Genetic Causes of Rickets

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Abstract

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

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Most cited references 121

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Vitamin D deficiency in children and its management: review of current knowledge and recommendations.

Madhusmita Misra, Danièle Pacaud, Anna Petryk … (2008)

Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated with these recommendations.

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Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

Jian Q. Feng, Leanne M. Ward, Shiguang Liu … (2006)

The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.

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Calcium metabolism in health and disease.

Munro Peacock (2009)

This brief review focuses on calcium balance and homeostasis and their relationship to dietary calcium intake and calcium supplementation in healthy subjects and patients with chronic kidney disease and mineral bone disorders (CKD-MBD). Calcium balance refers to the state of the calcium body stores, primarily in bone, which are largely a function of dietary intake, intestinal absorption, renal excretion, and bone remodeling. Bone calcium balance can be positive, neutral, or negative, depending on a number of factors, including growth, aging, and acquired or inherited disorders. Calcium homeostasis refers to the hormonal regulation of serum ionized calcium by parathyroid hormone, 1,25-dihydroxyvitamin D, and serum ionized calcium itself, which together regulate calcium transport at the gut, kidney, and bone. Hypercalcemia and hypocalcemia indicate serious disruption of calcium homeostasis but do not reflect calcium balance on their own. Calcium balance studies have determined the dietary and supplemental calcium requirements needed to optimize bone mass in healthy subjects. However, similar studies are needed in CKD-MBD, which disrupts both calcium balance and homeostasis, because these data in healthy subjects may not be generalizable to this patient group. Importantly, increasing evidence suggests that calcium supplementation may enhance soft tissue calcification and cardiovascular disease in CKD-MBD. Further research is needed to elucidate the risks and mechanisms of soft tissue calcification with calcium supplementation in both healthy subjects and CKD-MBD patients.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Res Pediatr Endocrinol

Journal ID (iso-abbrev): J Clin Res Pediatr Endocrinol

Journal ID (publisher-id): JCRPE

Title: Journal of Clinical Research in Pediatric Endocrinology

Publisher: Galenos Publishing

ISSN (Print): 1308-5727

ISSN (Electronic): 1308-5735

Publication date (Print): December 2017

Publication date (Electronic): 30 December 2017

Volume: 9

Issue: Suppl 2

Pages: 88-105

Affiliations

[1 ] Dokuz Eylül University Faculty of Medicine, Department of Pediatric Endocrinology, İzmir, Turkey

[2 ] King Faisal Specialist Hospital & Research Centre, Department of Genetics, Riyadh, Saudi Arabia

Author notes

* Address for Correspondence: King Faisal Specialist Hospital & Research Centre, Department of Genetics, Riyadh, Saudi Arabia E-mail: yufei@ 123456kfshrc.edu.sa

Article

Publisher ID: 3067

DOI: 10.4274/jcrpe.2017.S008

PMC ID: 5790329

PubMed ID: 29280738

SO-VID: 074eae76-9041-4d99-b7ea-99dc256b2113

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genetic Causes of Rickets

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Estudio del peso al nacer

Most cited references 121

Vitamin D deficiency in children and its management: review of current knowledge and recommendations.

Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

Calcium metabolism in health and disease.

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