Copyright: ©Author(s) 2026.
World J Clin Pediatr. Dec 9, 2026; 15(4): 122166
Published online Dec 9, 2026. doi: 10.5409/wjcp.122166
Published online Dec 9, 2026. doi: 10.5409/wjcp.122166
Table 1 Therapies available for X-linked hypophosphatemic rickets and their outcomes
| Treatment modalities | Dose | Improvement | No improvement | Caution |
| Oral phosphorus | Children: 20-60 mg/kg/day in 3-5 divided doses. Adolescents: 3 divided doses. Adults: 800-1600 mg/day in 2 divided doses | Children: (1) Height velocity; and (2) Lower limb deformities. Adults: (1) Osteomalacia related pain[68]; and (2) Periodontitis, dental function[69]. Clinical improvement has been seen in 1-2 years[72]. Corrective surgery for deformities is required in about half the adolescents. Over half may have short stature as adults | Children: Hearing loss. Adults: (1) Osteo-arthritis related pain; and (2) Enthesiopathies | (1) Acidic taste; (2) Gastric discomfort and diarrhoea (doses > 80 mg/kg/day); and (3) SHPT and sub-optimal radiological response, if given without activated forms of vitamin D |
| Calcitriol | Children: 20-30 ng/kg/day (0.5-1.5 μg/day) in 2-3 divided doses. Adults: 0.50-0.75 μg/day in 2-3 divided doses | (1) To be given only along with oral phosphorus in children; (2) Hypercalciuria; and (3) Nephrocalcinosis[69] | ||
| Alphacalcidiol | Children: 40-60 ng/kg/day (1-3 μg/day) in a single daily dose. Adults: 0.75-1.5 μg/day in a single daily dose | |||
| Burosumab[62,70] | Children: [Above 6months (as per United States-FDA) or 1 year (as per EMA)] start at 0.8 mg/kg body weight sub-cutaneously every 14 days. In children with weight < 10 kg, start at 1 mg/kg. Maximum dose 2 mg/kg or 90 mg every 14 days. Adults: Initiate at 1 mg/kg sub-cutaneously every 14 days. Increase to maximum dose of 1.8 mg/kg or 90 mg sub-cutaneously every 14 days | Children: (1) Height velocity (normalizes by 2 years); (2) Decreased periodontal abscess; (3) Physical function; and (4) Pain (12 months). Clinically deformities improve in 2-3 years[62]. Biochemically: TmP-GFR increases within 1 week, ALP normalises by 1 year[70]. Adults: (1) Musculoskeletal pain (6-12 months); (2) Decreased renal PO4 wasting and rise in serum PO4 levels (6 months); (3) Stiffness (12 months); (4) ALP (12 months); (5) Radiological signs (12 months); and (6) Fewer endo-dontic infections | Children: Catch-up growth may be slow. Adults: Physical function stiffness | (1) Stop oral phosphorus 1 week prior to initiation of burosumab; (2) Ensure adequate oral calcium intake; (3) Stop in adolescent and adult females who are sexually active unless using contraception; and (4) Contraindicated in pregnancy but not in lactation |
| Recombinant growth hormone | Children: 0.6-1 U/kg/week | Children: (1) Height velocity; and (2) PO4 retention | Children: No difference in final height compared to none | Adjunct to conventional therapy or burosumab. Pre-requisite: Adequately controlled bony deformities, ALP and PTH |
Table 2 Monitoring in X-linked hypophosphatemic rickets
| Domain | Assessment | Suggested frequency | Key considerations |
| Clinical evaluation | Growth (height, weight, BMI) | At every visit in children; 6-12 monthly in adults | Monitor growth velocity and disproportion |
| Limb deformities, gait, bone pain | Every visit | Assess progression and need for orthopedic referral | |
| Head shape, craniosynostosis signs | Regular in early childhood | Neuro symptoms warrant imaging | |
| Dental evaluation | Every 6 months after tooth eruption | High risk of abscesses and periodontal disease | |
| Hearing assessment | From approximately 8 years or if symptomatic | Sensorineural hearing loss may occur | |
| Functional status (mobility, fatigue) | Annually or as indicated | Include 6-minute walk test where feasible | |
| Biochemical monitoring | Serum calcium, phosphate, ALP, PTH, creatinine | Every 3-6 months (more frequent in active treatment) | ALP is a key marker of disease activity |
| 25-hydroxyvitamin D | Yearly | Maintain sufficiency | |
| 1,25-dihydroxyvitamin D | Annually (especially on targeted therapy) | Avoid excess contributing to hypercalciuria | |
| Urinary calcium (spot Ca/Cr or 24 hours) | Every 3-6 months | Monitor for hypercalciuria | |
| TmP/GFR and serum phosphate | Frequent during treatment initiation (2-4 weekly), then spaced | Especially important with burosumab | |
| Imaging | Radiographs (wrists/knees/long bones) | Every 1-2 years or if clinically indicated | Assess rickets healing and deformity |
| Renal ultrasonography | Every 1-2 years | Detect nephrocalcinosis | |
| Dental imaging (OPG/CBCT) | From approximately 6 years, based on need | Detect occult dental pathology | |
| Brain MRI | If neurological symptoms or craniosynostosis suspected | Not routine | |
| Spine MRI | If symptoms of stenosis or back pain | Targeted imaging only | |
| Cardiovascular | Blood pressure | At least annually | Hypertension may occur |
| Echocardiography | If persistent hypertension | Not routine screening | |
| Treatment monitoring | Clinical + biochemical response | Every 3-6 months initially | Adjust therapy based on trends, not single values |
| Adverse effects (nephrocalcinosis, hyperparathyroidism) | Ongoing | Especially with phosphate + active vitamin D | |
| Quality of life | Quality of life assessment tools | Every 1-2 years | Particularly in older children and adults |
Table 3 Rare forms of fibroblast growth factor 23 mediated Hereditary HR[113]
| No. | Entity | Gene (chromosome) | Inheritance | Physiological role | Phenotype | Comments |
| 1 | Raine syndrome (ARHR3) | FAM20C (7p22.3) | AR | Kinase for FGF-23 and calcium binding phosphoprotein family of proteins (including SIBLING group)[34] | Ocular proptosis, mid-facial hypoplasia, depressed nasal bridge, cerebral calcifications (in parietal and occipital periventricular white matter), micrognathia, cleft palate, choanal atresia, corpus callosum and hypophysis dysgenesis, osteosclerosis and periosteal reaction. In lethal forms, mortality within the 1st month of life. Non-lethal forms have developmental delay, seizures and hypoacusis, amongst others | No genotype-phenotype correlation. Differentials include congenital cytomegalovirus infection, Crouzon syndrome, osteopetrosis dysplasia and desmosterolosis. Cerebral calcifications, osteopetrosis and rickets may also be seen in RTA due to carbonic anhydrase type 2 deficiency, but the calcification is predominantly in basal ganglia and the cortex |
| 2 | HR with hyperparathyroidism | Translocation between chromosomes 13 and 9, and the breakpoint on chromosome 13 is located adjacent to the Klotho gene | AD | Implicated in regulation of FGF signaling, aging and calcium homeostasis | Hypercalcemia. Raised PTH (similar to values in CR) | Very rare entity - only 2 reported cases |
| 3 | Fibrous dysplasia | GNAS | Post-zygotic mutation, unlikely to be hereditary | Encodes alpha subunit of stimulatory G-protein required for receptor binding of various hormones | Precocious puberty, hyperthyroidism, thyroid nodular disease, café-au-lait macules. Up to half the patients may have hypophosphatemia | Anecdotal evidence exists in favor of use of burosumab. Bisphosphonates and denosumab have been found to reduce the risk of fractures but increased risk of hypophosphatemia |
| 4 | Opsismodysplasia | INPPL1 (11q13.4) | AR | Encodes Src homology 2 domain-containing inositol phosphatases. It functions as a 5-phosphatase that modulates intracellular signaling and metabolic pathway | Relative macrocephaly with frontal prominence, midfacial hypoplasia, a low nasal bridge, short nose with anteverted nostrils, and an elongated philtrum; a constricted thoracic cage; small hands and feet; delayed epiphyseal ossification, metaphyseal cupping, and platyspondyly | Raised FGF-23 not seen in all patients |
| 5 | Osteoglophonic dysplasia | FGFR1 (heterozygous gain of function mutations) | AD | Tyrosine kinase family of receptors required for modulation of bone development | Tower-shaped skull, craniosynostosis, prominent supraorbital ridge, maxillary hypoplasia, depressed nasal bridge, mandibular prognathism, dental anomalies, vertebral anomalies, rhizomelic short stature, non-ossifying fibromasbone mineralization defects | Comprises of craniosynostosis (classical of FGFR1 AND FGFR2 mutations) and dwarfism (as in FGFR3 mutations) related manifestations |
| 6 | Jansen metaphyseal chondrodysplasia | PTHR1 | AD (most cases de novo) | G-protein coupled receptor on kidney, bone and chondrocytes for PTH and PTHrP | Shortened limbs starting infancy. Radiographs reveal rachitic changes, bone erosions and cortical thinning. Patients biochemically have increased serum calcium, reduced phosphate levels, and raised alkaline phosphatase-are present, despite normal concentrations of PTH and PTHrP | H223R mutation has more severe hypercalcemia compared to the I458K and T410R mutations |
| 7 | Schimmel penning-Feuerstein-Mims syndrome/cutaneous skeletal hypophosphatemia syndrome | Somatic gain-of-function mosaicisms in RAS genes (HRAS, NRAS, and KRAS) | Encodes small GTPase proteins that act as molecular switches regulating fundamental cellular processes, including growth, proliferation, differentiation, survival, and motility | Burosumab was found to be effective in some cases |
Table 4 Inherited forms of Fanconi syndrome - treatment and outcomes
| Disease | Gene | Inheritance | Paraphrased salient features | Genotype-phenotype correlation | Precision medicine/targeted management | Outcomes |
| Cystinosis | CTNS | AR | Infantile nephropathic form usually presents in infancy with Fanconi syndrome, failure to thrive, polyuria, polydipsia, photophobia, and hypophosphatemic rickets; juvenile forms present later and are milder | Severe biallelic CTNS loss-of-function variants usually cause infantile nephropathic cystinosis; residual-function variants are associated with juvenile or ocular-predominant disease | Cysteamine to deplete lysosomal cystine, cysteamine eye drops for corneal crystals, kidney-supportive Fanconi replacement, and early kidney-transplant planning | Early cysteamine improves growth and delays CKD/ESKD; without treatment, progressive renal failure, bone disease, and extra-renal complications are typical |
| Galactosemia | GALT | AR | Neonatal cholestasis, hepatomegaly, sepsis risk, cataract, hypoglycemia, and occasionally Fanconi syndrome with rickets | Classic GALT deficiency produces severe neonatal disease; genotype influences residual enzyme activity and long-term neurodevelopmental risk | Immediate lifelong galactose/lactose restriction, treatment of liver failure/sepsis, and correction of tubular losses when Fanconi syndrome is present | Renal tubular dysfunction may improve with metabolic control; neurologic, reproductive, and developmental sequelae can persist despite diet |
| Tyrosinemia type 1 | FAH | AR | Failure to thrive, liver dysfunction, renal tubular Fanconi syndrome, hypophosphatemic rickets, and markedly elevated succinylacetone/alpha-fetoprotein | FAH deficiency causes fumarylacetoacetate toxicity; phenotype ranges from acute liver failure in infancy to later renal/rickets-predominant presentation | Nitisinone plus low-tyrosine/phenylalanine diet; liver transplantation for refractory disease or suspected malignancy; phosphate/alkali replacement for Fanconi syndrome | Early nitisinone improves survival and often heals rickets and tubular dysfunction; delayed diagnosis increases risk of hepatocellular carcinoma, CKD, and residual bone deformity |
| Hereditary fructose intolerance | ALDOB | AR | Vomiting, hypoglycemia, hepatomegaly, jaundice/cholestasis, and sometimes proximal tubular dysfunction after fructose exposure | Biallelic ALDOB variants impair fructose-1-phosphate aldolase activity; severity reflects exposure and residual activity more than a strict mutation-specific pattern | Strict avoidance of fructose, sucrose, and sorbitol; rapid correction of metabolic derangements and tubular losses when present | Excellent prognosis with avoidance; ongoing exposure can lead to liver injury, growth failure, renal tubular dysfunction, and rickets |
| Wilson disease | ATP7B | AR | Hepatic disease, neuropsychiatric manifestations, Kayser-Fleischer rings, and occasionally Fanconi syndrome with rickets/osteomalacia | ATP7B variants cause variable hepatic-predominant or neurologic-predominant phenotypes; genotype-phenotype correlation is incomplete | Copper chelation or zinc therapy, dietary copper reduction, and treatment of Fanconi-associated phosphate/alkali losses | Tubular dysfunction may improve with copper control; untreated disease progresses to cirrhosis, neurologic disability, and skeletal complications |
| Lowe syndrome | OCRL | XLR | Congenital cataract, hypotonia, developmental delay/intellectual disability, seizures, proximal tubulopathy/Fanconi syndrome, nephrocalcinosis, and rickets | OCRL defects cause oculocerebrorenal disease; truncating or severe loss-of-function variants are generally associated with classic multisystem disease | Multidisciplinary care, tubular replacement therapy, cataract/glaucoma management, seizure/developmental support, and CKD surveillance | Lifelong morbidity is common, with persistent neurodevelopmental impairment, rickets/short stature, and progressive CKD in many patients |
| Dent disease type 1 | CLCN5 | XLR | Low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, phosphaturia, and hypophosphatemic rickets; acidosis may be absent | CLCN5 variants account for most Dent disease; truncating variants may be associated with more severe tubular dysfunction, though correlation is variable | Supportive care with high fluid intake, cautious thiazide use, citrate, phosphate/calcitriol when needed for rickets, and CKD prevention | Progression to CKD in adulthood is common; recurrent stones/nephrocalcinosis and persistent bone disease can occur |
| Dent disease type 2 | OCRL | XLR | Dent phenotype plus variable extra-renal findings such as mild cataract or neurodevelopmental features; LMW proteinuria, hypercalciuria, nephrocalcinosis, and rickets | OCRL variants in Dent type 2 often produce a milder renal-predominant phenotype than classic Lowe syndrome, illustrating allelic heterogeneity | As for Dent disease, with additional ophthal | Renal decline, stones, and bone disease remain major outcomes; extra-renal complications are milder than in Lowe syndrome but may accumulate |
| Glycogen storage disease type 1A | G6PC | AR | Hepatomegaly, fasting hypoglycemia, hyperlactatemia, hyperuricemia, hyperlipidemia, growth failure, and occasionally Fanconi-like tubular dysfunction with rickets | G6PC deficiency impairs hepatic glucose release; metabolic control, rather than a tight genotype pattern, strongly influences renal and bone phenotype | Frequent complex-carbohydrate feeding/cornstarch, management of metabolic abnormalities, and renal-bone monitoring | Improved metabolic control reduces systemic complications, but chronic kidney disease, hepatic adenomas, and poor growth may still develop |
| Fanconi-Bickel syndrome | SLC2A2 (GLUT2) | AR | Hepatomegaly, fasting hypoglycemia, postprandial hyperglycemia/galactosemia, proximal tubulopathy, rickets, and growth failure | Biallelic SLC2A2 variants disrupt GLUT2; genotype-phenotype correlation is limited, but complete loss usually causes classic hepatorenal disease | Dietary management with frequent feeds/cornstarch, phosphate and alkali replacement, vitamin D, and supportive renal care | Many children survive into adulthood, but short stature, rickets, and chronic renal/hepatic complications may persist |
| Fanconi renotubular syndrome type 1 | GATM | AD | Isolated inherited Fanconi syndrome with rickets, metabolic acidosis, glycosuria, aminoaciduria, and low-molecular-weight proteinuria | Dominant GATM variants alter mitochondrial protein behavior in proximal tubules and can produce progressive tubulopathy with variable CKD risk | Supportive tubular replacement, CKD surveillance, and emerging interest in mutation-specific mitochondrial stress pathways as future targets | Persistent Fanconi syndrome is typical; progressive renal impairment can occur in some families |
| Fanconi renotubular syndrome type 2 | SLC34A1 | AR | Infant or childhood Fanconi syndrome with phosphaturia, glycosuria, aminoaciduria, metabolic acidosis, and rickets | Loss of NaPi-IIa impairs proximal phosphate transport; biallelic variants tend to cause early phosphate-wasting phenotypes | Phosphate and alkali replacement, rickets treatment, and kidney monitoring; genotype confirmation helps avoid misclassification with other phosphate-wasting disorders | Growth and rickets improve with treatment, but nephrocalcinosis/CKD risk depends on severity and long-term metabolic control |
| Fanconi renotubular syndrome type 3 | EHHADH | AD | Fanconi syndrome with rickets, hypokalemia, polyuria, glycosuria, phosphaturia, and aminoaciduria | A dominant mistargeting mechanism causes mitochondrial dysfunction in proximal tubular cells; currently reported in very few families | Supportive therapy only at present; precision medicine is mainly genetic diagnosis and family counseling | Long-term data are sparse, but chronic tubular losses and growth/bone complications can persist |
| Fanconi renotubular syndrome type 4 | HNF4A | AD | Proximal tubulopathy/Fanconi syndrome with rickets plus neonatal hyperinsulinism, macrosomia, glycosuria, and later diabetes in some patients | The recurrent p.Arg76Trp variant is strongly associated with this syndromic renal-metabolic phenotype | Personalized care includes management of hyperinsulinism or later diabetes in addition to tubular replacement and bone treatment | Variable long-term course; renal tubular dysfunction may persist, while endocrine manifestations evolve over time |
| Fanconi renotubular syndrome type 5 | NDUFAF6 | AR | Fanconi syndrome with rickets and mitochondrial disease features; reported cases may show pulmonary hypertension, polyuria, glycosuria, aminoaciduria, and phosphate wasting | NDUFAF6-related disease reflects mitochondrial complex I assembly defects; phenotype is multisystem and severity varies | Supportive renal care, management of mitochondrial complications, and precision diagnosis for counseling; no established disease-specific therapy | Outcomes depend on extra-renal mitochondrial involvement; renal tubular dysfunction and growth failure may be persistent |
| Condition | Gene (chromosome) | Mode of inheritance | Ca dose | Activated vitamin D (calcitriol/alfacalcidol) dose | Calcifediol dose | Vitamin D (cholecalciferol) dose | Biochemical response |
| VDDR1A | CYP27B1 (12q13) | AR | 30-75 mg/kg/day; (0.5-3 g/day) elemental Ca | Calcitriol: 10-100 ng/kg/day; 0.3-2 μg/day. Alfacalcidol: 10-100 ng/kg/day; 0.5-3 μg/day | Not useful | Not useful | ALP: 3-12 months; Ca: 5 months; PTH: 6 months (may not normalize) |
| VDDR1B | CYP2R1 (11p15) | AR/AD | 30-75 mg/kg/day; (0.5-2 g/day) elemental Ca) | Calcitriol: 10-100 ng/kg/day; 0.3-2 μg/day. Alfacalcidol: 10-100 ng/kg/day; 0.5-3 μg/day | 15-50 μg/day | Heterozygous: 5000-10000 IU/day. Homozygous: 600000 every 3 months | 3 months |
| VDDR2A | VDR (12q13) | AR | 3-5 g/day; 400-1400 mg/m2/day | 10-400 ng/kg/day; 5-60 μg/day (for both) | 20-200 μg/day | Not helpful | 6-12 months, may not occur in all children |
| VDDR2B | Unknown (post-receptor defect) | NK (isolated cases) | |||||
| VDDR3 | CYP3A4 (7q22) | AD (usually de novo mutations) | May be required (30-75 mg/kg/day) | Calcitriol: Low limit: 1 μg/day, upper limit: Not defined. Alfacalcidiol: Low limit: 2 μg/day, upper limit: Not defined | Low limit: 50 μg/day, upper limit: Not defined (metabolized rapidly) | 10000-50000IU per day | 3 months |
Table 6 Comparative pharmacology of vitamin D preparations
| Parameter | Cholecalciferol (Vitamin D3) | Calcidiol (25-hydroxyvitamin D3) | Alfacalcidol (1α-hydroxyvitamin D3) | Calcitriol (1,25-dihydroxyvitamin D3) |
| Biochemical form | Native vitamin D3 | 25-hydroxylated form | Synthetic 1α-hydroxylated analogue | Fully active hormonal form |
| Activation required | Hepatic + renal hydroxylation | Renal hydroxylation only | Hepatic hydroxylation only | None |
| Dependence on organ function | Liver and kidney dependent | Kidney dependent | Liver dependent | Independent of liver and kidney activation |
| Onset of action | Slow | Intermediate | Rapid | Rapid |
| Half-life | Long (weeks) | Intermediate (2-3 weeks) | Short (hours to days) | Very short (4-6 hours) |
| Mechanism of action | Prohormone | Circulating precursor | Converted to calcitriol in liver | Direct activation of vitamin D receptor |
| Clinical indications | Nutritional vitamin D deficiency | Malabsorption, obesity, liver disease | Chronic kidney disease, hypoparathyroidism | Severe hypocalcemia, CKD, hypoparathyroidism, VDDR |
| Risk of hypercalcemia | Low | Moderate | High | Highest |
| Monitoring requirements | Minimal | Intermittent | Frequent monitoring required | Close monitoring required |
- Citation: Pathak PP, Ray S. Non-nutritional rickets: Approach, precision medicine, and outcomes. World J Clin Pediatr 2026; 15(4): 122166
- URL: https://www.wjgnet.com/2219-2808/full/v15/i4/122166.htm
- DOI: https://dx.doi.org/10.5409/wjcp.122166