Primary Renal Fanconi Syndromes and Fanconi-Bickel Syndrome

Inherited generalised proximal tubulopathies of monogenic cause: renotubular Fanconi syndromes types 1 to 5 (GATM, SLC34A1, EHHADH, HNF4A, NDUFAF6) and Fanconi-Bickel syndrome (SLC2A2), with the approach to renal Fanconi syndrome in children and adults

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

Renal Fanconi syndrome denotes generalised dysfunction of the proximal convoluted tubule, with urinary loss of glucose despite normal blood glucose, of amino acids, phosphate, bicarbonate, urate and low-molecular-weight proteins [1]. The class covered in this article brings together the primary forms, in which the tubulopathy is the dominant manifestation rather than the consequence of a systemic storage disorder, and Fanconi-Bickel syndrome, which combines the tubulopathy with hepatic glycogen storage. The table summarises the entities; the differential diagnoses are given in section 6.

Sources for the table: OMIM, Orphanet and inheritance [2–12]; gene–disease validity [13]; patient numbers and ages [1, 14–17]; ERN [18, 19].

1. Introduction

1.1 Renal Fanconi syndrome as a class phenotype

The proximal convoluted tubule reabsorbs most of the glomerular filtrate: glucose, amino acids, phosphate, bicarbonate, urate, water and low-molecular-weight proteins taken up by endocytosis. When this function fails in a generalised way, renal Fanconi syndrome results, also known by the eponyms of De Toni, Debré and Fanconi, which the review by Albuquerque and colleagues calls Fanconi-Debré-de Toni syndrome [8, 20]. The causes are divided into acquired (drugs, heavy metals, monoclonal light chains, tubulointerstitial nephritis, Sjögren syndrome) and inherited; among the latter, the secondary forms result from systemic disorders that compromise the energy supply or endocytosis of the tubule, such as cystinosis, Lowe syndrome, Dent disease, galactosaemia, tyrosinaemia type 1, hereditary fructose intolerance, Wilson disease and mitochondrial disorders [1, 20, 21]. Cystinosis is the most frequent inherited cause of renal Fanconi syndrome in young children and should always be considered [22].

The primary forms, in which the tubulopathy is the dominant manifestation and there is no systemic accumulation of metabolites, have acquired a partial molecular basis over the last decade. The OMIM nomenclature and that of the 2026 Japanese review recognise five types: type 1 due to GATM (autosomal dominant), type 2 due to SLC34A1 (autosomal recessive), type 3 due to EHHADH (autosomal dominant), type 4 due to HNF4A (autosomal dominant) and type 5 due to NDUFAF6 (autosomal recessive), together with an idiopathic fraction with no known gene [1]. Fanconi-Bickel syndrome, due to deficiency of the glucose transporter GLUT2, is covered in the same class because it is a primary generalised proximal tubulopathy of the epithelium, although its hepatic picture brings it close to the glycogen storage diseases [17, 23].

1.2 Historical milestones and molecular discovery

Fanconi-Bickel syndrome was described by Fanconi and Bickel in 1949 in a Swiss boy with tubular nephropathy and hepatic glycogen storage [24]. For decades no enzymatic defect of carbohydrate metabolism was found; since the utilisation of glucose and galactose was impaired simultaneously, a primary defect of membrane transport was postulated. In 1997, Santer and colleagues identified homozygous mutations in the gene for the facilitative transporter GLUT2 in three families, including the original 1949 patient, with heterozygous parents and protein-truncating variants [25]. The same group's 2002 review consolidated the clinical picture and the absence of specific therapy [26], and the designation glycogen storage disease "type XI", used by some authors, does not correspond to the current OMIM numbering [27].

Type 3 was the first primary type with an identified gene. In 2014, Klootwijk and colleagues studied a five-generation Black family with dominantly transmitted isolated Fanconi syndrome, mapped the locus to 3q27 and identified the heterozygous variant NM_001966.4:c.7G>A p.(Glu3Lys) in the peroxisomal enzyme EHHADH, which creates a mitochondrial targeting signal; the mislocalised protein impairs oxidative phosphorylation in the proximal tubule [28]. In 2010, Magen and colleagues had described two siblings from a consanguineous family with recessive Fanconi syndrome and hypophosphataemic rickets, carrying a homozygous 21-base-pair in-frame duplication in SLC34A1 that prevented the NaPi-IIa cotransporter from reaching the membrane [29]; this family gave rise to type 2. In 2014, Hamilton and colleagues showed that a single HNF4A variant, historically designated R76W (historical numbering, = NM_175914.5:c.187C>T p.(Arg63Trp)), causes an atypical Fanconi syndrome with nephrocalcinosis alongside the beta-cell phenotype already known for the gene [14]. In 2016, Hartmannová and colleagues solved the Acadian variant, a tubulopathy with chronic kidney disease and pulmonary fibrosis specific to a founder population of Nova Scotia, by identifying a deep intronic variant in NDUFAF6, an assembly factor of mitochondrial complex I [30]. In 2018, Reichold and colleagues mapped a dominant form of Fanconi syndrome with kidney failure to 15q and identified heterozygous missense variants in GATM that cause fibrillar aggregation of the protein inside mitochondria [31].

Before molecular genetics, the inherited forms without cystinosis were known by designations such as adult Fanconi syndrome, Fanconi syndrome without cystinosis or Luder-Sheldon syndrome, and OMIM historically groups them under the FRTS1 entry [2]. Luder and Sheldon described in 1955 twin girls with a defect of glucose, amino acid and phosphate reabsorption, whose father and grandfather were mildly affected, and follow-up showed kidney failure in three members; dominant families with adult-onset osteomalacia followed, such as that of Smith and colleagues (1976) and the family originally studied by Dent and Harris, as well as Wisconsin families with early kidney failure, in one of which Lichter-Konecki and colleagues mapped the disease to 15q15.3 in 2001 [2]. Several of these families were included in the 2018 Reichold series [2, 31]. The FRTS3 family had been described by Tolaymat and colleagues in 1992 as an African American family with eight affected members over four generations, including male-to-male transmission [4]. The two FRTS2 siblings, from a consanguineous Arab family, had been described by Tieder and colleagues in 1988 with severe rickets, hypercalciuria and raised 1,25-dihydroxyvitamin D [3]. FRTS5 had been characterised clinically by Crocker and colleagues in 1997 in 13 Acadian families [6]. As for Fanconi-Bickel syndrome, Manz and colleagues introduced the eponym in 1987 when comparing nine patients and postulated a defect of the facilitative glucose and galactose transporter; the designation "glycogen storage disease type XI", proposed by Hug in the same year on the basis of a supposed phosphoglucomutase deficiency, is discouraged by OMIM because the glycogen accumulation is secondary to the transport defect [7]. The original 1949 patient was homozygous for p.Arg301Ter (= NM_000340.2:c.901C>T p.(Arg301Ter)) [7, 32].

1.3 Reclassifications and validity of the associations

The robustness of these associations is uneven, and the article presents it explicitly. For FRTS1, the ClinGen tubulopathy panel classified the GATM–FRTS1 relationship as moderate in February 2026, with eight missense variants in at least ten probands from six publications [13]. For FRTS2, the same panel considered the SLC34A1–FRTS2 relationship disputed in 2022 and maintained the classification in December 2025, because there is still a single variant in a single proband and no additional experimental evidence; the panel separated FRTS2 from infantile hypercalcaemia type 2, which is a definitive association of the same gene [12, 13]. In 2012, Mannstadt and colleagues showed, in other consanguineous families, that homozygous SLC2A2 variants can produce a recessive proximal tubulopathy with hypercalciuria and variable phosphaturia without the classic hepatic picture, which they called ARPTH, and concluded that this and Fanconi-Bickel syndrome are allelic variants [33]. For FRTS3, the peroxisomal disorders panel classified the relationship as limited in March 2026, with the same p.Glu3Lys variant in five probands [13]. FRTS4 has no specific ClinGen curation; type 5 rests on a founder variant segregating in nine patients and thirteen healthy siblings [30].

1.4 Definition of the entities

In this article, FRTS denotes inherited primary renotubular Fanconi syndrome, operationally defined as low-molecular-weight proteinuria accompanied by at least one of generalised aminoaciduria, glycosuria, hypophosphataemia, metabolic acidosis or hyperuricosuria, in the absence of an acquired cause, toxic exposure or a systemic disorder that would explain it [1]. Fanconi-Bickel syndrome is defined by the combination of hepatic glycogen storage, generalised proximal tubulopathy with disproportionately severe glycosuria and intolerance to glucose and galactose, confirmed by biallelic SLC2A2 variants [17, 26]. Recessive AGAT deficiency, caused by biallelic loss of function of the same GATM gene, is a cerebral creatine disorder without renal involvement [31, 34].

2. Molecular Genetics and Pathophysiology

2.1 Common principle: energy and trafficking in the proximal tubule

Reabsorptive transport in the proximal tubule depends on the sodium gradient created by the basolateral Na+/K+-ATPase, which consumes ATP produced mainly by oxidative phosphorylation. Three of the five primary types converge at this point: in FRTS1 the GATM protein aggregates inside mitochondria, in FRTS3 mislocalised EHHADH interferes with mitochondrial β-oxidation and with complex I, and in FRTS5 the mitochondrial isoform of a complex I assembly factor is missing [28, 30, 31]. FRTS3 was described by its authors as proof of the central role of mitochondria in proximal tubular function [28]. In Fanconi-Bickel syndrome the mechanism is different: glucose reabsorbed at the apical membrane does not exit across the basolateral membrane, accumulates with glycogen inside the cell and compromises the other transport processes [17, 35]. In FRTS4 the defect is transcriptional and the renal target remains unknown [14].

2.2 FRTS1: GATM, intramitochondrial fibrillar aggregation

GATM (15q21.1; MANE transcript NM_001482.3) encodes L-arginine:glycine amidinotransferase (AGAT), a mitochondrial enzyme that transfers the amidino group of arginine to glycine to form guanidinoacetate, the first step in creatine synthesis; it is expressed mainly in the kidney, liver, pancreas and brain [12, 31]. Biallelic loss of function causes AGAT deficiency, a cerebral creatine disorder with a normal kidney, and the Gatm-/- mouse has normal renal function [31, 34]. FRTS1 results from a distinct mechanism: heterozygous missense variants in a restricted region of the protein, roughly between residues 290 and 350, create a new interaction surface that leads to linear polymerisation of the enzyme and to fibrillar deposits inside enlarged and elongated mitochondria [13, 31]. These mitochondria produce more reactive oxygen species, activate the NLRP3 inflammasome, and increase expression of the profibrotic cytokine IL-18 and cell death; in LLC-PK1 cells, the p.Thr336Ala mutant increases transcription of fibronectin and smooth muscle actin [31]. ClinGen classifies the mechanism as gain of function [13]. In one patient studied, brain magnetic resonance spectroscopy showed a normal creatine peak, which separates FRTS1 from creatine deficiency [31].

The four variants in the original description were, in NM_001482.3, c.958C>T p.(Pro320Ser), c.1006A>G p.(Thr336Ala), c.1007C>T p.(Thr336Ile) and c.1022C>T p.(Pro341Leu) [31, 32]. The 2026 Japanese series added c.802C>G p.(Gln268Glu), c.958C>A p.(Pro320Thr), c.888T>A p.(Phe296Leu), c.1079T>A p.(Met360Lys), c.484G>A p.(Gly162Ser), the latter de novo, and the intronic variant c.288+8A>T, which in a minigene assay produces an in-frame six-nucleotide insertion, p.(Gly97_Arg98insValLys) [1]. The p.(Gln268Glu) variant lies outside the β-sheet in which the classic variants cluster; molecular dynamics simulations suggest that it increases the conformational flexibility of the intermediate region and favours polymerisation [36]. In ClinVar, p.(Pro320Ser) is listed as pathogenic with no assertion criteria and p.(Thr336Ala), p.(Thr336Ile) and p.(Pro341Leu) as of uncertain significance by an expert panel; these classifications coexist with complete segregation in the original families and should be read with the source and context of each submission [31, 32]. In each family of the original description, a variant segregated with complete penetrance and no unaffected relative was a carrier; in one family the variant arose de novo and was transmitted to the next generation [31]. In wild-type mice, 1% creatine in drinking water for one week reduced renal GATM mRNA by 27% and protein by 58%, through negative feedback on creatine synthesis [31].

2.3 FRTS2: SLC34A1 and the disputed association

SLC34A1 (5q35.3; MANE NM_003052.5) encodes NaPi-IIa, the main sodium-phosphate cotransporter of the proximal tubule brush border, electrogenic with 3:1 stoichiometry [12]. The homozygous 21-base-pair duplication in the Magen family abolished transporter function, as the protein did not reach the plasma membrane in Xenopus oocytes or in opossum kidney cells [29]. The gene has two more solid associations: infantile hypercalcaemia type 2 (OMIM 616963), autosomal recessive and definitive in ClinGen, in which renal phosphate loss suppresses FGF23, disinhibits 1α-hydroxylase and raises 1,25-dihydroxyvitamin D with hypercalcaemia and suppressed PTH; and hypophosphataemic nephrolithiasis or osteoporosis type 1 (OMIM 612286), autosomal dominant, based on heterozygous variants in 2 of 20 patients with stones or demineralisation and hypophosphataemia [12, 13, 37, 38]. For FRTS2, ClinGen assigned 0.5 of 12 points of genetic evidence and 0.5 of 6 of experimental evidence, and concluded that no valid evidence remains to support the association [13]. In practice, a generalised proximal tubulopathy with biallelic SLC34A1 variants requires exclusion of other causes, including SLC2A2, which Mannstadt and colleagues showed can cause tubulopathy with hypercalciuria and phosphaturia without a hepatic picture [33].

2.4 FRTS3: EHHADH, a peroxisomal protein in the wrong organelle

EHHADH (3q27.2; MANE NM_001966.4) encodes the peroxisomal L-bifunctional enzyme, with 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and isomerase activities, involved in β-oxidation of long-chain and dicarboxylic fatty acids and expressed in the proximal tubule [12]. The only known variant, NM_001966.4:c.7G>A p.(Glu3Lys), creates an N-terminal mitochondrial targeting motif; the protein enters mitochondria, is incorporated into the mitochondrial trifunctional protein, disturbs long-chain fatty acid oxidation, limits formation of complex I and of supercomplexes, reduces membrane potential and ATP and, consequently, Na+/K+-ATPase activity [12, 28, 32]. The Ehhadh knockout mouse has normal tubular cells, which indicates a dominant negative effect rather than haploinsufficiency [28]. EHHADH does not cause Zellweger syndrome or a peroxisome biogenesis disorder, and D-bifunctional protein deficiency belongs to the HSD17B4 gene; Orphanet entry 300 "Bifunctional enzyme deficiency" (OMIM 261515) refers to that other disease [8, 12]. In ClinVar, the variant is classified as likely pathogenic by one submitter [32].

2.5 FRTS4: HNF4A and a variant-specific phenotype

HNF4A (20q13.12) encodes the nuclear receptor HNF4α, a transcription factor for the hepatic, pancreatic, renal and intestinal programmes [12]. Heterozygous loss of function produces a biphasic phenotype: excess insulin secretion in the fetus and newborn, with a median increase in birth weight of about 790 g compared with non-carrier relatives, macrosomia in 56% of carriers and transient hyperinsulinaemic hypoglycaemia in 8 of 54 carrier infants versus none of 54 non-carriers; later, beta-cell failure and MODY1-type diabetes [14, 39]. In the history taken for monogenic diabetes, the median birth weight of carriers of HNF4A variants is 4.3 kg, versus 3 kg in those with GCK and 2.6 kg in those with HNF1B [40]. ISPAD reports macrosomia in about 50% of carriers and diazoxide-responsive neonatal hypoglycaemia in 15% [41]. FRTS4 is variant-specific: NM_175914.5:c.187C>T p.(Arg63Trp) in the MANE Select transcript, which corresponds to NM_000457.5:c.253C>T p.(Arg85Trp) and to the historical designation p.R76W with c.226C>T in the Chartier cDNA sequence; ClinVar classifies it as pathogenic by an expert panel [1, 14, 32, 42]. The residue lies in the DNA-binding domain and directly contacts the DR1 response element; modelling shows differences in charge and hydrophobicity at the interface, but the dysregulated renal target is unknown, and the renal phenotype did not occur in 20 patients with other HNF4A variants [14]. In the index family, the variant arose in the maternal grandfather, a germline and somatic mosaic with 26% of the mutant allele in leucocytes, without neonatal hypoglycaemia or Fanconi syndrome and with diabetes at 51 years [14]. HNF1A and HNF4A variants can also downregulate GLUT2 and produce Fanconi-Bickel features [43].

2.6 FRTS5: NDUFAF6 and the Acadian variant

NDUFAF6 (8q22.1; MANE NM_152416.4) encodes an early assembly factor of complex I, required for biogenesis of the MT-ND1 subunit [12]. The nine Acadian patients were homozygous for the ultra-rare intronic variant NM_152416.4:c.298-768T>C (rs575462405; chr8:96046914T>C in GRCh37), located 37 base pairs upstream of the alternative splicing variant c.298-731A>G (rs74395342); thirteen healthy siblings were heterozygous or non-carriers [30, 42]. The variant, alone or combined with rs74395342, alters splicing and isoform synthesis; the affected kidney and lung specifically lose the mitochondrial isoform, and the respiration and complex I biogenesis defects are corrected by cDNA transfection [30]. In patient fibroblasts there is reduced complex I activity, membrane potential and respiration, with raised markers of oxidative damage to DNA, lipids and proteins [12, 44]. The variant creates a new splice acceptor site and was found once among 104 individuals from a Puerto Rican sample of the 1000 Genomes Project [6]. In ClinVar the variant has conflicting classifications [32]. Because it is deep intronic, it is not detected by panels limited to coding regions and exon–intron junctions. Biallelic coding variants of NDUFAF6 cause a different phenotype, the Leigh spectrum with complex I deficiency (less than 5% of Leigh syndrome of nuclear cause, with dystonia and, in some patients, survival to young adulthood) [45].

2.7 Fanconi-Bickel syndrome: SLC2A2 and GLUT2

SLC2A2 (3q26.2; MANE NM_000340.2) has 11 exons and encodes GLUT2, a 524-amino-acid protein with 55% identity to GLUT1 [17, 42]. GLUT2 is a facilitative transporter with a high Michaelis constant (low affinity) for glucose and galactose, expressed in hepatocytes, at the basolateral membrane of reabsorptive cells of the proximal tubule and of enterocytes, and in the beta cell; in humans, the main facilitative transporter of the beta cell is GLUT1 and the rate-limiting step in glucose sensing is glucokinase [17]. In the hepatocyte, deficient GLUT2 functions as a faulty glucose sensor: during fasting, intracellular glucose and glucose-6-phosphate remain inappropriately high, which stimulates glycogen synthesis and inhibits gluconeogenesis and glycogenolysis, with fasting hypoglycaemia and glycogen storage; in the fed state, reduced hepatic uptake explains postprandial hyperglycaemia and hypergalactosaemia [17]. Intestinal absorption is maintained by alternative pathways (apical SGLT1 and a basolateral vesicular pathway) [17]. In the tubule, glucose and glycogen accumulate in the cells; in a mouse model with renal ablation of GLUT2, suppression of the transporter impaired lysosomal autophagy, an effect reversed by low glucose, which points to intracellular glucose toxicity [35]. Massive glycosuria, even with low blood glucose, aggravates hypoglycaemia and dehydration [17]. The contribution of reduced insulin secretion to hyperglycaemia remains controversial, but SLC2A2 variants cause neonatal diabetes, more often transient than permanent, and account for less than 1% of permanent neonatal diabetes [17, 46, 47].

More than 100 variants scattered throughout the gene have been described, and more than 70% of cases come from consanguineous families [17]. The genotype–phenotype correlation rests on oocyte assays: variants without function give the complete picture, whereas variants with residual activity give mild forms, down to isolated glycosuria. In the Hamburg series of 93 patients, the two-amino-acid deletion p.153_154delLI (published designation, = NP_000331.1:p.(Leu153_Ile154del); the nucleotide change is not given in the source) retained membrane expression and 5.8% of transport, and p.Val197Ile (= NM_000340.2:c.589G>A p.(Val197Ile)), the first GLUT2 variant identified, retained 8% [48]. In the Chinese series of 11 patients, biallelic missense variants were associated with milder metabolic acidosis than null variants; the p.Leu406Arg variant accounted for 18% of alleles, and two of five patients from non-consanguineous families had runs of homozygosity of 5.3 and 36.6 Mb, one of them covering the whole of chromosome 3, consistent with uniparental disomy [49]. The Palestinian cohort of 20 patients revealed the novel variants NM_000340.2:c.68A>G p.(Gln23Arg), NM_000340.2:c.1058_1059delinsGG p.(Thr353Arg) and an exon 7 deletion [50]. The 26-base-pair insertion and a complex rearrangement described in patients with Fanconi-Bickel syndrome are detectable by sequencing, but an exon deletion requires copy number analysis [46, 50]. The OMIM annotation of susceptibility to type 2 diabetes at the same locus is multifactorial and does not constitute another Mendelian disease [12].

2.8 Table of genes, mechanisms and allelic disorders

Sources: [1, 14, 17, 28–31, 33, 37, 46, 49].

3. Clinical Spectrum and Manifestations by System

3.1 Common manifestations of the proximal tubulopathy

Tubular loss of water, sodium and potassium produces polyuria, polydipsia, recurrent dehydration, hypokalaemia and febrile episodes attributed to dehydration; bicarbonate loss causes hyperchloraemic metabolic acidosis; phosphate loss and reduced calcitriol synthesis cause hypophosphataemic rickets in children and osteomalacia in adults; carnitine loss can deplete muscle [22, 51]. The proteinuria is tubular, of low molecular weight, without nephrotic syndrome [1]. These manifestations are common to the primary and secondary forms; what distinguishes the types is their intensity, the presence of extrarenal manifestations and the course of glomerular filtration. The following table separates what is natural history described in the series, mostly of patients already on replacement, from what is the course under treatment.

Sources: [1, 14, 15, 17, 24, 30, 31, 49, 52, 53].

3.2 FRTS1 (GATM)

In the five families of the original description, all affected individuals developed in childhood a Fanconi syndrome with glycosuria, hyperphosphaturia, generalised hyperaminoaciduria, low-molecular-weight proteinuria and metabolic acidosis, without debilitating rickets or bone deformities; the youngest child studied, at 18 months, had Fanconi syndrome without glomerular involvement [31]. In late adolescence or adulthood a rise in creatinine with renal fibrosis appeared, and dialysis or transplantation was required between the third and sixth decades; there were premature deaths from kidney failure in several families and no extrarenal findings [31]. Biopsy shows greatly enlarged mitochondria of the proximal epithelium filled with filamentous GATM deposits [31].

The 2026 Japanese series added seven patients to 35 already published. Age at onset ranged from 0.9 to 36 years; three patients with rickets or poor weight gain were diagnosed before 2 years of age, and the others were detected at school age or in adulthood through proteinuria, glycosuria or renal dysfunction on routine tests [1]. The phenotype was often incomplete: metabolic acidosis was absent in three of seven and hypophosphataemia in two of seven, although almost all published patients had them. Rickets occurred in about 20% of the combined series, including severe vitamin D-resistant forms; short stature in 8 of 11 published; nephrocalcinosis in four of six published; multiple fractures in two of eight; hypercalciuria in four of four; proteinuria never reached the nephrotic range (0/15) and there was no haematuria (0/5) or intellectual disability (0/35) [1]. In one patient with stage 4 chronic kidney disease, biopsy showed focal global glomerulosclerosis and interstitial fibrosis. Median renal survival, in 41 patients, was 51.9 years (95% confidence interval 46 to 66 years), with variable rates of decline even within the same family [1]. In the Indian cohort from Mumbai, one family with FRTS1 maintained renal function into the sixth decade [54]. These series result from ascertainment by nephrology centres and school urine screening, and do not represent the general population of carriers.

3.3 FRTS2 (SLC34A1)

The two siblings of the family described in 2010 had recessive Fanconi syndrome with hypophosphataemic rickets [29]. No other patients with this phenotype have been described [13]. The well-established phenotype of the gene is infantile hypercalcaemia type 2: in the first months, severe PTH-independent hypercalcaemia, hypercalciuria, failure to thrive, vomiting, dehydration and nephrocalcinosis against a background of renal phosphate loss, with phases of normal calcium and raised 1,25-dihydroxyvitamin D alternating with hypercalcaemic phases; it may present prenatally with normal-sized hyperechogenic kidneys and may manifest later through stones or nephrocalcinosis [12, 37, 55]. In 18 survivors of infantile hypercalcaemia due to CYP24A1 or SLC34A1, followed to a mean age of 24 years, there was nephrocalcinosis in 16 (88%), glomerular filtration rate below 90 mL/min/1.73 m² in 14 (77%) and below 60 in 5 (28%) [56]. This allelic disorder is part of the differential in section 6.

In the FRTS2 family, treated with neutral phosphate in 1988, bone pain, muscle strength and radiological signs of rickets improved and calciuria and 1,25-dihydroxyvitamin D normalised, but glomerular filtration, urate and losses of glucose, proteins and amino acids did not change; twenty years later, the two siblings had generalised tubulopathy, renal phosphate wasting, bone mineral deficit, reduced glomerular filtration, normocalciuria and vitamin D deficiency; the mother and a healthy sibling were heterozygous and the duplication was absent in 100 controls of the same origin [3].

3.4 FRTS3 (EHHADH)

In the original family, followed since the 1992 description, affected members had growth retardation and rickets with femoral deformities, bowed limbs and loss of bone density from childhood; not all had complete Fanconi syndrome, none developed diabetes or kidney failure, and the matriarch, with normal function at 58 years, had mild impairment at 74 [4]. The original family had dominantly transmitted isolated Fanconi syndrome over five generations [28]. The spectrum widened with a boy followed from 4 months to 12 years, who presented at 4 months with hypoglycaemia, ketonuria, lactic acidosis and hepatocellular injury; three months later Fanconi tubulopathy and nephrocalcinosis appeared, and hepatocytes showed reduced activity and quantity of respiratory chain complexes I and IV [52]. The father, a carrier of the same variant, was asymptomatic at 54 years, which documents incomplete penetrance [52]. In the Japanese series, a girl referred at 4 years after mild proteinuria on the 3-year screening had urinary β2-microglobulin of 85,520 µg/L and hypercalciuria, with normal renal function and biopsy; glycosuria appeared during follow-up and, at 28 years, she still had tubular proteinuria and hypercalciuria with an estimated filtration rate of 76.3 mL/min/1.73 m²; her father, a carrier, had similar proteinuria and mild impairment [1]. In the Indian cohort, one FRTS3 family had enthesopathy [54].

3.5 FRTS4 (HNF4A p.Arg63Trp)

The phenotype combines three components. In the neonatal period, macrosomia and diazoxide-responsive hyperinsulinism; in childhood, a Fanconi syndrome with intense low-molecular-weight proteinuria, aminoaciduria (mean urinary amino acid Z-score of 22.9 versus 0.2 in carriers of other variants), glycosuria, phosphaturia and hypouricaemia, with unusual features — nephrocalcinosis in all carriers, hypercalciuria with relative hypocalcaemia, hyperoxaluria and hypermagnesaemia — and without significant acidosis; and, from adolescence, MODY-type diabetes in some carriers [14, 41]. The first patient described, by Stanescu and colleagues in 2012, was a girl with a de novo variant, macrosomia and severe hyperinsulinaemic hypoglycaemia in the first hours of life, whose therapy was reduced over the years until it was stopped at 4 years; at one year of age she had rickets, raised alkaline phosphatase, hypophosphataemia, glycosuria, proteinuria and metabolic acidosis, as well as hepatomegaly with raised transaminases and abundant glycogen on liver biopsy, a picture reminiscent of Fanconi-Bickel syndrome [5]. In the index family, two sisters were diagnosed with Fanconi syndrome because of short stature and rickets after negative hypophosphataemic rickets panels, and one of them had a macrosomic son with neonatal hyperinsulinism treated with diazoxide [14]. The six carriers had renal impairment with a median creatinine of 114 µmol/L [14]. Of the three additional patients in the series, two developed diabetes at 20 and 12 years [5]. One patient described outside that series also had hepatomegaly with raised transaminases at 3 months and abundant glycogen on liver biopsy [14]. In the Japanese series, a boy with proteinuria detected at 3 years had, at 14 years, short stature, nephrocalcinosis and an estimated filtration rate of about 60 mL/min/1.73 m², stable at 18 years [1]. The authors suggest that glycosuria may delay diabetes, by analogy with SGLT2 inhibitors, without data to demonstrate it [14].

3.6 FRTS5 (Acadian variant, NDUFAF6)

The Acadian variant manifests from birth as a generalised proximal tubulopathy, followed by slowly progressive chronic kidney disease which, unlike typical Fanconi syndrome, progresses to kidney failure, and interstitial pulmonary fibrosis appears [30]. In the Crocker series (13 families), most patients presented between 3 and 10 years of age with genu valgum and growth retardation, all below −2 standard deviations in height and with progressive renal impairment in adolescence [6]. Wornell and colleagues described 19 Acadian patients with a mean age at presentation of 8.5 years, almost always with genu valgum due to hypophosphataemic rickets; rickets improved with alkali, phosphate and vitamin D, there was no hypokalaemia, half had chronic kidney disease at 13 years, almost all had proteinuria at 15 years and seven had hypertension [6]. In the Hartmannová series (12 patients from 7 families), 11 reached end-stage kidney disease and 8 were transplanted between 18 and 38 years of age; all had lung disease, diagnosed between 19 and 50 years — chronic interstitial fibrosis, reduced carbon monoxide diffusing capacity, bullous or centrilobular emphysema and pulmonary microlithiasis — and one patient had lung adenocarcinoma at 37 years [6]. In the 2026 Canadian series, four patients were diagnosed clinically between 8 and about 14 years, with hypophosphataemic rickets, severe bilateral genu valgum, tubular acidosis, normoglycaemic glycosuria, aminoaciduria, hypercalciuria or intermittent phosphaturia and chronic kidney disease; biopsy in one of them, at 14 years, showed chronic tubulointerstitial nephritis with normocellular glomeruli [15]. At the authors' institution, patients started kidney replacement therapy at a mean age of 30 years, and the mean loss of filtration before any intervention was 3.74 mL/min/1.73 m² per year [15]. Unlike the Leigh spectrum due to coding variants of the same gene, the Acadian variant has no neurological disease in the sources consulted [12, 45].

3.7 Fanconi-Bickel syndrome

The patient described by Fanconi and Bickel in 1949 was the son of consanguineous parents from a remote valley in the Swiss Alps; at 6 months he had failure to thrive, polydipsia and constipation, and at 2.7 and 3.7 years short stature of −6 standard deviations, a protuberant abdomen, marked hepatomegaly, facial obesity and generalised osteopenia; glycosuria was 10 to 30 g per day, up to 60 g, with constant hypophosphataemia, hyperaminoaciduria, fasting hypoglycaemia and ketonuria and postprandial hyperglycaemia; he was followed for more than 50 years [7]. In the series of Manz and colleagues (1987), with nine patients followed for 2 to 25 years, the first symptoms were fever, vomiting, failure to thrive and rickets between 3 and 10 months; glycosuria ranged from 40 to 200 g per 1.73 m² per day, with glucose clearance between 0.59 and 1.0 of inulin clearance regardless of blood glucose; glomerular filtration was normal or low-normal, without progression to glomerular failure; fractures and pancreatitis occurred as complications [7]. A family with reduced hepatic phosphorylase kinase activity, interpreted as another cause, turned out to have a homozygous GLUT2 variant, p.Pro417Leu (= NM_000340.2:c.1250C>T p.(Pro417Leu)); the reduction in phosphorylase kinase was secondary [7]. In Japanese families, heterozygotes for missense variants had glycosuria, which was not the case for a heterozygote for a nonsense variant [7].

Typical presentation occurs between 3 and 10 months, with hepatomegaly, Fanconi-type nephropathy with severe glycosuria, a tendency to fasting hypoglycaemia and intolerance to glucose and galactose in the fed state [17]. Hepatomegaly may be absent at first, and non-specific symptoms then predominate — fever, vomiting, chronic diarrhoea, tubular acidosis and failure to thrive [17]. With age, the protuberant abdomen, moon face and short stature bring the phenotype close to that of the other hepatic glycogen storage diseases; the kidneys enlarge through glycogen accumulation [17]. Hypophosphataemic rickets is the main bone consequence, with joint swelling, bowing of the limbs and pathological fractures; cognitive development is normal, but growth and puberty are severely delayed [17]. Patients have hyperlipidaemia and hyperuricaemia as in glycogen storage disease type I [27].

Recent series quantify this picture in populations with high consanguinity. In 11 Chinese children, hepatomegaly and short stature were initial symptoms in 10 and rickets in 7; all had low fasting blood glucose, bicarbonate and phosphorus and raised transaminases and alkaline phosphatase, and two were initially classified as transient neonatal diabetes [49]. In 11 Sudanese children from 10 families, consanguinity was 70%, mean weight and height at presentation were −5.3 and −5.4 standard deviations, 27% had severe chest deformity, all had rickets, three had insulin-treated neonatal diabetes and six families had lost undiagnosed siblings with a similar picture [24]. In 20 Palestinian patients, hepatomegaly occurred in 95%, developmental delay and rickets in 70%, failure to thrive in 68.4%, hypophosphataemia in 95% and hypertriglyceridaemia in all [50]. In a multicentre series of 11 patients, severity divided into a group with severe growth retardation and rickets and a group with mild signs, and all had massive glycosuria at diagnosis [57].

There are mild and atypical phenotypes. In the Hamburg series, five of 93 patients had an exceptionally mild course, some with glycosuria only [48]. An adolescent girl followed in Portugal with persistent glycosuria and short stature had proteinuria, aminoaciduria, hypercalciuria and hypouricaemia, and the variants NM_000340.2:c.218C>G p.(Ser73*) and NM_000340.2:c.371+5G>A, probably in trans; she was asymptomatic and was treated with vitamin D and dietary adjustments [58]. The ARPTH described by Mannstadt manifests as tubulopathy with hypercalciuria and variable phosphaturia [33]. Other presentations include neonatal diabetes, hypergalactosaemia on newborn screening and bilateral nuclear cataracts as the first sign [17, 46]. A 19-year-old girl, previously treated for "resistant" rickets, also had restrictive interstitial lung disease with pulmonary hypertension and cor pulmonale [59]. A Chinese child had hypokalaemia of 2.2 mmol/L and white matter signal changes on magnetic resonance imaging, without neurological symptoms [60]. A patient followed from infancy to young adulthood developed chronic kidney disease in childhood, with medullary nephrocalcinosis and diffuse glycogen in the proximal epithelium on biopsy [53].

3.8 Natural history and treated disease

Almost all clinical data come from patients on fluid and electrolyte replacement, alkali, phosphate and vitamin D, so the untreated natural history can only be inferred from old descriptions, from siblings who died undiagnosed and from projections of renal decline. In Fanconi-Bickel syndrome, metabolic decompensation with severe acidosis and renal failure resembling diabetic glomerulosclerosis were exceptional complications that caused death in childhood [17]; the Sudanese series record deaths of undiagnosed siblings [24]. In FRTS1, the renal progression described occurred despite the usual supportive treatment, which does not alter the aggregation mechanism [1, 31]. In FRTS5, electrolyte and bicarbonate replacement did not prevent progression [15].

4. Clinical Recognition and Warning Signs

4.1 When to suspect, by age

In the newborn, the combination of macrosomia and diazoxide-responsive hyperinsulinaemic hypoglycaemia, especially with a family history of young-onset diabetes, suggests an HNF4A variant; in the presence of glycosuria, aminoaciduria or nephrocalcinosis in this context, the p.Arg63Trp variant becomes the main hypothesis [12, 14, 61]. Neonatal hyperglycaemia with glycosuria and intervening hypoglycaemia, or hypergalactosaemia on newborn screening, raise the possibility of Fanconi-Bickel syndrome, which can be mistaken for transient neonatal diabetes [17, 49, 62]. Bilateral neonatal nuclear cataracts may be the first sign [17].

In infants between 3 and 10 months, failure to thrive, polyuria, polydipsia, vomiting, fever due to dehydration and rickets are the most frequent mode of presentation of any inherited Fanconi syndrome. The simultaneous presence of hepatomegaly, fasting hypoglycaemia and intense glycosuria points to Fanconi-Bickel syndrome; glycosuria with proteinuria in an infant of 3 to 6 months with failure to thrive points to cystinosis, which must always be excluded [22, 63]. In school-age children and adolescents, detection of proteinuria or glycosuria on urine screening, short stature and rickets resistant to usual treatment are the routes of presentation of FRTS1, FRTS3 and mild forms of Fanconi-Bickel syndrome [1, 58, 59]. In adults, unexplained chronic kidney disease with normoglycaemic glycosuria, hypophosphataemia or hypokalaemia, with or without a dominant family history, should prompt sequencing of GATM, and a biopsy that is non-diagnostic on standard histology should include ultrastructural study of the tubular epithelium [1, 31]. Adult hypophosphataemic osteomalacia may also be the presentation [54].

4.2 Clues pointing to the type

Sources: [1, 12, 14, 17, 21, 22, 30, 52].

4.3 Warning and emergency signs

Dehydration with severe hypokalaemia is the main emergency: in the Chinese child of the case in section 10, potassium fell to 2.2 mmol/L and the authors point out that a severe electrolyte disturbance can be fatal [60]. Fasting hypoglycaemia in Fanconi-Bickel syndrome and in the hyperinsulinism of FRTS4, severe metabolic acidosis decompensated by intercurrent illness and symptomatic hypercalcaemia in the differential diagnosis with infantile hypercalcaemia type 2 require immediate correction [12, 17, 61]. Deterioration of glomerular filtration, new nephrocalcinosis and, in the Acadian variant, dyspnoea with an interstitial pattern are signs of progression [1, 30, 53].

4.4 Newborn screening

There is no newborn screening targeted at FRTS. Fanconi-Bickel syndrome can be detected through hypergalactosaemia in programmes that measure total galactose [17, 62]. The Baby Detect neonatal genomic screening study (NCT05687474, completed, 6,824 newborns) included Fanconi-Bickel syndrome among the conditions screened [64].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Confirming the proximal tubulopathy

The first step is to demonstrate tubular dysfunction and its extent. The operational definition used in the Japanese series requires low-molecular-weight proteinuria and at least one of generalised aminoaciduria, glycosuria, hypophosphataemia, metabolic acidosis or hyperuricosuria [1]. The assessment includes venous blood gases, electrolytes with potassium and chloride, calcium, phosphate, magnesium, urate, alkaline phosphatase, PTH, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in blood; and, in urine, glucose with simultaneous blood glucose, amino acids, β2-microglobulin or α1-microglobulin or retinol-binding protein, calcium, phosphate with calculation of the tubular maximum reabsorption of phosphate corrected for glomerular filtration, urate and pH [12, 21]. Renal ultrasound looks for nephrocalcinosis and, in Fanconi-Bickel syndrome, enlarged kidneys; radiographs of the wrist and knees document rickets [17, 53]. In hypophosphataemic rickets, a raised C-terminal FGF23 can be misleading and delay the diagnosis of FRTS, as happened in two Indian probands [54].

5.2 Excluding acquired and secondary causes

Before considering a primary form, drugs that cause Fanconi syndrome are excluded (tenofovir, adefovir, cidofovir, ifosfamide, cisplatin, oxaliplatin, valproic acid, aminoglycosides, expired tetracyclines, deferasirox, imatinib, lenalidomide, fumaric acid and others), as are heavy metals (lead, cadmium, mercury, copper, iron), tubulointerstitial nephritis with or without uveitis, Sjögren syndrome and monoclonal light chain diseases [8, 21]. The secondary inherited causes have their own biochemical tests: leucocyte cystine (in cystinosis, more than 2 nmol ½ cystine/mg protein versus less than 0.2 in controls, according to the consensus, or 5 to 15 nmol according to the Saudubray chapter, with values in polymorphonuclear cells about twice those in mixed leucocytes) and slit-lamp examination for corneal crystals, always present by 18 months [22, 51]; galactosaemia, tyrosinaemia type 1, hereditary fructose intolerance and Wilson disease have their own biochemical markers; in mitochondrial disorders, lactic acidosis associated with any multisystem manifestation is highly suggestive and points towards study of the respiratory chain [12, 21, 65].

5.3 Guiding criteria by entity

For Fanconi-Bickel syndrome, the diagnosis is suggested by the combination of impaired glucose homeostasis, hepatic glycogen accumulation and Fanconi-type tubulopathy, with relatively severe glycosuria and drastically reduced or absent calculated tubular glucose reabsorption [17]. Oral load tests document fasting hypoglycaemia and intolerance to glucose and galactose; transaminases rise slightly without impairment of hepatic synthesis; lipids, uric acid and lactate are raised; raised serum biotinidase activity is a marker of hepatic glycogen storage disease useful in screening [17]. Continuous glucose monitoring shows the alternation between preprandial hypoglycaemia and postprandial hyperglycaemia [60]. Liver biopsy, rarely needed today, shows increased glycogen with normal activities of the glycogenolytic enzymes [12, 17]. The biochemical triad is not specific and the diagnosis requires biallelic SLC2A2 variants [12].

For FRTS4, nephrocalcinosis, hypercalciuria with relative hypocalcaemia, hypermagnesaemia and hyperoxaluria, without acidosis, distinguish the phenotype; a history of macrosomia and neonatal hypoglycaemia should be sought [14]. For FRTS3, the acylcarnitine profile may show accumulation of hydroxyacyl- and acylcarnitines, and magnetic resonance spectroscopy of urine showed raised mitochondrial metabolites in the original family [12, 28]. For FRTS5, respiratory chain enzymology in fibroblasts shows complex I deficiency, but the diagnosis rests on Acadian origin and the founder variant [15, 30]. To distinguish infantile hypercalcaemia type 2, the combination of hypercalcaemia or hypercalciuria with suppressed PTH and inappropriately raised 1,25-dihydroxyvitamin D identifies the vitamin D hypersensitivity group; in a cohort of 185 patients, no biochemical pattern separated CYP24A1, SLC34A1 and SLC34A3, although renal phosphate wasting points to SLC34A1 and the 24,25-dihydroxyvitamin D profile to CYP24A1 [12, 66].

5.4 Genetic testing: choice of test and yield

Genetic testing is the reference standard for inherited proximal tubulopathies, as recommended by the European guideline on Dent disease for its differential diagnosis [21]. A tubulopathy panel should include GATM, SLC34A1, EHHADH, HNF4A, NDUFAF6, SLC2A2, CLCN5, OCRL, CTNS and BCS1L, as in the Japanese panel [1]. In that series of 20 families with FRTS (14 paediatric and 6 adult index cases), the panel identified the cause in 13 (65%): GATM in seven, CLCN5 in two and HNF4A, BCS1L, CTNS and EHHADH in one each; intellectual disability occurred in 1 of 13 patients with a variant and in 4 of 7 without a variant [1]. Older panels that included neither GATM nor BCS1L missed diagnoses that the 2024 reanalysis recovered, and the BCS1L variants were found only by exome [1]. The yield depends on the population: in Japan cystinosis is rare because the 57 kb deletion common in Europe and the United States does not exist in East Asian and Middle Eastern populations [1].

5.5 Limits of the tests

A negative result does not exclude the diagnosis. The Acadian NDUFAF6 variant is deep intronic and escapes panels and exomes that cover only exons and junctions; it should be sought in a targeted way in patients of Acadian ancestry [30]. The GATM variant c.288+8A>T lies close to the junction but required a minigene assay to prove its effect [1]. Exon deletions of SLC2A2 require copy number analysis [50]. In infantile hypercalcaemia type 2, a pathogenic 21-base-pair deletion in SLC34A1 was filtered out of exome analysis because of its high population allele frequency and was found only on targeted reanalysis [12, 55]. Low-level mosaicism in a parent (26% in the grandfather of the FRTS4 index family) may go unnoticed on routine sequencing [14]. Runs of homozygosity and uniparental disomy explain rare homozygous variants in non-consanguineous families and change counselling [49].

5.6 Reporting and interpretation of variants

The report should state the gene, the transcript with version (MANE Select: GATM NM_001482.3, SLC34A1 NM_003052.5, EHHADH NM_001966.4, HNF4A NM_175914.5, NDUFAF6 NM_152416.4, SLC2A2 NM_000340.2), the HGVS c. and p. nomenclature, the zygosity and the ACMG/AMP class [42]. HNF4A nomenclature requires attention: the same variant appears in the literature as R76W, R85W and R63W depending on the reference sequence [14]. The ClinVar classifications for the GATM variants of the original description are heterogeneous, and interpretation should integrate family segregation and the region of the protein [1, 31, 32]. A variant of uncertain significance in a gene with a disputed relationship, such as SLC34A1 in FRTS2, does not establish the diagnosis [13]. Variants in trans should be confirmed by parental testing, and apparently de novo variants require trio analysis [1, 58].

5.7 Algorithm

Sources: [1, 21, 22, 30, 31].

5.8 Prenatal and preimplantation diagnosis

When the familial variants are identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are technically possible for any of the genes; in Fanconi-Bickel syndrome, which is recessively inherited, genetic counselling and prenatal diagnosis are presented as essential [59]. The known Acadian variant allows diagnosis and prevention in Acadian families [30]. Decisions depend on the expected severity, which varies with the type and, in Fanconi-Bickel syndrome, with the residual function of the variants [48].

6. Differential Diagnosis

6.1 Comparative table

Sources: [1, 12, 14, 21, 22, 33, 45, 51, 63, 67, 68]. XL: X-linked; TINU: tubulointerstitial nephritis with uveitis.

6.2 Cystinosis and Dent disease: the most frequent inherited causes

Cystinosis is, worldwide, the most frequent genetic cause of renal Fanconi syndrome in children; the first three to six months are usually asymptomatic and symptoms set in before 12 months, with pale cloudy urine, glycosuria and proteinuria, severe polyuria and rickets at 10 to 18 months if diagnosis is late [1, 51]. The practical difference from FRTS and Fanconi-Bickel syndrome is the existence of specific treatment with cysteamine, whose early initiation improves the renal prognosis [1, 22]. Dent disease rarely produces complete Fanconi syndrome (about 5% of cases) and glycosuria is absent or mild in most; it affects boys, runs with hypercalciuria and nephrocalcinosis and, in the Japanese series, both patients had incomplete Fanconi syndrome [1, 21].

6.3 Fanconi-Bickel syndrome and glycogen storage diseases

Hepatomegaly without splenomegaly with fasting hypoglycaemia suggests glycogen storage disease type I or III or Fanconi-Bickel syndrome; in the latter, glycogen storage is combined with tubulopathy and the appearance is that of a child with a rounded face and short stature [63]. In glycogen storage disease type I hypoglycaemia is more severe and there is lactic acidosis, whereas in Fanconi-Bickel syndrome the distinguishing finding is disproportionate glycosuria, even with low blood glucose, and galactose intolerance [17, 63]. Renal Fanconi syndrome with glycosuria, aminoaciduria and phosphaturia has been described in several patients with glycogen storage disease type I, but at least one of these patients turned out to have Fanconi-Bickel syndrome, which justifies genetic testing before attributing the tubulopathy to the glycogen storage disease [69]. Intermittent glycosuria also occurs in glycogen synthase deficiency (with ketotic hypoglycaemia), in glucose-galactose malabsorption and in crises of organic acidurias that can mimic diabetes [63].

6.4 FRTS1, FRTS3 and mitochondrial disorders

FRTS1 and FRTS3 are tubulopathies of mitochondrial basis without the usual extrarenal disease, whereas primary mitochondrial disorders with Fanconi syndrome are usually multisystem. The Oxford Desk Reference includes renal tubular dysfunction with generalised aminoaciduria and glycosuria among the features that, in association with lactic acidosis, suggest mitochondrial disease [65]. In Pearson syndrome, Fanconi syndrome accompanies anaemia and malabsorption, and renal biopsy shows giant mitochondria in the proximal tubules [68]. BCS1L deficiencies combine proximal tubulopathy, liver involvement, deafness and pili torti [1, 45]. FRTS3 can also present with liver dysfunction and deficiency of complexes I and IV, which brings it close to these forms [52].

6.5 FRTS4, hyperinsulinism and monogenic diabetes

FRTS4 is distinguished from other causes of neonatal hyperinsulinism by the tubulopathy and nephrocalcinosis; in the context of monogenic diabetes, the glycosuria of FRTS4 is renal and does not by itself indicate diabetic decompensation, unlike the glycosuria with hyperglycaemia of diabetes, and in HNF1A MODY there is a low renal threshold for glucose without Fanconi syndrome [12, 41]. Tyrosinaemia type 1 is part of the syndromic differential diagnosis of hyperinsulinism [70].

6.6 Infantile hypercalcaemia type 2 and tubulopathies with hypercalciuria

Infantile hypercalcaemia type 2 (SLC34A1) and type 1 (CYP24A1) share hypercalcaemia with suppressed PTH; the distinction determines treatment, because in type 2 withdrawal of vitamin D is not enough and the findings respond to phosphate [12, 37]. SLC2A2-related ARPTH enters the differential of any proximal tubulopathy with hypercalciuria [33]. In FRTS4, hypercalciuria is accompanied by relative hypocalcaemia and hypermagnesaemia [14].

7. Treatments and Risk Management Strategies

7.1 Framework and level of evidence

There is no specific guideline or consensus for FRTS or for Fanconi-Bickel syndrome, and no randomised trial has been conducted in these diseases; a search of ClinicalTrials.gov in October 2026 found no targeted interventional trials [12, 64]. Treatment rests on four sources: the protocol and outcomes of the Fanconi-Bickel series, especially the 2024 Chinese series and the 2020 multicentre series [49, 57]; recommendations for analogous conditions with proximal tubulopathy, Dent disease (2025 European recommendations) and nephropathic cystinosis (2014 international consensus and the Saudubray chapter) [21, 22, 51]; guidelines for the non-renal manifestations with their own treatment, hyperinsulinism (2024 international guideline) and monogenic diabetes (ISPAD 2022) [41, 61]; and case series of repurposed therapies [15, 71]. Doses from analogous conditions are extrapolations, declared as such, and all supportive drugs are used outside the approved indications for these diseases.

7.2 Water and electrolyte replacement

Water intake is adjusted to urine output, short-term weight change and, if necessary, plasma protein concentration, and increases with heat, fever and the volume of the supplements themselves [51]. Sodium losses may persist after the acidosis has been corrected, manifesting as hyponatraemia with failure to thrive [51]. Hypokalaemia requires supplements to keep serum potassium above 3 mmol/L; in cystinosis 4 to 10 mmol/kg/day are usually needed, and amiloride at 2 to 5 mg/day may help in some patients [51]. In the child of the clinical case in section 10, oral potassium citrate was not enough to keep potassium normal [60]. The practice of preparing all the supplements except vitamin D in advance in a bottle with the day's water makes regular administration easier [51]. When there is anorexia or frequent vomiting, an early feeding tube or gastrostomy facilitates nutrition and administration of medicines, and the diet should provide at least 100% of the recommended daily allowance for age, with no evidence of benefit above 150% [22].

7.3 Correction of acidosis

In cystinosis, sodium and potassium bicarbonate, with better gastric tolerance than citrate, is given to obtain plasma bicarbonate between 21 and 24 mmol/L, which may require up to 10 to 15 mmol/kg/day [51]. The Chinese Fanconi-Bickel protocol used sodium bicarbonate or citrate at 5 to 20 mEq/kg/day in patients with persistent acidosis; median bicarbonate rose from 14.6 to 21.4 mmol/L, but six of nine patients remained acidotic, and the authors suggest that carriers of biallelic null variants need more alkali [49]. In Dent disease, citrate may be considered especially with nephrocalcinosis or stones (grade C, weak recommendation), monitoring urinary pH because alkaline urine favours calcium phosphate precipitation [21]. In FRTS5, the patients of the Canadian series received bicarbonate and electrolytes, which did not prevent renal progression [15]. In FRTS4 there is no significant acidosis and alkalinisation is therefore not a constant requirement [14].

7.4 Phosphate and vitamin D

Sources: [21, 49, 51].

Phosphate and active vitamin D are the treatment of hypophosphataemic rickets in Fanconi-Bickel syndrome and in FRTS with rickets [17, 49]. The divergence between sources results from physiology: in Dent disease, 1,25-dihydroxyvitamin D is already raised and active vitamin D would worsen hypercalciuria, which is why the guideline advises against it [21]. The same reasoning applies to FRTS with hypercalciuria and nephrocalcinosis, such as FRTS4, in which hypercalciuria is a central feature, and to the FRTS1 cases with hypercalciuria and high-normal 1,25-dihydroxyvitamin D described in the Indian cohort (median 152 pg/mL) [14, 54]. In FRTS2 and in the differential diagnosis with infantile hypercalcaemia type 2, vitamin D should be used with great care and routine prophylaxis is dangerous; in the latter, withdrawal of vitamin D is not enough and phosphate is the targeted treatment, with a rapid response [12, 37, 55]. In all cases, treatment with phosphate and vitamin D is monitored with calcium, phosphate, alkaline phosphatase, PTH and calciuria, and with periodic renal ultrasound [21, 51].

7.5 Carnitine, indometacin and other adjuncts

Carnitine is lost in the urine in proximal tubulopathy; in cystinosis 100 mg/kg/day in four doses is proposed to correct muscle depletion, and all patients in the multicentre Fanconi-Bickel series received L-carnitine [51, 57]. Indometacin reduces water, potassium and sodium losses; in the cystinosis consensus it is used orally at 1 to 3 mg/kg/day, in two or three doses, with a 30 to 70% reduction in polyuria and better weight gain; there is no consensus on its use, it should be stopped in the event of dehydration or worsening renal function, and it can be harmful when renal perfusion depends on prostaglandins, as happens in severe Fanconi syndrome [22, 51]. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are used with caution in Fanconi syndrome with salt and water losses, at low doses, reduced or suspended in hot weather; in Dent disease they are not recommended as routine nephroprotective agents (grade C) [21, 22]. Thiazides reduce calciuria in short studies (chlortalidone 25 mg/day, hydrochlorothiazide above 0.4 mg/kg/day), but cause hypovolaemia and electrolyte disturbances, and the Dent disease guideline advises against systematic use (grade B) [21]. Growth hormone is considered only when growth retardation persists with adequate metabolic control or in chronic kidney disease stage 3 or higher (grade D) [21]; in the Chinese Fanconi-Bickel series, growth hormone at 0.1 to 0.2 IU/kg/day in four patients did not significantly improve height (p = 0.13) and the authors do not recommend it when stimulation tests are normal [49].

7.6 Fanconi-Bickel syndrome: dietary treatment

The aim is to stabilise glucose homeostasis and compensate for renal glucose losses with adequate caloric intake, frequent meals with slowly absorbed carbohydrates and, when indicated, continuous overnight tube feeding of oligosaccharide solutions [17]. Uncooked cornstarch improves metabolic control and growth, but overnight enteral nutrition appears superior [17]. In the series of Pennisi and colleagues, growth retardation improved markedly in the five patients treated with intensive overnight enteral nutrition and cornstarch, with normal final growth parameters, whereas the four severely affected patients treated with cornstarch alone did not catch up [57]. The Chinese protocol used uncooked cornstarch at 1.6 to 2.5 g/kg, four to six times a day, a diabetic-type diet in small frequent meals with 60 to 70% of calories from carbohydrate, 10 to 15% from protein and the rest from fat, and galactose restriction; in nine patients followed for a mean of seven years, hepatomegaly regressed in all, preprandial blood glucose, transaminases and triglycerides almost normalised, and mean height went from −4.1 to −3.5 standard deviations in the eight adherent patients (p = 0.02); the girl with poor adherence reached a final height of 110.1 cm (−9.14 standard deviations) [49]. Restriction of galactose, and of fructose if there is intolerance, is guided by tolerance [12]. Since fructose uses its own transporter (GLUT5) and its metabolism is preserved in Fanconi-Bickel syndrome, OMIM points to it as an alternative carbohydrate source; the diabetic-type diet in small frequent meals, with supplements of water, electrolytes and vitamin D and galactose restriction, was the regimen described by Manz and colleagues [7]. Continuous glucose monitoring helps to adjust cornstarch and meals, and allows detection of nocturnal hypoglycaemia and postprandial hyperglycaemia that escape capillary measurements [60, 72].

Treatment of hyperglycaemia with insulin is controversial. Some authors recommend avoiding it because of the risk of hypoglycaemia; others have used it in patients with hyperglycaemia or neonatal diabetes without symptomatic hypoglycaemia, under continuous monitoring [60]. In the Chinese series, an infant treated with insulin 0.15 U/kg/day at one month of age had hypoglycaemia of 2.0 to 3.0 mmol/L and was switched to glibenclamide 0.06 mg/kg/day at 3 months, stopped after the genetic diagnosis at 20 months [49]. Neonatal diabetes due to SLC2A2 requires insulin and does not respond to sulfonylureas, according to the GeneGuidance curation [12].

7.7 Fanconi-Bickel syndrome: SGLT2 inhibitors (experimental use)

The rationale is to shift the metabolic block: by inhibiting apical glucose entry into the proximal cell, sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the intracellular accumulation of glucose and glycogen that deficient GLUT2 cannot clear [35, 71]. In mice with renal ablation of GLUT2, dapagliflozin reduced tubular glycogen and improved metabolic acidosis and phosphaturia, normalising Napi2a and NHE3 expression; in one patient it was safe, improved serum potassium and phosphate and reduced glycogen in exfoliated urinary cells [35]. The retrospective series of Overduin and colleagues included seven patients from five families (three children aged 14 years 5 months, 2 years 9 months and 1 year 6 months) treated off-label with empagliflozin up to 25 mg/day; median age at initiation was 27 years and median follow-up 169 days. Markers of tubular integrity (urinary N-acetyl-glucosaminidase) and of tubular function (including urinary α1-microglobulin) improved in all, to varying degrees; in the three children, phosphate, alkali, carnitine and alfacalcidol supplements could be stopped completely, whereas in the four adults results were more variable; there was no symptomatic hypoglycaemia [71]. This evidence is at the level of an uncontrolled case series with short follow-up, and does not support routine use. In one patient with FRTS5, an SGLT2 inhibitor used for a short time had no apparent benefit [15].

Sources: [71, 73–75].

7.8 FRTS4: neonatal hyperinsulinism and diabetes

The hyperinsulinism of FRTS4 is treated according to the 2024 international guideline. Hypoglycaemia is corrected immediately with intravenous glucose and, once the diagnosis of hyperinsulinism is established, diazoxide is the first-line treatment (strong recommendation, moderate evidence) [61]. In the guideline, the therapeutic dose in infants and children is 5 to 15 mg/kg/day orally, in two or three doses given the half-life of 15 ± 5.3 hours, with no additional benefit above that range; in adults it indicates 3 to 8 mg/kg/day; it recommends starting a diuretic at the same time, especially in the newborn and with doses above 10 mg/kg/day (chlorothiazide 10 mg/kg/day or hydrochlorothiazide 1 to 2 mg/kg/day, in infants and children; no maximum dose defined in the source); if after five days at 15 mg/kg/day it is not possible to reduce the glucose infusion, diazoxide is stopped [61]. The US label for the oral suspension, for comparison, indicates a starting dose of 8 mg/kg/day in infants and newborns, titratable up to 15 mg/kg/day, and 3 mg/kg/day in older children and adults, titratable up to 8 mg/kg/day, and states that it should be stopped if there is no efficacy after two to three weeks; the approved indication is hypoglycaemia due to hyperinsulinism and does not mention the monogenic cause [12, 76]. Adverse effects include salt and water retention with oedema, hyponatraemia and respiratory failure, pulmonary hypertension (2.4% in a large cohort; reversible on withdrawal), hypertrichosis (84.1%), coarsening of facial features (24%), neutropenia (15.6%), thrombocytopenia (4.7%) and hyperuricaemia (5.0%); 9.7% of patients stop because of serious events [61]. The guideline recommends an echocardiogram one week after initiation and a full blood count with differential and uric acid every six months; the label warns of ketoacidosis and hyperosmolar coma during intercurrent illness, and of potentiation of the hyperglycaemic and hyperuricaemic effect with thiazides [61, 76]. In HNF4A hyperinsulinism, response to diazoxide is the rule and the condition tends to remit during infancy [41, 70]. On 31 October 2026, Infomed did not list any authorised and marketed diazoxide medicine in Portugal, so access, when needed, depends on import routes or exceptional authorisation that the sources consulted do not document [75].

The diabetes that appears from adolescence onwards is treated as HNF4A MODY. ISPAD 2022 states that these patients are very sensitive to sulfonylureas, which usually give better control than insulin; the starting dose should be low, about a quarter of the usual adult starting dose, and maintenance with low doses, for example gliclazide 20 to 40 mg/day, may last for decades; if there is hypoglycaemia, a slow-release preparation or a meglitinide at meals is used [41]. GeneReviews considers sulfonylureas the established first-line treatment of HNF4A-MODY [77]. In a cohort of 42 carriers of HNF4A variants, 51.6% of patients on sulfonylurea monotherapy had a significant and sustained fall in HbA1c over a median of about six years, and 48.4% needed additional drugs, including insulin; a normal body mass index was associated with response [12, 78]. Sulfonylurea labels indicate them for type 2 diabetes in adults, so use in paediatric MODY is off-label [12]. In Portugal, gliclazide is marketed as Diamicron® LM 30 mg and 60 mg modified-release tablets [75]. In the FRTS4 index family, non-diabetic carriers have an annual oral glucose tolerance test [14].

7.9 FRTS5: N-acetylcysteine (case series)

N-acetylcysteine is an antioxidant used on the basis of the oxidative stress component of complex I deficiency. In patient fibroblasts, five days of exposure partially restored complex I activity, membrane potential and respiration, and prevented oxidative damage [44]. In the 2026 retrospective series, four Acadian patients not on kidney replacement therapy received N-acetylcysteine 500 mg orally twice daily, started between 18 and 26 years of age with an estimated filtration rate of 28 to 55 mL/min/1.73 m², for 7 ± 1 years [15]. The loss of filtration went from −3.74 ± 0.92 to −1.27 ± 0.31 mL/min/1.73 m² per year; the mean difference in slope was 2.46 ± 0.82 (95% bootstrap confidence interval 1.17 to 3.76), not significant on the permutation test (p = 0.13); the projected age for kidney replacement went from 28 ± 3 to 42 ± 3 years [15]. The outcome is projected rather than observed, the projection method is simple and the series has four patients without controls; the authors call for further studies, and the therapy should be presented as experimental [12, 15]. In Portugal acetylcysteine is marketed in several presentations, for example 600 mg effervescent tablets, and use in this disease is off-label; chronic use has been mainly as a mucolytic [15, 75].

7.10 FRTS1 and FRTS3

There is no specific treatment for FRTS1. The hypothesis of suppressing production of the mutant protein with creatine, through negative feedback on synthesis, rests on the 27% reduction in mRNA and 58% reduction in GATM protein in wild-type mice and has not been tested in patients [13, 31, 34]. The GeneGuidance curation states that the renal phenotype does not respond to creatine; this statement and the hypothesis of the Reichold group are not based on clinical data, and creatine should not be presented as a treatment [12, 31]. The creatine monohydrate dose of 400 to 800 mg/kg/day refers to recessive AGAT deficiency and not to FRTS1 [12]. In FRTS3, a diet supplemented with medium-chain fatty acids, tried in one patient, did not improve the disease [52]. Treatment is supportive management of the tubulopathy and of chronic kidney disease [12, 79].

7.11 Agents and circumstances to avoid

In the forms with a mitochondrial basis (FRTS5 and, by extension of mechanism, FRTS1 and FRTS3), the Delphi consensus on drug safety in mitochondrial disease, cited by the GeneReviews chapter on the Leigh spectrum, recommends avoiding sodium valproate, avoiding lactate-containing solutions (Ringer's lactate) when there is a risk of lactic acidosis, monitoring anaesthesia because of the risk of respiratory failure, avoiding prolonged maintenance with propofol, minimising preoperative fasting and giving intravenous glucose during prolonged anaesthesia [12, 45, 80]. The extension to FRTS1 and FRTS3 is an extrapolation. Nephrotoxic drugs that cause acquired Fanconi syndrome (tenofovir, adefovir, ifosfamide, cisplatin, aminoglycosides, deferasirox and others) worsen the tubulopathy and should be avoided when an alternative exists [21]. Routine vitamin D prophylaxis is dangerous when there is vitamin D hypersensitivity, and active vitamin D worsens hypercalciuria in the forms with raised 1,25-dihydroxyvitamin D [12, 21]. Anti-inflammatory drugs, including indometacin, and renin-angiotensin system blockers require caution during dehydration [22]. In Fanconi-Bickel syndrome, prolonged fasting and galactose trigger decompensation [12, 17].

7.12 Perioperative care, intercurrent illness and transition

During surgery and intercurrent illness, tubular losses continue while intake falls: fasting should be short, glucose and electrolytes replaced intravenously and blood glucose monitored in Fanconi-Bickel syndrome and in hyperinsulinism [12, 61]. Empagliflozin, when used, is stopped at least three days before surgery or prolonged fasting [73]. Diazoxide has a half-life of about 30 hours and requires prolonged monitoring after an acute episode of ketoacidosis [76]. Transition to adult care is particularly relevant in FRTS1 and FRTS5, whose chronic kidney disease progresses in adulthood, and in FRTS4, because of diabetes; management in centres with experience in tubulopathies and metabolic disorders, linked to ERKNet and MetabERN, facilitates continuity [1, 15, 18, 19].

7.13 Advanced chronic kidney disease and transplantation

FRTS1 and FRTS5 progress to kidney failure; in FRTS1, dialysis or transplantation was required between the third and sixth decades [1, 15, 31]. In FRTS5, eight of 12 patients in the Hartmannová series were transplanted between 18 and 38 years of age, and in the Wornell series two patients died of pulmonary fibrosis after kidney transplantation, which makes pulmonary assessment part of the preparation for transplantation [6]. The sources consulted do not describe graft outcomes in FRTS1. In cystinosis, used for comparison, Fanconi syndrome does not recur in the transplanted kidney [51].

7.14 Pregnancy and lactation

Several pregnancies with a favourable outcome have been published in Fanconi-Bickel syndrome. In a 27-year-old woman, continuous glucose monitoring from 7 weeks showed blood glucose values from 38 mg/dL during overnight fasting to more than 400 mg/dL postprandially, with a time in range of 52%; iterative adjustment of long- and short-acting cornstarch and of nutritional therapy, adding protein to meals and to the cornstarch, brought the time in the 63 to 140 mg/dL range above 70%, and a healthy term baby was born without the need for insulin, considered at increased risk in this disease; the GLUT2 isoform was not detected in the placenta [72]. In a pregnant woman with intrahepatic cholestasis (bile acids above 50 µmol/L) and triglycerides above 700 mg/dL, ursodeoxycholic acid and a fibrate, with multidisciplinary follow-up, allowed induction at 37 weeks and vaginal delivery of a 2,785 g baby girl without hypoglycaemia; the review included describes other pregnancies with postprandial hyperglycaemia, polyhydramnios, caesarean section and haemodialysis [81]. A caesarean section with uncomplicated anaesthetic management has also been published [82]. In FRTS4, fetal exposure to maternal diabetes brings forward the onset of diabetes by about 12 years in HNF4A MODY, and the carrier fetus is at risk of macrosomia and neonatal hypoglycaemia [39, 41]. The sources consulted do not describe pregnancies in FRTS1, FRTS3 and FRTS5, nor lactation data.

7.15 Regulatory status

Sources: [41, 61, 73–76].

7.16 Interventional evidence and recent developments

Sources: [15, 35, 44, 49, 52, 57, 71].

None of these studies has a randomised control group, the outcomes are intermediate (tubular markers, filtration slope, height) and comparison between series is not legitimate, because age, severity and duration differ. The reduction in filtration loss with N-acetylcysteine corresponds, in absolute terms, to about 2.5 mL/min/1.73 m² per year in four patients, and the age at kidney replacement is a projection [15]. Negative results are included (medium-chain diet in FRTS3; SGLT2 inhibitor without benefit in one patient with FRTS5; growth hormone without gain in Fanconi-Bickel syndrome) [15, 49, 52]. In the last twelve months, the new developments are the N-acetylcysteine series in FRTS5 (published in 2026), the Japanese series that showed FRTS1 to be the most frequent and progressive genetic cause (2026), a new GATM variant outside the classic region with functional analysis (2026), the ClinGen reassessment that kept FRTS2 as disputed (December 2025) and FRTS3 as limited (March 2026) and the moderate classification of FRTS1 (2026) [1, 13, 15, 36]. There are no registered clinical trials, regulatory applications or authorisations for these diseases [64].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks by mode of inheritance

In Fanconi-Bickel syndrome, which is autosomal recessive, the parents of a patient are as a rule heterozygous and each sibling has a 25% probability of being affected [12, 46]. Consanguinity is frequent (more than 70% of cases; 70% in the Sudanese series), and in a child from a non-consanguineous family homozygosity resulted from uniparental disomy of chromosome 3, a situation in which only one parent is a carrier; the recurrence risk in that family depends on confirming that the other parent is not a carrier, which requires testing both [17, 24, 49]. In FRTS5, also recessive, the Acadian founder variant makes it possible to identify heterozygotes in the community and to counsel couples in whom both are carriers [30]. The FRTS2 described was recessive, but the fragility of the association precludes using SLC34A1 for prenatal diagnosis based on that relationship alone [13, 29].

In FRTS1, which is autosomal dominant, each child of a patient has a 50% probability of inheriting the variant; in the original families penetrance was complete, but the severity and rate of renal decline vary within the family [1, 31]. There are de novo variants confirmed by trio testing, subsequently transmitted to offspring [1, 31]. In FRTS3, also dominant, the transmission risk is 50%, but penetrance is incomplete: one carrier father was asymptomatic at 54 years and another had only proteinuria and mild impairment [1, 52]. In FRTS4, each child of a carrier has a 50% probability of inheriting p.Arg63Trp; in the index family the variant arose in a grandfather with germline and somatic mosaicism (26% in leucocytes), which means that, in the face of an apparently de novo case, siblings have a recurrence risk above that of the population [14].

8.2 Cascade testing and testing of minors

Once the variant has been identified, cascade testing of at-risk relatives is recommended in the dominant forms because early diagnosis allows monitoring of renal function and, in FRTS4, anticipation of macrosomia and neonatal hypoglycaemia in offspring and initiation of diabetes screening [1, 14, 41]. In asymptomatic relatives of patients with FRTS1, a urinalysis with tubular markers and glycosuria accompanies the genetic test, since many patients were detected through urinary abnormalities on routine testing [1]. Testing of asymptomatic minors is justified when it changes surveillance in childhood, as is the case in all forms of this class, in which the tubulopathy begins in childhood and rickets is preventable with replacement. In the recessive forms, carrier testing of healthy siblings can be deferred until the age at which the information has reproductive utility.

8.3 Prenatal and preimplantation diagnosis and at-risk pregnancy

With the familial variants known, prenatal diagnosis on chorionic villi or amniocytes and preimplantation genetic testing are possible; in Fanconi-Bickel syndrome, counselling and prenatal diagnosis are considered essential by the authors of a published case [59]. The pregnancy of a carrier of HNF4A p.Arg63Trp requires delivery planning for a newborn who may be macrosomic and have diazoxide-responsive hyperinsulinism [14, 41]. Reproductive decisions should take into account that Fanconi-Bickel syndrome has a favourable overall prognosis with treatment and normal cognitive development, whereas FRTS1 and FRTS5 progress to kidney failure in adulthood [1, 15, 17, 50].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

The prevalence of primary FRTS as a whole is unknown according to Orphanet [11]. For Fanconi-Bickel syndrome, Orphanet records about 200 cases or families worldwide and a point prevalence class below 1 per million, which is an upper limit and not a measured rate [11, 12]. The only population figure comes from a study of the incidence of metabolic disorders in southern Israel, which estimated 0.3 per 100,000 births overall and 0.5 per 100,000 in a consanguineous subpopulation [11, 16]. For FRTS4, Orphanet records seven cases or families and the same class below 1 per million [11]. For FRTS1, 42 patients had been described up to 2026, and the Japanese series, in which GATM was the most frequent gene among 20 families with FRTS, suggests that the form is underdiagnosed [1]. FRTS3 has five probands with the same variant, plus one non-indexed [13]. These numbers reflect published cases and not population prevalences.

9.2 Populations and geography

The American data include the extended US family in which FRTS1 was mapped to 15q (two of the five families were studied at the National Institutes of Health Clinical Center) and the five-generation Black family with FRTS3 [28, 31]. In Europe, the Hamburg series (93 patients with Fanconi-Bickel syndrome diagnosed in the same laboratory) and the multicentre Pennisi series define the genotype–phenotype correlation and nutritional treatment [48, 57]. FRTS5 is exclusive to the Acadian founder population of Atlantic Canada, where it is diagnosed clinically [15, 30]. Fanconi-Bickel syndrome is concentrated in populations with high consanguinity: Sudan (first series from sub-Saharan Africa), Palestine (largest single-centre cohort, 20 patients), Israel, India and China, where fewer than ten patients had been described before 2022 and the p.Leu406Arg variant accounts for 18% of alleles in one series [16, 24, 49, 50, 54, 60]. In Japan, cystinosis is rare among the causes of inherited Fanconi syndrome because of the absence of the 57 kb CTNS deletion, frequent in Europe and the United States, where cystinosis has a prevalence of 1 per 100,000 to 200,000 [1].

In Portugal, one case of mild Fanconi-Bickel syndrome in an adolescent girl has been published, with the variants c.218C>G p.(Ser73*) and c.371+5G>A [58]. From Brazil, the sources consulted include a review from Belo Horizonte on inherited Fanconi syndrome in children, which stresses that the form secondary to systemic disorders is the most common in the paediatric age group [20]. The sources consulted do not provide frequency data for Portugal or Brazil, which does not mean that such data do not exist.

9.3 Special populations

In children, growth retardation and rickets predominate and adherence to overnight treatment conditions final height [49, 57]. In adults, FRTS1 presents as unexplained chronic kidney disease, sometimes already at an advanced stage, and hypophosphataemic osteomalacia is a route of presentation [1, 54]. Pregnancy in Fanconi-Bickel syndrome requires continuous glucose monitoring and nutritional adjustment [72, 81].

9.4 European networks and associations

ERKNet, the European Reference Network for rare kidney diseases, covers the tubulopathies, and MetabERN, the European Reference Network for hereditary metabolic disorders, covers Fanconi-Bickel syndrome and the forms with a mitochondrial component [18, 19]. AGSD-UK, the British association of patients with glycogen storage diseases, is a resource for patients and families with hepatic glycogen storage diseases [83]. The sources consulted did not identify patient associations dedicated to FRTS.

10. Illustrative Clinical Case

10.1 Fanconi-Bickel syndrome with diabetes and severe hypokalaemia in an infant girl

Chen and colleagues described in 2022 a Chinese infant girl, the first child of consanguineous parents, born at 41 weeks weighing 2,780 g, without intrauterine growth restriction [60]. At 4 months, the urine became thick and foamy, without polyuria or fever; the dipstick showed glucose 4+, protein 2+ and ketones 1+, with raised transaminases (ALT 66 U/L, AST 196 U/L) and normal blood glucose. She was not treated for two months. At 6 months, transaminases had risen (ALT 508 U/L, AST 498 U/L) and potassium was 2.95 mmol/L; at the referral hospital, the lowest potassium was 2.2 mmol/L, with hypocalcaemia (calcium 1.95 mmol/L), hyperchloraemia (112.5 mmol/L), phosphorus 0.48 mmol/L, GGT 1,079 U/L, HbA1c 5.3%, PTH 39.3 pg/mL and 25-hydroxyvitamin D 14.8 ng/mL [60]. She weighed 6 kg (Z-score −2.03), measured 68 cm, had a body mass index Z-score of −2.96, a liver palpable 6 cm and spleen 2 cm below the costal margin, and could not sit steadily. Urinary α1-microglobulin and microalbumin were increased, with normal urea and creatinine, consistent with proximal tubular dysfunction without tubular acidosis, and urine output was 15 mL/kg/h [60].

Capillary blood glucose values above 11.1 mmol/L led to continuous glucose monitoring, which showed preprandial hypoglycaemia and postprandial hyperglycaemia (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9218529/figure/F2/) [60]. CT showed widening of the costochondral junctions and hepatomegaly with reduced liver density, radiographs of the hand and hip showed active rickets and brain MRI showed bilateral subcortical T2 hyperintensity with slightly delayed myelination, without neurological symptoms (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC9218529/figure/F3/) [60]. The parents declined liver biopsy. Trio exome sequencing, confirmed by Sanger, identified homozygosity for SLC2A2 NM_000340.2:c.1260G>A p.(Trp420*), with both parents heterozygous (pedigree in Figure 3E), classified as likely pathogenic (PVS1 and PM2); mitochondrial testing was negative [42, 60]. The article's abstract refers to compound heterozygosity, but the results and the pedigree show homozygosity.

Treatment included intravenous and oral potassium (oral potassium citrate did not keep potassium normal), monosodium and disodium phosphate, vitamin D, potassium citrate and low-dose insulin for postprandial hyperglycaemia, adjusted with continuous monitoring [60]. The case illustrates the difficulty of early diagnosis when hepatomegaly and hypoglycaemia are confused with neonatal diabetes, the value of continuous glucose monitoring and of the exome, and the risk of potassium losses. The use of insulin in this case diverges from the position of authors who advise against it in Fanconi-Bickel syndrome, and from the dietary treatment with uncooked cornstarch and overnight enteral nutrition described as the basis of therapy in the series [49, 57, 60]; it is not presented as routine management.

10.2 Note on the FRTS4 index family

For FRTS4, the family described by Hamilton and colleagues shows the typical course: two sisters with short stature and rickets, negative hypophosphataemic rickets panels, Fanconi syndrome with nephrocalcinosis, neonatal hyperinsulinism treated with diazoxide in the sisters and in the macrosomic son of one of them, and the p.Arg63Trp (R76W) variant inherited from a mosaic grandfather; the pedigree of the four families is in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC3932761/figure/JMEDGENET2013102066F1/) [14].

11. Prognosis and Long-Term Follow-up

11.1 Prognosis by entity

In Fanconi-Bickel syndrome, the prognosis with treatment is reasonably good; some of the original patients reached adulthood, and the main problems in adults are short stature and the orthopaedic sequelae of rickets and osteomalacia [17]. Cognitive development is normal [17]. Hepatic adenomas have not been observed, and one hepatocellular carcinoma without a previous adenoma has been described; severe acidosis and renal failure with diabetic-type glomerulosclerosis were exceptional and fatal complications in childhood [17]. Nephrocalcinosis is frequent under phosphate and calcitriol (5 of 7 patients with raised alkaline phosphatase in one series) and there are patients with chronic kidney disease from childhood [49, 53]. Puberty is delayed and final height depends on adherence to nutritional treatment [49, 57].

In FRTS1, the prognosis is determined by progressive chronic kidney disease, with a median renal survival of 51.9 years (95% confidence interval 46 to 66) in 41 patients and the need for dialysis or transplantation between the third and sixth decades in the original families [1, 31]. In FRTS5, kidney replacement occurs on average at about 30 years at the Canadian institution, with a projection of 28 ± 3 years without N-acetylcysteine; lung disease sets in between 19 and 50 years and was fatal after transplantation in two patients [6, 15]. In FRTS4, nephrocalcinosis is accompanied by mild to moderate renal impairment and diabetes appears from adolescence in some carriers; in HNF4A MODY, one cohort recorded retinopathy in 24.4%, nephropathy in 12.9% and coronary disease in 22.6% [1, 14, 78]. In FRTS3, renal function declined mildly up to 28 years in one case, and there are asymptomatic carriers [1, 52].

11.2 Surveillance table

The sources consulted do not define numerical intervals for most renal surveillance in these diseases, and the intervals given as "at each visit" or "periodic" follow the practice of the series and of the analogous guidelines [21, 22].

12. Summary and Concluding Remarks

Primary renotubular Fanconi syndromes and Fanconi-Bickel syndrome form a group of inherited generalised proximal tubulopathies in which tubular dysfunction is the dominant manifestation. Fanconi-Bickel syndrome, due to recessive deficiency of the GLUT2 transporter, is the most frequent and best described; it combines tubulopathy with disproportionate glycosuria with hepatic glycogen storage, fasting hypoglycaemia and postprandial hyperglycaemia and severe growth retardation, and its treatment, without approved specific therapy, rests on replacement of losses, phosphate and active vitamin D and a nutritional strategy in which overnight enteral feeding proved superior to cornstarch alone for growth. SGLT2 inhibitors, which act on apical glucose entry into the cell, are the only intervention targeting the mechanism and remain experimental.

The five FRTS types have uneven robustness. FRTS1 due to dominant GATM is a gain-of-function mitochondrial proteinopathy that progresses to kidney failure in middle age and emerges, in a Japanese series, as the most frequent genetic cause of primary Fanconi syndrome; FRTS3 due to EHHADH results from mitochondrial mislocalisation of a peroxisomal enzyme and has limited evidence; FRTS4 is a phenotype specific to the HNF4A p.Arg63Trp variant, with nephrocalcinosis, neonatal hyperinsulinism and MODY; FRTS5 is an Acadian founder disease due to an intronic NDUFAF6 variant, with kidney failure in young adulthood and pulmonary fibrosis, in which N-acetylcysteine is only a hypothesis in four patients; and FRTS2 due to SLC34A1 is now a disputed association, infantile hypercalcaemia type 2 being the established phenotype of the gene.

In practice, when faced with renal Fanconi syndrome, exclusion of acquired causes and of cystinosis precedes genetic testing by panel with copy number analysis, bearing in mind the technical limits (intronic Acadian variant, mosaicism, deletions) and the confusing nomenclature of HNF4A. Surveillance focuses on electrolytes, bone, calciuria and nephrocalcinosis, glomerular filtration and, depending on the type, blood glucose and lung function, with management in centres linked to the European networks ERKNet and MetabERN.

13. References

1. Inoki Y, Sakakibara N, Yamamoto A, Kimura Y, Aoyama S, Kondo A, et al. Genetic screening of patients with inherited Fanconi syndrome. Kidney Int Rep. 2026;11(7):106576. doi:10.1016/j.ekir.2026.106576. PMID:42282999
2. Online Mendelian Inheritance in Man, OMIM®. #134600 Fanconi renotubular syndrome 1; FRTS1. Baltimore (MD): Johns Hopkins University. Last edited 3 Dec 2024. https://omim.org/entry/134600 (accessed 31 Oct 2026)
3. Online Mendelian Inheritance in Man, OMIM®. #613388 Fanconi renotubular syndrome 2; FRTS2. Baltimore (MD): Johns Hopkins University. Last edited 10 Aug 2026. https://omim.org/entry/613388 (accessed 31 Oct 2026)
4. Online Mendelian Inheritance in Man, OMIM®. #615605 Fanconi renotubular syndrome 3; FRTS3. Baltimore (MD): Johns Hopkins University. Last edited 6 Apr 2020. https://omim.org/entry/615605 (accessed 31 Oct 2026)
5. Online Mendelian Inheritance in Man, OMIM®. #616026 Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young; FRTS4. Baltimore (MD): Johns Hopkins University. Last edited 16 May 2017. https://omim.org/entry/616026 (accessed 31 Oct 2026)
6. Online Mendelian Inheritance in Man, OMIM®. #618913 Fanconi renotubular syndrome 5; FRTS5. Baltimore (MD): Johns Hopkins University. Last edited 1 Apr 2026. https://omim.org/entry/618913 (accessed 31 Oct 2026)
7. Online Mendelian Inheritance in Man, OMIM®. #227810 Fanconi-Bickel syndrome; FBS. Baltimore (MD): Johns Hopkins University. Last edited 1 Oct 2019. https://omim.org/entry/227810 (accessed 31 Oct 2026)
8. Orphanet. Primary Fanconi renotubular syndrome (ORPHA:3337). https://www.orpha.net/en/disease/detail/3337
9. Orphanet. Fanconi-Bickel syndrome (ORPHA:2088). https://www.orpha.net/en/disease/detail/2088
10. Orphanet. Atypical Fanconi syndrome-neonatal hyperinsulinism syndrome (ORPHA:544628). https://www.orpha.net/en/disease/detail/544628
11. Orphanet. Orphadata — epidemiology and natural history: ORPHA:3337, 2088, 544628 (data of 23 Jun 2026). https://www.orphadata.com/
12. GeneGuidance. Genetic curation database: gene records for GATM, SLC34A1, EHHADH, HNF4A, NDUFAF6 and SLC2A2. 2026 version.
13. ClinGen. Gene-disease validity curations: GATM, SLC34A1, EHHADH, HNF4A, NDUFAF6 [Internet]. https://search.clinicalgenome.org/kb/gene-validity
14. Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, et al. The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a β cell phenotype. J Med Genet. 2014;51(3):165-9. doi:10.1136/jmedgenet-2013-102066. PMID:24285859
15. Al-Qadi M, Jose C, Gaudet J, Thibeault Y. Effects of n-acetyl-l-cysteine on the progression of kidney dysfunction in Acadian variant Fanconi syndrome: a case series. Nephron. 2026;150(5):342-8. doi:10.1159/000549747. PMID:41553940
16. Hazan G, Hershkovitz E, Staretz-Chacham O. Incidence of inherited metabolic disorders in southern Israel: a comparison between consanguinity and non-consanguinity communities. Orphanet J Rare Dis. 2020;15(1):331. doi:10.1186/s13023-020-01578-3. PMID:33239050
17. Santer R, Klepper J. Disorders of glucose and monocarboxylate transporters. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 8, section 8.5 Fanconi-Bickel syndrome (GLUT2 deficiency). doi:10.1007/978-3-662-63123-2_8
18. European Rare Kidney Disease Reference Network (ERKNet). https://www.erknet.org/
19. European Reference Network for Hereditary Metabolic Disorders (MetabERN). https://metab.ern-net.eu/
20. Albuquerque ALB, Dos Santos Borges R, Conegundes AF, Dos Santos EE, Fu FMM, Araujo CT, et al. Inherited Fanconi syndrome. World J Pediatr. 2023;19(7):619-34. doi:10.1007/s12519-023-00685-y. PMID:36729281
21. Bökenkamp A, Ariceta G, Böckenhauer D, Devuyst O, Emma F, van Bennekom D, et al. Dent disease: clinical practice recommendations. Nephrol Dial Transplant. 2025;40(5):852-64. doi:10.1093/ndt/gfaf003. PMID:39794284
22. Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, et al. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. doi:10.1093/ndt/gfu090. PMID:25165189
23. Walter JH, Labrune P, Laforêt P. The glycogen storage diseases and related disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 5, section 5.1.7. doi:10.1007/978-3-662-63123-2_5
24. Musa SA, Ibrahim AA, Hassan SS, Johnson MB, Basheer AT, Arabi AM, et al. Fanconi Bickel syndrome: clinical phenotypes and genetics in a cohort of Sudanese children. Int J Pediatr Endocrinol. 2020;2020(1):21. doi:10.1186/s13633-020-00091-5. PMID:33292488
25. Santer R, Schneppenheim R, Dombrowski A, Götze H, Steinmann B, Schaub J. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat Genet. 1997;17(3):324-6. doi:10.1038/ng1197-324. PMID:9354798
26. Santer R, Steinmann B, Schaub J. Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport. Curr Mol Med. 2002;2(2):213-27. doi:10.2174/1566524024605743. PMID:11949937
27. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 437–438 (Glycogen storage diseases: introduction).
28. Klootwijk ED, Reichold M, Helip-Wooley A, Tolaymat A, Broeker C, Robinette SL, et al. Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. N Engl J Med. 2014;370(2):129-38. doi:10.1056/NEJMoa1307581. PMID:24401050
29. Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N Engl J Med. 2010;362(12):1102-9. doi:10.1056/NEJMoa0905647. PMID:20335586
30. Hartmannová H, Piherová L, Tauchmannová K, Kidd K, Acott PD, Crocker JF, et al. Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. Hum Mol Genet. 2016;25(18):4062-79. doi:10.1093/hmg/ddw245. PMID:27466185
31. Reichold M, Klootwijk ED, Reinders J, Otto EA, Milani M, Broeker C, et al. Glycine amidinotransferase (GATM), renal Fanconi syndrome, and kidney failure. J Am Soc Nephrol. 2018;29(7):1849-58. doi:10.1681/ASN.2017111179. PMID:29654216
32. National Center for Biotechnology Information. ClinVar: variation IDs 156152, 96711, 917900, 917493–917496, 1702865. https://www.ncbi.nlm.nih.gov/clinvar/
33. Mannstadt M, Magen D, Segawa H, Stanley T, Sharma A, Sasaki S, et al. Fanconi-Bickel syndrome and autosomal recessive proximal tubulopathy with hypercalciuria (ARPTH) are allelic variants caused by GLUT2 mutations. J Clin Endocrinol Metab. 2012;97(10):E1978-86. doi:10.1210/jc.2012-1279. PMID:22865906
34. Stöckler-Ipsiroglu S, Mercimek-Andrews S, Salomons GS. Disorders of creatine metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 9, sections 9.1.4, 9.3, 9.5.4. doi:10.1007/978-3-662-63123-2_9
35. Trepiccione F, Iervolino A, D'Acierno M, Siccardi S, Costanzo V, Sardella D, et al. The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI. Sci Transl Med. 2023;15(720):eabn4214. doi:10.1126/scitranslmed.abn4214. PMID:37910600
36. Takayanagi S, Mori KP, Kang Y, Araki M, Matsumoto S, Sagae Y, et al. Functional analysis of a novel pathogenic glycine amidinotransferase mutant in hereditary Fanconi syndrome. Kidney Med. 2026;8(3):101267. doi:10.1016/j.xkme.2026.101267. PMID:41783431
37. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, et al. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol. 2016;27(2):604-14. doi:10.1681/ASN.2014101025. PMID:26047794
38. Prié D, Huart V, Bakouh N, Planelles G, Dellis O, Gérard B, et al. Nephrolithiasis and osteoporosis associated with hypophosphatemia caused by mutations in the type 2a sodium-phosphate cotransporter. N Engl J Med. 2002;347(13):983-91. doi:10.1056/NEJMoa020028. PMID:12324554
39. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118. doi:10.1371/journal.pmed.0040118. PMID:17407387
40. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 390–393 (Diabetes mellitus).
41. Greeley SAW, Polak M, Njølstad PR, Barbetti F, Williams R, Castano L, et al. ISPAD Clinical Practice Consensus Guidelines 2022: the diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2022;23(8):1188-211. doi:10.1111/pedi.13426. PMID:36537518
42. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-8. doi:10.1002/humu.23348. PMID:28967166. Service https://variantvalidator.org (accessed 31 Oct 2026)
43. Arnoux JB, de Lonlay P. Congenital hyperinsulinism and genetic disorders of insulin resistance and signalling. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 6, sections 6.1, 6.3, 6.6. doi:10.1007/978-3-662-63123-2_6
44. Al-Younis I, Martín-Jiménez R, Khan M, Baussan Y, Jose C, Thibeault Y, et al. N-acetyl-L-cysteine improves mitochondrial and oxidative defects in the acadian variant of fanconi syndrome. Exp Biol Med (Maywood). 2025;250:10448. doi:10.3389/ebm.2025.10448. PMID:40488120
45. Rahman S, Thorburn DR, Ball M. Nuclear gene-encoded Leigh syndrome spectrum overview. 2015 Oct 1 [updated 2025 May 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK320989/
46. De León DD, Pinney SE. Permanent neonatal diabetes mellitus. 2008 Feb 8 [updated 2024 Nov 14; revised 2025 Sep 25]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK1447/
47. Sansbury FH, Flanagan SE, Houghton JA, Shuixian Shen FL, Al-Senani AM, Habeb AM, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia. 2012;55(9):2381-5. doi:10.1007/s00125-012-2595-0. PMID:22660720
48. Grünert SC, Schumann A, Baronio F, Tsiakas K, Murko S, Spiekerkoetter U, et al. Evidence for a genotype-phenotype correlation in patients with pathogenic GLUT2 (SLC2A2) variants. Genes (Basel). 2021;12(11):1785. doi:10.3390/genes12111785. PMID:34828390
49. Du T, Xia Y, Sun C, Gong Z, Liang L, Gong Z, et al. Clinical, genetic profile and therapy evaluation of 11 Chinese pediatric patients with Fanconi-Bickel syndrome. Orphanet J Rare Dis. 2024;19(1):75. doi:10.1186/s13023-024-03070-8. PMID:38365697
50. Hodrob T, Abusalameh A, Ismail I, Dweikat I, Rmeilah SA, Sultan M, et al. Genetic, clinical, and biochemical characterization of a large cohort of Palestinian patients with Fanconi-Bickel syndrome. Clin Genet. 2025;107(3):335-40. doi:10.1111/cge.14648. PMID:39548873
51. Niaudet P. Cystinosis. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 26, sections 26.1.1, 26.1.4, 26.1.5. doi:10.1007/978-3-662-63123-2_26
52. Rollier P, Cospain A, Barth M, Milon V, Gueguen N, Homedan C, et al. The recurrent p.Glu3Lys variant in EHHADH is responsible for Fanconi syndrome with early liver dysfunction and mitochondrial abnormalities. Mol Genet Metab Rep. 2025;43:101214. doi:10.1016/j.ymgmr.2025.101214. PMID:40242153
53. Baqai K, Bassetti JA, Kovanlikaya A, Seshan SV, Akchurin O. Fanconi-Bickel syndrome complicated by nephrocalcinosis and GFR decline. Pediatr Nephrol. 2024;39(11):3201-4. doi:10.1007/s00467-024-06388-4. PMID:38847860
54. Ragate DC, Memon SS, Karlekar M, Lila AR, Sarathi V, Jamale T, et al. Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia. J Bone Miner Metab. 2024;42(2):155-65. doi:10.1007/s00774-023-01490-3. PMID:38310177
55. Verjans M, Hindryckx A, Rosier K, Devriendt K, Mekahli D, Bockenhauer D. Antenatal presentation and early postnatal treatment of infantile hypercalcemia type 2. Pediatr Nephrol. 2024;39(10):2911-3. doi:10.1007/s00467-024-06403-8. PMID:38753084
56. Janiec A, Halat-Wolska P, Obrycki Ł, Ciara E, Wójcik M, Płudowski P, et al. Long-term outcome of the survivors of infantile hypercalcaemia with CYP24A1 and SLC34A1 mutations. Nephrol Dial Transplant. 2021;36(8):1484-92. doi:10.1093/ndt/gfaa178. PMID:33099630
57. Pennisi A, Maranda B, Benoist JF, Baudouin V, Rigal O, Pichard S, et al. Nocturnal enteral nutrition is therapeutic for growth failure in Fanconi-Bickel syndrome. J Inherit Metab Dis. 2020;43(3):540-8. doi:10.1002/jimd.12203. PMID:31816104
58. Roque do Vale Afonso M, Nunes P, Travessa AM. Identification of an unusual variant of Fanconi-Bickel syndrome presenting as proximal tubulopathy and short stature. BMJ Case Rep. 2026;19(1):e266997. doi:10.1136/bcr-2025-266997. PMID:41494715
59. Shankar M, Shankar D, K VS, Sreedhara CG. A novel mutation of Fanconi-Bickel syndrome: a case report. J Assoc Physicians India. 2025;73(9S):58-60. doi:10.59556/japi.73.1005. PMID:40955991
60. Chen H, Lyu JJ, Huang Z, Sun XM, Liu Y, Yuan CJ, et al. Case report: Fanconi-Bickel syndrome in a Chinese girl with diabetes and severe hypokalemia. Front Pediatr. 2022;10:897636. doi:10.3389/fped.2022.897636. PMID:35757134
61. De Leon DD, Arnoux JB, Banerjee I, Bergada I, Bhatti T, Conwell LS, et al. International guidelines for the diagnosis and management of hyperinsulinism. Horm Res Paediatr. 2024;97(3):279-98. doi:10.1159/000531766. PMID:37454648
62. Berry GT, Walter JH, Fridovich-Keil JL. Disorders of galactose metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 14, section 14.5. doi:10.1007/978-3-662-63123-2_14
63. Saudubray JM, García-Cazorla Á. Clinical approach to inborn errors of metabolism in paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, sections 1.4.4, 1.4.19, 1.6.6, 1.6.9. doi:10.1007/978-3-662-63123-2_1
64. ClinicalTrials.gov. Trial records for the conditions "Fanconi-Bickel", "Fanconi syndrome", "Acadian", "GLUT2 deficiency" [Internet]. https://clinicaltrials.gov
65. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 491–492.
66. Molin A, Lemoine S, Kaufmann M, Breton P, Nowoczyn M, Ballandonne C, et al. Overlapping phenotypes associated with CYP24A1, SLC34A1, and SLC34A3 mutations: a cohort study of patients with hypersensitivity to vitamin D. Front Endocrinol (Lausanne). 2021;12:736240. doi:10.3389/fendo.2021.736240. PMID:34721296
67. Rahman S, Mayr JA. Disorders of oxidative phosphorylation. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 10, table of manifestations by organ. doi:10.1007/978-3-662-63123-2_10
68. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 410–411 (Pearson syndrome).
69. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 439–448 (Glycogenosis type I — von Gierke disease).
70. Gillis D. Nonsyndromic genetic hyperinsulinism overview. 2003 Aug 19 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK1375/
71. Overduin RJ, Grünert SC, Besouw MTP, Bolhuis MS, Groen J, Schreuder AB, et al. Repurposing SGLT2 inhibitors: treatment of renal proximal tubulopathy in Fanconi-Bickel syndrome with empagliflozin. J Inherit Metab Dis. 2024;47(5):1018-27. doi:10.1002/jimd.12752. PMID:38802119
72. Szmuilowicz ED, Fruzyna E, Madden N, Bolden JR, Kozek A, Vucko E, et al. Management of dysglycemia in a pregnancy complicated by Fanconi-Bickel syndrome. AACE Clin Case Rep. 2024;10(6):224-8. doi:10.1016/j.aace.2024.07.008. PMID:39734506
73. Boehringer Ingelheim. Jardiance (empagliflozin) tablets [prescribing information]. NDA 204629. DailyMed, version published on 2 Feb 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565
74. European Medicines Agency. Jardiance (empagliflozin): EPAR — product information (summary of product characteristics). https://www.ema.europa.eu/en/documents/product-information/jardiance-epar-product-information_en.pdf
75. INFARMED. Infomed — database of medicinal products for human use [records for diazoxide, Proglycem, Diamicron, Jardiance and acetylcysteine]. https://extranet.infarmed.pt/INFOMED-fo/
76. Diazoxide oral suspension [prescribing information]. ANDA 210799. Revision of 7 Aug 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=diazoxide
77. Naylor R, Knight Johnson A, del Gaudio D. Maturity-onset diabetes of the young overview. 2018 May 24. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. https://www.ncbi.nlm.nih.gov/books/NBK500456/
78. Crowley MT, Ng N, Goulden E, Sanchez-Lechuga B, Ludgate S, Burke M, et al. Sulphonylurea efficacy and end-organ outcomes in the management of HNF4A-MODY. Diabet Med. 2025;42(12):e70139. doi:10.1111/dme.70139. PMID:40954556
79. Walker E, Hayes W, Bockenhauer D. Inherited non-FGF23-mediated phosphaturic disorders: a kidney-centric review. Best Pract Res Clin Endocrinol Metab. 2024;38(2):101843. doi:10.1016/j.beem.2023.101843. PMID:38042745
80. De Vries MC, Brown DA, Allen ME, Bindoff L, Gorman GS, Karaa A, et al. Safety of drug use in patients with a primary mitochondrial disease: an international Delphi-based consensus. J Inherit Metab Dis. 2020;43(4):800-18. doi:10.1002/jimd.12196. PMID:32030781
81. Abu Jabal K, Beiruti Wiegler K, Sgayer I, Frank Wolf M, Jeries G, Bathish Y. Multidisciplinary management and individualized care in pregnancy with Fanconi-Bickel syndrome: a case report and review of the literature. Int Med Case Rep J. 2025;18:1237-45. doi:10.2147/IMCRJ.S531843. PMID:41019314
82. DeLeon AM, Gaiha RD, Peralta FM. The successful anesthetic management of a cesarean delivery in a patient with Fanconi-Bickel syndrome. Case Rep Anesthesiol. 2022;2022:3220486. doi:10.1155/2022/3220486. PMID:35846393
83. Association for Glycogen Storage Disease (UK). https://www.agsd.org.uk/