Non-nutritional rickets: Approach, precision medicine, and outcomes

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 ophthalmologic/neurodevelopmental assessment when indicated	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

CTNS: Cystinosin, lysosomal cystine transporter; GALT: Galactose-1-phosphate uridylyltransferase; FAH: Fumarylacetoacetate hydrolase; ALDOB: Aldolase, fructose-bisphosphate B; ATP7B: ATPase copper transporting beta; CLCN5: Chloride voltage-gated channel 5; OCRL: Oculocerebrorenal syndrome of Lowe; G6PC: Glucose-6-phosphatase catalytic subunit; SLC2A2: Solute carrier family 2 member 2; GLUT2: Glucose transporter type 2; GATM: Glycine amidinotransferase; SLC34A1: Solute carrier family 34 member 1; EHHADH: Enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase; HNF4A: Hepatocyte nuclear factor 4 alpha; NDUFAF6: NADH dehydrogenase (ubiquinone) complex I assembly factor 6; AR: Autosomal recessive; AD: Autosomal dominant; XLR: X-linked recessive inheritance; LMW: Low molecular weight; CKD: Chronic kidney disease; ESKD: End-stage kidney disease.