Forms of Hereditary Hypophosphatemic Rickets*
Form | Pattern of Inheritance | Gene (Location) | Gene Mutation Effect | Clinical Features |
|---|---|---|---|---|
X-linked hypophosphatemia (XLH) | PHEX (Xp22.1) | Inactivating mutation results in increased phosphatonin (FGF-23) production | Renal phosphate wasting with normal serum calcium, normal or low urine calcium, high alkaline phosphatase, normal or paradoxically high intact parathyroid hormone Rickets/osteomalacia, delayed dentition, dental abscess, craniofacial anomalies, hearing loss, hypertension, nephrocalcinosis (results from management) | |
Autosomal recessive hypophosphatemic rickets (ARHR) | ARHR1: DMP1 (4q22.1) ARHR2: ENPP1 (6q23.2) ARHR3: FAM20C (7p22.3)† | Loss-of-function mutations associated with inappropriate increases in FGF-23 | General features of renal phosphate wasting, normal serum calcium, low/normal urine calcium, and high alkaline phosphatase Rickets/osteomalacia, short stature, long bone deformities, spinal immobility, enthesopathies, dental and facial bony anomalies, learning disabilities | |
Autosomal dominant hypophosphatemic rickets (ADHR) | Autosomal dominant (variable penetrance) | FGF23 (12p13.32) | Unable to cleave FGF-23, leading to elevated serum levels | Although features can be similar to XLH, age at presentation and penetrance is variable. |
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) | SLC34A3 (9q34.3) | Normal/low FGF-23 Defect in the proximal tubule NaPi2c | Phosphate wasting and high 1,25-dihydroxyvitamin D3, causing hypercalciuria, stones, and nephrolithiasis and/or nephrocalcinosis | |
Hypophosphatemia, hypercalcemia, and nephrocalcinosis (HHN) | SLC34A1 (5q35) | Suppressed FGF-23 Abnormal NaPi2a | Elevated levels of 1,25-dihydroxyvitamin D3, hypophosphatemia, hypercalcemia, hypercalciuria, and nephrocalcinosis | |
Dent disease and Lowe syndrome | Dent disease: CLCN5 (Xp11.23) Lowe syndrome: OCRL1 (Xq26.1) | Proximal tubule cytotoxicity | Renal Fanconi syndrome with wasting of phosphorus as well as low-molecular weight proteinuria and renal tubular acidosis Hypercalciuria known to occur with features of nephrolithiasis and nephrocalcinosis | |
* This table provides a brief overview of single-gene forms of hereditary hypophosphatemic rickets associated with either increased FGF-23 or normal to suppressed FGF-23. | ||||
† This form can occur in osteosclerotic dysplasia and as part of Raine syndrome (a rare skeletal dysplasia). | ||||
FGF-23 = fibroblast growth factor-23; NaPi2a = renal type 2a sodium-phosphate cotransporter; NaPi2c = renal type 2c sodium-phosphate cotransporter. | ||||
Adapted from Bitzan M, Goodyer PR. Hypophosphatemic rickets. Pediatr Clin N Am. 2019;66(1):179–207. doi:10.1016/j.pcl.2018.09.004 | ||||