SLC34 mutation: Personal experience with six families and literature review

SLC34 mutation: Personal experience with six families and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article SLC34 mutation: Personal experience with six families and literature review Hamza Naciri Bennani, Imane Chtioui, Camille Allirot, Rim Somrani, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4613671/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Sep, 2024 Read the published version in Pediatric Nephrology → Version 1 posted 5 You are reading this latest preprint version Abstract Background Mutations in SLC34A1 and SLC34A2 genes, which encode co-transporters NaPi2a and NaPi2c, respectively, can lead hypophosphatemia due to renal phosphate loss. This condition results in hypercalcitriolemia and hypercalciuria, leading formation of kidney stones and nephrocalcinosis. Phenotype is highly variable. Management include hyperhydration, dietary modifications, and/or phosphate supplementation. Thiazides and azoles may be used, but randomized studies are needed to confirm their clinical efficacy. Methods We conducted a retrospective study in pediatric nephrology unit at Grenoble University Hospital from January 2010 to December 2023. Study aimed to describe clinical and biological symptoms of patients with confirmed SLC34A1 and SLC34A3 gene mutations and their outcomes. Results A total of 11 patients (9 females) from 6 different families had mutations in the SLC34A1 (5 patients) and SLC34A3 (6 patients) genes. Median age at diagnosis was 72 [1-108] months. Average follow-up duration was 8.1 ± 4.5 years. Presenting symptom was nephrocalcinosis (4 cases), followed by renal colic (3 cases). At diagnosis, 90% of patients had hypercalciuria and 45% had hypercalcitriolemia. Management included hyperhydration and dietary advice. All patients showed favorable outcomes with normal growth and school attendance. One patient with an SLC34A3 mutation showed regression of nephrocalcinosis. Renal function remained normal. Conclusion Clinical and biological manifestations of SLC34 gene mutations are highly variable, even among siblings; therefore, management must be personalized. Hygienic-dietary measures (such as hyperhydration, a low sodium diet, and age-appropriate calcium intake) result in favorable outcomes in most cases. Use of azoles (e.g., fluconazole) appears to be a promising therapeutic option. Nephrocalcinosis Nephrolithiasis Hypercalciuria Hypophosphatemia 1 25-dihydroxyvitamin D SLC34 Figures Figure 1 1. Introduction Nearly 85% of total phosphate is found in bones and about 10% in soft tissues, with the remaining 2–3% in serum forming a freely exchangeable and tightly regulated phosphate pool. Inorganic phosphate (Pi) is essential for bioenergetics (ATP, GTP), metabolic regulation (glycolysis, oxidative phosphorylation), intracellular signalling pathways, cell proliferation, and structures like bones and membranes [ 1 ]. Phosphorus homeostasis results from a balance between dietary phosphorus absorption, influx and efflux from bone and intracellular stores, and proximal renal tubule reabsorption [ 2 ]. About 80% of filtered phosphate is reabsorbed by the proximal renal tubule. This reabsorption is primarily controlled by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D), fibroblast growth factor 23 (FGF23), and acid-base balance. Three sodium-dependent co-transporters are responsible for the majority of renal phosphate reabsorption: NaPi2a (SLC34A1), NaPi2c (SLC34A3), and PiT-2 (SLC20A2) [ 3 – 7 ]. The human genes SLC34A1 and SLC34A3 are located on chromosome 5q35 and chromosome 9q34, respectively [ 8 , 9 ]. The primary site of NaPi2a expression is the proximal renal tubule within the brush border membrane microvilli, mediating approximately 70–80% of total phosphate reabsorption [ 6 , 10 ]. NaPi2c expression is exclusively found in the apical membranes of proximal renal tubules [ 6 , 10 ]. NaPi2a and NaPi2c share physical and functional similarities but differ in their capacity and requirement to interact with the Na/H exchanger regulatory factor 1 (NHERF1). NaPi2a expression requires interaction of its C-terminal region with NHERF1, which in turn interacts with cytoskeletal proteins [ 11 ]. The importance of NHERF1 in phosphate homeostasis is supported by studies showing that genetic deficiency of NHERF1 in mice [ 12 ] and humans [ 13 ] impairs NaPi2a expression, leading to renal phosphate loss and hypophosphatemia. The expression and action of NaPi2a and NaPi2c are decreased by PTH and FGF23, and at least for NaPi2a, increased by 1,25(OH)2D [ 14 , 15 ]. Furthermore, PiT-2 (SLC20A2) is located in the proximal renal tubule. Its exact role in renal phosphate reabsorption is unclear, but simultaneous genetic suppression of NaPi2a and NaPi2c in mice reduced renal phosphate reabsorption by more than 90%, suggesting its overall contribution might be minor [ 6 ]. Any defect in the regulation of co-transporter proteins or the expression of mutated proteins can lead to phosphocalcic metabolism disorders, which may cause rickets, osteomalacia, anemia, excessive tissue calcifications, nephrolithiasis, nephrocalcinosis, arteriosclerosis, and an increased risk of cardiovascular morbidity and mortality [ 6 ]. Indeed, homozygous and heterozygous mutations in SLC34A1 have been reported in patients with idiopathic infantile hypercalcemia (IIH) causing nephrolithiasis and osteoporosis [ 16 – 18 ], and homozygous and compound heterozygous loss-of-function mutations in SLC34A3 have been reported in patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) leading to limb deformities, muscle weakness, and bone pain [ 9 , 19 , 20 ], with a prevalence estimated at 1/250,000 [ 21 , 22 ]. Both diseases are characterized by hypophosphatemia due to renal phosphate loss, leading to reduced FGF23 and increased serum 1,25(OH)2D concentrations, resulting in decreased PTH and hypercalciuria [ 19 ]. Monoallelic pathogenic mutations in SLC34A1, SLC34A3, and SLC9A3R1 (NHERF1) appear to be very common in the general population and may cause a milder phenotype associated with renal stones and osteoporosis [ 23 ]. The presence of variants in several of these genes in a single patient is not unusual; therefore, these three genes should be routinely sequenced in subjects suspected of hereditary renal phosphate loss [ 24 ]. In this study, we describe 6 families, comprising 11 patients with phosphocalcic metabolism disorders secondary to mutations in SLC34A3 or SLC34A1. 2. Patients and methods We conducted a retrospective, single-center, observational study in our pediatric nephrology unit at Grenoble University Hospital from January 2010 to December 2023. We included all patients with a confirmed SLC34 mutation, comprising 11 patients from 6 different families. The objective of our study was to describe the clinical and biological symptoms of our patients and their outcomes following treatment primarily based on hyperhydration and dietary advice. Collected data and statistical analyses : Clinical and biological data were collected from electronic medical records using CristalNet and Easily software. Statistical analyses were performed using Excel 2016 software. Quantitative variables are presented as means ± standard deviations (SD) or as medians with quartiles (Q1–Q3). Qualitative data are presented as numbers and percentages. Statistical analyses were conducted using R statistical software. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by CNIL (French National Committee for Data Protection; approval number 1987785v0). The biobank collection number is BRIF BB-0033-00069. Informed consent was obtained from all subjects involved in the study. 3. Results We studied 11 patients from 6 families with mutations in either SLC34A3 (2 families, 6 patients, compound heterozygous mutation) or SLC34A1 (4 families, 5 patients, heterozygous mutation). The female-to-male sex ratio was 9:2. The median age at diagnosis was 72 months [range: 1-108 months]. The average follow-up duration was 8.1 ± 4.5 years. The most common presenting symptom was nephrocalcinosis in 4 cases, followed by renal colic in 3 cases. Four patients underwent systematic screening due to affected siblings. Nephrocalcinosis was found in 7 patients, with lithiasis in 4 patients. Only patient 9 had isolated lithiasis without nephrocalcinosis. Three patients (patients 3, 7, and 10) did not develop renal manifestations throughout the follow-up period. Only patient 8 had associated growth retardation at diagnosis. The clinical and biological characteristics of the patients are listed in Tables 1 and 2 . Biologically, at the time of diagnosis: All patients had high calciuria except for patient 10 (missing data). 45% of patients showed an increase in 1,25(OH)2D, but 82% had elevated levels during follow-up. One patient presented with hypophosphatemia with an SLC34A3 mutation, and four patients in total developed hypophosphatemia at least once during follow-up. Two patients experienced hypercalcemia. Only one patient with an SLC34A1 mutation showed an increase in 25(OH)D. 55% of patients showed a decrease in PTH. Figure 1 shows the evolution during follow-up of serum calcium, serum phosphorus, calciuria, 1,25(OH)2D, 25(OH)D, and PTH. All patients underwent annual renal ultrasound follow-up. Management for all patients included hydration and a low-sodium diet. Discontinuation of cholecalciferol supplementation was initiated for all patients initially, then resumed if 25(OH)D levels were below 50 nmol/L, exclusively as daily drops. Cholecalciferol ampoules were prohibited. During follow-up, four patients received potassium citrate due to low citrate excretion, and two patients received oral phosphate due to hypophosphatemia. None of the patients were treated with thiazides or azoles. The outcome was favorable for all patients, with no growth delay or abnormal schooling. Regression of nephrocalcinosis was noted only in patient 2 with an SLC34A3 gene mutation. Persistent hypercalciuria and elevated 1,25(OH)2D were observed in two patients. Renal function remained normal in all patients throughout the follow-up period. 3.a Family 1: Patient 1 A 15-year-old patient has been followed since the incidental discovery of medullary nephrocalcinosis at the age of 6 during a renal ultrasound, performed following recurrent urinary tract infections secondary to vesicoureteral reflux treated with Deflux®, with favorable evolution. At the age of 6, the patient weighed 25 kg, had a height of 120 cm, and a blood pressure of 95/58 mmHg. Biochemical tests at the discovery of nephrocalcinosis revealed calcitriol at 144 pmol/L, 25(OH)D at 63 nmol/L, phosphorus at 1.18 mmol/L, PTH at 33 ng/L, and calciuria at 1.25 mmol/mmol creatinine, leading to the discontinuation of vitamin D intake. Genetic testing revealed compound heterozygosity of the SLC34A3 gene. At the age of 15, the patient weighed 38 kg and had a height of 150 cm. The latest renal ultrasound showed kidneys of good size (98x45 mm on the right and 100x43 mm on the left) with a slightly echogenic appearance of the Malpighian pyramids, without stones. Patient 2 A 13-year-old female patient has been followed since July 2020 following the discovery of nephrocalcinosis on a renal ultrasound performed due to left ureteral lithiasis complicated by ureteral dilation, necessitating the placement of a JJ stent, which was removed after 2 months. Laboratory tests revealed a calcitriol level of 187 pmol/L, associated with a phosphorus level of 1.38 mmol/L and hypercalciuria at 2.22 mmol/mmol of creatinine. The course was marked by an incomplete left femoral fracture discovered following walking pain, requiring intervention in August 2023. In the last sampling in December 2023, serum calcium, phosphorus, and creatinine levels were normal. 25(OH)D was borderline low at 47 nmol/L, and calcitriol was at 229 pmol/L. Renal ultrasound showed kidneys of normal size (87x36 mm on the left and 91x40 mm on the right) with the disappearance of nephrocalcinosis and absence of stones. At 13 years of age, the patient weighed 36.8 kg and had a height of 151 cm. Patient 3 An 11-year-old female patient has been systematically followed since March 2021 following the discovery of a mutation in SLC34A3, present in her two sisters. Laboratory tests conducted in 2021 showed calciuria of 0.79 mmol/mmol of creatinine and a calcitriol level of 202 pmol/L. The rest of the tests were normal (serum calcium, phosphorus, creatinine, PTH, 25(OH)D). Renal ultrasound revealed a right kidney measuring 87x25 mm and a left kidney measuring 88x37 mm with good corticomedullary differentiation, without lithiasis or nephrocalcinosis. She does not present with statural or ponderal delay, with a current height of 140 cm and a weight of 34.4 kg. 3.b Family 2: Patient 4 A 19-year-old female patient has been followed since the incidental discovery of medullary nephrocalcinosis at the age of 5 during a renal ultrasound performed following acute pyelonephritis. At that time, her weight was 19 kg, her height was 115 cm, and her blood pressure was 90/65 mmHg. Her maternal grandmother and paternal grandfather had a history of recurrent kidney stones. Laboratory tests performed at the time of nephrocalcinosis discovery revealed a calcitriol level of 165 pmol/L, a 25(OH)D level of 57 nmol/L, a phosphorus level of 1.65 mmol/L, a calcium level of 2.42 mmol/L, a PTH level of 20.7 ng/L, and a calciuria of 1.29 mmol/mmol of creatinine. This prompted the cessation of cholecalciferol supplementation, which she was taking at a dose of 3 vials of 100,000 IU per year in September, December, and March. In addition to the usual treatment, the patient received sodium bicarbonate at a dose of 1 g per day. Genetic testing revealed a loss-of-function mutation of the heterozygous variant located at the beginning of intron 12 of the SLC34A1 gene. At the age of 19, the patient's weight was 58 kg, and her height was 174 cm. She experienced a left wrist fracture following a road traffic accident in 2018. The latest renal ultrasound showed kidneys of normal size (110x41 mm on the right and 110x43 mm on the left) with persistent medullary hyper echogenicity, without stones. 3.c Family 3: Patient 5 A 25-year-old female patient with a family history of kidney stones in her grandfather has been followed since birth due to a prenatal diagnosis of a right solitary kidney. She was born at term at 38 weeks of gestation, weighing 2630 g and measuring 48 cm. The occurrence of hyperalgesic nephritic colic in 2006 led to a renal ultrasound showing nephrocalcinosis with compensatory hypertrophy measuring 130 mm in its long axis, without stones or pyelocaliceal dilation. Her weight at the age of 7 was 27 kg, her height was 128.5 cm, and her blood pressure was 100/59 mmHg. Laboratory tests conducted at the discovery of nephrocalcinosis revealed a calcitriol level of 91 pmol/L, a 25(OH)D level of 71 nmol/L, a phosphorus level of 1.37 mmol/L, a calcium level of 2.49 mmol/L, a PTH level of 5 ng/L, and a calcinuria of 1.44 mmol/mmol of creatinine. In view of this clinicobiological picture, management initially consisted of stopping all vitamin D intake and increasing fluid intake. Potassium citrate was added from the age of 10 to 16. Subsequently, daily supplementation with small doses (2 drops per day of cholecalciferol) based on 25(OH)D levels (< 50 nmol/L) was introduced. Genetic testing revealed two heterozygous mutations in the SLC34A3 gene: a missense variation p. Ser138Phe on exon 5 and a deletion of 3 base pairs deleting the leucine at position 527 on exon 13. At the age of 22, her weight was 56 kg, and her height was 168 cm. During follow-up, she developed isolated microalbuminuria in 2019 at 192 mg/g, warranting treatment with perindopril. Patient 6 A 25-year-old female patient has been followed since the diagnosis of nephrocalcinosis in her twin sister (Patient 5). Genetic testing results were identical. She was born weighing 2350 g and measuring 47 cm. At the age of 7, at the beginning of follow-up, laboratory tests revealed a calcitriol level of 116 pmol/L, a 25(OH)D level of 31 nmol/L, a phosphorus level of 1.48 mmol/L, a calcium level of 2.53 mmol/L, a PTH level of 11 ng/L, and a calciuria of 1.9 mmol/mmol of creatinine. Renal ultrasound revealed bilateral nephrocalcinosis with normal-sized kidneys and good corticomedullary differentiation. The course was marked by the occurrence of hyperalgesic nephritic colic in 2015 requiring JJ stent placement, ureteroscopy, and LASER fragmentation. She also experienced four episodes of cystitis and acute pyelonephritis in 2019, with renal ultrasound revealing a spontaneously resolving 10 mm stone. Bilateral nephrocalcinosis persisted on renal ultrasound without affecting renal function. Patient 7 A 19-year-old female patient has been followed since the age of 5 due to a family history of SLC34A3 mutation. She was born at 40 weeks of gestation, weighing 3430 g and measuring 51 cm. Laboratory tests showed hypercalciuria, hypercalcemia, hypophosphatemia, and hypercalcitriolism. Renal ultrasounds throughout follow-up revealed normal-sized kidneys with good corticomedullary differentiation without stones or nephrocalcinosis. In addition to routine management, oral phosphorus supplementation at a dose of 75 drops three times per day was introduced in March 2019 due to hypophosphatemia and a TRP of 67%. At the age of 17, her weight was 56 kg, and her height was 167 cm. 3.d Family 4 : Patient 8 A 23-year-old female patient with growth retardation has been followed since it was discovered at the age of 3.5 years, revealing hypercalcemia at 3.2 mmol/L with hypercalciuria at 1.3 mmol/mmol, despite no vitamin D intake since the age of 6 months. Renal ultrasound showed marked hyperechogenicity of both normal-sized kidneys (67 mm in length on the right and 70 mm on the left), suggestive of bilateral nephrocalcinosis. At the age of 6, during a pediatric nephrology consultation, her weight was 17.4 kg, height was 105 cm, and blood pressure was 85/53 mmHg. Laboratory tests revealed a creatinine level of 38 µmol/L, calcium level of 2.42 mmol/L, phosphorus level of 1.49 mmol/L, PTH level of 7 ng/L, calcinuria of 1 mmol/mmol of creatinine, calcitriol level of 135 pmol/L, and 25(OH)D level of 63 nmol/L. Therapeutically, the patient received potassium citrate due to decreased citraturia and oral phosphorus starting at the age of 15 for 5 years at a dose of 25 drops three times per day due to hypophosphatemia during the course. Renal ultrasounds throughout follow-up showed persistent bilateral medullary hyperechogenicity with normal-sized kidneys without stones. Genetic testing revealed the presence of the recurrent variant c.2727_292del (p.Val91_Ala97del) in a heterozygous state of the SLC34A1 gene. Growth improvement was noted with a bone age of 10 years, showing no osteopenia or rickets. At the age of 21, her height was 156 cm, and her weight was 57 kg. 3.e Family 5 : Patient 9 A 3-year-old female patient was diagnosed antenatally with pyelocalyceal dilation, followed by the discovery of microlithiasis on ultrasound at 1 month in both kidneys without nephrocalcinosis. She has a family history of kidney stones in her maternal grandfather and paternal grandmother, with no consanguinity. At 2 months of age, laboratory findings showed hypercalcemia at 2.96 mmol/L, a calcitriol level of 452 pmol/L, 25(OH)D at 83 nmol/L, and calcinuria at 4.35 mmol/mmol of creatinine. Her weight was 5.3 kg, her height was 60 cm, and her head circumference was 40 cm. She was exclusively breastfed. Genetic testing revealed a variant in the heterozygous state in the SLC34A1 gene (p.Val160Ala). At 3 years, her weight was 15.2 kg, her height was 96 cm, and her blood pressure was 93/56 mmHg. Improvement in calcinuria to 0.94 mmol/mmol of creatinine and the disappearance of stone images on ultrasound were noted. Patient 10 A 5-year-old male patient has been followed due to the discovery of hypercalcitriolism and microlithiasis in his younger sister. Investigations revealed a calcitriol level of 186 pmol/L associated with PTH at 20 ng/L and 25(OH)D at 54 nmol/L in the absence of cholecalciferol supplementation. Genetic testing revealed the same genetic anomaly as his sister. The evolution was normal with hydration alone, and at 5 years, his weight was 17.6 kg, his height was 106 cm, and his blood pressure was 97/55 mmHg. Biochemical evaluation showed a normal phosphocalcic balance with calcium at 2.59 mmol/L, phosphorus at 1.58 mmol/L, PTH at 40 ng/L, 25(OH)D at 55 nmol/L, calcitriol at 129 pmol/L, and calcinuria at 0.14 mmol/mmol of creatinine. Renal ultrasound was normal. 3.f Family 6 : Patient 11 A 6-year-old patient has been followed since the prenatal diagnosis of hyperechogenic kidneys suggestive of nephrocalcinosis. At 1 month of age, hypercalcitriolism was discovered at 845 pmol/L, associated with hypercalciuria at 3.15 mmol/mmol of creatinine and an increase in 25(OH)D to 156 nmol/L, prompting the cessation of all vitamin D supplementation. Renal function was normal. Subsequently, medical management included the addition of potassium citrate to the usual treatment. Genetic testing revealed the presence of two heterozygous variants of the SLC34A1 gene. At 6 years, the patient's weight is 22 kg, height is 109.5 cm, and blood pressure is 115/59 mmHg. Biochemically, calcinuria decreased to 0.6 mmol/mmol of creatinine, and calcitriol is at 214 pmol/L. Serum calcium, phosphorus, PTH, and 25(OH)D are within normal ranges. Renal ultrasound shows persistent bilateral nephrocalcinosis with the presence of a lower left calyceal microlithiasis without pyelocalyceal dilation. Table 1 Clinical Characteristics of Patients Family 1 2 3 4 5 6 Patient 1 2 3 4 5 6 7 8 9 10 11 Sex (M/F) F F F F F F F F F H H Height at diagnosis (cm) 120 125 123 115 128.5 129 115 105 60 106 Weight at diagnosis (kg) 25 27 28 19 27 29 20.7 17.4 5.3 17.6 Parents’ Height (Father / Mother) 180 / 160 185 / 163 190 / 159 Age at diagnosis (months) 72 108 84 60 84 84 60 72 3 36 1 Blood Pressure at diagnosis (mmHg) 95/58 119/66 105/65 90/65 100/59 116/71 90/54 85/53 Follow-up duration (years) 9 4 3 13 12 12 13 12 3 2 6 Mode of discovery NC CN S NC CN S S NC DPC S NC Genetic study SLC34A3 SLC34A1 SLC34A3 SLC34A1 SLC34A1 SLC34A1 Table 2 Biological Characteristics of Patients at Diagnosis Patient 1 2 3 4 5 6 7 8 9 10 11 Serum Creatinine (µmol/L) 38 38 42 28 50 50 44 38 14 20 Serum calcium (mmol/L) 2.32 2.34 2.42 2.42 2.49 2.53 2.7 2.42 2.96 2.51 Serum phosphorus (mmol/L) 1.18 1.38 1.31 1.65 1.37 1.48 1.07 1.49 2.02 1.41 Parathyroid hormone (ng/L) 33 14 45 21 5 11 2.5 7 43 20 4 25(OH)D (nmol/L) 63 58 50 57 71 31 50 63 83 54 156 1,25(OH) 2 D (pmol/L) 144 187 202 165 91 116 165 135 452 186 845 Akaline phosphatase (UI/L) 280 219 262 343 232 243 244 227 345 365 Calcinuria (mmol/mmol of creatinine) 1.25 2.22 0.79 1.29 1.44 1.9 1.8 1 4.35 3.15 Phosphaturia (mmol/L) 2.76 30 6.6 7.3 32 10 16 16 Protéinuria (mg/L) 0.06 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.04 0.06 Phosphate reabsorption rate (%) 86 82 90 4. Discussion We reported the clinical and biological results and the evolution of 11 patients, with a female-to-male ratio of 9:2, from 6 families presenting a double heterozygous mutation in the SLC34A3 gene (2 families, 6 patients) or a heterozygous mutation in the SLC34A1 gene (4 families, 5 patients). These mutations affect the sodium-dependent cotransporters NaPi2c and NaPi2a, respectively, located in the renal proximal tubules, and are responsible, along with the PiT-2 cotransporter, for the reabsorption of most of the phosphate from the primary filtrate [ 7 ]. The median age at diagnosis was 72 [1-108] months, and the average follow-up duration was 8.1 ± 4.5 years. The most frequent mode of discovery was nephrocalcinosis (4 cases), followed by nephritic colic (3 cases). Four patients were systematically screened due to affected siblings. The involvement is solely renal for all patients except patient 8, who had growth retardation at diagnosis. Mutations in NaPi2a and NaPi2c are characterized by disturbed calcium homeostasis secondary to high concentrations of 1,25(OH)2D due to hypophosphatemia from renal phosphate loss, leading to decreased FGF23 levels [ 9 , 16 , 17 – 20 ]. Subsequently, decreased FGF23 leads to increased 1,25(OH)2D through at least two direct mechanisms: reduced inhibition of 1-α hydroxylase and reduced stimulation of 24-hydroxylase. Elevated serum calcitriol stimulates intestinal absorption of phosphate and calcium, leading to decreased PTH and hypercalciuria, which promotes the development of nephrolithiasis and/or nephrocalcinosis [ 6 , 16 ]. Depending on the type of mutation (homozygous, heterozygous, compound heterozygous, missense, etc.) and the site of the mutation, the associated phenotype is highly variable, ranging from severe conditions such as IIH (SLC34A1, CYP24A1 encoding the vitamin D 24-hydroxylase enzyme) or HHRH (SLC34A3) to milder forms characterized by renal stones and/or osteoporosis [ 6 , 23 – 29 ]. As of June 2, 2024, 77 different SLC34A1 mutations and 127 different SLC34A3 mutations are listed in the HGMD (Human Gene Mutation Database). HHRH is an autosomal recessive disorder linked to a mutation in the SLC34A3 gene, characterized by severe rickets, growth retardation, skeletal deformities, muscle weakness, and bone pain. Acar et al. [ 30 ] identified pathogenic mutations (PHEX and SLC34A3) in 21 Turkish patients from 15 unrelated families with hereditary hypophosphatemia, showing clinical variability. Approximately 25% of individuals with homozygous or compound heterozygous SLC34A3 mutations do not present with rickets/osteomalacia, and 50% do not have nephrolithiasis or nephrocalcinosis. In our cohort of patients with a double heterozygous SLC34A3 mutation, 67% developed nephrocalcinosis, 50% had renal calculi, and 1/3 of the patients did not exhibit renal manifestations, confirming the variability in clinical presentations, which can be observed within the same family and for the same mutation, likely influenced by the timing of diagnosis and hygienic-dietary measures. Zhu et al. [ 31 ] analysed clinical and biological records of 304 individuals (145 families) with an SLC34A3 mutation. The biological presentation of heterozygous carriers is characterized by decreased serum phosphate, reduced tubular phosphate reabsorption, normal FGF23 and PTH levels, but an increase in serum 1,25(OH)2D, leading to idiopathic hypercalciuria in 38%. Among our 6 patients with an SLC34A3 mutation, 3 patients from the same family showed mild hypophosphatemia during follow-up, necessitating oral phosphate supplementation in two of them. Conversely, we observed low PTH, hypercalciuria, and elevated 1,25(OH)2D levels in 83%, 100%, and 67% of the patients, respectively (Fig. 1 ). Regarding the SLC34A1 gene, the role of mutations in phosphate renal handling and renal function is not yet fully understood [ 1 ]. Biallelic mutations in CYP24A1 and SLC34A1 can cause severe forms of autosomal recessive IIH type 1 and 2, respectively, illustrating the links between vitamin D and phosphate metabolism. The milder form of IIH is often associated with heterozygous mutations in SLC34A1, frequently accompanied by a family history of kidney stones. However, although many IIH patients have mutations in CYP24A1 or SLC34A1, mutations in these two genes do not account for all IIH cases, indicating genetic heterogeneity [ 26 ]. Prié et al. [ 16 ] reported the cases of three patients with heterozygous missense mutations: p.Ala48Phe in one patient and p.Val147Met in the other two related patients. These cases showed low renal phosphate reabsorption (TmP/GFR < 0.7 mmol), hypercalciuria, and kidney stones. A second study described patients from a consanguineous Arab family carrying a homozygous 21 bp duplication (G154¬V160dup) in the SLC34A1 gene, who developed rickets, hypophosphatemia, hypercalciuria, and markedly elevated calcitriol levels [ 32 ]. Several other mutations have been discovered since improved access to genetics, with variable clinical and biological manifestations [ 33 , 34 ]. More recently, two mutations in the SLC34A1 gene (p.Gly543Cys and p.Ile456Asn) were found in two young male patients presenting with hypophosphatemia, kidney stones, and/or osteopenia [ 35 , 36 ]. In our cohort, different heterozygous mutations of SLC34A1 were identified depending on the family [c.2727_292del (p.Val91_Ala97del) for family 4 and p.Val160Ala for family 5]. Nephrocalcinosis was found in 60% of our patients. Additionally, two patients developed renal calculi associated with nephrocalcinosis in one case. Only one case of growth retardation at the time of diagnosis was identified at 3 years of age, with a favorable outcome. IIH remains a rare disorder with variable clinical and biochemical severity characterized by elevated serum concentrations of 1,25(OH)2D and low PTH levels. These patients may also exhibit hypercalciuria and alternate between chronic phases with normal calcium but inappropriate 1,25(OH)2D concentration and low PTH, and acute phases with hypercalcemia and suppressed PTH [ 37 ]. In our patient cohort, we found mild hypophosphatemia, low PTH, hypercalciuria, increased 1,25(OH)2D, and hypercalcemia at least once during follow-up in 20%, 40%, 80%, 80%, 60%, and 20% of patients, respectively (Fig. 1 ). IIH may present with mild to severe hypercalcemia during the first months of life [ 26 ], with severe cases exhibiting vomiting, dehydration, and nephrocalcinosis. Indeed, we also found that patients with an SLC34A1 mutation had an earlier onset than patients with an SLC34A3 mutation, with renal stones appearing as early as the first month of life in one patient and prenatal nephrocalcinosis detected in another. This early involvement was also reported by Molain et al. [ 37 ] in the only patient in their cohort with an SLC34A1 mutation, who had hyperechoic kidneys prenatally. Additionally, Molain et al. [ 37 ], in their study including 185 patients with PTH levels < 20 ng/L, hypercalcemia, and/or hypercalciuria, found biallelic mutations in CYP24A1 in 20 patients, SLC34A3 in 6 patients, and SLC34A1 in one patient, mainly associated with kidney disease (stones, nephrocalcinosis) in 86% of cases, indicating a broad phenotypic overlap. The serum 25(OH)D / 24,25(OH)2D ratio helps differentiate patients with an SLC34 mutation from those with a CYP24A1 mutation, as it is significantly higher in cases of CYP24A1 mutation [ 37 ]. Therefore, in cases of unexplained phosphocalcic metabolism disorders associated with renal manifestations of nephrocalcinosis and/or kidney stones, sequencing of at least these four genes (CYP24A1, SLC34A1, SLC34A3, and SLC9A3R1) seems judicious [ 23 , 24 , 37 ]. Management of patients with hypercalciuria secondary to SLC34 gene mutations typically relies on hydration and dietary advice, including a low-sodium diet with normal age-appropriate calcium intake. In cases of hypophosphatemia and abnormal bone mineralization, phosphate supplementation may be administered, at least during childhood [ 38 ]. The response to oral phosphate supplementation depends on the genetic status [ 31 ]. Long-term supplementation appears to reverse clinical and biochemical abnormalities in HHRH [ 25 ]. Management of our patients relied on hydration and a low-sodium diet. Discontinuation of cholecalciferol supplementation was initiated for all patients initially and restarted if the 25(OH)D level was below 50 nmol/L, exclusively in the form of daily drops. Cholecalciferol ampoules were proscribed. During follow-up, four patients received potassium citrate due to low citraturia, and two patients received oral phosphate due to hypophosphatemia. No patient was treated with thiazides or azoles. The evolution was favorable for all patients, with no stunted growth and normal schooling. Regression of nephrocalcinosis images was noted in only one patient. Renal function remained normal in all patients. However, two patients still had hypercalciuria and increased 1,25(OH)2D. Monitoring urinary calcium levels is critical in managing patients with nephrolithiasis/nephrocalcinosis associated with hypercalciuria and elevated 1,25(OH)2D levels. Normalizing and reducing urinary calcium can prevent and slow the progression of nephrocalcinosis/nephrolithiasis, thereby mitigating the risk of chronic kidney disease and bone complications in adulthood. However, standard interventions (low sodium intake, hydration, and potassium citrate) have limited impact on hypercalciuria [ 39 ]. As a result, alternative strategies have been explored, including the use of hydrochlorothiazide, though its clinical benefit remains uncertain due to frequent side effects such as hypokalemia, asthenia, and potential long-term dermatologic lesions [ 40 ]. Moreover, azoles, particularly ketoconazole, have been employed to inhibit 1α-hydroxylase activity, thereby reducing 1,25(OH)2D levels and calciuria in patients with vitamin D hypersensitivity [ 41 , 42 ]. However, this approach is associated with the risk of potential long-term hepatic toxicity [ 43 ]. Recently, fluconazole has demonstrated efficacy in reducing calciuria in certain patients with CYP24A1 or SLC34A3 mutations [ 44 , 45 ]. Consequently, a randomized trial named FLUCOLITH [ 39 ] is currently underway to evaluate the effectiveness of fluconazole in normalizing calciuria after 16 weeks of treatment. Conclusion The clinical and biological manifestations secondary to mutations in SLC34 genes exhibit considerable variability among patients, even within the same family; thus, management must be personalized. Hygienic and dietary measures, including adequate hydration, a low-sodium diet, and age-appropriate calcium intake, along with supplementation with phosphate or cholecalciferol drops based on 25(OH)D levels, lead to favorable outcomes in most cases. The use of azoles, such as fluconazole, appears to be a promising therapeutic option in cases of persistent hypercalciuria. References Wagner CA, Hernando N, Forster IC, Biber J (2014) The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 466:139-53. doi: 10.1007/s00424-013-1418-6. Kaneko I, Tatsumi S, Segawa H, Miyamoto KI (2017) Control of phosphate balance by the kidney and intestine. Clin Exp Nephrol 21(Suppl 1):21-26. doi: 10.1007/s10157-016-1359-4. Forster IC (2019) The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. Pflugers Arch 471:15-42. doi: 10.1007/s00424-018-2207-z. Jacquillet G (2019) Unwin RJ. Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi). Pflugers Arch 471:83-98. doi: 10.1007/s00424-018-2231-z. Villa-Bellosta R, Ravera S, Sorribas V, et al (2009) The Na+-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical mem- brane of rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296:F691-F699. doi: 10.1152/ajprenal.90623.2008. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N (2014) Genetic diseases of renal phosphate handling. Nephrol Dial Transplant 29 Suppl 4:iv45-54. doi: 10.1093/ndt/gfu217. Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34:386-95. doi: 10.1016/j.mam.2012.07.007. Kos CH, Tihy F, Econs MJ et al (1994) Localization of a renal sodium- phosphate cotransporter gene to human chromosome 5q35. Genomics 19:176–177. doi: 10.1006/geno.1994.1034. Bergwitz C, Roslin NM, Tieder M et al (2006) SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaP(i)-IIc in maintain- ing phosphate homeostasis. Am J Hum Genet 78: 179–192. doi: 10.1086/499409. Murer H, Forster I, Biber J (2004) The sodium phosphate cotransporter family SLC34. Pflugers Arch 447:763-7. doi: 10.1007/s00424-003-1072-5. Hernando N, Déliot N, Gisler SM, et al (2002) PDZ-domain inter- actions and apical expression of type IIa Na/P(i) cotransporters. Proc Natl Acad Sci U S A 99:11957-11962. doi: 10.1073/pnas.182412699 Shenolikar S, Voltz JW, Minkoff CM, Wade JB, Weinman EJ (2002) Targeted disruption of the mouse NHERF-1 gene promotes in- ternalization of proximal tubule sodium-phosphate cotransporter type IIa and renal phosphate wasting. Proc Natl Acad Sci U S A 99:11470-11475. doi: 10.1073/pnas.162232699. Karim Z, Gérard B, Bakouh N, et al (2008) NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med 359:1128-1135. doi: 10.1056/NEJMoa0802836. Barthel TK, Mathern DR, Whitfield GK, et al (2007) 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism. J Steroid Biochem Mol Biol 103:381-388. doi: 10.1016/j.jsbmb.2006.12.054. Martins JS, Liu ES, Sneddon WB, Friedman PA, Demay MB (2019) 1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice. Endocrinology 160:2204-2214. doi: 10.1210/en.2019-00186. Prié D, Huart V, Bakouh N, et al (2012) Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N. Eng. J. Med 347: 983–991. doi: 10.1056/NEJMoa020028. Kang SJ, Lee R, Kim HS (2019) Infantile hypercalcemia with novel compound heterozygous mutation in SLC34A1 encoding renal sodium-phosphate cotransporter 2a: a case report. Ann Pediatr Endocrinol Metab 24:64-67. doi: 10.6065/apem.2019.24.1.64. Pronicka E, Ciara E, Halat P, et al (2017) Biallelic mutations in CYP24A1 or SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with vitamin D hypersensitivity: molecular study of 11 historical IIH cases. J Appl Genet 58:349-353. doi: 10.1007/s13353-017-0397-2. Tieder M, Modai D, Samuel R, et al (1985) Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med 312:611-617. doi: 10.1056/NEJM198503073121003. Yu Y, Sanderson SR, Reyes M, et al (2012) Nouvelles mutations NaPi-IIc causant HHRH et hypercalciurie idiopathique dans plusieurs familles non apparentées : suivi à long terme dans une famille. Os 50:1100-6. DOI : 10.1016/j.bone.2012.02.015. Erratum dans : Os. 50(5) :1206. Bergwitz C, Miyamoto KI (2019) Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch 471:149-163. doi: 10.1007/s00424-018-2184-2. Amar A, Majmundar AJ, Ullah I, et al (2019) Gene panel sequencing identifies a likely monogenic cause in 7% of 235 Pakistani families with nephrolithiasis. Hum Genet 138:211-219. doi: 10.1007/s00439-019-01978-x Schlingmann KP, Ruminska J, Kaufmann M, et al (2016) Autosomal- Recessive Mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile Hypercalcemia. J Am Soc Nephrol 27:604-614. doi: 10.1681/ASN.2014101025. Brazier F, Courbebaisse M, David A, et al (2023) Relationship between clinical phenotype and in vitro analysis of 13 NPT2c/SCL34A3 mutants. Sci Rep 13:85. doi: 10.1038/s41598-022-25995-5. Bergwitz C, Juppner H (2012) FGF23 and syndromes of abnormal renal phosphate handling. Adv Exp Med Biol 728:41–64. doi: 10.1007/978-1-4614-0887-1_3. Lenherr-Taube N, Young EJ, Furman M, et al (2021) Mild Idiopathic Infantile Hypercalcemia-Part 1: Biochemical and Genetic Findings. J Clin Endocrinol Metab 106:2915-2937. doi: 10.1210/clinem/dgab431. Stürznickel J, Heider F, Delsmann A, et al (2022) Spectre clinique du rachitisme hypophosphatémique héréditaire avec hypercalciurie (HHRH). J Bone Miner Res 37:1580-1591. doi : 10.1002/JBMR.4630. Bizerea-Moga TO, Chisavu F, Ilies C, et al (2023) Phénotype de l’hypercalcémie infantile idiopathique associée à la variante pathogène hétérozygote de SLC34A1 et CYP24A1 . Enfants (Bâle) 10:1701. doi : 10.3390/children10101701. Wang Q, Chen JJ, Wei LY, et al (2024) Biallelic and monoallelic pathogenic variants in CYP24A1 and SLC34A1 genes cause idiopathic infantile hypercalcemia. Orphanet J Rare Dis 19 :126. doi : 10.1186/s13023-024-03135-8. Acar S, BinEssa HA, Demir K, et al (2018) Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3. PLoS One 13: e0193388. doi : 10.1371/journal.pone.0193388. Zhu Z, Bo-Ran Ho B, Chen A, et al (2024) An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Kidney Int 105:1058-1076. doi: 10.1016/j.kint.2024.01.031. Magen D, Berger L, Coady MJ, et al (2010) A loss-of-function mutation in NaPi-IIa and renal Fanconi’s syndrome. N Engl J Med 362:1102–1109. doi: 10.1056/NEJMoa0905647. Chen X, Xie Y, Wan S, et al (2019) A novel heterozygous mutation c.680A>G (p. N227S) in SLC34A1 gene leading to autosomal dominant hypophosphatemia: A case report. Medicine 98: e15617. doi: 10.1097/MD.0000000000015617. Ma Y, Lv H, Wang J, et al (2020) Heterozygous mutation of SLC34A1 in patients with hypophosphatemic kidney stones and osteoporosis: A case report. J. Int. Med. Res 48: 300060519896146. doi: 10.1177/0300060519896146. Giusti F, Marini F, Al-Alwani H, et al (2023) A Novel Heterozygous Mutation c.1627G>T (p.Gly543Cys) in the SLC34A1 Gene in a Male Patient with Recurrent Nephrolithiasis and Early Onset Osteopenia: A Case Report. Int J Mol Sci 24:17289. doi: 10.3390/ijms242417289. Fearn A, Allison B, Rice SJ, et al (2018) Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations. Physiol. Rep 6: e13715. doi: 10.14814/phy2.13715. Molin A, Lemoine S, Kaufmann M, et al (2021) Overlapping Phenotypes Associated With CYP24A1 , SLC34A1 , and SLC34A3 Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D. Front Endocrinol (Lausanne) 12:736240. doi: 10.3389/fendo.2021.736240. Haffner D, Emma F, Eastwood DM, et al (2019) Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 15:435–55. doi: 10.1038/s41581-019-0152-5. Bertholet-Thomas A, Portefaix A, Flammier S, et al (2022) Fluconazole in hypercalciuric patients with increased 1,25(OH) 2 D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial. Trials 23:499. doi: 10.1186/s13063-022-06302-z. Pottegard A, Hallas J, Olesen M, et al (2017) Hydrochlorothiazide use is strongly associated with risk of lip cancer. J Intern Med 282:322–31. doi: 10.1111/joim.12629. Tebben PJ, Milliner DS, Horst RL, et al (2012) Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab 97: E423–7. doi: 10.1210/jc.2011-1935. Nguyen M, Boutignon H, Mallet E, et al (2010) Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment. J Pediatr 157:296–302. doi: 10.1016/j.jpeds.2010.02.025 Young J, Bertherat J, Vantyghem MC, et al Compassionalte use Programme (2018) Hepatic safety of ketoconazole in Cushing's syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol 178:447-458. doi: 10.1530/EJE-17-0886. Sayers J, Hynes AM, Srivastava S, et al (2015) Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clin Kidney J 8:453–5. doi: 10.1093/ckj/sfv028. Bertholet-Thomas A, Tram N, Dubourg L, Lemoine S, Molin A, Bacchetta J (2019) Fluconazole as a new therapeutic tool to manage patients with NPTIIc (SLC34A3) Mutation: A Case Report. Am J Kidney Dis 73:886–9. Doi: 10.1053/j.ajkd.2018.12.026. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4613671","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":317064455,"identity":"1a3dc2f8-bffa-41a6-8528-0a7536f6f0ef","order_by":0,"name":"Hamza Naciri Bennani","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Hamza","middleName":"Naciri","lastName":"Bennani","suffix":""},{"id":317064456,"identity":"85c39a51-9d23-4673-805b-19ccb7540798","order_by":1,"name":"Imane Chtioui","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Imane","middleName":"","lastName":"Chtioui","suffix":""},{"id":317064457,"identity":"8ede94e0-db6b-469b-b6cf-7eb5366fcd36","order_by":2,"name":"Camille Allirot","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Camille","middleName":"","lastName":"Allirot","suffix":""},{"id":317064458,"identity":"4883927d-ead5-42ee-bf6a-6626b6588c4e","order_by":3,"name":"Rim Somrani","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Rim","middleName":"","lastName":"Somrani","suffix":""},{"id":317064459,"identity":"0b06917c-f42f-44c4-be73-373c8f3cf2ce","order_by":4,"name":"Thomas Jouve","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Jouve","suffix":""},{"id":317064460,"identity":"7fa27877-41c6-459a-950d-a111a4369696","order_by":5,"name":"Guylhene Bourdat-Michel","email":"","orcid":"","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":false,"prefix":"","firstName":"Guylhene","middleName":"","lastName":"Bourdat-Michel","suffix":""},{"id":317064461,"identity":"538b00bc-2003-4f64-9a47-55a19ac0146f","order_by":6,"name":"Lionel ROSTAING","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIie3PsUrDQBzH8R8I5/K3Wf8lQl/hpJAqCD6HW4JwLkUHlw4xBIS6OVss9BX0DU4C51L3gkug0MkhIHQMNpGWLpc6Ct53+XPHfbg7wOX6g7V+BgP7qVhvCuSAZyP1MV0R0lskBNppM6kuCn9L/Cz7KuLjq875fDEn3F57/p3JwwG4ZzGipRRrwzdHH6rXJbydjMbmUoZT8KG2EKIAWnD08tQX/kFppJz1A46GSNj2MKJuocsVGU2FTzDyrCYluIFIfh1yNGGqSCwlVyRtIkLx+wNHz6SC9hha8kyt/mLYSjzay4rBMokm99mCP5FI7/HC5EV8aiWbpK5Htl7vBEAnrUey+6TL5XL9u74BgABPY8vsvaoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5130-7286","institution":"CHU Grenoble Alpes: Centre Hospitalier Universitaire Grenoble Alpes","correspondingAuthor":true,"prefix":"","firstName":"Lionel","middleName":"","lastName":"ROSTAING","suffix":""}],"badges":[],"createdAt":"2024-06-20 20:02:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4613671/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4613671/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00467-024-06505-3","type":"published","date":"2024-09-10T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60600154,"identity":"d9ecff89-41ff-4b5d-b875-e5a0f4f87611","added_by":"auto","created_at":"2024-07-18 16:00:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":58884,"visible":true,"origin":"","legend":"\u003cp\u003eEvolution of Phosphocalcic Profile in Patients During Follow-up\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4613671/v1/16e0b5565f075e56d07eef3b.png"},{"id":64619059,"identity":"c2dfcfa9-e840-4c64-a031-0510a80383f4","added_by":"auto","created_at":"2024-09-16 16:11:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":667864,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4613671/v1/3343ea57-7ff3-44ee-b75b-3e0c0d6403b0.pdf"}],"financialInterests":"","formattedTitle":"SLC34 mutation: Personal experience with six families and literature review","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eNearly 85% of total phosphate is found in bones and about 10% in soft tissues, with the remaining 2\u0026ndash;3% in serum forming a freely exchangeable and tightly regulated phosphate pool. Inorganic phosphate (Pi) is essential for bioenergetics (ATP, GTP), metabolic regulation (glycolysis, oxidative phosphorylation), intracellular signalling pathways, cell proliferation, and structures like bones and membranes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePhosphorus homeostasis results from a balance between dietary phosphorus absorption, influx and efflux from bone and intracellular stores, and proximal renal tubule reabsorption [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. About 80% of filtered phosphate is reabsorbed by the proximal renal tubule. This reabsorption is primarily controlled by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D), fibroblast growth factor 23 (FGF23), and acid-base balance. Three sodium-dependent co-transporters are responsible for the majority of renal phosphate reabsorption: NaPi2a (SLC34A1), NaPi2c (SLC34A3), and PiT-2 (SLC20A2) [\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe human genes SLC34A1 and SLC34A3 are located on chromosome 5q35 and chromosome 9q34, respectively [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The primary site of NaPi2a expression is the proximal renal tubule within the brush border membrane microvilli, mediating approximately 70\u0026ndash;80% of total phosphate reabsorption [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. NaPi2c expression is exclusively found in the apical membranes of proximal renal tubules [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. NaPi2a and NaPi2c share physical and functional similarities but differ in their capacity and requirement to interact with the Na/H exchanger regulatory factor 1 (NHERF1). NaPi2a expression requires interaction of its C-terminal region with NHERF1, which in turn interacts with cytoskeletal proteins [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The importance of NHERF1 in phosphate homeostasis is supported by studies showing that genetic deficiency of NHERF1 in mice [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] and humans [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] impairs NaPi2a expression, leading to renal phosphate loss and hypophosphatemia. The expression and action of NaPi2a and NaPi2c are decreased by PTH and FGF23, and at least for NaPi2a, increased by 1,25(OH)2D [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, PiT-2 (SLC20A2) is located in the proximal renal tubule. Its exact role in renal phosphate reabsorption is unclear, but simultaneous genetic suppression of NaPi2a and NaPi2c in mice reduced renal phosphate reabsorption by more than 90%, suggesting its overall contribution might be minor [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAny defect in the regulation of co-transporter proteins or the expression of mutated proteins can lead to phosphocalcic metabolism disorders, which may cause rickets, osteomalacia, anemia, excessive tissue calcifications, nephrolithiasis, nephrocalcinosis, arteriosclerosis, and an increased risk of cardiovascular morbidity and mortality [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Indeed, homozygous and heterozygous mutations in SLC34A1 have been reported in patients with idiopathic infantile hypercalcemia (IIH) causing nephrolithiasis and osteoporosis [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and homozygous and compound heterozygous loss-of-function mutations in SLC34A3 have been reported in patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH) leading to limb deformities, muscle weakness, and bone pain [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], with a prevalence estimated at 1/250,000 [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Both diseases are characterized by hypophosphatemia due to renal phosphate loss, leading to reduced FGF23 and increased serum 1,25(OH)2D concentrations, resulting in decreased PTH and hypercalciuria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMonoallelic pathogenic mutations in SLC34A1, SLC34A3, and SLC9A3R1 (NHERF1) appear to be very common in the general population and may cause a milder phenotype associated with renal stones and osteoporosis [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The presence of variants in several of these genes in a single patient is not unusual; therefore, these three genes should be routinely sequenced in subjects suspected of hereditary renal phosphate loss [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we describe 6 families, comprising 11 patients with phosphocalcic metabolism disorders secondary to mutations in SLC34A3 or SLC34A1.\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cp\u003eWe conducted a retrospective, single-center, observational study in our pediatric nephrology unit at Grenoble University Hospital from January 2010 to December 2023. We included all patients with a confirmed SLC34 mutation, comprising 11 patients from 6 different families. The objective of our study was to describe the clinical and biological symptoms of our patients and their outcomes following treatment primarily based on hyperhydration and dietary advice.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"ItalicUnderline\" class=\"ItalicUnderline\" name=\"Emphasis\"\u003eCollected data and statistical analyses\u003c/span\u003e:\u003c/p\u003e \u003cp\u003eClinical and biological data were collected from electronic medical records using CristalNet and Easily software. Statistical analyses were performed using Excel 2016 software. Quantitative variables are presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations (SD) or as medians with quartiles (Q1\u0026ndash;Q3). Qualitative data are presented as numbers and percentages. Statistical analyses were conducted using R statistical software.\u003c/p\u003e \u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by CNIL (French National Committee for Data Protection; approval number 1987785v0). The biobank collection number is BRIF BB-0033-00069. Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eWe studied 11 patients from 6 families with mutations in either SLC34A3 (2 families, 6 patients, compound heterozygous mutation) or SLC34A1 (4 families, 5 patients, heterozygous mutation). The female-to-male sex ratio was 9:2. The median age at diagnosis was 72 months [range: 1-108 months]. The average follow-up duration was 8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 years. The most common presenting symptom was nephrocalcinosis in 4 cases, followed by renal colic in 3 cases. Four patients underwent systematic screening due to affected siblings. Nephrocalcinosis was found in 7 patients, with lithiasis in 4 patients. Only patient 9 had isolated lithiasis without nephrocalcinosis. Three patients (patients 3, 7, and 10) did not develop renal manifestations throughout the follow-up period. Only patient 8 had associated growth retardation at diagnosis. The clinical and biological characteristics of the patients are listed in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eBiologically, at the time of diagnosis:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAll patients had high calciuria except for patient 10 (missing data).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e45% of patients showed an increase in 1,25(OH)2D, but 82% had elevated levels during follow-up.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOne patient presented with hypophosphatemia with an SLC34A3 mutation, and four patients in total developed hypophosphatemia at least once during follow-up.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTwo patients experienced hypercalcemia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eOnly one patient with an SLC34A1 mutation showed an increase in 25(OH)D.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e55% of patients showed a decrease in PTH.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the evolution during follow-up of serum calcium, serum phosphorus, calciuria, 1,25(OH)2D, 25(OH)D, and PTH. All patients underwent annual renal ultrasound follow-up.\u003c/p\u003e \u003cp\u003eManagement for all patients included hydration and a low-sodium diet. Discontinuation of cholecalciferol supplementation was initiated for all patients initially, then resumed if 25(OH)D levels were below 50 nmol/L, exclusively as daily drops. Cholecalciferol ampoules were prohibited. During follow-up, four patients received potassium citrate due to low citrate excretion, and two patients received oral phosphate due to hypophosphatemia. None of the patients were treated with thiazides or azoles.\u003c/p\u003e \u003cp\u003eThe outcome was favorable for all patients, with no growth delay or abnormal schooling. Regression of nephrocalcinosis was noted only in patient 2 with an SLC34A3 gene mutation. Persistent hypercalciuria and elevated 1,25(OH)2D were observed in two patients. Renal function remained normal in all patients throughout the follow-up period.\u003c/p\u003e\n\u003ch3\u003e3.a Family 1:\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 1\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 15-year-old patient has been followed since the incidental discovery of medullary nephrocalcinosis at the age of 6 during a renal ultrasound, performed following recurrent urinary tract infections secondary to vesicoureteral reflux treated with Deflux\u0026reg;, with favorable evolution. At the age of 6, the patient weighed 25 kg, had a height of 120 cm, and a blood pressure of 95/58 mmHg. Biochemical tests at the discovery of nephrocalcinosis revealed calcitriol at 144 pmol/L, 25(OH)D at 63 nmol/L, phosphorus at 1.18 mmol/L, PTH at 33 ng/L, and calciuria at 1.25 mmol/mmol creatinine, leading to the discontinuation of vitamin D intake. Genetic testing revealed compound heterozygosity of the SLC34A3 gene. At the age of 15, the patient weighed 38 kg and had a height of 150 cm. The latest renal ultrasound showed kidneys of good size (98x45 mm on the right and 100x43 mm on the left) with a slightly echogenic appearance of the Malpighian pyramids, without stones.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 2\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 13-year-old female patient has been followed since July 2020 following the discovery of nephrocalcinosis on a renal ultrasound performed due to left ureteral lithiasis complicated by ureteral dilation, necessitating the placement of a JJ stent, which was removed after 2 months. Laboratory tests revealed a calcitriol level of 187 pmol/L, associated with a phosphorus level of 1.38 mmol/L and hypercalciuria at 2.22 mmol/mmol of creatinine. The course was marked by an incomplete left femoral fracture discovered following walking pain, requiring intervention in August 2023. In the last sampling in December 2023, serum calcium, phosphorus, and creatinine levels were normal. 25(OH)D was borderline low at 47 nmol/L, and calcitriol was at 229 pmol/L. Renal ultrasound showed kidneys of normal size (87x36 mm on the left and 91x40 mm on the right) with the disappearance of nephrocalcinosis and absence of stones. At 13 years of age, the patient weighed 36.8 kg and had a height of 151 cm.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 3\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAn 11-year-old female patient has been systematically followed since March 2021 following the discovery of a mutation in SLC34A3, present in her two sisters. Laboratory tests conducted in 2021 showed calciuria of 0.79 mmol/mmol of creatinine and a calcitriol level of 202 pmol/L. The rest of the tests were normal (serum calcium, phosphorus, creatinine, PTH, 25(OH)D). Renal ultrasound revealed a right kidney measuring 87x25 mm and a left kidney measuring 88x37 mm with good corticomedullary differentiation, without lithiasis or nephrocalcinosis. She does not present with statural or ponderal delay, with a current height of 140 cm and a weight of 34.4 kg.\u003c/p\u003e\n\u003ch3\u003e3.b Family 2:\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 4\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 19-year-old female patient has been followed since the incidental discovery of medullary nephrocalcinosis at the age of 5 during a renal ultrasound performed following acute pyelonephritis. At that time, her weight was 19 kg, her height was 115 cm, and her blood pressure was 90/65 mmHg. Her maternal grandmother and paternal grandfather had a history of recurrent kidney stones. Laboratory tests performed at the time of nephrocalcinosis discovery revealed a calcitriol level of 165 pmol/L, a 25(OH)D level of 57 nmol/L, a phosphorus level of 1.65 mmol/L, a calcium level of 2.42 mmol/L, a PTH level of 20.7 ng/L, and a calciuria of 1.29 mmol/mmol of creatinine. This prompted the cessation of cholecalciferol supplementation, which she was taking at a dose of 3 vials of 100,000 IU per year in September, December, and March. In addition to the usual treatment, the patient received sodium bicarbonate at a dose of 1 g per day. Genetic testing revealed a loss-of-function mutation of the heterozygous variant located at the beginning of intron 12 of the SLC34A1 gene. At the age of 19, the patient's weight was 58 kg, and her height was 174 cm. She experienced a left wrist fracture following a road traffic accident in 2018. The latest renal ultrasound showed kidneys of normal size (110x41 mm on the right and 110x43 mm on the left) with persistent medullary hyper echogenicity, without stones.\u003c/p\u003e\n\u003ch3\u003e3.c Family 3:\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 5\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 25-year-old female patient with a family history of kidney stones in her grandfather has been followed since birth due to a prenatal diagnosis of a right solitary kidney. She was born at term at 38 weeks of gestation, weighing 2630 g and measuring 48 cm. The occurrence of hyperalgesic nephritic colic in 2006 led to a renal ultrasound showing nephrocalcinosis with compensatory hypertrophy measuring 130 mm in its long axis, without stones or pyelocaliceal dilation. Her weight at the age of 7 was 27 kg, her height was 128.5 cm, and her blood pressure was 100/59 mmHg. Laboratory tests conducted at the discovery of nephrocalcinosis revealed a calcitriol level of 91 pmol/L, a 25(OH)D level of 71 nmol/L, a phosphorus level of 1.37 mmol/L, a calcium level of 2.49 mmol/L, a PTH level of 5 ng/L, and a calcinuria of 1.44 mmol/mmol of creatinine. In view of this clinicobiological picture, management initially consisted of stopping all vitamin D intake and increasing fluid intake. Potassium citrate was added from the age of 10 to 16. Subsequently, daily supplementation with small doses (2 drops per day of cholecalciferol) based on 25(OH)D levels (\u0026lt;\u0026thinsp;50 nmol/L) was introduced. Genetic testing revealed two heterozygous mutations in the SLC34A3 gene: a missense variation p. Ser138Phe on exon 5 and a deletion of 3 base pairs deleting the leucine at position 527 on exon 13. At the age of 22, her weight was 56 kg, and her height was 168 cm. During follow-up, she developed isolated microalbuminuria in 2019 at 192 mg/g, warranting treatment with perindopril.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 6\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 25-year-old female patient has been followed since the diagnosis of nephrocalcinosis in her twin sister (Patient 5). Genetic testing results were identical. She was born weighing 2350 g and measuring 47 cm. At the age of 7, at the beginning of follow-up, laboratory tests revealed a calcitriol level of 116 pmol/L, a 25(OH)D level of 31 nmol/L, a phosphorus level of 1.48 mmol/L, a calcium level of 2.53 mmol/L, a PTH level of 11 ng/L, and a calciuria of 1.9 mmol/mmol of creatinine. Renal ultrasound revealed bilateral nephrocalcinosis with normal-sized kidneys and good corticomedullary differentiation. The course was marked by the occurrence of hyperalgesic nephritic colic in 2015 requiring JJ stent placement, ureteroscopy, and LASER fragmentation. She also experienced four episodes of cystitis and acute pyelonephritis in 2019, with renal ultrasound revealing a spontaneously resolving 10 mm stone. Bilateral nephrocalcinosis persisted on renal ultrasound without affecting renal function.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 7\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 19-year-old female patient has been followed since the age of 5 due to a family history of SLC34A3 mutation. She was born at 40 weeks of gestation, weighing 3430 g and measuring 51 cm. Laboratory tests showed hypercalciuria, hypercalcemia, hypophosphatemia, and hypercalcitriolism. Renal ultrasounds throughout follow-up revealed normal-sized kidneys with good corticomedullary differentiation without stones or nephrocalcinosis. In addition to routine management, oral phosphorus supplementation at a dose of 75 drops three times per day was introduced in March 2019 due to hypophosphatemia and a TRP of 67%. At the age of 17, her weight was 56 kg, and her height was 167 cm.\u003c/p\u003e\n\u003ch3\u003e3.d Family 4 :\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 8\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 23-year-old female patient with growth retardation has been followed since it was discovered at the age of 3.5 years, revealing hypercalcemia at 3.2 mmol/L with hypercalciuria at 1.3 mmol/mmol, despite no vitamin D intake since the age of 6 months. Renal ultrasound showed marked hyperechogenicity of both normal-sized kidneys (67 mm in length on the right and 70 mm on the left), suggestive of bilateral nephrocalcinosis. At the age of 6, during a pediatric nephrology consultation, her weight was 17.4 kg, height was 105 cm, and blood pressure was 85/53 mmHg. Laboratory tests revealed a creatinine level of 38 \u0026micro;mol/L, calcium level of 2.42 mmol/L, phosphorus level of 1.49 mmol/L, PTH level of 7 ng/L, calcinuria of 1 mmol/mmol of creatinine, calcitriol level of 135 pmol/L, and 25(OH)D level of 63 nmol/L. Therapeutically, the patient received potassium citrate due to decreased citraturia and oral phosphorus starting at the age of 15 for 5 years at a dose of 25 drops three times per day due to hypophosphatemia during the course. Renal ultrasounds throughout follow-up showed persistent bilateral medullary hyperechogenicity with normal-sized kidneys without stones. Genetic testing revealed the presence of the recurrent variant c.2727_292del (p.Val91_Ala97del) in a heterozygous state of the SLC34A1 gene. Growth improvement was noted with a bone age of 10 years, showing no osteopenia or rickets. At the age of 21, her height was 156 cm, and her weight was 57 kg.\u003c/p\u003e\n\u003ch3\u003e3.e Family 5 :\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 9\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 3-year-old female patient was diagnosed antenatally with pyelocalyceal dilation, followed by the discovery of microlithiasis on ultrasound at 1 month in both kidneys without nephrocalcinosis. She has a family history of kidney stones in her maternal grandfather and paternal grandmother, with no consanguinity. At 2 months of age, laboratory findings showed hypercalcemia at 2.96 mmol/L, a calcitriol level of 452 pmol/L, 25(OH)D at 83 nmol/L, and calcinuria at 4.35 mmol/mmol of creatinine. Her weight was 5.3 kg, her height was 60 cm, and her head circumference was 40 cm. She was exclusively breastfed. Genetic testing revealed a variant in the heterozygous state in the SLC34A1 gene (p.Val160Ala). At 3 years, her weight was 15.2 kg, her height was 96 cm, and her blood pressure was 93/56 mmHg. Improvement in calcinuria to 0.94 mmol/mmol of creatinine and the disappearance of stone images on ultrasound were noted.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 10\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eA 5-year-old male patient has been followed due to the discovery of hypercalcitriolism and microlithiasis in his younger sister. Investigations revealed a calcitriol level of 186 pmol/L associated with PTH at 20 ng/L and 25(OH)D at 54 nmol/L in the absence of cholecalciferol supplementation. Genetic testing revealed the same genetic anomaly as his sister. The evolution was normal with hydration alone, and at 5 years, his weight was 17.6 kg, his height was 106 cm, and his blood pressure was 97/55 mmHg. Biochemical evaluation showed a normal phosphocalcic balance with calcium at 2.59 mmol/L, phosphorus at 1.58 mmol/L, PTH at 40 ng/L, 25(OH)D at 55 nmol/L, calcitriol at 129 pmol/L, and calcinuria at 0.14 mmol/mmol of creatinine. Renal ultrasound was normal.\u003c/p\u003e\n\u003ch3\u003e3.f Family 6 :\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePatient 11\u003c/b\u003e \u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA 6-year-old patient has been followed since the prenatal diagnosis of hyperechogenic kidneys suggestive of nephrocalcinosis. At 1 month of age, hypercalcitriolism was discovered at 845 pmol/L, associated with hypercalciuria at 3.15 mmol/mmol of creatinine and an increase in 25(OH)D to 156 nmol/L, prompting the cessation of all vitamin D supplementation. Renal function was normal. Subsequently, medical management included the addition of potassium citrate to the usual treatment. Genetic testing revealed the presence of two heterozygous variants of the SLC34A1 gene. At 6 years, the patient's weight is 22 kg, height is 109.5 cm, and blood pressure is 115/59 mmHg. Biochemically, calcinuria decreased to 0.6 mmol/mmol of creatinine, and calcitriol is at 214 pmol/L. Serum calcium, phosphorus, PTH, and 25(OH)D are within normal ranges. Renal ultrasound shows persistent bilateral nephrocalcinosis with the presence of a lower left calyceal microlithiasis without pyelocalyceal dilation.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical Characteristics of Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex (M/F)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eH\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight at diagnosis (cm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e128.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight at diagnosis (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e20.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParents\u0026rsquo; Height (Father / Mother)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e180 / 160\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e185 / 163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003e190 / 159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge at diagnosis (months)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlood Pressure at diagnosis (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95/58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119/66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e105/65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e90/65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100/59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e116/71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e90/54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e85/53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFollow-up duration (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMode of discovery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDPC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNC\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGenetic study\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eSLC34A3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLC34A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eSLC34A3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSLC34A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eSLC34A1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eSLC34A1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiological Characteristics of Patients at Diagnosis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum Creatinine (\u0026micro;mol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum calcium (mmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerum phosphorus (mmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParathyroid hormone (ng/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e25(OH)D (nmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e156\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1,25(OH)\u003c/b\u003e\u003csub\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sub\u003e\u003cb\u003eD (pmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e187\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e116\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e452\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e186\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e845\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAkaline phosphatase (UI/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e280\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e365\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCalcinuria (mmol/mmol of creatinine)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e3.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhosphaturia (mmol/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eProt\u0026eacute;inuria (mg/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePhosphate reabsorption rate (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eWe reported the clinical and biological results and the evolution of 11 patients, with a female-to-male ratio of 9:2, from 6 families presenting a double heterozygous mutation in the SLC34A3 gene (2 families, 6 patients) or a heterozygous mutation in the SLC34A1 gene (4 families, 5 patients). These mutations affect the sodium-dependent cotransporters NaPi2c and NaPi2a, respectively, located in the renal proximal tubules, and are responsible, along with the PiT-2 cotransporter, for the reabsorption of most of the phosphate from the primary filtrate [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The median age at diagnosis was 72 [1-108] months, and the average follow-up duration was 8.1 ± 4.5 years. The most frequent mode of discovery was nephrocalcinosis (4 cases), followed by nephritic colic (3 cases). Four patients were systematically screened due to affected siblings. The involvement is solely renal for all patients except patient 8, who had growth retardation at diagnosis.\u003c/p\u003e \u003cp\u003eMutations in NaPi2a and NaPi2c are characterized by disturbed calcium homeostasis secondary to high concentrations of 1,25(OH)2D due to hypophosphatemia from renal phosphate loss, leading to decreased FGF23 levels [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Subsequently, decreased FGF23 leads to increased 1,25(OH)2D through at least two direct mechanisms: reduced inhibition of 1-α hydroxylase and reduced stimulation of 24-hydroxylase. Elevated serum calcitriol stimulates intestinal absorption of phosphate and calcium, leading to decreased PTH and hypercalciuria, which promotes the development of nephrolithiasis and/or nephrocalcinosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDepending on the type of mutation (homozygous, heterozygous, compound heterozygous, missense, etc.) and the site of the mutation, the associated phenotype is highly variable, ranging from severe conditions such as IIH (SLC34A1, CYP24A1 encoding the vitamin D 24-hydroxylase enzyme) or HHRH (SLC34A3) to milder forms characterized by renal stones and/or osteoporosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e–\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. As of June 2, 2024, 77 different SLC34A1 mutations and 127 different SLC34A3 mutations are listed in the HGMD (Human Gene Mutation Database).\u003c/p\u003e \u003cp\u003eHHRH is an autosomal recessive disorder linked to a mutation in the SLC34A3 gene, characterized by severe rickets, growth retardation, skeletal deformities, muscle weakness, and bone pain. Acar et al. [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] identified pathogenic mutations (PHEX and SLC34A3) in 21 Turkish patients from 15 unrelated families with hereditary hypophosphatemia, showing clinical variability. Approximately 25% of individuals with homozygous or compound heterozygous SLC34A3 mutations do not present with rickets/osteomalacia, and 50% do not have nephrolithiasis or nephrocalcinosis. In our cohort of patients with a double heterozygous SLC34A3 mutation, 67% developed nephrocalcinosis, 50% had renal calculi, and 1/3 of the patients did not exhibit renal manifestations, confirming the variability in clinical presentations, which can be observed within the same family and for the same mutation, likely influenced by the timing of diagnosis and hygienic-dietary measures.\u003c/p\u003e \u003cp\u003eZhu et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] analysed clinical and biological records of 304 individuals (145 families) with an SLC34A3 mutation. The biological presentation of heterozygous carriers is characterized by decreased serum phosphate, reduced tubular phosphate reabsorption, normal FGF23 and PTH levels, but an increase in serum 1,25(OH)2D, leading to idiopathic hypercalciuria in 38%. Among our 6 patients with an SLC34A3 mutation, 3 patients from the same family showed mild hypophosphatemia during follow-up, necessitating oral phosphate supplementation in two of them. Conversely, we observed low PTH, hypercalciuria, and elevated 1,25(OH)2D levels in 83%, 100%, and 67% of the patients, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRegarding the SLC34A1 gene, the role of mutations in phosphate renal handling and renal function is not yet fully understood [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Biallelic mutations in CYP24A1 and SLC34A1 can cause severe forms of autosomal recessive IIH type 1 and 2, respectively, illustrating the links between vitamin D and phosphate metabolism. The milder form of IIH is often associated with heterozygous mutations in SLC34A1, frequently accompanied by a family history of kidney stones. However, although many IIH patients have mutations in CYP24A1 or SLC34A1, mutations in these two genes do not account for all IIH cases, indicating genetic heterogeneity [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrié et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] reported the cases of three patients with heterozygous missense mutations: p.Ala48Phe in one patient and p.Val147Met in the other two related patients. These cases showed low renal phosphate reabsorption (TmP/GFR \u0026lt; 0.7 mmol), hypercalciuria, and kidney stones. A second study described patients from a consanguineous Arab family carrying a homozygous 21 bp duplication (G154¬V160dup) in the SLC34A1 gene, who developed rickets, hypophosphatemia, hypercalciuria, and markedly elevated calcitriol levels [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Several other mutations have been discovered since improved access to genetics, with variable clinical and biological manifestations [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. More recently, two mutations in the SLC34A1 gene (p.Gly543Cys and p.Ile456Asn) were found in two young male patients presenting with hypophosphatemia, kidney stones, and/or osteopenia [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In our cohort, different heterozygous mutations of SLC34A1 were identified depending on the family [c.2727_292del (p.Val91_Ala97del) for family 4 and p.Val160Ala for family 5]. Nephrocalcinosis was found in 60% of our patients. Additionally, two patients developed renal calculi associated with nephrocalcinosis in one case. Only one case of growth retardation at the time of diagnosis was identified at 3 years of age, with a favorable outcome.\u003c/p\u003e \u003cp\u003eIIH remains a rare disorder with variable clinical and biochemical severity characterized by elevated serum concentrations of 1,25(OH)2D and low PTH levels. These patients may also exhibit hypercalciuria and alternate between chronic phases with normal calcium but inappropriate 1,25(OH)2D concentration and low PTH, and acute phases with hypercalcemia and suppressed PTH [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In our patient cohort, we found mild hypophosphatemia, low PTH, hypercalciuria, increased 1,25(OH)2D, and hypercalcemia at least once during follow-up in 20%, 40%, 80%, 80%, 60%, and 20% of patients, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIIH may present with mild to severe hypercalcemia during the first months of life [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], with severe cases exhibiting vomiting, dehydration, and nephrocalcinosis. Indeed, we also found that patients with an SLC34A1 mutation had an earlier onset than patients with an SLC34A3 mutation, with renal stones appearing as early as the first month of life in one patient and prenatal nephrocalcinosis detected in another. This early involvement was also reported by Molain et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] in the only patient in their cohort with an SLC34A1 mutation, who had hyperechoic kidneys prenatally.\u003c/p\u003e \u003cp\u003eAdditionally, Molain et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], in their study including 185 patients with PTH levels \u0026lt; 20 ng/L, hypercalcemia, and/or hypercalciuria, found biallelic mutations in CYP24A1 in 20 patients, SLC34A3 in 6 patients, and SLC34A1 in one patient, mainly associated with kidney disease (stones, nephrocalcinosis) in 86% of cases, indicating a broad phenotypic overlap. The serum 25(OH)D / 24,25(OH)2D ratio helps differentiate patients with an SLC34 mutation from those with a CYP24A1 mutation, as it is significantly higher in cases of CYP24A1 mutation [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Therefore, in cases of unexplained phosphocalcic metabolism disorders associated with renal manifestations of nephrocalcinosis and/or kidney stones, sequencing of at least these four genes (CYP24A1, SLC34A1, SLC34A3, and SLC9A3R1) seems judicious [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eManagement of patients with hypercalciuria secondary to SLC34 gene mutations typically relies on hydration and dietary advice, including a low-sodium diet with normal age-appropriate calcium intake. In cases of hypophosphatemia and abnormal bone mineralization, phosphate supplementation may be administered, at least during childhood [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. The response to oral phosphate supplementation depends on the genetic status [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Long-term supplementation appears to reverse clinical and biochemical abnormalities in HHRH [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eManagement of our patients relied on hydration and a low-sodium diet. Discontinuation of cholecalciferol supplementation was initiated for all patients initially and restarted if the 25(OH)D level was below 50 nmol/L, exclusively in the form of daily drops. Cholecalciferol ampoules were proscribed. During follow-up, four patients received potassium citrate due to low citraturia, and two patients received oral phosphate due to hypophosphatemia. No patient was treated with thiazides or azoles. The evolution was favorable for all patients, with no stunted growth and normal schooling. Regression of nephrocalcinosis images was noted in only one patient. Renal function remained normal in all patients. However, two patients still had hypercalciuria and increased 1,25(OH)2D.\u003c/p\u003e \u003cp\u003eMonitoring urinary calcium levels is critical in managing patients with nephrolithiasis/nephrocalcinosis associated with hypercalciuria and elevated 1,25(OH)2D levels. Normalizing and reducing urinary calcium can prevent and slow the progression of nephrocalcinosis/nephrolithiasis, thereby mitigating the risk of chronic kidney disease and bone complications in adulthood. However, standard interventions (low sodium intake, hydration, and potassium citrate) have limited impact on hypercalciuria [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. As a result, alternative strategies have been explored, including the use of hydrochlorothiazide, though its clinical benefit remains uncertain due to frequent side effects such as hypokalemia, asthenia, and potential long-term dermatologic lesions [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, azoles, particularly ketoconazole, have been employed to inhibit 1α-hydroxylase activity, thereby reducing 1,25(OH)2D levels and calciuria in patients with vitamin D hypersensitivity [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. However, this approach is associated with the risk of potential long-term hepatic toxicity [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Recently, fluconazole has demonstrated efficacy in reducing calciuria in certain patients with CYP24A1 or SLC34A3 mutations [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Consequently, a randomized trial named FLUCOLITH [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] is currently underway to evaluate the effectiveness of fluconazole in normalizing calciuria after 16 weeks of treatment.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eThe clinical and biological manifestations secondary to mutations in SLC34 genes exhibit considerable variability among patients, even within the same family; thus, management must be personalized. Hygienic and dietary measures, including adequate hydration, a low-sodium diet, and age-appropriate calcium intake, along with supplementation with phosphate or cholecalciferol drops based on 25(OH)D levels, lead to favorable outcomes in most cases. The use of azoles, such as fluconazole, appears to be a promising therapeutic option in cases of persistent hypercalciuria.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWagner CA, Hernando N, Forster IC, Biber J (2014) The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch 466:139-53. doi: 10.1007/s00424-013-1418-6. \u003c/li\u003e\n\u003cli\u003eKaneko I, Tatsumi S, Segawa H, Miyamoto KI (2017) Control of phosphate balance by the kidney and intestine. Clin Exp Nephrol 21(Suppl 1):21-26. doi: 10.1007/s10157-016-1359-4.\u003c/li\u003e\n\u003cli\u003eForster IC (2019) The molecular mechanism of SLC34 proteins: insights from two decades of transport assays and structure-function studies. 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Res 48: 300060519896146. doi: 10.1177/0300060519896146.\u003c/li\u003e\n\u003cli\u003eGiusti F, Marini F, Al-Alwani H, et al (2023) A Novel Heterozygous Mutation c.1627G\u0026gt;T (p.Gly543Cys) in the \u003cem\u003eSLC34A1\u003c/em\u003e Gene in a Male Patient with Recurrent Nephrolithiasis and Early Onset Osteopenia: A Case Report. Int J Mol Sci 24:17289. doi: 10.3390/ijms242417289.\u003c/li\u003e\n\u003cli\u003eFearn A, Allison B, Rice SJ, et al (2018) Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations. Physiol. Rep 6: e13715. doi: 10.14814/phy2.13715.\u003c/li\u003e\n\u003cli\u003eMolin A, Lemoine S, Kaufmann M, et al (2021) Overlapping Phenotypes Associated With \u003cem\u003eCYP24A1\u003c/em\u003e, \u003cem\u003eSLC34A1\u003c/em\u003e, and \u003cem\u003eSLC34A3\u003c/em\u003e Mutations: A Cohort Study of Patients With Hypersensitivity to Vitamin D. 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J Intern Med 282:322\u0026ndash;31. doi: 10.1111/joim.12629.\u003c/li\u003e\n\u003cli\u003eTebben PJ, Milliner DS, Horst RL, et al (2012) Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab 97: E423\u0026ndash;7. doi: 10.1210/jc.2011-1935.\u003c/li\u003e\n\u003cli\u003eNguyen M, Boutignon H, Mallet E, et al (2010) Infantile hypercalcemia and hypercalciuria: new insights into a vitamin D-dependent mechanism and response to ketoconazole treatment. J Pediatr 157:296\u0026ndash;302. doi: 10.1016/j.jpeds.2010.02.025\u003c/li\u003e\n\u003cli\u003eYoung J, Bertherat J, Vantyghem MC, et al Compassionalte use Programme (2018) Hepatic safety of ketoconazole in Cushing\u0026apos;s syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol 178:447-458. doi: 10.1530/EJE-17-0886.\u003c/li\u003e\n\u003cli\u003eSayers J, Hynes AM, Srivastava S, et al (2015) Successful treatment of hypercalcaemia associated with a CYP24A1 mutation with fluconazole. Clin Kidney J 8:453\u0026ndash;5. doi: 10.1093/ckj/sfv028.\u003c/li\u003e\n\u003cli\u003eBertholet-Thomas A, Tram N, Dubourg L, Lemoine S, Molin A, Bacchetta J (2019) Fluconazole as a new therapeutic tool to manage patients with NPTIIc (SLC34A3) Mutation: A Case Report. Am J Kidney Dis 73:886\u0026ndash;9. Doi: 10.1053/j.ajkd.2018.12.026.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Nephrocalcinosis, Nephrolithiasis, Hypercalciuria, Hypophosphatemia, 1,25-dihydroxyvitamin D, SLC34","lastPublishedDoi":"10.21203/rs.3.rs-4613671/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4613671/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMutations in SLC34A1 and SLC34A2 genes, which encode co-transporters NaPi2a and NaPi2c, respectively, can lead hypophosphatemia due to renal phosphate loss. This condition results in hypercalcitriolemia and hypercalciuria, leading formation of kidney stones and nephrocalcinosis. Phenotype is highly variable. Management include hyperhydration, dietary modifications, and/or phosphate supplementation. Thiazides and azoles may be used, but randomized studies are needed to confirm their clinical efficacy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective study in pediatric nephrology unit at Grenoble University Hospital from January 2010 to December 2023. Study aimed to describe clinical and biological symptoms of patients with confirmed SLC34A1 and SLC34A3 gene mutations and their outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 11 patients (9 females) from 6 different families had mutations in the SLC34A1 (5 patients) and SLC34A3 (6 patients) genes. Median age at diagnosis was 72 [1-108] months. Average follow-up duration was 8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5 years. Presenting symptom was nephrocalcinosis (4 cases), followed by renal colic (3 cases). At diagnosis, 90% of patients had hypercalciuria and 45% had hypercalcitriolemia. Management included hyperhydration and dietary advice. All patients showed favorable outcomes with normal growth and school attendance. One patient with an SLC34A3 mutation showed regression of nephrocalcinosis. Renal function remained normal.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eClinical and biological manifestations of SLC34 gene mutations are highly variable, even among siblings; therefore, management must be personalized. Hygienic-dietary measures (such as hyperhydration, a low sodium diet, and age-appropriate calcium intake) result in favorable outcomes in most cases. Use of azoles (e.g., fluconazole) appears to be a promising therapeutic option.\u003c/p\u003e","manuscriptTitle":"SLC34 mutation: Personal experience with six families and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 16:00:53","doi":"10.21203/rs.3.rs-4613671/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2024-07-08T11:59:52+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-06-21T02:40:36+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-20T23:43:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-20T21:43:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2024-06-20T16:01:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ce927a06-b69a-4f52-bc07-4c0a63a427f7","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-16T16:01:32+00:00","versionOfRecord":{"articleIdentity":"rs-4613671","link":"https://doi.org/10.1007/s00467-024-06505-3","journal":{"identity":"pediatric-nephrology","isVorOnly":false,"title":"Pediatric Nephrology"},"publishedOn":"2024-09-10 15:57:24","publishedOnDateReadable":"September 10th, 2024"},"versionCreatedAt":"2024-07-18 16:00:53","video":"","vorDoi":"10.1007/s00467-024-06505-3","vorDoiUrl":"https://doi.org/10.1007/s00467-024-06505-3","workflowStages":[]},"version":"v1","identity":"rs-4613671","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4613671","identity":"rs-4613671","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}