Dent Disease (Types 1 and 2) and Lowe Syndrome

X-linked proximal tubulopathies caused by defective endocytosis in the proximal tubule: Dent disease type 1 (CLCN5), Dent disease type 2 (OCRL) and the oculocerebrorenal syndrome of Lowe (OCRL), which form a clinical and molecular spectrum with low-molecular-weight proteinuria as a constant finding.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Founding clinical descriptions

The first entity of the spectrum to be described was the oculocerebrorenal syndrome. In 1952, Lowe, Terrey and MacLachlan published in the American Journal of Diseases of Children their observation of boys with organic aciduria, decreased renal ammonia production, hydrophthalmos and mental retardation, which they proposed as an autonomous clinical entity [25]. The combination of congenital cataract, neurological deficit and renal tubular dysfunction described in that paper remains the triad that defines the syndrome [26].

Dent disease has a more fragmented history, because the same disorder was described under different names in different countries before the gene was known. In 1964, Dent and Friedman reported hypercalciuric rickets associated with renal tubular damage in two unrelated patients [27]. In 1991, Frymoyer and colleagues studied a family from upstate New York with 162 members over six generations, in which nine males had calcium stones and proteinuria from childhood, followed by nephrocalcinosis, a urinary concentrating defect and renal failure, with transmission through the mothers, no male-to-male transmission and biopsies showing tubular atrophy, interstitial fibrosis and glomerulosclerosis; they named it X-linked recessive nephrolithiasis (XRN) and observed that the disease had not recurred in a patient transplanted seven years earlier [28]. In 1993, Bolino and colleagues described an Italian family with X-linked recessive hypophosphataemic rickets, in which five males had rickets or osteomalacia, hypophosphataemia, hypercalciuria and proteinuria and developed nephrocalcinosis with progressive renal failure in adulthood, and mapped the locus to Xp11.2 [17]. In 1994, Wrong, Norden and Feest brought together 15 males and 10 females from five families, spanning up to three generations and including the two original patients of Dent and Friedman, with a familial form of renal Fanconi syndrome with hypercalciuria, LMWP, nephrocalcinosis and slowly progressive renal failure, much more severe in males, and proposed the name Dent's disease [29]. In Japan, annual school urine screening identified children with "idiopathic" LMWP: Suzuki and colleagues described in 1985 five boys with asymptomatic proteinuria in whom more than half of the urinary proteins had a molecular weight below 40 kDa, and in the same year Geary and colleagues described three cases in England, showing that the entity was not confined to Japan [18]; Igarashi and colleagues, in 1995, described seven such patients and suggested that the entity was identical to British Dent disease [30].

1.2. Milestones in the molecular discovery

The Lowe syndrome locus was mapped to Xq24–q26 by Silver, Lewis and Nussbaum in 1987, by linkage analysis with restriction fragment length polymorphisms in four families [31]. In 1992, Attree and colleagues cloned the OCRL gene from the breakpoint of an X;autosome translocation in a woman with the syndrome: the transcript was absent in the two women with de novo translocations and absent or of abnormal size in 9 of 13 affected males, and the predicted protein had 71% similarity to inositol polyphosphate 5-phosphatase, which led to the syndrome being proposed as an inborn error of inositol phosphate metabolism [32].

XRN was linked to Xp11.22 by Scheinman and colleagues in 1993, in a family of 102 members [11]. In 1994, Fisher and colleagues identified in a Dent family a microdeletion of less than 515 kb in this region and isolated a cDNA of a chloride channel of the ClC family, expressed mainly in the kidney and absent in patients with the microdeletion [33]; the following year they characterised the complete open reading frame of CLCN5, which encodes a predicted protein of 746 amino acids, with 12 coding exons over 25–30 kb [34]. In 1996, Lloyd and colleagues demonstrated, in 11 families, CLCN5 variants (nonsense, missense, splicing, an intragenic deletion and a whole-gene microdeletion) that abolished or reduced chloride currents in Xenopus oocytes, in patients with Dent disease, XRN and XLRH, establishing a common molecular basis for three hereditary stone-forming diseases [4]. In 1997, the same group found four CLCN5 variants in four Japanese families with idiopathic LMWP, unifying the Japanese form as well [35].

Genetic heterogeneity was recognised in 2004, when Hoopes and colleagues found CLCN5 variants in only 19 of 32 males meeting strict criteria for Dent disease, with no clinical differences between the groups [36]. In 2005, the same group identified OCRL variants in 5 of 13 families without a CLCN5 variant, with markedly reduced phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity in fibroblasts, normal ocular slit-lamp examination, absence of metabolic acidosis and mild intellectual disability in three of the five patients, defining Dent disease type 2 [37]. In 2009, Shrimpton and colleagues showed that one of the original patients of Dent and Friedman had an OCRL variant, that is, Dent disease type 2 [38]. The clinical practice recommendations of ERKNet (European Rare Kidney Disease Reference Network) and ESPN (European Society for Paediatric Nephrology), published in 2025, are the first formal clinical guidance document for Dent disease [14].

1.3. Current nomenclature and classifications

OMIM keeps four phenotype entries linked to CLCN5, which it describes together as the "Dent disease complex" or X-linked hypercalciuric nephrolithiasis [17], corresponding to the designations used before the gene was discovered: Dent disease 1 (300009), X-linked recessive hypophosphataemic rickets (300554), X-linked recessive nephrolithiasis with renal failure (310468) and low-molecular-weight proteinuria with hypercalciuric nephrocalcinosis (308990). These forms differ in the severity of the bone disease and of the renal failure, but are the same molecular entity [3, 4]. Orphanet groups them under subtype ORPHA:93622 and keeps the historical names as synonyms of ORPHA:1652 [1, 2]. GeneReviews uses the single designation "Dent disease" and does not recognise other allelic phenotypes of CLCN5 [10].

The Orphanet classification is hierarchical: Dent disease (ORPHA:1652, disorder level) is divided into type 1 (ORPHA:93622, isolated renal phenotype, CLCN5) and type 2 (ORPHA:93623, frequent but sometimes mild and unrecognised extrarenal involvement, OCRL); Lowe syndrome (ORPHA:534) is an independent entity, classified as a malformation syndrome [1, 2, 5, 7]. Saudubray's reference textbook of metabolic diseases classifies Lowe syndrome and DD2 among the disorders of phosphoinositide phosphorylation and among the disorders of cellular trafficking, alongside other 5-phosphatases (INPP5E, Joubert syndrome; INPP5K, congenital muscular dystrophy with cataracts and intellectual disability) [39, 40]. GeneReviews prefers the formal term "oculocerebrorenal syndrome" to avoid the eponym, but accepts "Lowe syndrome" as a synonym [8].

About 25–35% of patients with a clinical diagnosis of Dent disease have no variant in CLCN5 or OCRL [14]. GeneReviews recorded 20 of 110 males in this situation, in an unpublished observation by the authors [10]. This group is informally called "Dent 3" by the UK Kidney Association, with no gene or OMIM entry of its own [41]. It is not a single molecular entity, and some of these cases are phenocopies of other genetic causes [42].

1.4. Definition of the entities and organisation of the article

Dent disease is defined as an X-linked proximal tubulopathy with obligatory LMWP, usually accompanied by hypercalciuria and at least one other finding among nephrocalcinosis, nephrolithiasis, haematuria, hypophosphataemia, CKD or a family history compatible with X-linked inheritance [10, 14]. DD1 is the form caused by hemizygous CLCN5 variants. DD2 is the form caused by OCRL variants, in which the renal picture is accompanied by mild extrarenal manifestations, without the dense congenital cataracts, tubular acidosis and severe neurological deficit of Lowe syndrome [8, 14]. Lowe syndrome is an X-linked multisystem disease caused by OCRL variants, with dense congenital cataracts in all affected boys, central hypotonia, intellectual disability and proximal tubular dysfunction with progressive CKD [7, 8]. Because DD2 and Lowe syndrome are allelic and form a clinical continuum, the three entities are treated as a class, with dedicated subsections where the clinical picture, diagnosis or management diverge [43, 44].

2. Molecular Genetics and Pathophysiology

2.1. The endocytic pathway of the proximal tubule

Low-molecular-weight proteins filtered at the glomerulus, such as retinol-binding protein (RBP, retinol-binding protein), β2-microglobulin and α1-microglobulin, are normally almost entirely reabsorbed by the proximal tubule, through endocytosis mediated by the brush-border receptors megalin and cubilin, and degraded in lysosomes [8, 10]. Albumin lies at the upper size limit of these proteins and the small filtered fraction is reabsorbed by the same pathway [8]. Endocytosis depends on progressive acidification of endosomes, which separates ligands from receptors and allows the latter to recycle to the apical membrane. In Dent disease and Lowe syndrome, the defect in this pathway results in urinary loss of LMWP, albumin and lysosomal enzymes such as N-acetyl-β-D-glucosaminidase (NAG), with no specific circulating biochemical deficiency [3, 8].

2.2. CLCN5 and the ClC-5 exchanger

The CLCN5 gene is located at Xp11.23 (HGNC:2023; NCBI Gene 1184; UniProt P51795) [3]. The transcript used in GeneReviews and in the historical literature (NM_000084, 12 exons, NP_000075.1 isoform of 746 amino acids) differs from the current MANE Select transcript, NM_001127898.4, which encodes an 816-amino-acid isoform (NP_001121370.1) with 70 additional codons at the amino-terminal end; the same variant therefore has different nucleotide and amino acid numbers depending on the transcript, with a constant offset of 210 nucleotides and 70 codons [10, 13]. The ClC-5 protein is a voltage-dependent electrogenic 2Cl⁻/H⁺ exchanger, expressed in the kidney in proximal tubular cells, in α- and β-intercalated cells of the cortical collecting duct and in the thick ascending limb of the loop of Henle, and located in the subapical early endosomes involved in the reabsorption of filtered proteins [10, 14]. Chloride entry mediated by ClC-5 is required for the vacuolar proton ATPase to acidify the endosomal lumen; without it, receptor-mediated endocytosis fails [3].

Mouse models with loss (knock-out) or alteration (knock-in) of Clcn5 show loss or reduction of megalin and cubilin at the brush border, defective endocytosis and lysosomal processing, and impaired internalisation of apical transporters [14]. The functional classification of Grand and colleagues, applied to nine missense variants, distinguished four groups: retention in the endoplasmic reticulum (group 1); processed protein but without electrical currents, with failed endosomal acidification (group 2); abnormal subcellular localisation of the mature protein (group 3); and protein at the plasma membrane with reduced currents (group 4) [10, 45]. A mouse carrying the ClC-5 p.Glu211Ala variant (published designation of the murine protein, with no associated human transcript), which uncouples chloride and proton transport, has more severe disease than the null mouse (polyuria, interstitial fibrosis, glomerular changes, cysts, reduced WT1 and nephrin), suggesting that missense variants may have effects that simple loss of function does not explain [46].

2.3. OCRL and the OCRL1 5-phosphatase

The OCRL gene is located at Xq26.1 (HGNC:8108; NCBI Gene 4952; UniProt Q01968) and has 24 exons, 23 of them coding [6, 10]. The alternative exon 18a (24 base pairs, 8 additional amino acids) is expressed mainly in neural tissue; the MANE Select transcript, NM_000276.4 (isoform a, NP_000267.2), includes it, and isoform b, NM_001587.4, does not, so positions downstream of this exon differ by 8 codons between the two transcripts [10, 13]. OCRL1 is an 884-amino-acid inositol polyphosphate 5-phosphatase that removes the phosphate at position 5 of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), located in the trans-Golgi network, clathrin-coated pits, early endosomes, lysosomes and the primary cilium [6, 10]. It is expressed in brain, skeletal muscle, heart, kidney, lung, gonads, fibroblasts, placenta and platelets [8].

Loss of OCRL1 activity leads to accumulation of PI(4,5)P2 on endosomal membranes, causing uncontrolled actin polymerisation into "cages" around organelles and defective trafficking of receptors such as megalin; accumulation of PI(4,5)P2 on autolysosomal membranes disturbs autophagic flux [14]. The effects are pleiotropic and involve membrane composition, the actin cytoskeleton, endocytosis, the lysosomal-autophagic pathway and the formation and function of the primary cilium; GeneReviews links the endocytic defect mainly to the LMWP and the other tubular abnormalities, and the ciliary abnormalities mainly to the ophthalmological complications [8]. In platelets, OCRL1 takes part in the RhoA pathway, and its absence explains a defect of primary haemostasis with normal coagulation [47, 48]. The 2026 French PNDS mentions the expression of OCRL in podocytes, suggesting a direct role in glomerular dysfunction, and summarises the platelet defect: lower OCRL content in platelets, defective spreading, actin disorganisation and reduced myosin light chain phosphorylation, with preserved secretion and integrin activation, but defective adhesion to fibrinogen and clot retraction; the cytoskeletal abnormality during megakaryopoiesis would explain the mild thrombocytopenia [24]. The mechanism is loss of function [8]. The clinical overlap between DD1 and DD2 is explained by a common defect of endosomal vesicular trafficking [10].

2.4. Calcium, phosphate and vitamin D metabolism

The hypercalciuria of Dent disease is accompanied by elevated or upper-normal 1,25-dihydroxyvitamin D (1,25(OH)2D) and low or lower-normal intact parathyroid hormone (PTH), and decreases largely with dietary calcium restriction, indicating that intestinal hyperabsorption is its main component [10]. Urinary loss of vitamin D-binding protein reduces tubular reabsorption of 25-hydroxyvitamin D (25-OH-D), while synthesis of 1,25(OH)2D increases; the result is slightly low 25-OH-D and high-normal calcitriol even in late CKD, and the usual assays, which measure the total rather than the free fraction, become difficult to interpret [14]. In a Mayo Clinic study of 10 adults and 9 children with DD1, fibroblast growth factor 23 (FGF23) was lower than in adults with idiopathic calcium stone disease and correlated with 24,25-dihydroxyvitamin D; the ratio of 25-OH-D to 24,25(OH)2D was above the limit in 5 of 10 adults and 6 of 9 children, and patients with low 24,25(OH)2D had lower FGF23, higher 1,25(OH)2D and more calciuria and proteinuria [49].

Progression to CKD still lacks a complete explanation; proposed mechanisms include maladaptive proliferation, dedifferentiation, autophagy and metabolic adaptation of tubular cells, overload of distal segments by tubular proteinuria and expression of ClC-5 and OCRL in podocytes, which would explain the glomerular lesions seen on biopsy [14]. The mechanism of stone formation and renal failure has not been elucidated, and renal deterioration also occurs without nephrocalcinosis [10].

2.5. Inheritance, penetrance and expression in females

All three entities have X-linked recessive inheritance. Penetrance in hemizygous males is complete, with variable severity within the same family [8, 10]. In Dent disease, more than half of carrier females have mild LMWP, about 30% have hypercalciuria, about 20% later develop nephrocalcinosis and stones, and CKD is occasional; typical manifestations in a female are rare and are attributed to skewed X inactivation [14]. In Lowe syndrome, about 95% of post-pubertal heterozygous females have characteristic lens opacities [8]. The full clinical picture in a female requires an X;autosome translocation with a breakpoint in OCRL, two pathogenic variants or extremely skewed inactivation of the normal X, as in the family described by Cau and colleagues, in which a familial X-inactivation defect inherited from the father left the maternal X carrying the variant active in 100% of cells [8, 50]. The first female with overt DD1 due to skewed X inactivation was published in 2024 and is described in section 10 [51].

2.6. CLCN5 variant spectrum and nomenclature

The number of known variants has grown over time and the counts in the sources depend on their date: GeneReviews, using 2016 data from the Human Gene Mutation Database (HGMD), reports 228 pathogenic variants in the text and 245 in the molecular testing table, about 53% truncating, 39% non-truncating and 7–8% complex rearrangements, 74% of them described in a single family [10]; the 2025 recommendations report more than 300 variants, with no hotspots [14]; and the CLCN5 database of the Mayo Clinic and the Rare Kidney Stone Consortium (RKSC), published in 2026, brings together 524 unique pathogenic or likely pathogenic variants (31% missense, 37% insertions/deletions, 14% nonsense, 13% splicing, 5% large deletions), 74% reported only once, with the highest density in exon 10 of NM_001127898.4 and constrained functional regions in helices H and O–Q [52]. De novo variants occur in about 12% of patients with DD1 [14, 53]. The review by Mansour-Hendili and colleagues brought together 192 published variants in 377 males and a French cohort of 117 patients from 90 families, with 42 novel variants [53].

The following table converts the CLCN5 variants mentioned in the text to the MANE transcript; all correspondences were obtained from VariantValidator (GRCh38) and none was calculated manually [13]. The variant described in GeneReviews as c.1637A>G p.Lys546Glu encodes, according to VariantValidator, p.(Lys546Arg) on NM_000084.5; the confirmed form is the one used here [10, 13].

2.7. OCRL variants and the boundary between DD2 and Lowe syndrome

About 360 pathogenic OCRL variants have been described [56]. In Lowe syndrome, GeneReviews places 93% of variants in exons 10–18 and 19–23, mainly in exon 15 [8]. The 2016 data in the Dent GeneReviews listed 42 DD2 variants, 85% private, with 47.5% truncating, 47.5% non-truncating and 5% multiexon deletions, including a deletion of exons 3–4 [10, 57]. Recker and colleagues found, in 28 new patients with Lowe syndrome, hotspots at CpG dinucleotides, a carrier mother in 30.4% of those investigated and a complete OCRL deletion with repetitive elements at the breakpoints [58].

The position of the variant is the main known determinant of phenotype. Truncating DD2 variants cluster in exons 1–7, which encode the pleckstrin homology (PH) domain, and those of Lowe syndrome in exons 8–24; missense DD2 variants lie mainly in exons 4–15, in the catalytic domain [14, 44]. The Lowe GeneReviews refers to the "first 8 exons" and the Dent GeneReviews to the "first 7 exons"; later functional studies clarify the discrepancy. Sakakibara and colleagues cloned an OCRL isoform initiated at codons in exon 8: the full gene gives rise to proteins of 105 and 80 kDa, DD2 variants only the 80-kDa protein (with more than 50% enzyme activity) and Lowe variants neither, which explains why a premature stop codon upstream of exon 8 spares the short isoform [59]. In an analysis of 28 splicing variants in minigenes, variants in exons 1–7 were associated with DD2 and those in exons 9–24 with Lowe syndrome, and the variant NM_000276.4:c.561-2A>G (NC_000023.11:g.129558838A>G), which affects exon 8, was associated with DD2 because it preserves the alternative initiation codon Met206 (the alternative codons are Met187 and Met206) [60]. In a Chinese series of 83 children, truncating variants accounted for 70.8% (34/48) in patients with Lowe syndrome and 31.4% (11/35) in patients with DD2 [61]. The correlation is not absolute: five OCRL variants have been described with a Lowe phenotype in one family and a DD2 phenotype in another, and codon 318 is a DD2 hotspot [14, 44]. Unrelated patients with the same variant may have different clinical courses, although no family has been described with one male with Lowe syndrome and another with DD2 due to the same variant [8].

The DD2 variants of Shrimpton and colleagues (R301H, G304E, L56DfsX1, S149X, P161PfsX3, M170IfsX1) are published designations in historical protein notation, with no transcript given in the source [38].

2.8. Genotype–phenotype correlations in CLCN5

In the French cohort of Blanchard and colleagues (109 males with DD1), severe variants (large deletions, frameshift, nonsense, splicing) and missense variants did not differ in age at diagnosis, estimated glomerular filtration rate (eGFR), proteinuria or hypercalciuria [67]. The European survey by Burballa and colleagues (163 males with a confirmed variant) found reduced GFR more often with variants affecting the pore or the cystathionine β-synthase (CBS) domains than with those causing premature termination [68]. In the RKSC registry (162 patients from 121 families, 82 variants classified according to the American College of Medical Genetics and Genomics), carriers of truncating variants had earlier stone formation and greater albuminuria, and the lifetime burden of stone events correlated with the course of CKD; of the 13 patients who reached kidney failure, 11 had a truncating variant and 2 a missense variant that markedly reduces Cl⁻/H⁺ exchange; 84% of non-truncating variants lay in the middle exons, in the ClC domain [69]. The family with the p.(Gly506Glu) variant (historical) illustrates intrafamilial variability, with phenotypes ranging from severe disease in several members to isolated hypercalciuria without proteinuria, nephrocalcinosis or CKD in one individual [10, 54]. It is unknown how many carriers of CLCN5 variants have only asymptomatic hypercalciuria or proteinuria without CKD [10].

2.9. Allelic disorders, modifiers and phenocopies

For CLCN5, GeneReviews recognises no phenotypes other than those encompassed by Dent disease [10]. For OCRL, the allelic phenotypes are DD2 and Lowe syndrome; in a 2012 compilation cited by OMIM, OCRL variants were found in 43 of 72 families (59.7%) with a Dent phenotype and no CLCN5 variant, and in a series of 8 boys from 6 families with DD2 none had tubular acidosis, about half had nephrocalcinosis and two had cognitive impairment, one of them with early nuclear lens densities [19]. Intermediate patients exist between the two phenotypes: three patients with DD2 with mild peripheral cataract and nine with some intellectual disability in a series of 93 patients [43]; a patient from southern China with Lowe syndrome without congenital cataract [70]. The typical manifestations of DD2 (mild intellectual disability, rare cataract, raised muscle enzymes) should not be attributed to a CLCN5 variant [3]. No genetic modifiers with clinical application have been identified. Cases with a clinical diagnosis of Dent disease without a CLCN5 or OCRL variant include phenocopies with another cause: a patient with an atypical Dent phenotype, with features of focal segmental glomerulosclerosis (FSGS) and an Ellis-van Creveld-like syndrome, had a variant of uncertain significance (VUS) in WT1 and a pathogenic variant in EVC2 [42]; a patient with an OCRL VUS also had a pathogenic 16p11.2 deletion [56].

3. Clinical Spectrum and Manifestations by System

3.1. Dent disease: presentation and evolution with age

In boys younger than about 10 years, Dent disease often presents only as asymptomatic LMWP and hypercalciuria, detected on a urine test performed for another reason or on screening; stones or nephrocalcinosis may be present and, less often, aminoaciduria, phosphaturia and glycosuria [10]. The most common presentation in the European survey of 163 males with DD1 was proteinuria (49.1%) [68]. Proteinuria may reach several grams per day and lead to a misdiagnosis of steroid-resistant nephrotic syndrome; other patients present with rickets, stones with or without nephrocalcinosis or undiagnosed CKD, and some are diagnosed only in adulthood [14]. In the Korean cohort published in 2026 (48 males from 44 families, median age at diagnosis 6.8 years, 42 with DD1), the classic triad (LMWP, hypercalciuria and nephrocalcinosis or stones) was present at diagnosis in 37.0% and isolated LMWP in 26.1% [71].

The manifestations change with age. LMWP is present throughout the course of the disease; hypercalciuria is seen in 61–73% of children and young adults, but in only 14–19% of adults, possibly because of the fall in GFR; nephrocalcinosis is detectable from childhood and stones appear later [14]. In the French cohort, hypercalciuria was absent in 40% of patients younger than 30 years and in 85% of those older than 30 years [67]; in the European survey, it was present at the last visit in 73.4% of children and 19.0% of adults [68]. In series from Europe and North America, hypercalciuria was described in more than 90% of patients, compared with about 50–70% in series from Japan, Korea and China; urinary calcium values may be normal, but low-normal values are not seen [14].

Proteinuria reaches the nephrotic range in about half of patients, with a substantial albumin fraction, but plasma albumin is normal or near normal and there is no nephrotic syndrome [14]. Complete Fanconi syndrome is usually absent and glycosuria is absent or mild in most [14]. Plasma phosphate remains low even in advanced CKD; plasma potassium falls by about 0.1 mmol/L per decade and half of patients older than 18 years have hypokalaemia (<3.5 mmol/L) despite the fall in eGFR; bicarbonate is normal in most until CKD stage 5 [14, 67]. Wrong and colleagues also described a urinary concentrating defect, with maximum osmolalities of 300–400 mOsm/kg, mainly in adults with advanced CKD [14].

3.2. Frequency of findings in DD1 and DD2

The table compiles the frequencies published in the main series, according to the 2025 recommendations [14].

In DD2, creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) are above normal in most patients, although less so than in Lowe syndrome; congenital cataract strongly suggests DD2, and mild intellectual disability and short stature (mean height standard deviation (SD) −2.1) favour DD2 [14]. In a series cited by GeneReviews, mean height was −0.58 SD in DD1 and −2.10 SD in DD2 [10]. The own cohort of Gianesello and colleagues (35 males with DD2, plus a review of all published cases) found at least one extrarenal manifestation in 39%, muscle being the most frequent (52%) and the eye the least frequent (11%), and impaired growth in 27% of patients with DD1 and 54% of those with DD2 [14, 44]. The Japanese comparison of 85 males (72 with DD1, 13 with DD2) found in DD2 higher values of AST, alanine aminotransferase (ALT), LDH, CK, potassium, phosphate, uric acid, urinary protein/creatinine (median 3.5 versus 1.6 mg/mg) and urinary calcium/creatinine, and lower eGFR (median 84 versus 127 mL/min/1.73 m²), with no differences in nephrocalcinosis, intellectual disability or autism spectrum disorders [72]. Several studies suggest earlier onset of loss of function in DD2, which the French cohort did not confirm [14, 67]. In the comparison of 93 patients with DD1, DD2 and Lowe syndrome, nephrocalcinosis was more prevalent in DD1 and tubular acidosis, aminoaciduria and renal failure more frequent in Lowe syndrome, and height was intermediate in DD2, supporting a DD2–Lowe phenotypic continuum [43].

3.3. Renal function: cohorts and natural history

GeneReviews states that 30–80% of affected males reach end-stage kidney disease between 30 and 50 years of age, sometimes only in the sixth decade or later, and that deterioration also occurs without nephrocalcinosis [10]. The 2025 recommendations place kidney failure between the third and fifth decades, in the same proportion of 30–80% of males [14]. The published cohorts allow the loss of function to be described in more detail and show differences between populations and between recruitment periods, which may reflect the age of the patients included and the mode of ascertainment more than biological differences.

On biopsy, when performed, interstitial fibrosis and mainly global, rather than focal segmental, glomerulosclerosis are seen, with calcinosis in about 20%; the degree of global sclerosis correlates with age and function, with no independent prognostic value [14]. Focal global sclerosis is very frequent in Dent disease and cases misdiagnosed as FSGS continue to be published [10, 76, 77]. Some males with a CLCN5 variant and a family history reached kidney failure with proteinuria, without stones, nephrocalcinosis or bone disease [10].

3.4. Dent disease: bone, growth and extrarenal manifestations

Hypophosphataemic rickets and osteomalacia were the presentation of Dent and Friedman and define the former designation XLRH [4, 27]. Bone disease was not prominent in a French series and more prominent in a Chinese series, for reasons that are unclear [10, 78]. Alkaline phosphatase was elevated in all patients with clinical rickets in Wrong's series [10]. Short stature is common but mild in DD1, and more marked in DD2 [10, 14]. Urinary loss of RBP can cause vitamin A deficiency, with night blindness and dry eyes, reversible with replacement [14]. Cortical and medullary renal cysts have been described in 33% of patients with DD1 [14]. Muscle enzymes are frequently raised, with no need for specific screening [10].

3.5. Lowe syndrome: manifestations by system

Eyes. Dense congenital cataracts are present in all affected boys; they are present at birth but may only be detected in the first weeks of life, and are rarely so mild that they do not compromise visual development until adolescence [8]. They result from abnormal metabolism and migration of the embryonic lens epithelium [8]. Infantile glaucoma occurs in about 50%, is difficult to control, causes buphthalmos and progressive visual loss and is often detected only after removal of the lenses [8]. Microphthalmia, enophthalmos, strabismus, retinal dystrophy, corneal scarring and calcific band keratopathy with corneal keloid may be present [8]. Corrected visual acuity is rarely better than 20/100, nystagmus appears early even after uncomplicated early surgery, and self-stimulation (hand flapping, eye rubbing, rocking) is frequent; progression may lead to blindness [8]. In a series of 6 children operated on at a mean age of 9 weeks, all had nystagmus, 5 had strabismus and secondary glaucoma developed in 5 of 12 eyes of 3 children [79]. The 2026 French PNDS reports nystagmus in 69–100%, strabismus in 35–80% (with good surgical results when there is no severe low vision), glaucoma in about 50–55% and corneal scarring in 18%; the latter are subepithelial fibrovascular proliferations, appear mainly after 5–7 years and may be favoured by contact lenses [24]. Glaucoma may be congenital, associated with the cataract, or secondary to surgery; gonioscopy shows an open angle with anterior iris insertion, a narrow ciliary band and a poorly visible scleral spur [24]. The risk of secondary glaucoma increases with surgery at a younger age, with small axial length and corneal diameter, with thick pachymetry and with persistent fetal vasculature, and secondary glaucoma is bilateral in 45%; on ultrasound biomicroscopy, a fusiform iris and an involutional lens might be associated with greater risk [24]. More than half of patients end up with a final visual acuity below 1/10, mainly due to glaucoma, followed by corneal lesions and retinal disease [24].

Central nervous system and behaviour. Hypotonia of central origin is present at birth, with tendon reflexes generally absent, and improves slowly without normal tone and strength ever being reached; it causes difficulties with head control, sucking and swallowing [8]. About 25% of boys walk unsupported between 3 and 6 years and 75% between 6 and 13 years; some never walk [8]. Seizures occur in about 50%, mainly generalised and before 6 years [8, 80]. Intellectual disability is almost universal: 10–25% of patients have low-normal or borderline intelligence, about 25% mild to moderate disability and 50–65% severe to profound disability [8, 81]. In a series of 47 males, mean intelligence quotient was in the range of moderate disability, with a wide distribution compatible with normal intelligence in some cases, and maladaptive behaviours (stubbornness, tantrums, stereotypies) were very frequent, in more than 80% [81]. Obsessive-compulsive behaviours, violent tantrums, aggression and self-injury have been described [8]. Language is delayed, but most communicate verbally to some extent by 7 years [8]. Some patients have hyperosmia or hyperacusis [58]. In adulthood, most live with their family; some live in group homes or independently with support [8]. Induced pluripotent stem cell (iPSC) models show reduced neuronal excitability, increased Notch-dependent gliogenesis and mitochondrial dysfunction with impaired Sonic Hedgehog and ciliary signalling, with no established clinical translation [82, 83]. The 2026 PNDS places the median age of independent walking at about 4 years, rarely before 3 and sometimes only acquired between 6 and 13 years; the words "dada" and "mama" appear on average at 26 months, understanding of simple action verbs at around 3 years and word combinations after 3 years, with comprehension exceeding expression [24]. Mean IQ lies between 40 and 60, and about 25% of males would have an IQ ≥70 [24]. Areflexia is not accompanied by electrophysiological abnormalities of nerve or muscle; hypotonia, of central origin, may be aggravated by malnutrition and metabolic disturbances, improves with age without disappearing and, together with osteomalacia, favours scoliosis and hypermobility [24]. The most frequently reported neurodevelopmental comorbidities are autism spectrum disorder, formally diagnosed in only a minority, and obsessive-compulsive disorder; attention deficit hyperactivity disorder, generalised anxiety, specific phobias and impulse control disorders are occasional diagnoses, and families describe sensory hypersensitivity [24]. Self- or other-directed aggressive behaviours, irritability, complex repetitive movements and stereotypies appear mainly at school age [24]. Epilepsy occurs in 25–50%, with a median age at onset between 5 and 9 years; generalised tonic-clonic seizures and absences predominate, followed by myoclonus and tonic, atonic and focal seizures [24]. Brain magnetic resonance imaging often shows non-specific abnormalities (ventriculomegaly, hypoplasia of the corpus callosum or cerebellum) and bilateral, symmetrical periventricular or peritrigonal white matter lesions, hyperintense on T2 and hypointense on T1, with small millimetric cysts [24].

Kidney. LMWP is detectable soon after birth and may precede aminoaciduria [8, 84]. All boys have LMWP and albuminuria, which reaches the nephrotic range (>1 g/m²/day) in more than half, with normal serum albumin [8]. Most have aminoaciduria; some have complete Fanconi syndrome (bicarbonaturia with proximal tubular acidosis, phosphaturia with hypophosphataemia and rickets, sodium and potassium wasting, polyuria), and few have glycosuria [8]. Others have little bicarbonaturia and phosphaturia, but hypercalciuria with nephrocalcinosis and calcium oxalate and phosphate stones, in a Dent-like picture [8]. Bockenhauer and colleagues, in 16 patients, found LMWP and albuminuria in all, raised lysosomal enzymuria in the 11 assessed, hypercalciuria in 15, aminoaciduria in 14, a need for bicarbonate in 7 and for phosphate in 3, and none with detectable glycosuria or clinical rickets, and described the nephropathy as a selective proximal tubulopathy rather than a Fanconi syndrome [85]. Symptoms of the tubulopathy generally appear at 6–12 months [8, 10]. Progressive glomerulosclerosis leads to CKD and kidney failure between the second and fourth decades, according to the 2019 GeneReviews [8]; the older Dent GeneReviews reports failure "after 10–20 years" [10], and the cohort data in section 3.6 place the median at 32 years [21]. The 2026 French PNDS reports, in severely expressed forms, early growth delay with polyuria, hyperchloraemic acidosis in 30–80%, hypophosphataemia in 50% (with signs of rickets towards the end of the first year), hypercalciuria and hyperaminoaciduria in 80%, a tendency to hypokalaemia due to secondary hyperaldosteronism and frequent salt wasting; nephrocalcinosis or calcium stones affect half of patients, with no correlation with age or calciuria, and hypercalciuria decreases with GFR [24]. In moderate forms, growth is normal and monitoring shows mild acidosis, slight hypophosphataemia, LMWP and a tendency to hypercalciuria [24]. The protocol defines the nephrotic range of proteinuria as a protein/creatinine ratio >300 mg/mmol (3 g/g) in adults and >200 mg/mmol (2 g/g) in children; being tubular in origin, it is accompanied by normal serum proteins, but true nephrotic syndrome is possible owing to glomerular dysfunction linked to OCRL1 [24]. Diagnosis is sometimes late, at 2–4 years, in late childhood or, exceptionally, in young adulthood, even though the first signs appear in the first weeks of life [24].

Growth and feeding. Length at birth is usually normal, but growth velocity is low and short stature is evident by one year of age; mean adult height is about 155 cm [8]. In the National Institutes of Health (NIH) study of 23 patients, linear growth slowed after the first year and bone age lay between chronological and height age [86]. CKD, acidosis and rickets contribute to short stature [8]. Weight gain is slow owing to insufficient caloric intake; gastro-oesophageal reflux is common, especially in infancy, and aspiration and ineffective cough lead to atelectasis, pneumonia and chronic lung disease; abdominal hypotonia causes chronic constipation and hernias, mainly inguinal [8]. The 2026 PNDS treats oral feeding difficulties as a priority, because of the risk to the efficacy and safety of feeding, estimates gastro-oesophageal reflux at about 25% and describes constipation as very frequent, linked to hypotonia and dehydration [24]. It also describes delayed bone age and prolonged post-pubertal growth, with variable final height, generally subnormal [24].

Bone and joints. Bone disease results from phosphaturia, insufficient renal production of 1,25(OH)2D, chronic acidosis and CKD, and shows classic rickets on radiography; some patients have repeated pathological fractures with poor healing even when the Fanconi syndrome is corrected [8]. Scoliosis occurs in about 50%, and hypermobility causes dislocations of the hips and knees; in adolescents and adults, joint swelling, arthritis, tenosynovitis and subcutaneous fibromas appear on the hands, feet and areas of repeated trauma [8]. Many patients develop disabling arthropathy [26]. The 2026 PNDS organises musculoskeletal involvement into four mechanisms: hypotonia with joint hypermobility, responsible for chronic pain, hip and knee dislocations, genu valgum and scoliosis (50%); rachitic deformities due to phosphaturia and acidosis; multifactorial bone fragility, with vertebral fractures (platyspondyly, dorsal kyphosis) and long-bone fractures; and a specific rheumatological involvement, with deforming arthropathy, probably metabolic, palmoplantar fibrosis, and symmetrical polyarticular arthritis and tenosynovitis (proximal interphalangeal, metacarpophalangeal, wrists, elbows, knees and ankles), which appear in 50% at around 20 years and cause contractures and retractions [24]. Fractures are more frequent before 15 years, predominate in the lower limbs and heal with usual treatment [24].

Other systems. Serum CK, AST and LDH are typically raised, and plasma carnitine is low in about one third [8, 86]. Cryptorchidism occurs in about one third, puberty may be delayed and secondary sexual development is normal [8]. The deciduous teeth show generalised mobility and reduced or dysplastic dentine [8]. Superficial epidermal cysts appear in the mouth and skin (scalp, lumbar region, buttocks), which may be painful or become infected, and cysts on renal and brain imaging [8]. Primary haemostasis is impaired: closure times on the PFA-100 platelet function analyser are prolonged with normal coagulation, there is prolonged or delayed bleeding after surgery, and about 20% have low or low-normal platelets [8, 47]. The 2026 review describes, in a subgroup, impaired thrombus growth under flow, delayed platelet spreading on fibrinogen, abnormal clot retraction and immature platelets, with raised plasma fibrinogen, von Willebrand factor and factor VIII that may compensate for the defect [48]. A case of paediatric mixed-phenotype acute leukaemia in a patient with Lowe syndrome has been published, with no established association [87]. The 2026 PNDS reports cryptorchidism in about 50% (about one third in GeneReviews), delayed puberty and non-specific thyroid dysfunction, mainly in adults [8, 24]. In the mouth, it describes enamel hypoplasia and hypomineralisation, taurodontism (elongation of the pulp chamber of the molars), enlarged pulp chambers in the deciduous dentition, delayed exfoliation and mobility of deciduous teeth, out-of-sequence eruption, eruption cysts, impacted teeth, narrow arches, anterior open bite with tongue protrusion, vertical overgrowth, crowding and incisal gingival hyperplasia; in a series cited by the protocol, 56.2% of patients required dental treatment [24]. In the skin, it describes cysts of variable size and location (also oral, renal and cerebral), painful and sometimes infected in the lumbar region and buttocks, subcutaneous fibrous lesions and hidradenitis suppurativa-like lesions in the axillary, inguinal and perianal folds [24]. In haemostasis, platelets fall moderately, to 100–140 × 10⁹/L, in a large proportion of patients, and most have moderate microcytic anaemia without iron deficiency; prothrombin time and activated partial thromboplastin time are normal, with no factor deficiency, whereas fibrinogen, factor VIII and von Willebrand factor are raised (the last two about 2 times control values, without raised C-reactive protein) [24]. PFA closure times are prolonged in half of patients, up to 1.5 times those of controls, with no correlation with the bleeding score; light transmission aggregometry, platelet glycoproteins and activation markers by flow cytometry are generally normal, and only specialised methods (adhesion in a perfusion chamber over collagen and fibrinogen) reveal the defect [24]. In a French study of 15 patients and 15 controls cited in the PNDS supporting document, 9 patients (60%) had a bleeding score above the reference and 7 (47%) mild thrombocytopenia, always above 100 × 10⁹/L; normal haemostasis tests therefore do not exclude bleeding risk [24].

Survival. Most patients do not live beyond 40 years; in older patients, death is due to progressive renal failure or scoliosis, and at all ages dehydration, pneumonia and infections are causes of death [8, 26]. In a 1991 historical cohort cited by the 2026 PNDS, life expectancy was estimated at 40 years, with kidney failure and lung infection as the main causes of death; lung infection is favoured by scoliosis, bone deformities and hypotonia [24].

3.6. Lowe syndrome: renal function cohorts

The Japanese national cohort of Ando and colleagues included 54 males from 51 families, paediatric and adult, with the clinical criteria of congenital cataract, Fanconi syndrome and central nervous system involvement; median age at diagnosis was 9 months and age at the last visit 14.5 years (2–45) [21]. eGFR was calculated with the original Schwartz formula, because the CKD-EPI and Cockcroft-Gault formulae are inappropriate given the low muscle mass of these patients [21]. The table summarises the results.

Only age was associated with eGFR in multiple regression, with a steep fall from 10 years; nephrocalcinosis, hypercalciuria and location of the variant in the 5-phosphatase or RhoGAP domain had no impact [21]. The retrospective international cohort of Zaniew and colleagues (106 boys: 88 with Lowe syndrome and 18 with DD2) found a median eGFR of 58.8 in Lowe syndrome and 87.4 mL/min/1.73 m² in DD2 (P<0.01), CKD stage II to V in 82%, moderate to severe CKD in 58% of patients with Lowe syndrome and 28% of those with DD2, CKD 5 in 3 boys (3%), all with Lowe syndrome, and faster progression in Lowe syndrome; in multivariate analysis, eGFR depended only on age, with no association with nephrocalcinosis, hypercalciuria or proteinuria [88]. In the NIH study, proteinuria was 1.38±0.77 g/m²/day (normal ≤0.10), aminoaciduria 686±505 µmol/kg/day (normal 94±45) and the fractional excretion of carnitine 0.10±0.05 (normal 0.03±0.01); the reciprocal of creatinine fell linearly with age, predicting kidney failure in the fourth decade [86]. The UK Kidney Association states that most patients reach kidney failure in the fourth or fifth decade [89]. The differences between these figures reflect the age of the patients included and the duration of follow-up: paediatric cohorts capture few cases of kidney failure, and the Japanese cohort, with adults, documents failure in the third and fourth decades.

The 2026 French PNDS reports CKD stage 4 or 5 in 80% of adults, classically reached in the fourth decade, cites the Japanese series (kidney failure in two thirds of patients older than 30 years) and mentions a French national cohort of 25 adults [21, 24]. Serial biopsies show initially normal histology, followed by non-specific interstitial fibrosis and tubular atrophy and, later, glomerulosclerosis; progression does not correlate with hypercalciuria, nephrocalcinosis or proteinuria, no genotype–phenotype correlation has been shown in paediatric data, and intra- and interfamilial variability points to a multifactorial cause [24]. In stages 3–5, tubular proteinuria may reach 3–4 g/day [24].

To estimate GFR, the PNDS notes that creatinine-based equations overestimate it because of low muscle mass and proposes the Schwartz formula with k = 26 (creatinine in µmol/L), compared with 36.5 in the 2009 Schwartz equation [24]. The value comes from Bockenhauer and colleagues, who derived a mean k of 26±1 from 14 ⁵¹Cr-EDTA clearance measurements in 7 patients, comparing it with the k of 40 then used in healthy children [85]. The PNDS gives preference to equations with standardised cystatin C (for example, the CKiD U25 with cystatin C) and, in line with KDIGO 2024, mentions CKiD U25 between 1 and 25 years and the European Kidney Function Consortium (EKFC) equation as a continuous lifelong alternative, useful at transition [24]. The k of 26 was derived in 2008, before enzymatic creatinine became widespread, and the sources consulted do not describe its revalidation with that method or in adults; the Japanese cohort used the original Schwartz formula [21, 85].

3.7. Heterozygous females

Dent disease. Most carrier females are asymptomatic or have only biochemical abnormalities; more than half have LMWP, about 30% hypercalciuria and about 20% later nephrocalcinosis and stones [14]. GeneReviews describes stones and moderate LMWP in carrier females from large families, a woman with renal failure and nephrocalcinosis in a Dent family, without molecular testing, and a carrier with a known variant who developed symptomatic stones and CKD stage 3B at 65 years [10]. Many symptomatic carriers have other unaffected sons [10]. The woman described in 2024 with full DD1 due to a de novo variant and skewed X inactivation is presented in section 10 [51].

Lowe syndrome. About 95% of post-pubertal heterozygous females have, on dilated slit-lamp examination by an experienced ophthalmologist, numerous punctate, irregular, whitish opacities in the lens cortex, more anterior than posterior, in radial bands around the equator, with the nucleus spared; on retroillumination they form a radial pattern of dense wedges of one to two "clock hours" alternating with wedges free of opacities [8]. About 10% have a dense central white cataract at the posterior pole, which may be visually significant and be operated on in the fourth decade without its diagnostic significance being recognised [8]. The opacities may appear before puberty, but their absence does not exclude heterozygosity [8]. The other manifestations occur only with an X;autosome translocation or extremely skewed X inactivation [8, 50]. The 2026 French PNDS describes, in carrier females, posterior polar lens opacities or anterior lenticonus on slit-lamp examination and partial cortical or posterior subcapsular cataracts, generally bilateral, which appear in the second or third decade and do not always require surgery; in a symptomatic woman with no family history, other causes should be excluded before attributing the picture to OCRL [24].

4. Clinical Recognition and Warning Signs

4.1. When to suspect Dent disease

Dent disease should be considered in a boy or man with persistent non-orthostatic proteinuria, especially when plasma albumin is normal and there is no oedema; with hypercalciuria, nephrocalcinosis or stones; with unexplained hypokalaemia or CKD; and, in particular, when there are male relatives on the maternal side with kidney failure [14]. The settings that most often lead to diagnosis are proteinuria detected on a routine urine test or one done for another reason; isolated hypercalciuria in a child, which may be the whole phenotype; nephrocalcinosis or calcium oxalate or phosphate stones in a boy; proteinuria with a biopsy showing FSGS or focal global glomerulosclerosis in a man with a family history compatible with X-linked inheritance; hypophosphataemic rickets or osteomalacia with hypercalciuria; and CKD of unexplained cause in a young man with a maternal family history [3, 10]. In adults with unexplained CKD, systematic measurement of LMWP allows the diagnosis to be considered [14]. Cataract, mild intellectual disability, marked short stature or raised CK, AST and LDH in a patient with a Dent renal picture point to DD2 [14].

4.2. When to suspect Lowe syndrome

Lowe syndrome should be considered in any male newborn or infant with dense bilateral congenital cataracts and hypotonia of central origin with absent reflexes [8, 89]. The cataracts are present at birth but may only be noticed in the first weeks of life [8]. LMWP is detectable soon after birth and may precede aminoaciduria, so very early urinary amino acid screening may be negative and should be repeated; Fanconi syndrome becomes symptomatic at 6–12 months [8, 84, 90]. In the metabolic investigation of a congenital cataract, proteinuria may be the first clue to the tubulopathy of Lowe syndrome and justifies assessment of urine osmolality, phosphate, urine and plasma amino acids, serum calcium and phosphate and a skeletal survey for rickets [90]. A mother of an apparently isolated case with radial punctate lens opacities strengthens the suspicion [8, 90]. The absence of congenital cataract does not exclude the diagnosis, as shown by a Chinese patient with Lowe syndrome without cataract [70]. The 2026 French PNDS recommends considering the syndrome in the presence of neonatal hypotonia and bilateral cataract, even without renal involvement, and in the presence of congenital glaucoma and cataract; severe neonatal hypotonia with congenital cataract or with early signs of delay warrants a renal work-up (glycosuria, aminoaciduria, phosphaturia, proteinuria) and a prompt specialist opinion [24]. Early feeding and oral-motor difficulties are part of the initial picture, and suspicion may arise on prenatal ultrasound, especially with associated brain anomalies [24].

4.3. Warning and emergency signs

4.4. Screening

There is no newborn screening for Dent disease or Lowe syndrome [8, 10]. In Japan, annual school urine screening from 3 years of age identified the Japanese form of Dent disease, initially described as idiopathic LMWP with hypercalciuria and nephrocalcinosis [30, 35].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria for Dent disease

GeneReviews proposes suspecting Dent disease when three criteria are met, in the absence of other causes of proximal tubular dysfunction: LMWP at least five times (often ten times) the upper limit of normal; hypercalciuria; and at least one of nephrocalcinosis, calcium oxalate or phosphate stones, micro- or macroscopic haematuria, hypophosphataemia, CKD or a family history compatible with X-linked inheritance. The diagnosis is "possible" with LMWP and at least one other criterion [10, 36]. The 2025 recommendations regard LMWP as obligatory and hypercalciuria as non-obligatory; the combination of LMWP and hypercalciuria in a male is highly suggestive and should be confirmed or excluded by genetic testing (grade B, strong recommendation) [14]. The diagnosis is established in a male by identification of a hemizygous pathogenic variant in CLCN5 (DD1) or OCRL (DD2) [10, 14].

The ERKNet/ESPN recommendations were developed between 2021 and 2023 by the ERKNet metabolic diseases working group and the ESPN inherited kidney diseases group, following the RIGHT statement, with a core group of paediatric and adult nephrologists, a geneticist and a patient representative, a systematic search up to January 2022 and a Delphi panel with adoption at ≥70% agreement; the evidence was graded according to the American Academy of Pediatrics (grades A to D and X; strength strong, moderate or weak), and many statements could not be graded because of scarce evidence; the document was endorsed by the European Renal Association (ERA) and ESPN [14].

5.2. Urinary biomarkers and thresholds

For those younger than 18 years, GeneReviews proposes the 95th percentiles of the random urine calcium/creatinine ratio of Matos and colleagues; the 2025 recommendations refer to the age-specific reference values of So and colleagues (2001) and Sargent and colleagues (1993) [10, 14, 92].

Source: [10, 92].

LMWP is also the sensitive and specific test for identifying affected male relatives in a known family, but it does not establish the diagnosis in a new case or distinguish the gene; this distinction matters because DD2 has extrarenal manifestations [3, 10]. The assessment table in the Lowe GeneReviews gives a hypercalciuria threshold of "calcium/creatinine >0.02" without a unit; this value is not used here and age-specific reference values are preferred [8, 14].

5.3. Diagnostic algorithm

The algorithm of the 2025 recommendations starts with testing for LMWP in all patients with persistent proteinuria; the combination of LMWP and hypercalciuria strongly suggests Dent disease, and confirmation is genetic [14]. Practice can be summarised in the following steps, all based on that source and on GeneReviews [8, 10, 14]:

5.4. Genetic testing: indications, strategy and limits

The 2025 recommendations indicate genetic testing of CLCN5 and OCRL (grade B, strong recommendation) in males with isolated, persistent LMWP or with mixed nephrotic-range proteinuria; in males of any age with persistent LMWP and any other sign of proximal dysfunction, stones, nephrocalcinosis, rickets or CKD; and in males with CKD of unknown cause; and recommend including both genes in panels for unexplained CKD in males, whatever their age (grade B, strong) [14]. GeneReviews proposes, as an alternative to a panel, sequential sequencing of CLCN5 and then OCRL; in a female with negative sequencing of both genes, targeted deletion and duplication analysis of CLCN5 and then OCRL [10]. In advanced CKD, only genetic testing allows the diagnosis, because the tubular abnormalities lose specificity [14].

The percentages of 92% and 95% express the proportion of known variants that each method detects, not the clinical sensitivity of the test: with about a quarter of patients with a Dent phenotype having no variant in either gene, a negative result does not exclude the clinical diagnosis [10, 14]. CNV detection on panels and exome depends on the technique used, so the laboratory should state whether deletion and duplication analysis was performed [14]. Exon-targeted sequencing does not assess deep intronic regions or detect balanced rearrangements; in females with Lowe syndrome and no detected variant, karyotyping may reveal an X;autosome translocation with a breakpoint at Xq26.1 [8]. Somatic mosaicism in the index case is not described in the sources consulted as a cause of false negatives, but maternal germline mosaicism is documented (section 8) [8, 10].

The report should state the gene, the transcript with version (for CLCN5, the MANE Select NM_001127898.4 differs from the historical transcript NM_000084.5; for OCRL, NM_000276.4), the variant in HGVS (Human Genome Variation Society) nomenclature at DNA and protein level, the zygosity (hemizygous in a male, heterozygous in a female) and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [13, 69]. Because most CLCN5 variants are private, classification often depends on family segregation and functional data [45, 52]. Testing the mother distinguishes a carrier from a de novo variant, which helps interpret a VUS; testing other relatives shows in whom the variant arose [14]. GeneReviews recommends storing DNA from probands without a molecular diagnosis [10].

5.5. Diagnosis of Lowe syndrome

Lowe syndrome is suspected in the presence of dense bilateral congenital cataracts, congenital infantile hypotonia, developmental delay and proximal tubular dysfunction with LMWP (RBP, NAG and albumin), aminoaciduria and variable degrees of bicarbonaturia and acidosis, phosphaturia and hypophosphataemia and hypercalciuria; LMWP may appear early even without significant aminoaciduria and is probably the most sensitive early marker [8, 84]. It is established in a male with typical findings and a hemizygous OCRL variant, and in a female with the same findings and a heterozygous variant, then looking for a second variant, an X;autosome translocation or another cause of highly skewed inactivation of the normal X [8]. With a suggestive phenotype, sequencing of OCRL followed by deletion/duplication analysis is recommended, or a multigene panel that includes such analysis; with an atypical phenotype, exome or genome sequencing and, if the exome is not diagnostic, array-based exon deletion/duplication testing [8].

When molecular testing yields a VUS or is negative in a male with a compatible picture, the activity of inositol polyphosphate 5-phosphatase OCRL1 in cultured skin fibroblasts is below 10% of normal in affected individuals and abnormal in more than 99% of males with the syndrome, with a high negative predictive value in patients with only partial clinical overlap [6, 8, 57]. This assay is not suitable for identifying carrier females, because random X inactivation produces intermediate activities [8, 93].

The 2026 French PNDS proposes a hierarchical strategy that weighs the clinical picture, sex and family history [24]. In a boy with bilateral congenital cataract, persistent neonatal axial hypotonia and a Fanconi-type tubulopathy, first-line testing is analysis of OCRL by next-generation or Sanger sequencing, alone or, preferably, within a panel of oculocerebrorenal syndromes or hereditary tubulopathies, covering the coding exons and splice sites [24]. If sequencing is negative with a suggestive picture, genome sequencing looks for deep intronic variants, structural variants and variants in phenocopy genes, and transcript analysis assesses the effect of a deep intronic variant on splicing [24]. In the presence of a VUS, OCRL1 enzyme activity or protein quantification by Western blot in skin fibroblasts, and cellular imaging of endosomes, strengthen the classification; research tests (primary cilium length, pattern of actin stress fibres and α-actinin) may support pathogenicity, and interpretation follows ACMG criteria with discussion at a multidisciplinary meeting [24]. In France, very high-throughput sequencing is performed on the SeqOIA and AURAGEN platforms of the France Genomic Medicine Plan 2025, and several laboratories offer targeted OCRL analysis or panels for tubulopathies and ocular developmental disorders [24]. The protocol's decision tree first confirms Fanconi syndrome in blood and urine; with the typical triad, it proceeds to OCRL; with an incomplete picture, it looks for differential diagnoses (leucocyte cystine, galactosaemia, intoxications, other genetic tubulopathies, metabolic diseases) and, if these are excluded, performs an exome and, if negative, a genome [24].

5.6. Renal biopsy

Renal biopsy shows nephrocalcinosis, interstitial fibrosis and focal segmental or focal global glomerulosclerosis, but does not establish the diagnosis and is not necessary [10]. The 2025 recommendations advise against biopsy in patients with Dent disease and recommend excluding LMWP before biopsying a patient with nephrotic proteinuria and normal serum albumin (grade B, strong); biopsy is accepted only exceptionally, when genetic testing is unavailable and diseases with specific treatment must be excluded [14]. This position differs from that of the 2017 GeneReviews, which considered a biopsy reasonable to exclude other causes of proteinuria or CKD [10].

5.7. Bone and ophthalmological assessment at diagnosis

The 2025 recommendations advise biochemical monitoring of bone health (calcium, phosphate, alkaline phosphatase, bicarbonate, 25-OH-D and PTH) and a hand radiograph if the tests are abnormal in children (grade B, moderate), and an ophthalmological examination for cataract in patients with an OCRL variant [14]. The complete initial assessment is in section 7.2.

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known (section 8) [8, 10, 14]. In Lowe syndrome, early cataracts can be detected by slit lamp after birth [90]. A 2026 Egyptian report describes prenatal diagnosis in a family with an affected son (bilateral congenital cataracts, profound delay, heart disease, hypotonia, proximal tubular dysfunction with minimal renal involvement, cerebral and corpus callosum atrophy): the OCRL variant c.688C>T p.(Arg230Ter), identified by exome and confirmed by Sanger sequencing in the son, was found in the hemizygous state in the fetus [62]. The 2026 French PNDS recommends analysis of OCRL, targeted or by high-throughput sequencing, when a bilateral ocular anomaly is seen on prenatal ultrasound [24].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis starts once LMWP has been demonstrated and covers all hereditary and acquired causes of proximal tubular dysfunction; genetic testing is the reference standard for each suspicion [14]. Two features guide it: Dent disease rarely has complete Fanconi syndrome and glycosuria is absent or mild, and LMWP, although present in any Fanconi syndrome, in cystinosis, in tubular nephrotoxicity (for example, from aminoglycosides) and in tubulointerstitial graft rejection, is more prominent in Dent disease and Lowe syndrome [8, 14]. Renal Fanconi syndrome implies more generalised proximal dysfunction, with glycosuria, aminoaciduria and renal tubular acidosis [10].

6.2. Hereditary and acquired proximal tubulopathies

The table brings together the list of differentials in the 2025 recommendations and the distinguishing features they indicate, supplemented by GeneReviews, Saudubray's textbook and a 2026 Japanese genetic series.

The Japanese genetic series of 20 families with primary renal Fanconi syndrome (2016–2024) achieved a diagnosis in 13 (65%): GATM in 7, CLCN5 in 2 and HNF4A, BCS1L, CTNS and EHHADH in 1 each; Fanconi syndrome was often incomplete in patients with GATM, and median renal survival was 51.9 years, which led the authors to propose GATM in the differential of incomplete proximal tubulopathy and unexplained CKD [102]. Orphanet groups the primary forms under ORPHA:3337 (primary renal Fanconi syndrome or DeToni-Debré-Fanconi syndrome) [101]. Saudubray's textbook includes Dent disease among the tubulopathies of inborn errors of metabolism and in the differential of primary hyperoxaluria [103]. Glycosuria accompanied by proteinuria in an infant of 3–6 months with growth delay is a warning sign for cystinosis [103].

6.3. Dent disease and glomerular disease

Nephrotic-range proteinuria, FSGS or global sclerosis on biopsy and haematuria lead many patients with Dent disease to be classified as having primary glomerular disease or steroid-resistant nephrotic syndrome [10, 14]. Most FSGS is idiopathic or associated with obesity or CKD of any cause; the FSGS of Dent disease is identified by prominent LMWP with normal serum albumin and is confirmed genetically [10, 77]. An α1-microglobulin/creatinine ratio >120 mg/g and a urinary albumin/total protein ratio <21% distinguish tubular from glomerular proteinuria with acceptable accuracy [14]. In the Chinese series of Deng and colleagues, 17 of 31 boys with Dent disease had been biopsied, with minimal change lesions, mesangial proliferative glomerulonephritis and FSGS [104].

6.4. Hypophosphataemic rickets and hypercalciuria

X-linked recessive hypophosphataemic rickets due to CLCN5 (OMIM 300554) is distinguished from X-linked dominant hypophosphataemic rickets due to PHEX by hypercalciuria, nephrocalcinosis, LMWP and progression to renal failure [105]. In the rickets of Dent disease, 1,25(OH)2D is high-normal and PTH low [10], in contrast with vitamin D-dependent rickets. Idiopathic hypercalciuria differs by the absence of LMWP; a family with the CLCN5 variant p.(Gly506Glu) had one member with hypercalciuria only, showing that apparently idiopathic hypercalciuria may be a mild form of Dent disease [54]. In recurrent stone disease without LMWP or hypercalciuria, with radiolucent stones and round brown crystals with a Maltese cross in the urinary sediment, the differential includes APRT deficiency, treatable with xanthine oxidoreductase inhibitors.

6.5. Lowe syndrome and other causes of congenital cataract with hypotonia

Firth and Hurst's reference textbook recommends, in the investigation of a congenital cataract, urinalysis for proteinuria and amino acids (to be repeated if the first screen was very early), serum calcium and phosphate, a skeletal survey and targeted OCRL testing when the picture is recognised; Lowe carrier females are distinguished by punctate opacities and Nance-Horan carriers by posterior sutural opacities [90]. In the table of manifestations of cellular trafficking disorders, Lowe syndrome also appears in the groups for cataract, nodular skin lesions and CKD, alongside the congenital disorders of glycosylation, cystinosis and Wolcott-Rallison syndrome [40].

The 2026 French PNDS organises the differential along axes [24]. On the ocular axis, it includes isolated or syndromic congenital cataracts of metabolic (galactosaemia, glutathione synthetase deficiency), infectious (rubella, congenital toxoplasmosis) or genetic (CRYAA, GJA8, PAX6) cause [24]. On the renal axis, Dent disease type 1 is the main differential, without ocular or neurological involvement; the Dent 2 phenotype due to OCRL makes genetic testing indispensable for classification; cystinosis is distinguished by raised leucocyte cystine, photophobia due to corneal crystals and normal brain development; and Donnai-Barrow syndrome (LRP2) is included depending on the context [24]. On the neurological axis, in the presence of congenital hypotonia, global delay and brain abnormalities (periventricular leucomalacia, neuronal migration anomalies), metabolic encephalopathies (pyruvate dehydrogenase deficiency, organic acidurias, mitochondrial diseases) and other syndromes, such as Joubert, Aicardi-Goutières and Zellweger syndromes, are considered; in the presence of cataract with hypotonia without renal involvement, the protocol includes FMR1-related disorders and Warburg Micro syndrome [24].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no disease-modifying treatment and no authorised drug for Dent disease or Lowe syndrome in any jurisdiction consulted; all the drugs mentioned are used off-label or by analogy with other tubulopathies [3, 6]. In Dent disease, the aims are to reduce hypercalciuria, prevent stones and nephrocalcinosis, correct mineral losses and delay CKD progression, but there are no controlled trials with clinical outcomes, and the recommendations rest on pathophysiology, animal models and surrogate outcomes [10, 14]. Mineral losses are treated with oral supplements, as in other forms of Fanconi syndrome, aiming to improve serum concentrations, which often do not normalise [14]. The 2025 recommendations advise involving a tertiary centre with experience of the disease (grade B, strong), in shared care between the local nephrologist and the tertiary unit, which provides the diagnosis, patient education, urology for stones and paediatric endocrinology when there is growth failure [14]. In Lowe syndrome, care requires a team with paediatric ophthalmology, nephrology, biochemical genetics, nutrition, endocrinology, neurology, developmental and behavioural paediatrics, rehabilitation, general surgery, orthopaedics and dentistry [8]. For Lowe syndrome, the first national protocol is the French PNDS of March 2026, developed by the SORARE reference centre within the ORKiD filière according to the 2012 HAS method; it coexists with the 2019 GeneReviews and with the UK Kidney Association page for clinicians, which brings together paediatric guidance for nephrologists [8, 24, 89]. The PNDS assigns coordination to the paediatric nephrologist and then to the adult nephrologist, ideally with a coordinating nurse, with ophthalmology, neurology and genetics and, depending on complications, endocrinology, rheumatology, gastroenterology, maxillofacial surgery, dentistry and haemostasis, alongside psychology or child psychiatry, psychomotor therapy, physiotherapy, speech therapy, occupational therapy, social services and nutrition [24]. Up to 6 years of age, children in France are followed in early medico-social action centres (CAMSP), which help coordinate care; the general practitioner supports coordination, monitoring of renal function, treatment of acute complications and family adherence [24]. The protocol identifies no curative treatment targeting OCRL and attributes to early, coordinated symptomatic care the improvement in functional prognosis, growth, development and quality of life [24].

7.2. Assessment after diagnosis

7.3. Dent disease: hypercalciuria, stones and nephrocalcinosis

Thiazides. Thiazides reduce calciuria in Dent disease, but the 2025 recommendations advise against their routine use and, if prescribed, recommend close monitoring of electrolytes and renal function (grade B, moderate) [14]. In the randomised crossover trial of Raja and colleagues, 8 males with Dent disease (6–49 years) and 8 with idiopathic hypercalciuria received chlortalidone 25 mg, amiloride 5 mg or the combination, for 2 weeks each, with doses halved in boys younger than 12 years; chlortalidone, alone or with amiloride, significantly reduced calciuria, which normalised (<4.0 mg/kg/day) in all patients but one per group, lowered the supersaturation ratios of calcium oxalate by 25% and calcium phosphate by 35%, and reduced citraturia; amiloride alone had no effect [106]. In the uncontrolled study of Blanchard and colleagues, 7 boys received amiloride 5 mg/day and increasing doses of hydrochlorothiazide (<0.2, 0.2–0.4 and 0.4–0.8 mg/kg/day, 2 months each); doses above 0.4 mg/kg/day reduced calciuria by 42%, at the cost of cramps in 2 boys, biochemical hypovolaemia in 7 and symptomatic hypovolaemia in 1, hypokalaemia in 4 and hyponatraemia in 1, all reversible [10, 91]. Cohorts record thiazide use in 11–34% of patients, with no long-term data on renal function or stones; DD2 is even more susceptible to severe dehydration and acute kidney injury with thiazides [14, 88]. Outside Dent disease, the NOSTONE trial, in 416 patients with recurrent calcium stones followed for a median of 2.9 years, found no dose–response relationship and no benefit of hydrochlorothiazide 12.5, 25 or 50 mg/day versus placebo on recurrence (59% with placebo; 49% with 50 mg, rate ratio 0.92, 95% CI 0.63–1.36), with more hypokalaemia, gout, new-onset diabetes, skin allergy and a rise in creatinine above 150% of baseline [107]. In a 12-year-old boy with DD2, hydrochlorothiazide 1 mg/kg/day, combined with citrate, was stopped because of severe hypokalaemia [64]. In Portugal, the SmPC of chlortalidone (Hygroton® 50 mg) includes prophylaxis of recurrent calcium oxalate stones in idiopathic normocalcaemic hypercalciuria, with an optimal dose of 25 mg/day in most cases and no gain in efficacy above 50 mg/day, and contraindicates it in refractory hypokalaemia and in conditions with increased potassium loss, which is relevant in a disease in which half of adults have hypokalaemia [14, 108]. Because the guideline gives no dose, the reference doses, when a thiazide is chosen, are those of the studies in Dent disease: hydrochlorothiazide above 0.4 mg/kg/day (0.4–0.8 mg/kg/day) with amiloride 5 mg/day, and chlortalidone 25 mg/day in adults, half below 12 years, daily [91, 106]. The labels, cited for comparison, differ: the US label for hydrochlorothiazide gives 1–2 mg/kg/day in children, above the study dose, and the Portuguese SmPC for hydrochlorothiazide alone reserves it for adults (12.5–25 mg/day in hypertension) and advises against it in children and adolescents; the Portuguese SmPC for chlortalidone gives 0.5–1 mg/kg every 48 hours in children (maximum 1.7 mg/kg every 48 hours), rather than daily as in the Raja trial [108–110].

Citrate. The 2025 recommendations suggest that citrate may be considered, especially with nephrocalcinosis or stones (grade C, weak) [14]. Citrate excretion is normal in most patients, but lower than in other Fanconi syndromes; potassium citrate reduces recurrent calcium oxalate stones in idiopathic hypercalciuria with hypocitraturia, and a citrate-rich diet delayed CKD progression in Clcn5 null mice, but there are no human trials in Dent disease, and citrate is prescribed to 13–25% of patients [14, 111]. Citrate is metabolised to bicarbonate and is useful in acidosis; urinary pH should be monitored, because alkaline urine favours calcium phosphate precipitation, and adverse effects are upper gastrointestinal (gastric pain, bloating, nausea) and rash [14]. The guideline gives no dose, so the label doses are used (Acalka® in Portugal: 20 mEq 3 times daily; Urocit-K® in the USA: 30–60 mEq/day), in the table in section 7.11 [112, 113].

Diet. GeneReviews notes that hypercalciuria decreases largely with dietary calcium restriction, as a pathophysiological finding demonstrating intestinal hyperabsorption [10]. Neither GeneReviews nor the 2025 recommendations recommend calcium restriction as treatment, and the 2025 recommendations do not address calcium, sodium or fluid intake [10, 14]. Mild or moderate hypophosphataemia can be corrected by increasing dietary phosphate [14].

7.4. Dent disease: proteinuria and CKD progression

The 2025 recommendations suggest not using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) routinely for nephroprotection (grade C, moderate) [14]. They are used in 11–42% of patients in the series; advocates invoke nephrotic proteinuria, glomerulosclerosis, podocyte effacement and podocyte expression of CLCN5 and OCRL, but there are no studies on progression, the series show no reduction in proteinuria (which is tubular in origin) and the risk of hypotension increases with hypovolaemia [14]. GeneReviews had already noted that angiotensin blockade does not appear to affect LMWP significantly [10]. In a different direction, in the Chinese series of Deng and colleagues, 13 boys treated with ACE inhibitors and/or ARBs for more than 3 months had, after a median of 1.7 years, a 54% reduction in microalbumin/creatinine, with good tolerance [104]. In a 23-year-old patient with DD2, dapagliflozin 10 mg/day for 12 weeks did not change urinary protein/creatinine (1206 to 1339 mg/g) or α1-microglobulin/creatinine (289 to 306 mg/g), with a fall in albumin/creatinine from 243 to 178 mg/g and glycosuria of 4.4 g/L confirming the action of the drug; in a Clcn5 knock-in mouse, empagliflozin did not modify LMWP, hypercalciuria, fibrosis or GFR decline [63]. With loss of function, follow-up intensifies as in any progressive CKD, and with GFR <45 mL/min/1.73 m² GeneReviews recommends monitoring for hypertension, anaemia and secondary hyperparathyroidism and treating cardiovascular risk factors more intensively [10, 14].

7.5. Dent disease: bone, vitamins and growth

Phosphate. The 2025 recommendations suggest phosphate salts in the case of hypophosphataemia with signs of rickets or osteomalacia (grade X, weak); they propose starting with a small amount, for example 20 mg/kg/day of elemental phosphorus in three or four doses, and titrating by alkaline phosphatase and by improvement of the rickets and deformities; phosphate increases phosphaturia and the risk of nephrocalcinosis and stones, so calciuria and renal ultrasound should be monitored during treatment [14]. Bone disease, when present, responds to vitamin D and phosphate in patients with raised alkaline phosphatase, according to Wrong's series [10]. In the Mayo Clinic study, oral phosphate 1 g/day for 14 days reduced calciuria in adults with DD1 and in controls with idiopathic stones [49, 114].

Vitamin D. The 2025 recommendations suggest measuring 25-OH-D and supplementing if low, with native vitamin D according to the recommendations for the healthy population and close monitoring of serum and urinary calcium, 25-OH-D, alkaline phosphatase and, if available, 1,25(OH)2D (grade X, weak); the 25-OH-D target is unknown [14]. Active vitamin D (calcitriol, alfacalcidol) is not indicated in Dent disease, because calcitriol is already raised and worsens hypercalciuria [14].

Vitamin A. The 2025 recommendations advise monitoring for ocular symptoms of vitamin A deficiency (night blindness, dry eyes), measuring retinol if they appear and supplementing if low (grade B, moderate); symptoms reverse with replacement [14]. The guideline gives no dose. The only vitamin A label with an indication for deficiency identified in the sources consulted, that of injectable retinyl palmitate (Aquasol A®), reserves the parenteral route for when the oral route is not possible and recommends, after the loading treatment, an oral preparation with 10,000–20,000 international units (IU) daily in adults and children older than 8 years and 5,000–10,000 IU in infants and younger children, for two months; prolonged daily administration of more than 25,000 IU requires close supervision [115]. In Dent disease, the oral route is the usual one; applying these doses is an extrapolation from vitamin A deficiency in general, to be adjusted by serum retinol, whose interpretation is difficult because its carrier protein, RBP, is lost in the urine [14, 115].

Growth hormone. The 2025 recommendations suggest considering somatropin for short stature only if growth failure persists despite adequate metabolic control or in CKD stage 3 or higher (grade D, weak), with the usual indications (growth hormone deficiency, advanced CKD) according to existing guidelines; reports of improved growth velocity are few, with short observation and no final height [14, 116]. Sheffer-Babila and colleagues described improved growth without harm to renal function [116]. In the 12-year-old boy with DD2 and severe growth delay (height −3.54 SD, bone age 9 years), stimulation tests with clonidine and glucagon showed growth hormone peaks of 2.84 and 0.63 µg/L, interpreted as deficiency; somatropin (Omnitrope®) was started at 1.3 mg/day and increased to 1.7 mg/day, and after 13 months height went from 131 to 136 cm (velocity about 4.6 cm/year), with no improvement in SD (−3.69); the authors consider that the relative contribution of the tubulopathy and of the hormonal deficiency cannot be separated [64]. The Portuguese Summary of Product Characteristics (SmPC) for somatropin (Genotropin®) includes growth disturbance in chronic renal insufficiency, with renal function below 50% of normal and growth assessed over one year with optimised conservative treatment; the US label of the same product does not include CKD [117, 118].

7.6. Dent disease: advanced CKD, dialysis and transplantation

Haemodialysis, peritoneal dialysis and kidney transplantation are suitable options, and the disease does not recur in the graft [10, 14, 28]. A deceased donor, the father and an unaffected brother are safe donors; the mother and half of the sisters are carriers, unless the variant is de novo, and experience with the maternal kidney is limited to one elderly woman without proteinuria or other signs [14]. The 2025 recommendations suggest a very cautious approach to donation by carrier females, which may be considered in an older asymptomatic woman (normal eGFR, no stones, nephrocalcinosis or proteinuria) (grade X, weak), and, when the risk is difficult to assess, preferring an unrelated donor, in line with the British guidelines on living donation [14]. Nephrotoxins (non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, intravenous contrast) should be avoided, especially with GFR <45 mL/min/1.73 m² [10].

7.7. Dent disease type 2: specific aspects

Patients with DD2 follow the same renal recommendations [14]. Mild intellectual disability at school age warrants an individual education plan and special education, and cataracts, if present, receive standard treatment [10]. Ophthalmological examination for cataract is part of the initial assessment of patients with an OCRL variant [14]. The increased risk of dehydration and acute kidney injury with thiazides requires even greater caution [14, 88].

7.8. Lowe syndrome: eyes

Cataracts should be removed early, to allow visual stimulation and development, with postoperative optical correction by spectacles replacing the power of the lens [8]. In the series of Eibenberger and colleagues, 6 children underwent simultaneous bilateral surgery at 8.98±3.58 weeks (lensectomy, posterior capsulotomy and anterior vitrectomy), lasting 35.8 minutes per eye, with one desaturation below 93% in one case; there was no opacification of the visual axis, but 5 of 12 eyes of 3 children developed secondary glaucoma, treated with eye drops in one child, bilateral trabeculectomy in another and synechiolysis with iridectomy in the third [79]. GeneReviews advises against contact lenses, because of the risk of corneal keloid and the complexity of care, and recommends extreme caution with primary intraocular lens implantation, because the risk of glaucoma appears higher, with continuous IOP monitoring, under anaesthesia if necessary [8]. Glaucoma is treated with standard medical and surgical measures, but is difficult to control and almost always ends up requiring surgery [8]. Behavioural problems may require anaesthesia for eye examinations [8]. The 2026 French PNDS recommends early surgery for an occluding cataract, as an inpatient, possibly bilateral under the same general anaesthesia after discussion with the anaesthetist; the procedure starts with an examination under anaesthesia with corneal diameters, keratometry, pachymetry, axial length, B-mode ultrasound of the posterior segment, IOP measurement and, if possible, baseline gonioscopy [24]. In bilateral congenital forms, the child is left aphakic, without a primary implant, after phacoaspiration, posterior capsulorhexis and anterior vitrectomy, with postoperative optical correction of the residual hypermetropia; contact lenses are not first line, because of the corneal risk [24]. Preventive tranexamic acid is discussed before surgery, although the bleeding risk in cataract and glaucoma surgery appears very low [24]. Early primary or secondary glaucomas are generally treated surgically (trabeculectomy and goniotomy, the most used; valves, apparently with similar efficacy; combined phacophagy, vitrectomy and 360° trabecular surgery as an option), and late secondary glaucomas may initially be treated with prostaglandin analogue (latanoprost) or beta-blocker (timolol) eye drops [24]. The US label for latanoprost indicates 1 drop in the affected eye once daily, in the evening, not exceeding one daily application, and does not establish paediatric safety and efficacy [119]; that of preservative-free timolol indicates 1 drop of 0.25% twice daily, increased to 0.5% if the response is insufficient, establishes use from 2 years of age and contraindicates it in asthma, severe chronic obstructive pulmonary disease, sinus bradycardia, second- or third-degree atrioventricular block and overt heart failure [120]. Amblyopia is monitored and treated as after any congenital cataract surgery, with orthoptics between visits [24]. In carrier females, cataracts in the second or third decade do not always require surgery [24].

7.9. Lowe syndrome: neurodevelopment, behaviour and epilepsy

Early intervention, preschool education and an individual education plan are the basis of developmental support, and behavioural problems are treated with a behaviour modification programme, sometimes with medication [8]. Seizures, present in about 50% of patients, are treated with antiepileptic drugs [8, 80]. The sources consulted identify no preferred antiepileptic and no doses specific to Lowe syndrome, so the choice follows general epilepsy recommendations, with three adjustments dictated by the disease. First, renal function: levetiracetam, which is renally excreted, requires dose adjustment to creatinine clearance according to the US label (adults: 500–1500 mg every 12 hours with clearance >80 mL/min/1.73 m²; 500–1000 mg with 50–80; 250–750 mg with 30–50; 250–500 mg with <30; 500–1000 mg every 24 hours on dialysis, with a supplementary dose of 250–500 mg after each session), and creatinine-based estimation of clearance underestimates the loss of function in these patients with low muscle mass [21, 121]. Second, acidosis and stones: topiramate, a carbonic anhydrase inhibitor, causes hyperchloraemic metabolic acidosis through renal bicarbonate loss, increases calciuria, markedly reduces citraturia and increases the risk of stones, nephrocalcinosis and osteomalacia, and the label recommends avoiding it with other drugs that cause metabolic acidosis and measuring baseline and periodic serum bicarbonate; in a disease with tubular acidosis, hypercalciuria and nephrocalcinosis, these effects add to those of the tubulopathy [21, 122]. Third, tubular nephrotoxicity: valproate is among the drugs that cause acquired Fanconi syndrome [14]. The paediatric reference doses of levetiracetam are given in table 7.11. The 2026 French PNDS recommends early rehabilitation of hypotonia (physiotherapy and, depending on progress, occupational therapy and psychomotor therapy), adapted mobility aids (adapted pushchair, positioning chair, manual or electric wheelchair), sometimes a standing frame to prevent deformities and stimulate motor development, orthoses (splints, braces) and adapted home equipment [24]. An early neuropsychological assessment guides school support, speech therapy, special education and the personalised schooling plan, with integration into mainstream education with an assistant for some children or, more often, in a medico-educational institute [24]. For epilepsy, generally well controlled, the protocol prefers benzodiazepines, GABA reuptake inhibitors and certain hepatically metabolised antiepileptics, chosen according to renal function [24]. Tiagabine, a GABA reuptake inhibitor, is approved in the USA as adjunctive therapy for focal seizures from 12 years of age; in patients on enzyme inducers, it starts at 4 mg/day and is increased weekly up to 32 mg/day in adolescents and 56 mg/day in adults, in 2 to 4 doses, with lower doses in others, and its pharmacokinetics are not altered in renal insufficiency [123]. For behavioural problems (aggression, self-injury, repetitive behaviours and stereotypies), the protocol recommends a psychological, educational and vocational programme, reports partial response to neuroleptics and benzodiazepines and more promising results with clomipramine, paroxetine and risperidone, with no disease-specific doses [24]. The label doses of these three drugs, cited by extrapolation from other indications, are given in table 7.11; for clomipramine, seizures are the most important risk on the label, dose-dependent, which weighs in a disease with epilepsy in 25–50% [24, 124].

7.10. Lowe syndrome: tubulopathy, bone, growth and other systems

Acidosis and electrolyte losses. Proximal tubular acidosis and hypokalaemia are treated with oral sodium and potassium bicarbonate or citrate, at doses titrated individually by trough serum concentrations (before the next dose) of sodium, potassium, chloride and total carbon dioxide [8]. Most patients require alkalinisation and many benefit from potassium, phosphate, calcium or carnitine supplements [86]. In the Japanese cohort, 74% had metabolic acidosis (supplement or bicarbonate <22 mmol/L) [21]; in Bockenhauer's series, 7 of 16 patients required bicarbonate and 3 phosphate [85]. GeneReviews gives no numerical doses; the reference doses come from nephropathic cystinosis, the most studied hereditary Fanconi tubulopathy, and their application to Lowe syndrome is an extrapolation. In cystinosis, sodium and potassium bicarbonates, with better gastric tolerance than citrate, are adjusted for a plasma bicarbonate between 21 and 24 mmol/L and may require up to 10–15 mmol/kg/day of buffer; potassium is kept above 3 mmol/L, with 4–10 mmol/kg/day usually needed; and amiloride 2–5 mg/day may help in some cases [94]. The tubulopathy of Lowe syndrome is more selective than that of cystinosis, with milder aminoaciduria and rare glycosuria, and in Bockenhauer's series only 7 of 16 patients required bicarbonate; titration therefore starts from serum concentrations and not from the maximum doses described in cystinosis [8, 85, 86]. The UK Kidney Association recommends regular screening for acidosis, hypophosphataemia and hyperparathyroidism, with frequency according to symptoms, and notes that citrate provides alkali and may reduce calcium precipitation [89]. In illnesses with vomiting, diarrhoea or fasting (including surgery), fluids, bicarbonate and electrolytes are replaced intravenously [8]. The 2026 French PNDS prefers, in hyperchloraemic acidosis, potassium citrate, which may also limit the progression of nephrocalcinosis, as a compounded preparation (oral suspension of 3.75 g/15 mL or capsules) at 100–150 mg/kg/day in 3 to 4 doses, or under a named-patient temporary use authorisation (Urocit-K®); in the absence of citrate or as a complement, depending on the degree of acidosis, it uses sodium or potassium bicarbonate in 3 to 4 doses, monitoring digestive tolerance, citraturia and serum bicarbonate, and indicates that most patients need 2 to 4 mEq/kg/day of alkalinising agents [24]. In adults, the plasma bicarbonate target is 23–26 mmol/L, with sodium bicarbonate or, if there is hypokalaemia or nephrocalcinosis, potassium citrate or bicarbonate; potassium supplementation is needed in about 10% of adults [24]. The protocol allows off-label discussion of prolonged-release granules of potassium citrate and bicarbonate (Sibnayal®), which allow fewer doses [24]. In the European Union, Sibnayal® was authorised on 30 April 2021 for distal renal tubular acidosis from 1 year of age; the SmPC gives starting doses of 4 mEq/kg/day (1–3 years), 2 mEq/kg/day (4–11 years) and 1 mEq/kg/day (12 years or older and adults), in 2 doses, titrated by plasma bicarbonate up to a maximum of 10 mEq/kg/day or 336 mEq/day, and contraindicates it with GFR ≤44 mL/min/1.73 m², which excludes many adults with Lowe syndrome [125]. Abundant hydration is essential in polyuria, especially in patients without independent access to water, and gastrostomy may help in severe cases; the diet is normal in protein and sodium, with calcium and vitamin D in physiological amounts, and normal salt, appropriate for a salt-wasting nephropathy with normal or low blood pressure, may contribute to hypercalciuria [24]. The protocol does not recommend hydrochlorothiazide for hypercalciuria, because of the risk of hypovolaemia and electrolyte disturbances, nor ACE inhibitors or ARBs for albuminuria or mixed proteinuria, which do not reduce it when it is tubular and expose the patient to acute kidney injury during dehydration and to hyperkalaemia with reduced GFR; SGLT2 inhibitors have not been evaluated, and NSAIDs are contraindicated [24].

Phosphate and active vitamin D. Hypophosphataemia and renal rickets are treated with oral phosphate and oral calcitriol, with doses titrated by trough serum phosphate, 1,25(OH)2D, calcium and intact PTH [8]. The UK Kidney Association notes that, because 1α-hydroxylation occurs in the proximal tubule, patients often need alfacalcidol, adjusted to plasma PTH, and that excess may worsen nephrocalcinosis [89]. This guidance differs from the recommendation for Dent disease, in which active vitamin D is not indicated because calcitriol is raised (section 7.14) [14]. In Lowe syndrome there is no guideline dose, and the reference dose, by extrapolation from another Fanconi syndrome, is that of cystinosis, in which 1α-hydroxycolecalciferol or calcitriol 0.10–0.50 µg/day is used, mainly in symptomatic rickets, adjusted by serum calcium, and sodium or potassium phosphate 0.3–1 g/day, with a plasma phosphate target slightly above 1.0–1.2 mmol/L, poorly tolerated and with a risk of nephrocalcinosis if excessive [94]. The US calcitriol label covers secondary hyperparathyroidism in pre-dialysis CKD, hypocalcaemia on dialysis and hypoparathyroidism, not the rickets of Fanconi syndrome [6, 126]. In Portugal, the SmPC of calcitriol (Rocaltrol®) includes renal osteodystrophy in chronic renal failure and vitamin D-resistant hypophosphataemic rickets, with a starting dose of 0.25 µg/day in the morning in rickets, increases at intervals of 2 to 4 weeks and serum calcium at least twice weekly during titration, but considers paediatric safety and efficacy insufficiently studied to recommend doses; the cystinosis dose is therefore outside the label conditions [127]; the Portuguese SmPC of alfacalcidol (Etalpha®) includes renal osteodystrophy and hypophosphataemic osteodystrophy [128]. Even with the tubulopathy corrected and without rickets, some patients have repeated fractures, whose relationship with immobility or with a primary bone defect has not been studied [8]. The 2026 French PNDS indicates phosphate (Phosphoneuros®) usually at 20–40 mg/kg/day in 3 to 4 doses, combined with an active vitamin D derivative, with the aim of keeping alkaline phosphatase and PTH normal and serum phosphate at the lower limit of normal for age, avoiding secondary hyperparathyroidism [24]. The protocol designates this derivative as 1,25(OH)2-vitamin D3 and gives Un-Alfa® as an example, which is alfacalcidol (1α-hydroxycolecalciferol), a prodrug that the liver converts to calcitriol; the Portuguese SmPC of alfacalcidol (Etalpha®) is listed in table 7.11 [128]. In adults, phosphate is needed in about one third, should not be taken at the same time as calcium (precipitation and reduced absorption), may contribute to nephrocalcinosis without proof that it accelerates CKD and is reduced in advanced CKD according to serum phosphate; colecalciferol is titrated to the lower limit of normal of 25-OH-D, and calcitriol or alfacalcidol, with the support of an experienced rheumatologist, should be neither excessive (hypercalciuria and stones) nor insufficient (hyperparathyroidism); alkaline phosphatase is the useful marker for this adjustment [24]. In symptomatic osteoporosis with radiologically confirmed fractures, the protocol proposes bisphosphonates adapted to renal function, without giving a dose [24]. The paediatric reference regimen, by analogy with paediatric osteoporosis, is that of intravenous pamidronate infused over 3–4 hours: below 1 year, 0.5 mg/kg every 2 months; 1–2 years, 0.25–0.5 mg/kg/day for 3 days every 3 months; 2–3 years, 0.375–0.75 mg/kg/day for 3 days every 3 months; above 3 years, 0.5–1 mg/kg/day for 3 days every 4 months; maximum 60 mg per dose and 11.5 mg/kg/year; contraindicated in hypocalcaemia and severe renal insufficiency [129]. In a patient with Lowe syndrome, severe osteoporosis and hypophosphataemic rickets, monthly intravenous pamidronate from 17.8 years, with somatropin, raised the bone mineral density Z-score from −7.3 to −3.3 without worsening renal function [130].

Carnitine. Plasma carnitine is low in about one third of patients, owing to urinary loss; the need for and efficacy of supplementation have never been studied, and the decision is individual [8, 86]. When supplementation is given, the reference dose is that of cystinosis, an analogous condition with tubular carnitine loss: 100 mg/kg/day in four doses [94]. The labels, cited for comparison, give in the Portuguese SmPC (Disocor®) age-specific doses from 150 mg/kg/day (0–2 years) to 75 mg/kg/day (6–12 years), advising against prolonged high oral doses in severe renal impairment [131], and in the US label 50–100 mg/kg/day in infants and children, with a maximum of 3 g/day [132].

Growth and feeding. Growth hormone improves growth velocity in some patients, but short stature persists and the benefits must be weighed against costs and limitations [8, 88]. A patient with the OCRL variant c.1124A>G p.(His375Arg), treated with potassium citrate, phosphate and calcitriol, had an initial favourable effect of somatropin [65]. Feeding difficulties in infancy are treated with a nasogastric tube or gastrostomy, with or without fundoplication, and gastro-oesophageal reflux with standard treatment [8, 89]. The 2026 French PNDS does not recommend growth hormone routinely, for lack of evidence in this disease; in marked growth delay, growth hormone deficiency may be sought and, if confirmed, treatment exceptionally discussed in a specialised centre; it also notes that somatropin might improve bone density, with a low level of evidence [24]. Cryptorchidism may require treatment [24]. Reflux generally responds to positioning, feeding and, if necessary, drugs, and only severe cases require surgery [24].

Advanced CKD. Chronic dialysis and kidney transplantation may be successful in some patients [8]. In the Japanese cohort, 3 of the 8 patients with kidney failure received replacement therapy: haemodialysis at 22 years via a catheter and under sedation, maintained for 11 years; haemodialysis at 40 years via an arteriovenous fistula without sedation; and a transplant [21]. Decisions on kidney replacement in a patient with severe intellectual disability and behavioural problems involve the family and the team. The 2026 French PNDS proposes starting discussion of transplantation from CKD stage 3, applies the usual criteria for kidney replacement and reports peritoneal dialysis followed by transplantation in a 49-year-old patient; severe neurological and visual impairment and agitation may make dialysis impossible, the decision also depends on family or institutional support, pre-emptive living-donor transplantation may be considered and, under conservative treatment, dedicated support for the patient and family is organised, with each situation discussed case by case [24]. Transplantation and graft biopsy require multidisciplinary haemostatic planning [24]. In adults, follow-up continues within a network with nephrology, neurology, psychiatry, rheumatology, ophthalmology and dentistry (in France, the HandiDent network) [24].

Orthopaedics, skin and teeth. Severe or progressive scoliosis and joint hypermobility are treated with orthoses or surgery; cutaneous fibromas and cysts are excised if painful, recurrently infected or limiting function; paediatric dentistry monitors mobility of the deciduous teeth and subrachitic changes [8]. The 2026 PNDS adds, for the musculoskeletal system, calcium and active vitamin D supplementation adjusted to nephrology and PTH, early psychomotor therapy, physiotherapy and rehabilitation, adapted physical activity against a sedentary lifestyle, analgesia adjusted to pain scales, limited or contraindicated use of NSAIDs, decisions shared with the nephrologist on disease-modifying and biological treatments for inflammatory arthritis, and orthopaedics (physiotherapy, brace, surgery) for scoliosis [24]. For the mouth, it recommends assessment from eruption of the deciduous teeth, brushing by the parents with fluoride toothpaste of age-appropriate concentration from about 6 months, monitoring of the first permanent molars at around 6 years, topical fluoride and fissure sealants, swallowing rehabilitation and texture adaptation, orthodontics when cooperation allows, conscious sedation (nitrous oxide–oxygen mixture, or anxiolytics) or general anaesthesia for treatment, and haemostatic assessment before any oral surgery; in France, the centres of the O-Rares network support the dentist [24]. For the skin, in the presence of hidradenitis suppurativa-type lesions, the protocol combines general measures (nutrition, physical activity, smoking cessation, psychological support, education, pain control) and avoids NSAIDs, which favour flares [24]. With fewer than 4 flares per year, it treats each flare with amoxicillin-clavulanic acid or pristinamycin 1 g 3 times daily for 7 days and local care; with more than 4 flares per year, it adds prophylaxis with doxycycline 100 mg/day, co-trimoxazole 400/80 mg 1 tablet daily or azithromycin 500 mg 3 times weekly; in severe forms, dermatology considers anti-TNF or anti-IL-17 biologics, and surgery is guided by the Hurley classification (no surgery in stage 1; deroofing of sinus tracts in stage 2; wide excision in stage 3) [24]. Cysts are excised if their location threatens complications or their appearance is doubtful, taking the haemostatic defect into account [24].

Haemostasis and surgery. Surgeons should be warned of the risk of delayed bleeding after apparent haemostasis in the immediate postoperative period [8]. The UK Kidney Association proposes considering tranexamic acid for prolonged bleeding and before surgery, with the opinion of a haemostasis specialist [89]. The 2026 review recommends caution before surgery and with drugs that worsen bleeding [48]. The Portuguese SmPC for oral tranexamic acid (Tafixyl®) contraindicates it in patients with a history of seizures, present in about 50% of patients with Lowe syndrome, and has no experience below 15 years, which requires the risk to be weighed case by case with the haemostasis specialist [8, 133]. The dose is not defined for Lowe syndrome; by analogy with dental extraction in haemophilia, the Portuguese SmPC indicates 25 mg/kg orally 3 to 4 times daily for 6 to 8 days, after an intravenous dose, and the US label for intravenous tranexamic acid indicates 10 mg/kg immediately before the procedure and then 3 to 4 times daily for 2 to 8 days, with reduction in renal insufficiency, and reports no important pharmacokinetic differences between adults and children, with limited data [134].

Haemostasis according to the 2026 PNDS. The protocol recommends referring the patient to a bleeding disorders centre of the MHEMO network soon after diagnosis, because conventional tests do not identify patients at risk, and repeating the consultation before each planned surgery to define a protocol adapted to the procedure; as there are no studies allowing a strategy to be recommended, the principles derive from pathophysiology and from the protocols for constitutional bleeding disorders [24]. Table 7.10a summarises the measures.

Table 7.10a. Prevention and treatment of bleeding in Lowe syndrome according to the 2026 PNDS

The PNDS paediatric dose (20 mg/kg divided into 2 to 3 doses) is lower than that of the Portuguese SmPC for oral tranexamic acid in dental extraction (25 mg/kg per dose, 3 to 4 times daily), the duration (10–12 days) is longer than that of the SmPC (6–8 days) and the US label (2–8 days), and the protocol does not mention the Portuguese contraindication in patients with a history of seizures (section 7.14) [24, 133, 134].

7.11. Dosage and sources

The table brings together the drugs used, all off-label for Dent disease or Lowe syndrome; doses come from the source indicated, and when the source is a label for another indication or an analogous condition, the extrapolation is declared. The reference dose is that of the guideline or, failing that, that of the study or analogous condition cited; the label dose (Portuguese SmPC, FDA or EMA) is given for comparison, with the difference indicated, and is the dose used only when there is no other source.

The Brazilian brand names come from active registrations in the ANVISA open data; the Brazilian package inserts could not be read (the database returned a server error), so the doses approved in Brazil are not represented [139]. The Portuguese SmPCs for amiloride, oral phosphate, oral bicarbonate, levetiracetam and retinol were not obtained.

7.12. Agents and situations to avoid

7.13. Regulatory status

No drug has an approved indication for Dent disease or Lowe syndrome from the US Food and Drug Administration (FDA) or in the Portuguese SmPCs consulted; the initial authorisation dates come from Drugs@FDA [3, 118, 126]. The European information available in the sources consulted is limited to the Portuguese SmPCs (somatropin, alfacalcidol, chlortalidone, calcitriol, hydrochlorothiazide, potassium citrate, levocarnitine and tranexamic acid); the Brazilian information, to the ANVISA registrations [139]; no information was obtained from the European Medicines Agency (EMA) for these nationally authorised drugs.

7.14. Divergences between sources and recommendations

The 2025 ERKNet/ESPN recommendations supersede the statement in the 2017 GeneReviews that there were no guidelines for Dent disease [10, 14]. There are five main divergences. The first concerns renal biopsy, which GeneReviews considered reasonable to exclude other causes and the 2025 recommendations advise against [10, 14]. The second concerns thiazides, which GeneReviews presented as effective in reducing calciuria above 0.4 mg/kg/day, with close monitoring, and which the 2025 recommendations advise against routinely, in light of the absence of long-term benefit and the NOSTONE trial [10, 14, 107]. The third concerns ACE inhibitors and ARBs, which the 2025 recommendations do not recommend for nephroprotection, whereas a Chinese paediatric series described a partial reduction in albuminuria [14, 104]. The fourth concerns active vitamin D, contraindicated in Dent disease by the 2025 recommendations because calcitriol is raised, and proposed by the UK Kidney Association and GeneReviews in Lowe syndrome, adjusted to PTH or 1,25(OH)2D; the difference reflects distinct pathophysiologies, because in Lowe syndrome acidosis, early CKD and insufficient renal production of 1,25(OH)2D contribute to the bone disease [8, 14, 89]. The fifth concerns the target serum phosphate: the 2025 recommendations propose starting with 20 mg/kg/day of elemental phosphorus and titrating by alkaline phosphatase, and cystinosis uses 0.3–1 g/day with a plasma phosphate target; both sources warn of nephrocalcinosis [14, 94]. The 2026 French PNDS, the first national protocol for Lowe syndrome, adds divergences of its own, presented as a dated French position [24]. (1) Ophthalmological monitoring: visits every 2–3 months in the first year and every 4–6 months thereafter, more frequent than the six-monthly IOP in GeneReviews [8, 24]. (2) Alkalinisation: the PNDS prefers potassium citrate and estimates 2–4 mEq/kg/day, well below the 10–15 mmol/kg/day described in cystinosis, which preferred bicarbonate for gastric tolerance; titration by serum concentrations remains the common rule [8, 24, 94]. (3) Phosphate: 20–40 mg/kg/day in the PNDS, compared with 20 mg/kg/day initially in Dent disease and 0.3–1 g/day in cystinosis [14, 24, 94]. (4) Active vitamin D: the PNDS calls Un-Alfa® 1,25(OH)2-vitamin D3, whereas it is alfacalcidol; the molecule is the one the UK Kidney Association also proposes [24, 89, 128]. (5) Antiepileptics: the PNDS prefers hepatically metabolised drugs, but valproate, which is hepatically metabolised, can cause acquired Fanconi syndrome, and levetiracetam, which is renally excreted, remains usable with adjustment to renal function [14, 24, 121]. (6) Tranexamic acid: paediatric dose, duration and omission of the Portuguese contraindication with seizures (section 7.10) [24, 133]. (7) Growth hormone: the PNDS does not recommend it routinely, whereas GeneReviews reports improved growth velocity in some patients [8, 24]. (8) Frequencies: cryptorchidism in about 50% in the PNDS and about one third in GeneReviews; epilepsy in 25–50% with median onset at 5–9 years, compared with about 50% mainly before 6 years; IQ ≥70 in about 25%, compared with 10–25% with low-normal or borderline intelligence [8, 24]. (9) GFR estimation: Bockenhauer's k of 26 was derived by comparison with the k of 40 of the era before enzymatic creatinine, and not with the 36.5 cited by the PNDS; the protocol prefers cystatin C [24, 85]. (10) Internal inconsistencies: renal ultrasound is annual in childhood in the text and in the follow-up annex, but every two years in the summary for the general practitioner; amniocentesis is indicated from 15 weeks of gestation in one section and from 16 in another; the 8% frequency of stones in monitoring contrasts with nephrocalcinosis or stones in half of patients in the initial description [24]. (11) ACE inhibitors and ARBs: also advised against in Lowe syndrome, in line with the 2025 recommendation for Dent disease [14, 24].

7.15. Trials and intervention studies

None of these studies has hard clinical outcomes (stones, kidney failure, fractures) in Dent disease or Lowe syndrome: the thiazide and phosphate studies measure calciuria over weeks to months, and the ACE inhibitor/ARB series are retrospective. The results cannot be compared with each other, because the populations, doses and outcomes differ. The NOSTONE trial, although conducted outside Dent disease, is the only randomised trial with a clinical outcome and was negative [107]. The APHP paediatric hydrochlorothiazide trial was terminated [147]. A ClinicalTrials.gov search in October 2026 found no active therapeutic trials in Dent disease; the active registrations are observational (RKSC registry, NCT00588562; prospective ProRKS study with patients with Dent disease and Lowe syndrome, NCT02780297; RaDaR, NCT06065852) [147]. The absence of results in one search does not show that there are no trials in other registries.

7.16. Developments in the last 12 months and research

Earlier preclinical studies open several lines of research, none with human data. Alpelisib, an inhibitor of the p110α subunit of phosphatidylinositol 3-kinase, reduced aberrant actin polymerisation in human renal cells lacking OCRL and, in a humanised Ocrl Y/− mouse, restored megalin at the membrane and improved LMWP uptake [149]. An inhibitor of phosphatidylinositol-4-phosphate 5-kinase restored neuronal excitability and Notch signalling in iPSC-derived organoids from patients with Lowe syndrome [82]. An adenine base editor corrected the OCRL variant p.(Arg844Ter) in patient fibroblasts, restoring mRNA, protein, ciliogenesis and the cytoskeleton [66]. In DD1, a lentiviral vector carrying human CLCN5 was effective for only 3 months in the adult mouse, probably because of an immune response, whereas neonatal administration in null mice gave durable expression and phenotypic improvement [150]; 4-phenylbutyrate, a chemical chaperone, reduced LMWP in a knock-in mouse with the p.(Val523del) variant (historical numbering), which partially retains ClC-5 in the endoplasmic reticulum [55]; and bone marrow transplantation improved proximal dysfunction in null mice [14]. The 2025 recommendations emphasise the need for therapeutic validation, the difficulty of human trials (insidious decline, no surrogate marker) and the role of prospective registries [14].

7.17. Special populations: pregnancy, lactation, surgery and transition

The sources consulted do not describe pregnancies in women with overt Dent disease or give specific guidance for pregnancy in carrier females; males with Lowe syndrome have no known offspring [8, 14]. In pregnancy, vitamin A above the recommended daily allowance is contraindicated and the safety of more than 6,000 IU daily has not been established, and the topiramate label warns of fetal and neonatal metabolic acidosis [115, 122]. The vitamin A label recommends 5,000 IU daily for breastfeeding women [115].

In Lowe syndrome, surgery requires intravenous replacement of fluids, bicarbonate and electrolytes during fasting, warning surgeons of the risk of delayed bleeding and haemostatic assessment, with tranexamic acid to be considered [8, 89]. Anaesthesia may be needed for eye examinations and IOP measurements [8]. In Dent disease, intravenous contrast and perioperative NSAIDs should be avoided, especially with reduced GFR [10].

Transition to adult nephrology occurs in a disease in which hypercalciuria tends to decrease and renal function to decline, and in which kidney failure appears mainly between the third and fifth decades in Dent disease and between the third and fourth in Lowe syndrome [14, 21]. The sources consulted do not describe dedicated transition programmes; the 2025 recommendations advise continued involvement of an experienced tertiary centre, and the Schwartz formula used in patients with Lowe syndrome is not validated in adults [14, 21]. In Lowe syndrome, most adults live with their family, and planning includes residential support and continuity of ophthalmological and renal care [8]. The 2026 French PNDS starts transition between 15 and 18 years, depending on the setting, to an adult team trained in the disease and coordinated by a reference physician, usually a nephrologist, with ophthalmology, neurology or physical and rehabilitation medicine, endocrinology, rheumatology and, where appropriate, psychiatry, and with medico-social support; adolescence is a period of risk that requires closer follow-up [24]. Before any surgery, the protocol requires an analysis of bleeding risk (section 7.10) [24]. The parents' testimonies included in the protocol describe neonatal feeding difficulties given little weight in the maternity unit and the time families need to accept the diagnosis [24].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

All three entities have X-linked recessive inheritance. The father of an affected boy is neither affected nor a carrier and does not need testing [8, 10]. In a family with more than one affected individual, the mother is an obligate carrier [8, 10]. In an isolated case, the mother may be a carrier, have germline mosaicism or the variant may have arisen de novo in the patient; the proportion of de novo variants is about 12% in DD1, up to 30% in DD2 and about 32% in Lowe syndrome [8, 14]. The 2026 French PNDS reports a carrier mother in about 70% and a de novo variant in about 30%, and estimates maternal germline mosaicism classically below 5%, consistent with the 4.5% in GeneReviews; with a carrier mother, each daughter has a 50% risk of being a carrier, a healthy brother is not affected and a symptomatic brother can have the diagnosis confirmed by testing, and information to at-risk maternal relatives is given through the mother or through the legal procedure for informing relatives [8, 24]. In France, the genetics consultation, with a medical geneticist or genetic counsellor, should take place promptly after diagnosis, and psychological support is systematically offered after diagnosis, in an at-risk pregnancy and in the preconception phase [24].

8.2. Cascade testing and assessment of relatives

The 2025 recommendations advise testing the mother of the index case to distinguish a carrier from a de novo variant (grade X, strong) and female relatives of reproductive age on the carrier maternal line (grade X, strong), and accept genetic confirmation in brothers when the mother is a carrier and they have LMWP (grade X, moderate) [14]. Genetic counselling should be offered to all, for shared decision-making [14]. GeneReviews recommends assessing at-risk male relatives to identify early those who will benefit from treatment and prevention: by molecular testing if the familial variant is known, and by urinary excretion of LMWP (α1-microglobulin, RBP), a sensitive and specific test in males, if it is not [10].

8.3. Carrier detection

Dent disease. LMWP is often raised in carrier females, but the sensitivity and specificity of this marker for detecting them have not been established, and its absence does not exclude carrier status [10, 14]. Detection is by molecular testing when the familial variant is known [10]. The 2025 recommendations suggest assessing carrier females at least once in adulthood (renal ultrasound, urinary calcium/creatinine, LMWP and renal function) (grade C, moderate) [14].

Lowe syndrome. Molecular testing is the most informative method, especially when the proband's variant is known [8]. Dilated slit-lamp examination, with direct illumination and retroillumination, performed by an experienced ophthalmologist, shows characteristic findings in about 95% of heterozygous females older than 15 years [8]. In the study by Lin and colleagues, in 31 at-risk women from 3 families examined by an observer blinded to genetic status, there was one false negative (a 5-year-old girl) and no false positives, which makes the examination very accurate at reproductive age [93]. The examination is inexpensive and useful, but a normal result does not exclude heterozygosity, especially before puberty [6, 8]. The mother of an isolated case should be examined by an experienced ophthalmologist [8]. The OCRL1 enzyme assay in fibroblasts is not reliable in heterozygous females, because of X inactivation [8, 93].

8.4. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known, subject to local legislation, and are a personal decision after discussion with a multidisciplinary team; views on prenatal diagnosis differ between professionals and families [10, 14]. In Lowe syndrome, because of the 4.5% rate of germline mosaicism, GeneReviews recommends offering DNA-based prenatal diagnosis to every mother of an affected boy whose variant is known, even without a family history and even when slit-lamp examination or DNA testing suggests she is not heterozygous [8]. Risk, discussion of prenatal diagnosis and preimplantation testing, and family planning should take place before pregnancy, and DNA from probands without a molecular diagnosis should be stored [8, 10]. The 2026 Egyptian report illustrates DNA-based prenatal diagnosis after identification of the variant in the affected son [62]. In France, where there is no list of eligible diseases and each request is discussed case by case (articles L2131-1 to L2131-5 of the Public Health Code), the 2026 PNDS describes a stepwise pathway: non-invasive fetal sex determination by testing for SRY sequences in maternal serum from 10 weeks of gestation, with ultrasound confirmation of a female fetus, in which the risk is exceptional and does not justify proceeding; in a male fetus, chorionic villus sampling from 11–12 weeks or amniocentesis from 15–16 weeks to test for the familial variant, with a low risk of miscarriage explained to the couple [24]. When the mother is not a carrier and the risk is limited to germline mosaicism, the same pathway may be followed as a precaution, at the couple's request, and non-invasive testing for the familial variant in maternal serum may be discussed for a male fetus [24]. Preimplantation genetic testing, subject to the same framework, is performed in one of the 5 French centres, and oocyte donation is another option; requests for termination of pregnancy for medical reasons are assessed by the multidisciplinary prenatal diagnosis centre, with no gestational age limit under French law [24]. The prenatal disclosure takes place in a joint or successive consultation with a geneticist, paediatrician and obstetrician, and delivery and the neonatal period are planned in a tertiary centre [24].

8.5. Counselling of minors

The 2025 recommendations propose deferring presymptomatic screening of daughters of carriers of Dent disease until 18 years; if there is no screening in childhood, parents should inform their children of the risk when they reach adulthood [14]. GeneReviews recommends offering genetic counselling to young adults who are affected, carriers or at risk [8, 10]. Brothers at risk of Dent disease may be assessed in childhood by LMWP, because the diagnosis has consequences for monitoring [10, 14].

8.6. Kidney donation by relatives

Unaffected male relatives and the father are safe donors, but donation by carrier females requires caution, because some later develop nephrocalcinosis, stones or CKD (section 7.6) [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The total estimate for Dent disease includes DD2 (about 15%), so it overestimates the fraction due to CLCN5, and clinical variability and lack of a family history probably lead to underdiagnosis [3, 10]. Lowe syndrome is pan-ethnic and has been described in the Americas, Europe, Australia, Japan and India [8].

9.2. Geographical differences

Series from Europe and North America describe hypercalciuria in more than 90% of patients with Dent disease, compared with about 50–70% in series from Japan, Korea and China [14]. In Japan, the disease was identified through school urine screening: in the series of 86 patients, hypercalciuria was present in only 51%, rickets in 2% and nephrocalcinosis in 35%, and the authors concluded that the Japanese spectrum is broader than the European and American one [35, 73]. Bone disease was not prominent in the French series and more prominent in a Chinese series, with no established environmental or genetic explanation [10, 78]. In European cohorts, kidney failure occurs mainly from the fourth decade [67, 68]; in the British registry, the median age at kidney failure in the Dent/Lowe group was 55 years [75]; and in the Korean paediatric cohort no patient reached kidney failure [71]. These differences may reflect the mode of ascertainment (school screening versus clinical presentation) and the age of the cohorts. In Lowe syndrome, the Japanese national paediatric and adult cohort is the main source of long-term data [21], and the retrospective international cohort of Zaniew and colleagues brings together the paediatric data [88]. No founder variants of CLCN5 or OCRL have been described; the variants are mostly private [10, 52].

9.3. Portugal and Brazil

The sources consulted include no epidemiological data or patient series from Portugal or Brazil, and the European survey by Burballa and colleagues, which brought together several networks and societies, does not break down the countries in the abstract read [68]. Absence from the sources does not show that no patients have been described in these countries. The Portuguese SmPCs of the main drugs and the Brazilian ANVISA registrations were consulted (section 7.11) [139]; the Brazilian package inserts could not be read.

9.4. Special populations

Carrier females are a population with a risk of their own, mainly of nephrocalcinosis and stones in adulthood, and benefit from at least one renal assessment [14]. Adult males with unexplained CKD are a population in which the diagnosis of Dent disease is often missed; the 2025 recommendations advise including CLCN5 and OCRL in CKD panels, whatever the age [14]. In patients with Lowe syndrome, creatinine-based estimation of renal function is biased by low muscle mass [21].

9.5. European reference networks, registries and patient associations

ERKNet (https://www.erknet.org/) coordinated and funded the 2025 recommendations through its working group on metabolic diseases and tubulopathies [14, 23]. ERN-EYE is the relevant network for the cataracts and glaucoma of Lowe syndrome. In the United Kingdom, the UK Kidney Association maintains the RaDaR registry and information pages for clinicians on Dent disease and Lowe syndrome [41, 75, 89]. The RKSC, based at the Mayo Clinic, maintains a registry, a biobank and the prospective ProRKS study with patients with Dent disease and Lowe syndrome, and the CLCN5 variant database [10, 52, 147]. The Lowe Syndrome Association (USA; https://lowesyndrome.org/) supports more than 300 boys and men in more than 35 countries and organises conferences for families and professionals [154]. The Lowe Syndrome Trust (United Kingdom; https://lowetrust.org.uk/) provides information for families and general practitioners, an information sheet for emergency services and research funding [155]. GeneReviews also mentions Metabolic Support UK, the Kidney Foundation of Canada, the National Kidney Foundation and the National Eye Institute's eyeGENE resource, and Firth and Hurst's textbook mentions the CLIMB association [8, 10, 90]. The Italian association of patients with Lowe syndrome provided data for the prevalence estimate [8]. In France, Lowe syndrome is managed by the SORARE (Toulouse), MAREGE (Lyon) and MARHEA (Paris) reference centres of the ORKiD filière, by the centres of the MHEMO network and the reference centre for constitutional platelet disorders (coordinated in Marseille), by the O-Rares network for oral and dental diseases and by the Maladies Rares Info Services helpline [24]. From diagnosis, the paediatric nephrologist applies for 100% coverage as a long-term condition (ALD), including all manifestations, and the social services organise support from the Maison départementale des personnes handicapées (MDPH), the allocation d’éducation de l’enfant handicapé (AEEH), the allocations journalières de présence parentale (AJPP) and the prestation de compensation du handicap (PCH); in adulthood, recognition as a disabled worker (RQTH), the allocation aux adultes handicapés (AAH) and, depending on the intellectual disability, a legal protection measure [24]. Therapeutic education covers eye drops and prevention of eye trauma, early stimulation, losses of bicarbonate, phosphate, salt and water, hydration and signs of decompensation, and bleeding risk [24]. Contact with associations is systematically offered: the Association française du Syndrome de Lowe (ASL; www.syndrome-lowe.org), AIRG-France, France REIN and national associations in Italy, the United Kingdom, Germany, Spain and Denmark, as well as the Lowe Syndrome Association [24].

10. Illustrative Clinical Case

D'Ambrosio and colleagues, from the London Tubular Centre (University College London), published in 2024 the case of a 19-year-old woman with full Dent disease type 1 [51]. She was referred to a tertiary tubulopathy service for hypophosphataemic rickets, diagnosed at 2 years of age and attributed first to vitamin D deficiency and then to Fanconi syndrome. She had no history of stones, renal colic or urosepsis, the family history was negative, blood pressure was normal and height was 140 cm. Serum creatinine was 106 µmol/L, with eGFR 68 mL/min/1.73 m², and serum phosphate 0.73 mmol/L, with the rest of the serum biochemistry normal. In the urine, RBP was markedly raised (62,900, for a reference of 20–40, in units given in the paper as mg/L), with RBP/creatinine of 25,160; there was hypercalciuria (calcium/creatinine 1 mmol/mmol, for a reference of 0.3–0.7), hyperphosphaturia (fractional excretion of phosphate 48%, normal <20%) and reduced maximum phosphate reabsorption (TmP/GFR 0.62 mmol/L, reference 0.84–1.23). Computed tomography of the kidneys, ureters and bladder and abdominal ultrasound showed extensive bilateral medullary nephrocalcinosis, documented in figures 1 (tomography; https://pmc.ncbi.nlm.nih.gov/articles/PMC11170036/figure/fig1/) and 2 (ultrasound; https://pmc.ncbi.nlm.nih.gov/articles/PMC11170036/figure/fig2/) of the paper [51].

A next-generation sequencing panel on lymphocyte DNA identified, in the heterozygous state, the CLCN5 variant c.2152C>T p.(Arg718*), described on transcript NM_001127899.3; it corresponds to NM_001127898.4:c.2152C>T p.(Arg718Ter) on the MANE transcript and to NM_000084.5:c.1942C>T p.(Arg648Ter) in historical numbering, and is a known pathogenic variant [13, 51]. Neither parent carried the variant, which was classified as de novo. Methylation analysis of the androgen receptor gene, by fluorescent PCR with and without the methylation-sensitive restriction enzyme HpaII, revealed non-random inactivation of the maternally derived X [51]. The authors did not determine on which X chromosome the variant arose; preferential inactivation of the maternal X is compatible with a variant on the active paternal X. After 2 years of follow-up on oral supplements, the patient was asymptomatic, with stable eGFR and serum phosphate at the lower limit of normal [51].

The case illustrates three points of this article. The first is that Dent disease can be fully expressed in a woman when X inactivation is highly skewed; the authors consider it the first published case of overt DD1 in a woman by this mechanism, after cases of DD2 and Lowe syndrome [8, 51]. The second is that a negative family history does not exclude an X-linked disease, because de novo variants are frequent [14]. The third is diagnostic delay: the rickets, present from 2 years of age, received a molecular diagnosis only at 19, after being attributed to vitamin D deficiency and Fanconi syndrome, which reinforces the recommendation to measure LMWP and perform genetic testing in hypophosphataemic rickets with hypercalciuria [14]. The management (oral supplementation, which the paper does not specify beyond normalising phosphate) is consistent with the 2025 recommendations, which suggest phosphate salts in hypophosphataemia with rickets and warn of the risk of worsening nephrocalcinosis; the paper does not describe the dose or the course of the nephrocalcinosis [14, 51]. The recommendations for carrier females (at least one renal assessment in adulthood) apply all the more to a manifesting heterozygous female, who should be followed as a patient [14].

A second case, published in 2026 with full text, shows DD2 in an adult: a 23-year-old man with the OCRL variant c.821T>C p.(Ile274Thr), with attention and learning difficulties in childhood, clear lenses, no rickets, fractures or stones, blood pressure of 100/60 mmHg without ACE inhibitors or ARBs, body mass index of 32, creatinine of 1.62 mg/dL (eGFR 56 mL/min/1.73 m² by the European Kidney Function Consortium equation, EKFC), urinary protein/creatinine of 1206 mg/g, fractional excretion of calcium of 2.54% and ultrasound without nephrocalcinosis; dapagliflozin had no antiproteinuric effect over 12 weeks [63]. The absence of nephrocalcinosis, cataract and severe intellectual disability and the presence of mild school difficulties exemplify the subtle extrarenal phenotype of DD2 [14, 63].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis of Dent disease

Kidney failure occurs in 30–80% of males with Dent disease, mainly between the third and fifth decades, sometimes only in the sixth or later [10, 14]. The mean eGFR decline is about 1.5 mL/min/1.73 m²/year in European series, with median ages of about 13–14 years for stage 2, 17–25 years for stage 3, 33–35 years for stage 4 and 40–52 years for stage 5 [14, 67, 68]. In the British registry, the median age at kidney failure was 55 years and 10-year renal survival 0.79 in the pooled Dent and Lowe group [75]. Proteinuria is not significantly related to GFR, in either DD1 or DD2; glomerular and tubulointerstitial fibrosis correlates with function but not with proteinuria or the rate of decline; mild focal podocyte effacement correlated with progression; and nephrocalcinosis, or its severity, was not associated with GFR decline, kidney failure also occurring without nephrocalcinosis [14, 76]. In the RKSC registry, the burden of stone events and truncating variants were associated with a worse course [69]; the UK Kidney Association states that failure may occur independently of stones, but that recurrent episodes contribute [41]. The disease does not recur after transplantation [14].

11.2. Prognosis of Lowe syndrome

In Lowe syndrome, CKD progresses with age, independently of nephrocalcinosis, hypercalciuria and proteinuria: in the Japanese cohort, the median age was 11 years for stage 3, 27 years for stage 4 and 32 years for kidney failure, with kidney failure in 67% of patients aged 30 years or older [21, 88]. Life expectancy rarely exceeds 40 years; the causes of death are renal failure and scoliosis in older patients and dehydration, pneumonia and infections at all ages [8, 26]. Corrected visual acuity rarely exceeds 20/100, and glaucoma may lead to blindness [8]. Functional prognosis depends on the degree of intellectual disability, which is severe to profound in 50–65% [8]. The 2026 French PNDS reports CKD stage 4–5 in 80% of adults, in the fourth decade, a life expectancy of 40 years in a 1991 cohort, with death from kidney failure and lung infection, and a final visual acuity below 1/10 in more than half of patients [24].

11.3. Monitoring in Dent disease

11.4. Monitoring in Lowe syndrome

11.5. Follow-up at transition and in adulthood

In Dent disease, transition to adult care coincides with the fall in calciuria, persistence of hypophosphataemia and the appearance of hypokalaemia in half of patients, and with the onset of the loss of function that leads to CKD stage 3 at around 17–25 years [14]. Renal monitoring intensifies as function falls, as in any progressive CKD [14]. In Lowe syndrome, IOP monitoring continues every 6 months throughout life and renal function at least annually, with timely preparation of the decision on dialysis and transplantation [8, 21]. The 2026 French PNDS proposes preparing transition from 15–18 years and maintaining at least an annual assessment in adults with CKD 1–3, closer in CKD 4–5 or on dialysis [24].

12. Summary and Final Considerations

Dent disease and Lowe syndrome are X-linked proximal tubulopathies that share a defect of endocytosis in the proximal tubule and have LMWP as their constant finding. DD1, caused by variants in CLCN5, which encodes the endosomal exchanger ClC-5, and DD2, caused by OCRL variants in the early exons, which spare a short isoform of the 5-phosphatase OCRL1, present with LMWP, hypercalciuria, nephrocalcinosis, stones, hypophosphataemia and slowly progressive CKD, with kidney failure in 30–80% of males between the third and fifth decades; DD2 adds mild intellectual disability, growth delay, raised muscle enzymes and, rarely, cataract. Lowe syndrome, caused by OCRL variants in exons from 8 onwards, combines dense congenital cataracts, glaucoma in half of patients, central hypotonia, usually severe intellectual disability, a selective proximal tubulopathy with acidosis, a defect of primary haemostasis and kidney failure at around 30 years, with a life expectancy that rarely exceeds 40.

The diagnosis of Dent disease starts with testing for LMWP in every male with persistent proteinuria, especially when serum albumin is normal, and is confirmed by genetic testing of CLCN5 and OCRL, without renal biopsy; a negative test, which occurs in about a quarter of cases with a clinical diagnosis, does not exclude the disease. The diagnosis of Lowe syndrome should be considered in any boy with congenital cataracts and hypotonia, and is confirmed by OCRL testing and, in inconclusive cases, by enzyme activity in fibroblasts. The MANE transcript of CLCN5 (NM_001127898.4) has numbering shifted by 70 codons relative to the historical numbering, and variant conversion should be done with validation tools.

There is no disease-modifying treatment. The 2025 ERKNet/ESPN recommendations direct the treatment of Dent disease towards supportive measures with limited evidence: citrate to be considered in nephrocalcinosis or stones, phosphate in hypophosphataemia with rickets, native vitamin D if low and never active vitamin D, vitamin A if deficient, somatropin only in selected cases, and thiazides, ACE inhibitors and ARBs not routinely, with follow-up in a tertiary centre, monitoring every 3–6 months and annual ultrasound. In Lowe syndrome, early cataract surgery without contact lenses, six-monthly IOP monitoring, titrated correction of acidosis and hypophosphataemia, attention to haemostasis before any surgery and developmental support are the basis of care, now organised by the first national protocol, the 2026 French PNDS, which adds haemostatic assessment from diagnosis, ophthalmological monitoring every 2–6 months in the first years and rheumatological, dental and dermatological follow-up. Genetic counselling must take into account de novo variants, maternal germline mosaicism (4.5% in Lowe syndrome), carrier detection by lens slit-lamp examination in Lowe syndrome and the manifestations of carrier females in Dent disease. Therapeutic developments (piclidenoson, phosphoinositide kinase inhibitors, gene therapy and base editing) are at the preclinical stage or in a pilot trial not yet started.

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