Dent disease is a familial renal tubular disorder with a X-linked recessive mode of inheritance (88). It is caused by mutations in the Chloride Channel, Voltage-Sensitive 5 (CLCN5), or Oculocerenrorenal Syndrome of Lowe (OCRL) (phosphatidylinositol 4,5-polyphosphate-5-phosphatase) (88). First discovered by Dent and Friedman in 1964, the disease is classified as hypercalciuric rickets associated with renal tubular damage (89). The clinical manifestations of this disease include poor growth, proximal renal tubule defect, decreased renal tubular phosphate reabsorption, nephrocalcinosis, nephrolithiasis, rickets, osteomalacia, increased fractures, bone pain, lower limb deformities, low weight proteinuria, hypercalciuria, hypophosphatemia, hyperphosphaturia, aminoaciduria, glycosuria, and microscopic hematuria (89, 90). Symptoms generally arise in males before the age of 10, and by the age of 30, 30-50% of patients are diagnosed with ESKD (86). Genetic testing has an important role in confirming diagnosis, and to determine the specific gene that is mutated (88). Since Dent Disease is a congenital genetic disease, available treatment focuses on relieving symptoms including preventing nephrolithiasis, and reduction of hypercalciuria (88). Approximately 50-60% of patients with Dent Disease have CLCN5 mutations, 15% have mutations to OCRL and the remaining 25% have possible defects in other genes (86). The majority of CLCN5 mutations are nonsense resulting in an early stop codon and truncated protein leading to loss of chloride conductance (86). Mutations in OCRL mainly occur in the 5’ region of the gene in exons 4 to 15 which is the phosphatase domain of the protein (86). Dent Disease is also considered to be a form of hereditary nephrocalcinosis (91). With the loss of renal chloride channel CLNC5 in the proximal tubule, there is a decrease in chloride reabsorption and therefore a decrease in calcium reabsorption, as well as prevention of charge dissipation creating an acidic environment, both leading to the development of calcium kidney stones ( Figure 4 ) (91, 92). Previous studies have found that approximately 30% of patients with Dent Disease caused by CLCN5 mutations have nephrolithiasis, and this has an early age of onset with a mean of 23 (93). OCRL is involved in the trans-Golgi system, and in the processes of receptor endocytosis and recycling by proximal tubular cells (94). Wu et al. (2012) also described OCRL as an inhibitor of the Transient receptor potential vanilloid subfamily member 6 (TRPV6)calcium channel which could cause hypercalciuria and calcium nephrolithiasis due to increased calcium absorption (95).

Lowe syndrome is a rare multisystem disorder with X-linked recessive inheritance, affecting the eyes, nervous system, and kidneys (96). About 1 in 500,000 individuals suffer from Lowe Syndrome (96). This disorder is characterized clinically by symptoms including short stature, cataracts, glaucoma, renal failure, skeletal defects, osteomalacia, renal rickets, hypertonia, intellectual disability, seizures, Renal Fanconi syndrome, proximal renal tubular acidosis, bicarbonaturia, proteinuria, aminoaciduria, phosphaturia, elevated serum acid phosphatase, and elevated serum protein (97). In nearly half of nephrolithiasis cases, stones are composed of calcium oxalate and calcium phosphate (98). Most patients are in the pediatric population as Lowe Syndrome is a congenital genetic disorder (99). Life expectancy is no greater than 40 years, as the CKD is seen in the first year of life (stages 1 and 2) and progresses to stages 4 to 5 after age 20 (99). Treatment consists of removing cataracts, oral supplements of sodium and potassium bicarbonate or citrate to manage acidosis, oral supplementation of phosphate and calcitriol to manage hypophosphatemia and renal rickets, as well as growth hormones (100). The disorder is caused by mutations to the OCRL gene which encodes the protein phosphatidylinositol 4,5-polyphosphate-5-phosphatase (96). The OCRL gene on chromosome at position Xq26.1 when mutated causes a reduction in this protein and accumulation of the substrate phosphatidylinositol 4,5-polyphosphate (96). Affected patients have altered cell signaling pathways, defective actin cytoskeleton polymerization essential for formation of tight and adherens junctions in the renal proximal tubule, and protein trafficking abnormalities (96). Recent findings have also shown that OCRL is necessary for closure of endocytic vesicles which is important for recycling the megalin receptor in the proximal tubule (99). This defective recycling results in low molecular weight proteins in patients with Lowe syndrome (99). Due to allelism described above ( Figure 3 ), pathogenic mutations in OCRL also cause Dent Disease. However, unlike Lowe Syndrome, patients do not have metabolic acidosis, ocular nor brain involvement (96). In patients with Lowe Syndrome, mutations to OCRL occur closer to the 3’ end of the gene in exons 9 to 22 which encode large functional domains (86). This contrasts Dent Disease which, as previously mentioned, has most deleterious mutations at the 5’ end of OCRL in exons 4 to 15 (86). Figure 3 depicts the OCRL exons and disease-causing regions. Due to the broad and variable symptoms of Lowe Syndrome, gene-targeted testing for OCRL (single-gene) or other potentially causative genes is important in providing a concrete diagnosis (100). Since this is an X-linked recessive disease, when a mother is a heterozygous carrier, there is a 25% chance of an affected son, and 25% chance of a heterozygous daughter (100). Some affected families may opt to do prenatal and preimplantation genetic testing, which is available once the familial OCRL pathogenic variant is detected (100).

FHHNC is an autosomal recessive renal tubular disorder characterized mainly by excessive calcium and magnesium excretion, and has early onset (101). Additionally, patients with FHHNC suffer from polyuria, nephrocalcinosis, bilateral nephrocalcinosis, hypomagnesemia, hyperuricemia, hypermegnesiuria, hypercalciuria, hypocitraturia, hematuria, recurrent urinary tract infection, nephrolithiasis, progressive chronic renal failure, seizures, and issues with eyesight (101). Due to progressive loss of kidney function, 50% of patients require renal replacement therapy as early as age 20 years (102). As with other rare genetic disorders, there is no specific treatment for FHHNC, though patients are given oral magnesium supplementation and thiazide diuretics to help combat the progression of nephrolithiasis and nephrocalcinosis, though this does not protect renal function (101). FHHNC is caused by mutations to members of the claudin protein family, CLDN16 and CLDN19 (102). Claudin proteins are transmembrane proteins required for tight junction barrier formation in epithelia (102). Both CLDN16 and CLDN19 are necessary for the reabsorption of calcium and magnesium into the blood (103). When these proteins are dysfunctional, calcium and magnesium build up in the urine and cause nephrolithiasis and nephrocalcinosis ( Figure 5 ) (103). CLDN16 is located on chromosome 3q28 and is expressed exclusively in renal epithelial cells in the thick ascending limb of Henle and is important for reabsorption of divalent cations (104). Allelism has been in observed in patients with FHHNC. For example, a cohort of 69 patients with FHHNC due to pathogenic mutation to CLDN16 showed that the age of onset for complete loss-of-function mutations is 2.2 years compared to mutations resulting in partial loss-of-function, which is 5.6 years (105). CLDN19 is located on chromosome 1p34.2 and is expressed in the thick ascending limb of Henle as well as in the retinal pigment epithelium causing ocular defects in patients with CLDN19 mutation distinguishing them from CLDN16 patients (106). A study conducted by Val-Palomar found that in a Spanish cohort with 30 FHHNC patients who underwent exonic sequencing of CLDN19 and CLND16, 90% of the patients analyzed had a mutation in CLDN19 (106). Of the 90% with pathogenic CLDN19 mutations, 74% had the homozygous glycine to aspartic acid change at amino acid position 20 mutation (p.G20D) (106). This mutation is common in the South of Europe due to a common ancestor and has no change in CKD survival rate compared to patients with CLND19 mutations (106). The mean age of onset of disease was 1.71 years (106). Nephrolithiasis has been reported in FHHNC patients with CLDN16 and CLDN19 mutations at a rate of 25% and 42% respectively (107). Variable expressivity has been described in families with FHHNC mutations; some present with isolated nephrolithiasis and/or hypercalciuria, but no other symptoms, suggesting that CLDN16 may be associated with idiopathic calcium kidney stones (107). Recent research has also suggested CLDN14 as a possible risk factor for the development of calcium-containing stone (108). CLDN16 and CLDN19 complex with Claudin 3, allowing for cation permeability in the thick ascending limb (TAL) tight junction of the loop of Henle (109). Claudin 14 (CLDN14) interacts with Claudin 16 (CLDN16) allowing calcium to flow through the junction, but mutations to CLDN14 upregulate the protein and can cause nephrolithiasis (109). It has also been hypothesized that due to the interactions with CLDN16 and the calcium-sensing receptor CASR, overexpression of CLDN14 could cause hypomagnesemia, hypercalciuria and nephrocalcinosis as well, though this has not yet been related specifically to FHHNC (108).

Distal RTA is an autosomal recessive or dominant kidney tubulopathy characterized by the inability to decrease urine pH to 5.3-5.5 when systemic metabolic acidosis is present (110). In this disease there is a defect in excreting H+ in the distal tubule and collecting duct of the nephron which leads to alkaline urine pH as well as calcium phosphate precipitation ultimately leading to kidney stones (111). General symptoms include nephrolithiasis, nephrocalcinosis, rickets, osteomalacia, primary distal renal tubular acidosis, hyperchloremic hypokalemic metabolic acidosis, urine pH>6.4 despite systemic acidosis, hypercalciuria, and hypocitraturia (110). Treatment of this disease includes alkali treatment which aims to correct metabolic acidosis and prevent rickets and stunted growth (112). There are three genes known to cause distal RTA including ATPase, H+ Transporting, Lysosomal V0 subunit A4 (ATP6V0A4), ATP6V1B1, and Solute Carrier Family 4, Anion Exchanger, Member 1 (SLC4A1) (110). ATP6V0A4 and ATP6V1B1 encode for different components of a multiunit V-ATPase enzyme that mediates acidification of eukaryotic intracellular compartments (110). In addition to the previously listed symptoms, individuals with a pathogenic or likely pathogenic mutation in ATP6V0A4 or ATP6V1B1 may also suffer from mild to severe levels of sensorineural hearing loss, as well as a higher risk in developing nephrolithiasis and CKD (112). The average age of diagnosis for distal RTA caused by mutation to ATP6V0A4 or ATP6V1B1 is 5.5 years, as clinical manifestations normally begin at infancy (112). A member from the solute carrier family, SLC4A1, encodes for a protein expressed in the erythrocyte plasma membrane and in kidney cells and acts as a chloride/bicarbonate transporter for carbon dioxide transport from tissues to lungs, and in tubular acid excretion respectively (113). Some mutations to SLC4A1 can therefore have pleiotropic effects in the kidney and red blood cells, which manifests as the autosomal recessive disease, distal RTA 4 with hemolytic anemia, while other mutations cause the autosomal dominant disease distal RTA 1 (113). For individuals with family history of pathogenic distal RTA mutations, prenatal genetic testing is available (114). Genetic testing to confirm the disease is also important since diagnosis can be challenging as it requires the physician’s conjecture and measurement of urinary pH after an acid load, which would normally lower urine pH to 5.3 (111, 114).

RTA is caused by tubulopathy that creates alkaline urine due to the inability to lower urinary pH (110). Osteoporosis is a common disease with little known about pathogenesis, although data now shows that acid-base balance has a profound impact on the homeostasis of bone calcium, in the presence of a positive acid balance, alkali is released from the bone (115). This prolonged release of alkali from the bone causes increased bone resorption and a decrease in total bone substance, increasing the likelihood of developing osteoporosis (115). The clinical manifestations of this autosomal recessive disease are outlines in Table 2 . RTA with Osteoporosis is caused by a mutation to the gene Carbonic Anhydrase II (CA2), which encodes a protein that catalyzes reversible hydration of carbon dioxide (116). CA2 deficiency has also been determined to play a direct role in the loss of calcium from mineralized substrates and contributes to a rapid loss of bone mass, leading to osteoporosis (116). Both RTA type 1 (distal) and 2 (proximal) can lead to osteoporosis, though it is more common in type 2 (117). Osteoporosis is increasingly prevalent in the pediatric population due to increased disorders associated with bone loss including RTA with osteoporosis (118).

HHRH is a rare autosomal recessive disorder caused by a defective sodium-phosphate co-transporter NPT2c due to loss-of-function mutations in the gene Solute Carrier Family 34 Member 3 (SLC34A3) (119). Pathogenic mutations in this gene are characterized by poor growth, renal phosphate wasting, decreased tubular maximum for phosphate reabsorption per glomerular filtration rate, calcium nephrolithiasis, rickets, increased fractures, bone pain, limb deformities, widened cranial sutures, muscle weakness, hypophosphatemia, increased serum 1,25-didroxyvitamin D3, increased serum alkaline phosphatase, decreased serum parathyroid hormone (PTH), and hypercalciuria ( Figure 6 ) (119). The age of onset for HHRH is during infancy or early childhood. Treatment includes taking oral phosphate supplementation and potassium citrate, which can be enhanced by treatment with recombinant human growth hormone, fluconazole, and salt restriction (119). The solute transporter, SLC34A3, is expressed in proximal tubule cells of the kidney and transports phosphate into cells via sodium transport; its loss of function results in renal tubular defects (47). HHRH caused by mutations to both SLC34A3 alleles (i.e. recessive disease) increase the risk of kidney stones to 46% compared to the general population risk of approximately 10% (120). It has been determined that heterozygous carriers of SLC34A3 mutations can also develop isolated nephrolithiasis (120). Mutational screening for pathogenic variants in genes either through whole exome sequencing or gene panel testing is the method of choice to confirm the diagnosis (121). Genetic testing is also important in the family members since heterozygous mutations can also lead to stone disease, owing to the loss-of-function nature of SLC34A3 (121).

Hypercalciuria is a metabolic abnormality that causes excess calcium in the urine and is closely linked to causing calcium oxalate stones (122). There are many genetic disorders which are related to hypercalciuria and nephrolithiasis, including Dent Disease, FHHNC, HHRH, Autosomal Dominant Hypocalcemic Hypercalciuria (ADHH) and some forms of Bartter Syndrome, which are discussed in this review (122). Another form of hypercalciuria called Familial Idiopathic Hypercalciuria (FIH) is dominantly inherited and is caused by mutation to the gene, Soluble Adenyly Cyclase (ADCY10). The role of the ADCY10 protein is to catalyze the formation of the cAMP (123). FIH is common in children, and the main goal of treatment is to prevent recurrence of stones by reducing urinary calcium oxalate which can be accomplished by increasing fluid intake, low-salt diet, and some drugs including thiazides, diuretics, and potassium citrate (124). It has also been shown that in 69% of pediatric patients who suffered from nephrolithiasis and hypercalciuria there is a family history of the disorders (125).

Hypercalcemia occurs when calcium is two standard deviations above normal calcium levels over a period of three months (126). Genetic forms of hypercalcemia including Familial Hypocalciuric Hypercalcemia (FHH), and Infantile Idiopathic Hypercalcemia (IIH) (126).

FHH follows an autosomal dominant pattern with 65% of cases being caused by heterozygous inactivating mutations of the CASR on chromosome 3, and has variable age of onset (127). FHH is normally benign and asymptomatic, therefore diagnosis may be missed, or misdiagnosed as Primary Hyperparathyroidism which can result in unwarranted treatment or surgery if not correctly classified (127). Features of disease may include nephrolithiasis, pancreatitis, parathyroid adenoma, hypocalciuria, hypercalciuria, hypercalcemia, hypermagnesemia, and normal PTH (127). Most FHH cases do not require treatment, though calcimimetic drugs may be used if patients suffer from pancreatitis (127). Most cases of FHH that lead to death are due to improper and unnecessary treatment and surgery, which is why genetic testing for CASR is crucial (127).

Infantile Idiopathic Hypercalcemia (IIH) is an autosomal recessive disorder that is characterized by severe hypercalcemia (128). There are two types of IIH, type one is caused by mutation in the Cytochrome P450, Family 24, Subfamily A, Polypeptide 1 (CYP24A1), and type two is caused by mutations in the Solute Carrier Family 34 (SLC34A1) (128). General symptoms include failure to thrive, polyuria, nephrocalcinosis, hypotonia, hypercalciuria and hypercalcemia (128). Additionally, patients with Type 1 IIH may experience weight loss, vomiting, nephrolithiasis, central nervous system lethargy, and dehydration, whereas patients with Type 2 IIH may experience reduced tubular phosphate reabsorption, hypophosphatermia, elevated calcitriol, and low PTH (128). The age of onset for IIH is between 20 days and 10 months with failure to thrive and polyuria the most common presenting symptoms (128). There is strong evidence exhibiting nephrolithiasis in IIH Type 1 patients, though further research is needed to address the association of nephrolithiasis to IIH Type 2 (128).

Bartter Syndrome is composed of a group of rare autosomal recessive genetic disorders causing defects in the kidney’s ability to reabsorb salt in the thick ascending loop of Henle (129). Bartter Syndrome is characterized by renal salt wasting, polyuria, hypokalemic metabolic alkalosis, elevated renin and aldosterone levels, and variable risk of developing kidney stones (129). There are 6 types of Bartter Syndrome with varying symptoms, and causative genes (129). Bartter Syndrome I (BARTS1) is antenatal in onset and is caused by mutation to the gene, SLC12A1 (129). BARTS1 is a life-threatening form of the disease which presents with intrauterine growth retardation, premature delivery, low birth weight, failure to thrive, severe dehydration in the neonatal period, hypochloremia, hypercalciuria, hypercalcemia, increased urinary potassium and chloride, nephrocalcinosis, muscle weakness and cramping, as well as developmental delay (130). Currently, there are over 100 described mutations in the gene SLC12A1 described in patients with BARTS1 (131). Bartter Syndrome II (BARTS2) is caused by mutations to Potassium Channel Inwardly Rectifying Subfamily J, Member 1 (KCNJ1), a gene that codes for the renal outer medullary potassium channel, ROMK, which controls resting potential, membrane excitability and is necessary for sodium chloride reabsorption in the ascending loop of Henle (132). Infants presenting with BARTS2 have polyhydramnios and premature delivery, failure to thrive, dehydration, nephrocalcinosis, muscle weakness, hypercalciuria, increased urine potassium and chloride, hyposthenuria, hyperprostaglandinuria, large head, prominent forehead, and large eyes, as well as neurological issues and muscle weakness and cramps (133). Studies have shown that 1 in 5 patients with BARTS2 also have nephrolithiasis (134). Although it is uncommon, there have been few cases reporting late-onset BARTS2 in adolescence and adulthood (132). Bartter Syndrome III (BARTS3) is caused by mutations to the kidney Chloride Channel, Voltage-sensitive Kb (CLCNKB), resulting in reduction of chloride and sodium reabsorption in renal tubules and subsequent loss of salt in urine (63). Additional symptoms of individuals with BARTS3 include low blood pressure, choroidal lesions and placoid calcified lesions to the eye, renal potassium wasting, impaired reabsorption of chloride, muscle weakness, dehydration, and increased serum bicarbonate, urinary potassium, and chloride (63). Pathogenic mutations in CLCNKB have also been proven to cause hypercalciuric nephrolithiasis (79). Previous work by Cheng et al. correlated severity of CLCNKB genotypes to age of onset, plasma chloride concentration, and urine excretion rate: milder missense mutations have a later age of onset (135), while truncating variants of CLCNKB cause a more severe, early onset BARTS3 phenotype (63). Bartter Syndrome IVA is caused by mutations to the gene Barttin CLCNK-type Accessory Subunit Beta, BSND. This disease normally develops in neonates during the second trimester (136). Infants with this disorder have additional symptoms including failure to thrive, sensorineural deafness, inability to concentrate urine, decreased glomerular filtration rate, renal failure, glomerulosclerosis, intellectual and motor disability, hyponatremia, hypochloremia, as well as increased urinary sodium, potassium, and chloride (136). Bartter Syndrome IVB is a digenic disorder caused by mutations to both kidney chloride channels, CLCNKB and Chloride Voltage-gated Channel Ka (CLCNKA) (129). Bartter Syndrome type 5 (BARTS5) is caused by X-linked recessive mutation of the gene Melanoma Antigen, Family D2 (MAGED2), and is a severe antenatal form of Bartter Syndrome (137). Almost all infants born with BARTS5 are premature, with 38% being born before gestational week 8 (137). These patients have a very high mortality rate and additional symptoms including severe renal sodium and chloride loss, hypercalciuria, nephrocalcinosis, preterm delivery, early onset severe polyhydramnios, hyponatremia hypochloremia, hyperreninemia, and elevated calcium to creatinine ratio (137). Prenatal genetic testing for MAGED2 is important to prevent unnecessary diagnostic measures and harmful treatment in pregnant women (137). Studies have also classified an autosomal dominant form of BARTS5 as Hypocalcemia with Bartter Syndrome, which is caused by mutation to the gene CASR, and symptoms include kidney stones (129).

Hypocalcemia is an electrolyte imbalance that can be potentially fatal, and in children, persistent hypocalcemia can be detrimental to bone growth and overall health (138). Patients with hypocalcemia have symptoms including short stature, laryngospasm, hypercalciuria, nephrocalcinosis, nephrolithiasis, decreased renal function, osteoarthritis, seizures, paresthesia, hypocalcemia, low PTH concentration, mildly elevated serum phosphate, hypomagnesemia, hypokalemia, hyperreninemia, and hyperaldosteronemia (139). Treatment for hypocalcemia aims to raise serum calcium to reduce symptoms therefore knowing the etiology of the disease is essential (139). Heterozygous mutations to the calcium-sensing receptor, CASR, cause genetic forms of hypocalemia (140). The protein encoded by CASR is a plasma membrane G-protein-coupled receptor that senses changes in circulating calcium concentration, coupling this information with parathyroid hormone regulatory pathways (140). A genetic form of hypocalcemia is ADHH (122). These patients have mild hypocalcemia that is generally asymptomatic but is can be associated with carpo-pedal spasm and seizures. The causative mutations is a gain of function mutation in the CASR gene (122), leading to hypercalciuria in these patients and subsequently nephrolithiasis (141). There are over 40 different CASR mutations, with many families having a unique deleterious mutation (122). Some forms of hypocalcemia do not have hypercalciuria, which is classified as Autosomal Dominant Hypocalcemia (ADH) (142). A study by Roszko showed that the 81% of patients were diagnosed with ADH1 before the age of 18, and the median age for diagnosis with hypocalcemia-related disorders is 4 years (141). These patients also have mutations to CASR which causes its activation and can lead to development of ADH with BARTS5 (142). About 50% of patients with ADH have symptomatic hypocalcemia, and over 30% have intracerebral calcifications (142). Patients with ADH are treated with calcium supplements and active vitamin D metabolites to raise serum calcium, though this in itself can predispose patients to development of nephrolithiasis, as well as nephrocalcinosis and hypercalciuria (142). Genetic testing has an important place in diagnosis and treatment for the various types of hypocalcemia and should be performed along with genetic counselling for result interpretation and subsequent disclosures and explanations (141).