Table 1.

Types of hypophosphataemia based on pathophysiology

Type	Cause/genetic basis	FGF23 levels	Pathogenesis
Group I: Excess FGF23 production/action
ADHR	FGF23	↑	Resistance of FGF23 to proteolytic cleavage, resulting in prolonged action [10]. Iron deficiency likely cause of disease manifestation through increased FGF23 expression [11]
XLH	PHEX	↑	↑ FGF23 expression in bone [12]
ARHR 1	DMP1 (dentin matrix protein)	↑	DMP1 encodes a bone matrix protein; mutation results in ↑ FGF23 by unclear mechanisms [13]
ARHR 2	ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase)	↑	ENPP1 generates extracellular pyrophosphate. The mechanism for ↑ FGF23 is unclear; however, the same mutation is also implicated in GACI [14]
ARHR 3	FAM20C (family with sequence similarity 20C)	↑	FAM20C encodes GEF-CK, a phosphorylation enzyme. This phosphorylation defect is the proposed mechanism for ↑ FGF23 [15]
Group II: Defective renal tubular phosphate reabsorption due to defective NPT2c
HHRH	SLC34A3	↓	↑ 1,25(OH)2D, defective NPT2C function, hypercalciuria and nephrocalcinosis [7]
Group III: Acquired disorders of excess FGF23
TIO	Paraneoplastic syndrome	↑	FGF23 production from mesenchymal tumoural cells [16]
Group IV: Phosphate loss due to global renal tubular dysfunction
Proximal tubular dysfunction	CLCN5: Dent’s disease Xq26.1: Lowe syndrome Xq26: Fanconi’s syndrome CTNS: Cystinosis	Normal or ↑	Proximal renal tubulopathy, ↓ 1,25(OH)2D
Group V: Drug-induced hypophosphataemia
1	Aluminium containing antacids	↓	Binding of phosphate causing reduced absorption [17]
2	Elemental infant formula	↓	Reduced bioavailabilitya of phosphate [18, 19]
3	Sodium valproate, cisplatin, ifosfamide, tenofovir, deferasirox	↓	Proximal tubular dysfunction (drug-induced Fanconi’s syndrome) [20]
4	Intravenous iron preparations	↓	↑ FGF23 mediated phosphate loss [21]
5	Imatinib mesylate	↑	Inhibition of PDGF receptors on osteoblasts and osteoclasts [22]

Representation of various causes of hypophosphataemic rickets/osteomalacia based on pathophysiology of phosphate loss and co-relation with FGF23 levels

ADHR autosomal dominant hypophosphataemic rickets, ARHR autosomal recessive hypophosphataemic rickets, FGF23 fibroblast growth factor 23, GACI generalised arterial calcification of infancy, GEF-CK golgi-enriched fraction casein kinase, HHRH hereditary hypophosphataemic rickets with hypercalciuria, NPT sodium-phosphate co-transporter, PDGF platelet-derived growth factor, PHEX phosphate-regulating gene with homologies to endopeptidases on the X chromosome, SLC34 solute carrier 34, TIO tumour-induced (or oncogenic) osteomalacia, XLH X-linked hypophosphataemic rickets

^aThe reported cases were infants and children on Neocate^® feed