, as the name suggests, happens primarily because of a lack of calcium, which is most commonly due to a low availability or defective functioning of vitamin D in the body (Figure 1). Hence, calcipenic rickets can occur due to severe vitamin D deficiency (nutritional), inability to form either 25-hydroxyvitamin D (as in liver failure/drug intoxication; e.g., phenytoin) or 1,25-dihydroxy vitamin D (as in chronic kidney disease), or due to end-organ resistance to 1,25-dihydroxy vitamin D3Jagtap V.S. Sarathi V. Lila A.R. et al.Hypophosphatemic rickets.Indian J Endocrinol Metab. 2012; 16: 177-182Crossref PubMed Google Scholar. As a result, calcium absorption in the gut is decreased, which in turn increases parathyroid hormone (PTH) secretion by the parathyroid gland. PTH aims to preserve blood calcium levels by (i) activating bone resorption mediated by increasing RANKL by osteoblasts, (ii) decreasing renal calcium loss, and (iii) increasing renal phosphate loss by internalization and subsequent degradation of sodium-dependent phosphate cotransporter protein (NaPi-2a and NaPi-2c), which decreases tubular phosphate reabsorption.8Mughal M.Z. Rickets.Curr Osteoporos Rep. 2011; 9: 291-299Crossref PubMed Scopus (28) Google Scholar The common pathway in the development of rickets in both calcipenic and phosphopenic forms is reduced phosphate concentration.2Carpenter T.O. Shaw N.J. Portale A.A. et al.Rickets.Nat Rev Dis Primers. 2017; 3: 17101Crossref PubMed Scopus (57) Google Scholar,9Sabbagh Y. Carpenter T.O. Demay M.B. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes.Proc Natl Acad Sci U S A. 2005; 102: 9637-9642Crossref PubMed Scopus (171) Google Scholar Vitamin D plays an essential role in skeletal health by regulating normal blood levels of calcium and phosphorus (Figure 2).10Thomas M.K. Lloyd-Jones D.M. Thadhani R.I. et al.Hypovitaminosis D in medical inpatients.N Engl J Med. 1998; 338: 777-783Crossref PubMed Scopus (1227) Google Scholar,11Yan X. Han X. Zhang H.F. [Interpretation for the global consensus recommendations on prevention and management of nutritional rickets].Zhonghua er ke za zhi. 2016; 54: 891-895PubMed Google Scholar There are 2 main forms of vitamin D: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is primarily derived from plant sources. In addition to being present in foods such as fish, eggs, milk, and cod liver oil, the synthesis of vitamin D3 occurs naturally through the conversion of dehydrocholesterol to cholecalciferol in the skin by sunlight (ultraviolet B in the 290–315-nm range). Vitamin D binds to the vitamin D binding protein and is transported to the liver for hydroxylation, and converted by 25-hydroxylase (encoded by CYP2R1, Cytochrome P450 Family 2 Subfamily R Member 1) into calcidiol (also known as hydroxyl-cholecalciferol, 25-hydroxyvitamin, calcifediol) which is then absorbed in the proximal tubule of the kidney through the endocytic receptors megalin and cubilin12Kaseda R. Hosojima M. Sato H. et al.Role of megalin and cubilin in the metabolism of vitamin D(3).Ther Apher Dial. 2011; 15: 14-17Crossref PubMed Scopus (42) Google Scholar and hydroxylated by the enzyme 1 alpha-hydroxylase (encoded by CYP27B1, Cytochrome P450 Family 27 Subfamily B Member 1) to form the active metabolite of vitamin D, calcitriol (also known as 1,25-dihydroxy vitamin D).13Mozos I. Marginean O. Links between vitamin D deficiency and cardiovascular diseases.Biomed Res Int. 2015; 2015: 109275Crossref PubMed Scopus (127) Google Scholar 1,25-dihydroxy vitamin D acts on the vitamin D receptor in intestinal cells to increase the gut absorption of calcium by upregulating the calcium channel, TRPV6 (Transient receptor potential cation channel subfamily V member 6).14Christakos S. Dhawan P. Benn B. et al.Vitamin D.Ann N Y Acad Sci. 2007; 1116: 340-348Crossref PubMed Scopus (105) Google Scholar As shown in Figure 3, there is a complex interaction between the hormones produced by the kidneys (1,25 dihydroxy vitamin D), bone (FGF-23), and PTH. Understanding these interactions is essential for proper management of rickets. Hypocalcemia, hypophosphatemia, and PTH stimulate the synthesis of 1,25-dihydroxy vitamin D. FGF-23, a hormone produced by osteocytes, plays an important role in bone metabolism. It inhibits the synthesis of 1,25-dihydroxy vitamin D and binds with the FGF receptors with the help of klotho, a membrane-bound protein, and increases the renal excretion of phosphate by reducing the number of the main renal phosphate transporters, sodium-dependent phosphate transport proteins, NaPi-2a and NaPi-2c, on the apical surface of proximal renal tubular cells.15Martin A. David V. Quarles L.D. Regulation and function of the FGF23/klotho endocrine pathways.Physiol Rev. 2012; 92: 131-155Crossref PubMed Scopus (342) Google Scholar FGF-23 is regulated by 2 major proteins in bone: phosphate-regulating neutral endopeptidase homolog (PHEX) and dentin matrix acidic phosphoprotein 1 (DMP1). Both of which are made primarily in bone, specifically by osteocytes. Dysregulation of these proteins results in osteomalacia, suggesting that osteocytes play a role in the regulation of skeletal mineralization. Nutritional rickets is the most common form of bone disease, primarily affecting infants and young children. Although primarily caused by vitamin D deficiency, calcium and phosphate deficiencies also play a significant role. Vitamin D regulates calcium and phosphorus in the blood and deficiency of vitamin D does result in inadequate mineralization of osteoid produced by osteoblasts.16Wharton B. Bishop N. Rickets.Lancet. 2003; 362: 1389-1400Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar The primary cause of vitamin D deficiency usually involves interplay of nutritional inadequacy and lack of sunlight exposure with overlapping contributions by cultural, environmental, and genetic factors.17Konradsen S. Ag H. Lindberg F. et al.Serum 1,25-dihydroxy vitamin D is inversely associated with body mass index.Eur J Nutr. 2008; 47: 87-91Crossref PubMed Scopus (154) Google Scholar Table 1 shows the classification of the severity of vitamin D deficiency.18Munns C.F. Shaw N. Kiely M. et al.Global consensus recommendations on prevention and management of nutritional rickets.J Clin Endocrinol Metab. 2016; 101: 394-415Crossref PubMed Scopus (431) Google Scholar There is no clear consensus on the definition of normal vitamin D concentration in healthy children and guidelines differ in their target levels for optimal vitamin D status.19Shroff R. Wan M. Nagler E.V. et al.Clinical practice recommendations for native vitamin D therapy in children with chronic kidney disease Stages 2–5 and on dialysis.Nephrol Dial Transplant. 2017; 32: 1098-1113Crossref PubMed Scopus (35) Google Scholar The Global Consensus meeting on the prevention and management of nutritional rickets defined deficiency as vitamin D level <30 ng/ml.18Munns C.F. Shaw N. Kiely M. et al.Global consensus recommendations on prevention and management of nutritional rickets.J Clin Endocrinol Metab. 2016; 101: 394-415Crossref PubMed Scopus (431) Google Scholar Both skeletal and extraskeletal manifestations are present in patients with nutritional rickets. Skeletal symptoms include swollen wrists and ankles, delayed tooth eruption, leg deformity, rachitic rosary, frontal bossing, craniotabes, and bone pain.8Mughal M.Z. Rickets.Curr Osteoporos Rep. 2011; 9: 291-299Crossref PubMed Scopus (28) Google Scholar,16Wharton B. Bishop N. Rickets.Lancet. 2003; 362: 1389-1400Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar On the other hand, extraskeletal findings include muscle weakness and hypocalcemic seizures.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,18Munns C.F. Shaw N. Kiely M. et al.Global consensus recommendations on prevention and management of nutritional rickets.J Clin Endocrinol Metab. 2016; 101: 394-415Crossref PubMed Scopus (431) Google Scholar Nutritional/medical history, biochemical testing, and radiographs are used to diagnose nutritional rickets. Along with low level of 25 (OH) vitamin D, laboratory findings are also helpful in its diagnosis as well as in differentiating it from other causes of rickets (Table 2).4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,18Munns C.F. Shaw N. Kiely M. et al.Global consensus recommendations on prevention and management of nutritional rickets.J Clin Endocrinol Metab. 2016; 101: 394-415Crossref PubMed Scopus (431) Google Scholar,20Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D, Calcium. The National Academies Collection: Reports funded by National Institutes of Health.in: Ross A.C. Taylor C.L. Yaktine A.L. Del Valle H.B. Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press, National Academy of Sciences, Washington, DC2011: 345-402Google Scholar,21Ariganjoye R. Pediatric hypovitaminosis D.Glob Pediatr Health. 2017; 4 (2333794X16685504)PubMed Google Scholar 25 (OH)D, 25-hydroxy vitamin D; 1,25 (OH)2 D, 1,25 dihydroxy vitamin D; N, normal levels; PTH, parathyroid hormone; ↑, increased levels; ↓, decreased levels. The treatment of nutritional vitamin D deficiency with cholecalciferol consists of an intensive phase followed by a maintenance phase. The National Osteoporosis Society in the United Kingdom recommends 3000 IU (in infants <6 months old), 6000 IU (6 months–12 years old), and 10,000 IU (12–18 years old) of cholecalciferol per day in the intensive phase followed by 400 to 600 IU/d in the maintenance phase.22Aspray T.J. Bowring C. Fraser W. Gittoes N. et al.National Osteoporosis Society vitamin D guideline summary.Age Ageing. 2014; 43: 592-595Crossref PubMed Scopus (108) Google Scholar The U.S. Endocrine Society recommends 2000 IU/d cholecalciferol for 6 weeks for all age groups in the intensive phase followed by 400 to 1000 IU/d in the maintenance phase.23Holick M.F. Binkley N.C. Bischoff-Ferrari H.A. et al.Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2011; 96: 1911-1930Crossref PubMed Scopus (5620) Google Scholar Also, evaluation of nutritional calcium intake of the child is important. The recommended daily dietary allowance of calcium is 200 mg for infants 0 to 6 months, 260 mg for infants 7 to 12 months, 700 mg for children 1 to 3 years old, 1000 mg for 4 to 8 years old, and 1300 mg for children 9 to 18 years old.24Graf L. Reidy K. Kaskel F.J. Nutrition management in childhood kidney disease: an integrative and lifecourse approach.in: Avner E.D. Harmon W.E. Niaudet P. Pediatric Nephrology. Springer, Berlin2016: 341-360Crossref Scopus (1) Google Scholar Table 3 shows age-based normal values of serum calcium and phosphorus in children.25National Kidney FoundationK/DOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease.Am J Kidney Dis. 2005; 46: S1-S122Abstract Full Text PDF PubMed Google Scholar In children in whom calcium deficiency is the primary cause of nutritional rickets, calcium supplements (≥1000 mg/d) is recommended.2Carpenter T.O. Shaw N.J. Portale A.A. et al.Rickets.Nat Rev Dis Primers. 2017; 3: 17101Crossref PubMed Scopus (57) Google Scholar To convert units: calcium 1 mg/dl = 0.25 mmol/l; phosphorus 1 mg/dl = 0.32 mmol/l. Along with nutritional factors, vitamin D deficiency can be compounded by a multitude of non-nutritional factors. Differences among racial groups, including skin pigmentation, substantially affect vitamin D status. From 2008 to 2012, 110 children younger than 5 in the Norwegian Patient Registry were diagnosed with active rickets, of whom 42 children were classified as having nutritional rickets (vitamin D deficiency). Although the number was substantially low in comparison to years before 2008 to 2012, 93% of the patients had a non-Caucasian background.26Meyer H.E. Skram K. Berge I.A. et al.Nutritional rickets in Norway: a nationwide register-based cohort study.BMJ Open. 2017; 7e015289Crossref PubMed Scopus (6) Google Scholar A cohort study conducted among the South Asian and white population suggested the effect of both seasonal variation and skin pigmentation. During the summer, the median 25-hydroxyvitamin level in the South Asian group was 9.1 ng/ml, which decreased to 5.8 ng/ml in the winter. In comparison, the Caucasians also had a decrease in winter vitamin D levels but from a median of 26.2 ng/ml during the summer to 18.9 ng/ml in the winter.27Kift R. Berry J.L. Vail A. et al.Lifestyle factors including less cutaneous sun exposure contribute to starkly lower vitamin D levels in U.K. South Asians compared with the white population.Br J Dermatol. 2013; 169: 1272-1278Crossref PubMed Scopus (62) Google Scholar Apart from skin pigmentation, sociocultural issues also play an important role. As discussed, ultraviolet radiation is essential for the production of vitamin D,4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,28Lo C.W. Paris P.W. Holick M.F. Indian and Pakistani immigrants have the same capacity as Caucasians to produce vitamin D in response to ultraviolet irradiation.Am J Clin Nutr. 1986; 44: 683-685Crossref PubMed Scopus (108) Google Scholar but despite having plentiful sunlight and average summer seasonal temperature of 45 °C, 100% of young healthy Saudi female individuals suffer from vitamin D deficiency. In a study of the 465 female participants, all participants had low vitamin D levels (25-hydroxyvitamin <75 nmol/l) with a mean level of 18.34 ± 8.2 nmol/l.29Al-Mogbel E.S. Vitamin D status among adult Saudi females visiting primary health care clinics.Int J Health Sci. 2012; 6: 116-126Crossref Google Scholar This paradox might be secondary to the traditional requirement of Muslim women in Saudi Arabia to be covered from head to toe, thus hindering sun exposure. Ultraviolet radiation, although important, is not necessarily the only important cause for vitamin D deficiency. Despite India’s geographic location giving its population excessive amounts of sunlight exposure, vitamin D deficiency has been reported significantly in the range of 70% to 100% in the adult population, which may be due to the widespread practice of a vegetarian-based diet.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,30Dhas Y. Mishra N. Banerjee J. Vitamin D deficiency and oxidative stress in type 2 diabetic population of India.Cardiovasc Hematol Agents Med Chem. 2017; 14: 82-89Crossref PubMed Scopus (11) Google Scholar Infancy is another age group quite vulnerable to 25-hydroxy vitamin D deficiencies. During pregnancy, there is a transfer of vitamin D between the mother and fetus and hence if the mother has low vitamin D level storage then so does the fetus.31Thandrayen K. Pettifor J.M. Maternal vitamin D status: implications for the development of infantile nutritional rickets.Endocrinol Metab Clin North Am. 2010; 39 (table of contents): 303-320Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Even if the mother’s vitamin D level is adequate, infants get a maximum of approximately 40 IU of vitamin D per 750 ml of the breast milk. On the other hand, formula-fed infants receive plentiful amounts of vitamin D because of the fortification of minerals within the milk. Hence, vitamin D deficiency is uncommon in formula-fed infants. A cohort study was undertaken in northwest England with breast-fed infants reporting a rate of 67% of vitamin D deficiency, whereas formula-fed infants had a 2% rate of deficiency.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,32Emmerson A.J.B. Dockery K. Mughal M.Z. et al.Vitamin D status of white pregnant women and infants at birth and 4 months in North West England: a cohort study.Matern Child Nutr. 2018; 14Crossref PubMed Scopus (7) Google Scholar Preterm infants, especially those with birth weight <1000 g are also at a high risk for rickets primarily because of calcium and phosphate deficiency.2Carpenter T.O. Shaw N.J. Portale A.A. et al.Rickets.Nat Rev Dis Primers. 2017; 3: 17101Crossref PubMed Scopus (57) Google Scholar Prevention of vitamin D deficiency can be practiced through adequate sun exposure, vitamin D supplementation, fortification of dietary intake, and meeting the normal calcium intake. Regular vitamin D supplementation is recommended for infants from birth until 12 months of age (400 IU/d). For those older, 600 IU/d of vitamin D through diet or supplementation is advised.4Sahay M. Sahay R. Rickets-vitamin D deficiency and dependency.Indian J Endocrinol Metab. 2012; 16: 164-176Crossref PubMed Google Scholar,11Yan X. Han X. Zhang H.F. [Interpretation for the global consensus recommendations on prevention and management of nutritional rickets].Zhonghua er ke za zhi. 2016; 54: 891-895PubMed Google Scholar,18Munns C.F. Shaw N. Kiely M. et al.Global consensus recommendations on prevention and management of nutritional rickets.J Clin Endocrinol Metab. 2016; 101: 394-415Crossref PubMed Scopus (431) Google Scholar,33Sahay M. Sahay R. Renal rickets-practical approach.Indian J Endocrinol Metab. 2013; 17: S35-S44Crossref PubMed Google Scholar, 34Robinson P.D. Hogler W. Craig M.E. et al.The re-emerging burden of rickets: a decade of experience from Sydney.Arch Dis Child. 2006; 91: 564-568Crossref PubMed Scopus (152) Google Scholar, 35Prentice A. Nutritional rickets around the world.J Steroid Biochem Mol Biol. 2013; 136: 201-206Crossref PubMed Scopus (85) Google Scholar, 36Gartner L.M. Greer F.R. Prevention of rickets and vitamin D deficiency: new guidelines for vitamin D intake.Pediatrics. 2003; 111: 908-910Crossref PubMed Scopus (394) Google Scholar Occurring generally during the first year of life, vitamin D–dependent type 1 rickets (VDDR I) is a rare autosomal recessive disease of vitamin D metabolism that occurs due to homozygous inactivating mutations in the CYP27B1 gene leading to impaired production of the enzyme 1 alpha-hydroxylase, which in turn leads to low serum levels of the active metabolite calcitriol.37Takeda E. Yamamoto H. Taketani Y. et al.Vitamin D-dependent rickets type I and type II.Acta Paediatr Jpn. 1997; 39: 508-513Crossref PubMed Scopus (35) Google Scholar, 38Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (963) Google Scholar, 39Ting T.H. Devnani A.S. Vitamin-D-deficiency rickets even with abundant sunlight -A case to highlight emerging problem.Med J Malaysia. 2016; 71: 354-356PubMed Google Scholar Specific clinical manifestations include typical features of rickets, such as growth failure, hypotonia, rachitic rosary, genu valgum, and increased susceptibility to fractures, despite the patient getting sufficient vitamin D intake.37Takeda E. Yamamoto H. Taketani Y. et al.Vitamin D-dependent rickets type I and type II.Acta Paediatr Jpn. 1997; 39: 508-513Crossref PubMed Scopus (35) Google Scholar The laboratory findings (Table 2) would typically show low calcium, low phosphate, elevated PTH, and high alkaline phosphatase, but in contrast to nutritional rickets they will have normal or high 25-hydroxyvitamin levels and low calcitriol levels.37Takeda E. Yamamoto H. Taketani Y. et al.Vitamin D-dependent rickets type I and type II.Acta Paediatr Jpn. 1997; 39: 508-513Crossref PubMed Scopus (35) Google Scholar,38Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (963) Google Scholar As expected, these children will not respond to high doses of cholecalciferol but respond to physiologic doses of calcitriol or 1α-hydroxyvitamin D (1–2 μg daily). Adequate intake of dietary calcium (30–75 mg/kg per day of elemental calcium) should be maintained.33Sahay M. Sahay R. Renal rickets-practical approach.Indian J Endocrinol Metab. 2013; 17: S35-S44Crossref PubMed Google Scholar Typically, radiological healing occurs within 6 to 8 weeks of therapy. These children should be monitored for potential side effects of hypercalcemia, hypercalciuria, and nephrocalcinosis secondary to calcitriol therapy.33Sahay M. Sahay R. Renal rickets-practical approach.Indian J Endocrinol Metab. 2013; 17: S35-S44Crossref PubMed Google Scholar Regular blood work (serum creatinine and calcium, phosphate), urine examination for urine calcium and creatinine ratio, and kidney ultrasound examination should be performed. Also occurring during infancy, VDDR type 2 (VDDR II) or hereditary vitamin D–resistant rickets, is a rare autosomal recessive disease caused by a defect in the calcitriol vitamin D receptor.38Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (963) Google Scholar The defect causes the body to be irresponsive to calcitriol.38Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (963) Google Scholar Children with VDDR II present early in life and may have hypocalcemia, rickets, growth failure, seizures, enamel hypoplasia, and dental caries. Alopecia also occurs in two-thirds of cases due to a lack of vitamin D receptor activity within keratinocytes and is a marker of disease severity.33Sahay M. Sahay R. Renal rickets-practical approach.Indian J Endocrinol Metab. 2013; 17: S35-S44Crossref PubMed Google Scholar,40Forghani N. Lum C. Krishnan S. et al.Two new unrelated cases of hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene.J Pediatr Endocrinol Metab. 2010; 23: 843-850Crossref PubMed Scopus (25) Google Scholar The laboratory tests show high levels of calcitriol, hypocalcemia, hypophosphatemia, high serum levels of alkaline phosphatase, and PTH (Table 2).37Takeda E. Yamamoto H. Taketani Y. et al.Vitamin D-dependent rickets type I and type II.Acta Paediatr Jpn. 1997; 39: 508-513Crossref PubMed Scopus (35) Google Scholar,41Choudhury S. Jebasingh K.F. Ranabir S. et al.Familial vitamin D resistant rickets: end-organ resistance to 1,25-dihydroxyvitamin D.Indian J Endocrinol Metab. 2013; 17: S224-S227Crossref PubMed Google Scholar Low levels of 1,25 dihydroxy vitamin D differentiates VDDR II from VDDR I, among which the levels are usually high. Because VDDR II is a hereditary disease resistant to 1,25-dihydroxyvitamin D, no completely proven treatment is available.38Holick M.F. Resurrection of vitamin D deficiency and rickets.J Clin Invest. 2006; 116: 2062-2072Crossref PubMed Scopus (963) Google Scholar,42Fraser D. Scriver C.R. Familial forms of vitamin D-resistant rickets revisited. X-linked hypophosphatemia and autosomal recessive vitamin D dependency.Am J Clin Nutr. 1976; 29: 1315-1329Crossref PubMed Scopus (31) Google Scholar Despite its difficulty, the most plausible way is to saturate the normal receptors through mega-doses of calcitriol and calcium. Without treatment, the disorder further leads to severe skeletal deformity, respiratory infections, and most likely death by age 8.37Takeda E. Yamamoto H. Taketani Y. et al.Vitamin D-dependent rickets type I and type II.Acta Paediatr Jpn. 1997; 39: 508-513Crossref PubMed Scopus (35) Google Scholar Therapy consists of high doses of calcitriol, starting at low dose
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