FGF23 is elevated in Gambian children with rickets☆
Introduction
Fibroblast growth factor 23 (FGF23) is a recently discovered humoral factor involved in extracellular phosphate homeostasis [1], [2], [3]. It affects renal phosphate handling, by inhibiting phosphate reabsorption and thus promoting phosphate excretion. Elevated plasma concentrations of FGF23, resulting from an increased production or decreased inactivation of the protein, are associated with hypophosphatemia, phosphate wasting and impaired bone mineralization in a variety of syndromes, including tumor-induced osteomalacia (TIO) [4], fibrous dysplasia of bone [5], and possibly autosomal dominant hypophosphatemic rickets (ADHR) [6], [7], and X-linked hypophosphatemic rickets (XLH) [4]. Recent evidence suggest that FGF23 is part of a homeostatic system for phosphate and vitamin D [1], [3], [8], [9], circulating at low concentrations in healthy adults and children [4], [10], [11].
Rickets in children is generally associated with vitamin D deficiency and is most common in infancy [12]. However, in recent years, there have been reports from Africa and Asia of rickets in older children with normal or near-normal plasma concentrations of 25-hydroxyvitamin D (25OHD) [13], [14], [15], [16]. The incidence of rickets in some areas is high, with, for example, as many as 9% of young children in the central plateau region of Nigeria having clinical features suggestive of rickets [13]. These children live in populations where calcium intake is typically very low and close to the biological requirement for normal bone growth [15], [17], [18], and there is good evidence that affected children respond to calcium treatment alone [15], [18], [19]. This suggests that dietary calcium deficiency may be the primary cause, possibly combined with an underlying genetic predisposition [20]. However, to date, the exact etiology of the disease remains elusive and attempts to define risk factors in some studies have proved unsuccessful, suggesting there may be other contributory factors [12].
The common finding of a low plasma phosphate (PO4) in severe cases of calcium-deficiency rickets [15], [16], [18] suggests that perturbations of phosphate regulation may play a role in the pathogenesis of this disease. This paper describes an investigation of plasma FGF23 concentration, and its relationship to plasma PO4, in a series of children who presented at two clinics in The Gambia, West Africa, with clinical rickets and 25OHD in the normal range.
Section snippets
Background
The Gambia is situated in sub-Saharan West Africa, latitude 13°N. The climate is hot and dry, with a single rainy season from July to October. Tropical sunshine is abundant all year and there are no cultural restrictions on dress or lifestyle that prevent regular sunshine exposure. Demand breast-feeding of infants is universal. Complementary foods are introduced at 3–6 months and breast-feeding is stopped at about 2 years. The calcium content of the local diet, including breast-milk, is low.
At presentation
The 46 patients ranged in age from 1.1 to 16.4 years. The age distribution was positively skewed with a geometric mean (− 1SD, + 1SD) of 3.4 (1.9, 6.4) years. More boys presented than girls (30 M, 65%; 16 F, 35%).
Thirteen patients (28%) had active rickets, as defined by a total ALP > 960 U/l (n = 7), a Thacher Score > 1.5 (n = 1) or both (n = 5). Of those patients with bone deformity but without active rickets (the non-active rickets group), the majority had one or more X-ray signs of healed rickets or
Discussion
Bone deformities associated with rickets and osteomalacia have been reported from a number of African and Asian countries among children without overt vitamin D deficiency [13], [14], [15], [16], [27]. Such children are characterized by lower 25OHD, elevated 1,25(OH)2D and, in severe cases, by lower plasma PO4, lower plasma Ca and raised PTH compared with local controls [13], [14], [15], [16], [18], [28]. Dietary calcium deficiency has been identified as a likely cause [14], [15], [27] and both
Acknowledgments
This paper is dedicated to the memory of the late Dr Bakary Dibba, who first drew our attention to bone deformities in Gambian children and initiated the investigations that led to this paper. We are indebted to Dr Tom Thacher, Dept of Family Medicine, Jos University Teaching Hospital, Jos, Nigeria and Dr Phil Fischer, Dept of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, USA, for their expert advice and input into conceptual development. We would like to thank the
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Conflict of interest: None of the authors has a conflict of interest with respect to the study reported in this paper.