Elsevier

The Lancet

Volume 362, Issue 9393, 25 October 2003, Pages 1389-1400
The Lancet

Seminar
Rickets

https://doi.org/10.1016/S0140-6736(03)14636-3Get rights and content

Summary

Rickets, once thought vanquished, is reappearing. In some less developed countries it hardly went away. This seminar reviews the effects of genes, stage of development, and environment on clinical expression of the disease. Rickets can be secondary to disorders of the gut, pancreas, liver, kidney, or metabolism; however, it is mostly due to nutrient deficiency and we concentrate on this form. Although calcium deficiency contributes in communities where little cows' milk is consumed, deficiency of vitamin D is the main cause. There are three major problems: the promotion of exclusive breastfeeding for long periods without vitamin D supplementation, particularly for babies whose mothers are vitamin D deficient; reduced opportunities for production of the vitamin in the skin because of female modesty and fear of skin cancer; and the high prevalence of rickets in immigrant groups in more temperate regions. A safety net of extra dietary vitamin D should be re-emphasised, not only for children but also for pregnant women. The reason why many immigrant children in temperate zones have vitamin D deficiency is unclear. We speculate that in addition to differences in genetic factors, sun exposure, and skin pigmentation, iron deficiency may affect vitamin D handling in the skin or gut or its intermediary metabolism.

Section snippets

What is rickets?

Endochondral ossification is the process by which cartilage is transformed into bone. The cartilage matrix produced by hypertrophic chondrocytes is calcified before being reabsorbed and replaced with woven bone, which in turn is removed and replaced with mature lamellar bone. During these processes, there is extensive deposition of new unmineralised bone tissue, known as osteoid. Rickets is the failure to mineralise this newly formed osteoid. Bones grow longer during childhood, and they must

Genetics and molecular biology

There is little evidence of any specific genetic predisposition to nutritional rickets. Polymorphisms of the vitamin D receptor (VDR) have been studied extensively in adults, but less so in children. Fischer and colleagues reported an increased frequency of the VDR FF genotype in Nigerian children with rickets.42 Paradoxically, the FF genotype is thought to encode a “better functioning” receptor. However, Nigerian children are at risk of calcium-deficiency rickets rather than that caused by

Vitamin D metabolism

Failure to convert calcidiol to calcitriol causes rickets. Such failure is caused by a defect in the gene encoding vitamin D 1α-hydroxylase, which is expressed in the mitochondria of proximal tubular and, to a lesser extent, collecting-duct cells of the kidney. This enzyme is regulated by calcium, phosphate, parathyroid hormone, calcitonin, calcitriol, and intracellular vitamin-D-binding protein 1.45 The clinical picture with this gene defect is one of severe rickets with hypocalcaemia commonly

Phosphate

Studies of three different disorders of phosphate metabolism have advanced the concept of a circulating factor (or factors) that might have a role in regulating phosphate homoeostasis.38 The commonest inherited form of rickets is X-linked hypophosphataemic rickets, which is caused by mutations in PHEX (Phosphate-regulating gene with Homologies to Endopeptidases, on the X chromosome). PHEX is predominantly expressed in osteoblasts. Individuals with this disorder have higher than normal urinary

Stages of development

Three components of development are relevant to rickets: growth, body composition, and biological events. Figure 3 explains why simple rickets is most common in infancy and at puberty and emphasises the importance of later fetal life and infancy for events affecting bones and teeth subsequently.51, 52, 53, 54, 55, 56

Growth is rapid in late fetal life (slowing somewhat during the last 2–3 weeks) and early infancy. The rate falls in the toddler years then rises for the prepubertal growth spurt

Sunlight

The contribution of the sun to vitamin D synthesis depends on latitude, season, exposure to direct sunlight, and skin colour (panel 6). Ultraviolet B radiation of wavelength 290–310 nm leads to the conversion (photolysis) of 7-dihydrocholesterol in the skin to precholecalciferol, which then undergoes thermally induced rearrangement of its double bonds to form cholecalciferol (vitamin D3).

There may be wider evolutionary concepts. The clinical gradation of skin colour could be related to levels

Prevention

Methods of prevention are the same as for any other nutrient deficiency, plus the need to promote exposure to sunlight. The parts played by the methods listed in panel 7 will vary according to country depending on the physical environment, cultural factors, diet (including national policies on food fortification), and socioeconomic factors (access to health services including policies for and provision of supplements).

Search strategy

The first aim was to examine the effects of genes, stage of development, and environment on rickets, and to relate these influences to clinical and public-health concerns. Literature searches of PubMed were done with the keywords “rickets” or “vitamin D” alone and then with “genes, or genetics”, specified ages, “sun”, “treatment”, “prevention”, and specific countries, with subsearches as necessary (eg, “weaning + calcium + phytate”). The choice of papers to quote was related to their

References (138)

  • N Andiran et al.

    Risk factors for vitamin D deficiency in breast-fed newborns and their mothers

    Nutrition

    (2002)
  • BL Salle et al.

    Perinatal metabolism of vitamin D

    Am J Clin Nutr

    (2000)
  • MJ Park et al.

    Bone mineral content is not reduced despite low vitamin D status in breast milk-fed infants versus cow's milk based formula-fed infants

    J Pediatr

    (1998)
  • SR Kreiter et al.

    Nutritional rickets in African American breast-fed infants

    J Pediatr

    (2000)
  • D Heldenberg et al.

    Effect of iron on serum 25-hydroxy vitamin D and 24,25-dihydroxy vitamin D concentrations

    Am J Clin Nutr

    (1992)
  • AC Looker et al.

    Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES 111

    Bone

    (2002)
  • L Muhe et al.

    Case control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children

    Lancet

    (1997)
  • JM Pettifor et al.

    Rickets in children of rural origin in South Africa: is low dietary calcium a factor?

    J Pediatr

    (1978)
  • LM Oginni et al.

    Healing of rickets after calcium supplementation

    Lancet

    (1999)
  • E Mellanby

    An experimental investigation of rickets

    Lancet

    (1919)
  • K Huldschinsky

    Die Behandlung der Rachitis durch Ultraviolet-bestrahlung

    Z Orthop Chir

    (1920)
  • EB Olson et al.

    Vitamin D: metabolism and mechanism of action

    World Rev Nutr Diet

    (1973)
  • BA Wharton et al.

    Infantile hypercalcaemia

  • P Wilton

    Cod-liver oil, vitamin D and the fight against rickets

    Can Med Assoc J

    (1995)
  • BH Bloc et al.

    Characteristics of children with florid vitamin D deficient rickets in the Auckland region in 1998

    N Z Med J

    (2000)
  • NJ Shaw et al.

    Vitamin D deficiency in UK Asian families: activating a new concern

    Arch Dis Child

    (2002)
  • JM Nozza et al.

    Vitamin D deficiency in mothers of infants with rickets

    Med J Aust

    (2001)
  • ZA Karrar

    Vitamin D deficiency rickets in developing countries

    Ann Trop Paediatr

    (1998)
  • AM Parfitt

    Vitamin D and the pathogenesis of rickets and osteomalacia

  • JM Pettifor et al.

    Is craniotabes a pathognomonic sign of rickets in 3-month-old infants?

    S Afr Med J

    (1984)
  • A Jacobi

    Nervous system in rhachitis. Cited by DeJong AR, Callahan CA, Weiss J. Pseudotumor cerebri and nutritional rickets

    Eur J Pediatr

    (1985)
  • M Hanafy et al.

    Benign intracranial hypertension in vitamin D deficiency rickets associated with malnutrition

    J Trop Pediatr

    (1967)
  • TD Thacher et al.

    The usefulness of clinical features to identify active rickets

    Ann Trop Paediatr

    (2002)
  • A Bereket et al.

    Brown tumour as a complication of secondary hyperparathyroidism in severe long-lasting vitamin D deficiency rickets

    Eur J Pediatr

    (2000)
  • P Gaffney

    Vitamin deficiency in a toddler reluctant to use her arm

    Eur J Emerg Med

    (2001)
  • TD Thacher et al.

    Radiographic scoring method for the assessment of the severity of nutritional rickets

    J Trop Pediatr

    (2000)
  • S Eek et al.

    Prematurity and rickets

    Pediatrics

    (1957)
  • B Bulloch et al.

    Cause and clinical characteristics of rib fractures in infants

    Pediatrics

    (2000)
  • D Uysall et al.

    Cardiac functions in children with vitamin D deficiency rickets

    Pediatr Cardiol

    (1999)
  • S Ozsoylu

    Rickets related myelofibrosis

    Eur J Pediatr

    (2000)
  • WB Grant

    An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates

    Cancer

    (2002)
  • IA van der Mei et al.

    Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation

    Neuroepidemiology

    (2001)
  • OG Brooke et al.

    Intrauterine vitamin D nutrition and postnatal growth in Asian infants

    BMJ

    (1981)
  • BE Clayton et al.

    Clinical biochemistry and the sick child, 2nd edn

    (1994)
  • R Vieth et al.

    How much vitamin D supplementation do adults require to ensure a serum 25(OH)D optimal for suppression of PTH?

    J Bone Miner Res

    (2000)
  • P Glendenning

    Issues of standardization and assay-specific clinical decision limits for the measurement of 25-hydroxyvitamin D

    Am Soc Clin Nutr

    (2003)
  • ED Daniels et al.

    Serum osteocalcin has limited usefulness as a diagnostic marker for rickets

    Eur J Pediatr

    (2000)
  • H Narchi et al.

    Rickets as an unusual initial presentation of abetalipoproteinemia and hypobetalipoproteinemia

    J Pediatr Endocrinol

    (2001)
  • MR Clements et al.

    The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency

    Clin Endocrinol

    (1992)
  • GL Klein et al.

    Hepatic osteodystrophy in chronic cholestasis: evidence for a multifactorial etiology

    Pediatr Trans

    (2002)

    • Cited by (0)

    View full text
    Copyright © 2003 Elsevier Ltd. All rights reserved.