Skip to main content
. 2019 May 8;15(7):435–455. doi: 10.1038/s41581-019-0152-5

Table 2.

Characteristics of inherited or acquired causes of phosphopenic rickets in comparison to calcipenic rickets

Disorder (abbreviation; OMIM#) Gene (location) Ca P ALP UCa UP TmP/GFR FGF23 PTH 25 (OH)Da 1,25 (OH)2D Pathogenesis
Rickets and/or osteomalacia with high PTH levels (calcipenic rickets)
Nutritional rickets (vitamin D and/or calcium deficiency) NA N, ↓ N, ↓ ↑↑↑ ↓ Varies ↓ N ↑↑↑ ↓↓, N Varies Vitamin D deficiency
Vitamin-D-dependent rickets type 1A (VDDR1A; OMIM#264700) CYP27B1 (12q14.1) ↓ N, ↓ ↑↑↑ ↓ Varies ↓ N, ↓ ↑↑↑ N ↓ Impaired synthesis of 1,25(OH)2D
Vitamin-D-dependent rickets type 1B (VDDR1B; OMIM#600081) CYP2R1 (11p15.2) ↓ N, ↓ ↑↑↑ ↓ Varies ↓ N ↑↑↑ ↓↓ Varies Impaired synthesis of 25(OH)D
Vitamin-D-dependent rickets type 2A (VDDR2A; OMIM#277440) VDR (12q13.11) ↓ N, ↓ ↑↑↑ ↓ Varies ↓ N, ↓ ↑↑↑ N ↑↑ Impaired signalling of the VDR
Vitamin-D-dependent rickets type 2B (VDDR2B; OMIM#164020) HNRNPC (14q11.2) ↓ N, ↓ ↑↑↑ ↓ Varies ↓ N ↑↑↑ N ↑↑ Impaired signalling of the VDR
Vitamin-D-dependent rickets type 3 (VDDR3; OMIM# pending) CYP3A4 (7q21.1) ↓ ↓ ↑↑↑ ↓ Varies ↓ ? ↑↑↑ ↓ ↓ ↑ Inactivation of 1,25(OH)2D
Phosphopenic rickets and/or osteomalacia due to dietary phosphate deficiency or impaired bioavailability
• Breastfed very-low-birthweight infants NA N, ↑ ↓ ↑, ↑↑ ? ↓ Nb N, ↓ N N N, ↑ Phosphate deficiency
• Use of elemental or hypoallergenic formula diet or parental nutrition
• Excessive use of phosphate binders
• Gastrointestinal surgery or disorders
Phosphopenic rickets and/or osteomalacia with renal tubular phosphate wasting due to elevated FGF23 levels and/or signalling
X-linked hypophosphataemia (XLH; OMIM#307800) PHEX (Xp22.1) N ↓ ↑, ↑↑ ↓ ↑ ↓ ↑, N N, ↑c N Nd ↑ FGF23 expression in bone and impaired FGF23 cleavage
Autosomal dominant hypophosphataemic rickets (ADHR; OMIM#193100) FGF23 (12p13.3) N ↓ ↑, ↑↑ ↓ ↑ ↓ ↑, N N, ↑c N Nd FGF23 protein resistant to degradation
Autosomal recessive hypophosphataemic rickets 1 (ARHR1; OMIM#241520) DMP1 (4q22.1) N ↓ ↑, ↑↑ ↓ ↑ ↓ ↑, N N, ↑c N Nd ↑ FGF23 expression in bone
Autosomal recessive hypophosphataemic rickets 2 (ARHR2; OMIM#613312) ENPP1 (6q23.2) N ↓ ↑, ↑↑ ↓ ↑ ↓ ↑, N N, ↑c N Nd ↑ FGF23 expression in bone
Raine syndrome associated (ARHR3; OMIM#259775) FAM20C (7q22.3) N ↓ ↑, ↑↑ ? ↑ ↓ ↑, N N, ↑c N Nd ↑ FGF23 expression in bone
Fibrous dysplasia (FD; OMIM#174800) GNAS (20q13.3) N, ↓ ↓ ↑, ↑↑ ↓ ↑ ↓ N, ↑ N, ↑c N Nd ↑ FGF23 expression in bone
Tumour-induced osteomalacia (TIO) NA N, ↓ ↓ ↑, ↑↑ ↓ ↑ ↓ N, ↑ N, ↑c N Nd ↑ FGF23 expression in tumoural cells
Cutaneous skeletal hypophosphataemia syndrome (SFM; OMIM#163200) RAS (1p13.2) N, ↓ ↓ ↑, ↑↑ ↓ ↑ ↓ N, ↑ N, ↑c N Nd Unknown
Osteoglophonic dysplasia (OGD; OMIM#166250) FGFR1 (8p11.23) N ↓ ↑, N N ↑ ↓ N N, ↑c N Nd ↑ FGF23 expression in bone
Hypophosphataemic rickets and hyperparathyroidism (OMIM#612089) KLOTHO (13q13.1) N ↓ ↑, ↑↑ ↓ ↑ ↓ ↑ ↑↑ N Nd Unknown; translocation of the KLOTHO promoter
Phosphopenic rickets and/or osteomalacia due to primary renal tubular phosphate wasting
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH; OMIM#241530) SLC34A3 (9q34.3) N ↓ ↑(↑↑) N, ↑ ↑ ↓ ↓ Low N, ↓ N ↑↑ Loss of function of NaPi2c in the proximal tubule
X-linked recessive hypophosphataemic rickets (OMIM#300554) CLCN5 (Xp11.23) N ↓ ↑(↑↑) N, ↑ ↑ ↓ Varies Varies N ↑ Loss of function of CLCN5 in the proximal tubule
Hypophosphataemia and nephrocalcinosis (NPHLOP1; OMIM#612286) and Fanconi reno-tubular syndrome 2 (FRTS2; OMIM#613388) SLC34A1 (5q35.3) N ↓ ↑(↑↑) ↑ ↑ ↓ ↓ Varies N ↑ Loss of function of NaPi2a in the proximal tubule
Cystinosis (OMIM#219800) and other hereditary forms of Fanconi syndrome CTNS (17p13.2) N, ↓ ↓ ↑(↑↑) N, ↑ ↑ N, ↓ N, ↑e N, ↑e N Nd Cysteine accumulation in the proximal tubule
Iatrogenic proximal tubulopathy NA N ↓ ↑(↑↑) Varies ↑ ↓ ↓ Varies N ↑ Drug toxicity

N, normal; ↑, elevated; ↑↑ or ↑↑↑, very elevated; ↑(↑↑), might range widely; 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, cholecalciferol; ALP, alkaline phosphatase; Ca, serum levels of calcium; FGF23, fibroblast growth factor 23; NA, not applicable; P, serum levels of phosphate; PTH, parathyroid hormone; TmP/GFR, maximum rate of renal tubular reabsorption of phosphate per glomerular filtration rate; UCa, urinary calcium excretion; UP , urinary phosphate excretion; VDR, vitamin D receptor. Data from ref.58. aCave: prevalence of vitamin D deficiency was reported to be up to 50% in healthy children. bNormal after restoration of P, but falsely reduced before restoration. cPTH might be moderately elevated. dDecreased relative to the serum phosphate concentration. eDepending on the stage of chronic kidney disease.