Table 4.

Hereditary Disorders with Renal Phosphate Wasting in the Differential Diagnosis of X-Linked Hypophosphatemia

Gene(s)DisorderMOIComment / Key Features
CLCN5 Dent disease type 1XL
  • Hypophosphatemia & hypercalciuria
  • Suppressed FGF23
  • 1,25-dihydroxyvitamin D may be ↑, normal, or low due to proximal tubular dysfunction.
  • Low molecular weight proteinuria
OCRL Dent disease type 2; Lowe syndrome
DMP1
ENPP1 1		AR hypophosphatemic rickets (OMIM 241520; 613312)AR
  • Renal phosphate wasting w/o hypercalciuria
  • Extremely rare
EHHADH
GATM
HNF4A
NDUFAF6 		Fanconi renotubular syndrome (types 1-5) (OMIM PS134600)AD
AR		Proximal renal tubule transport of many different substances impaired, incl phosphate, glucose, & low molecular weight proteins
FAM20C Raine syndrome, milder form (OMIM 259775) 2AR
  • Hypophosphatemia
  • ↓ DMP1 activity leads to ↑ FGF23 production.
  • Osteosclerotic skeletal changes
FGF23 AD hypophosphatemic rickets (ADHR) (OMIM 193100)AD
  • Renal phosphate wasting w/o hypercalciuria
  • Onset can be delayed; rarely, phosphate wasting resolves later in life.
  • The full-length active form of the protein is stabilized, leading to prolonged or enhanced FGF23 action.
  • ADHR is much rarer than XLH.
FGFR1 Osteoglophonic dysplasia AD
  • Severe skeletal dysplasia
  • Hypophosphatemia & lower than expected 1,25-dihydroxyvitamin D levels
  • ↑ FGF23 production from abnormal bone
INPPL1 Opsismodysplasia (OMIM 258480)AR
GNAS Fibrous dysplasia / McCune-Albright syndrome Not inherited 3
  • Hypophosphatemic rickets
  • Fibrous dysplasia of the bone; precocious puberty; café au lait macules
  • Overproduction of FGF23 by the fibrous dysplastic bone results in renal phosphate wasting.
HRAS
KRAS
NRAS 		Cutaneous skeletal hypophosphatemia syndrome 4 (OMIM 163200)Not inherited 3
  • Hypophosphatemia is frequent & biochemically indistinguishable from that seen in XLH.
  • Multiple cutaneous nevi; radiologic evidence of fibrous dysplasia
  • FGF23 is the cause of the phosphate wasting. 5
KL Hypophosphatemic rickets w/hyperparathyroidism 6AR
  • Hypophosphatemia; inappropriately normal 1,25-dihydroxyvitamin D level
  • Hyperparathyroidism
  • ↑ alpha-klotho & ↑ FGF23
PTH1R Metaphyseal dysplasia, Jansen type (OMIM 156400)AD
  • Very short stature, more pronounced skeletal dysplasia
  • Hypophosphatemia; hypercalciuria
  • ↑ 1,25-dihydroxyvitamin D
  • Osteopenia, prominent nephrolithiasis/nephrocalcinosis
SLC34A3 Hereditary hypophosphatemic rickets w/hypercalciuria (OMIM 241530)AR
  • Hypophosphatemia; hypercalciuria
  • ↑ 1,25-dihydroxyvitamin D
  • Osteopenia, prominent nephrolithiasis/nephrocalcinosis

AD = autosomal dominant; AR = autosomal recessive; FGF23 = fibroblast growth factor 23; MOI = mode of inheritance; XL = X-linked

1.

ENPP1 pathogenic variants are associated with generalized arterial calcification of infancy as an allelic disorder.

2.
3.

Caused by postzygotic somatic activating variants

4.

Also referred to as Schimmelpenning-Feuerstein-Mims syndrome, linear sebaceous nevus syndrome, or epidermal nevus syndrome

5.
6.

From: X-Linked Hypophosphatemia

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.