Nail-Patella Syndrome

Autosomal dominant patellar dysostosis due to LMX1B loss of function, with nail dysplasia, anomalies of the knee, elbow and pelvis, glomerular nephropathy and open-angle glaucoma; includes isolated LMX1B glomerulopathy (FSGS10) as an allelic form.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Nail-patella syndrome (NPS) is an autosomal dominant dysostosis caused by loss of function of one allele of LMX1B, a gene encoding a transcription factor with two LIM domains and a homeodomain. The classic tetrad brings together nail anomalies, an abnormal and unstable patella with knee changes, limited elbow mobility and iliac horns on pelvic radiography; to these are added a glomerular nephropathy with proteinuria, with or without haematuria, in 30%–50% of patients, end-stage kidney disease in up to 15% in the older series, and primary open-angle glaucoma and ocular hypertension that are more frequent and earlier than in the general population [1]. Expressivity varies between families and within the same family, so that an individual may have one severe manifestation and others mild or absent, whereas penetrance in heterozygotes is complete [1, 4].

This article covers three entities with different degrees of autonomy. The first is classic NPS (OMIM 161200; ORPHA:2614), with its skeletal, nail, renal, ocular, neurological and gastrointestinal spectrum. The second is isolated LMX1B glomerulopathy, now designated in OMIM as focal segmental glomerulosclerosis type 10 (FSGS10; OMIM 256020; ORPHA:2613, "nail-patella-like renal disease"), defined as an autosomal dominant kidney disease with glomerulopathy without extrarenal manifestations, caused by specific missense variants of the LMX1B homeodomain [5, 10]. The third, which only enters the differential diagnosis and the discussion of the mechanism, is the 9q33.3q34.11 microdeletion syndrome (ORPHA:495818), in which the contiguous deletion includes LMX1B and STXBP1, both assigned a role in the phenotype by Orphanet [29].

1.2. Historical descriptions

The first description of congenital defects of the nails, elbows and patellae in one patient is attributed to Chatelain, in 1820 [21, 30]. The hereditary nature was recognised by Pye-Smith in 1883 and substantiated by Little in 1897, who, citing Sedgwick, brought together 18 individuals from four generations with nail dysplasia and absent or hypoplastic patellae; Little's report, limited to the patellar defect, is the one most cited as the initial description [30, 31]. Wrede added elbow involvement in 1909, and Österreicher (1931) and Turner (1933) described the nail-knee-elbow triad and its dominant transmission; the Turner of this eponym is J. W. Turner, unrelated to H. H. Turner and monosomy X [1, 30]. Aschner published in 1934 the association of nail dystrophy with a congenital defect of the patella and the radial head [3].

Iliac horns were described by Kieser in 1939 and by Turner in patients with NPS before E. E. Fong, in 1946, described them as symmetrical posterior processes of the ilia in a woman undergoing intravenous pyelography, without relating them to the syndrome; the eponym "Fong disease" derives from that report [1, 32]. Mino and Thompson confirmed the tetrad in 1948–1949, Hawkins and Smith drew attention to the nephropathy in 1950 (although Kieser had described it in 1939), and Darlington documented it at necropsy in 1967 [4, 30]. The ophthalmological link was consolidated at the end of the 20th century with the cosegregation of open-angle glaucoma and NPS in two Michigan families described by Lichter and colleagues in 1997 [33].

1.3. From genetic linkage to the gene

NPS holds a place in the history of human genetics. James Renwick used it, more than 50 years ago, to develop methods of linkage analysis in humans, and the linkage between the NPS locus and that of the ABO blood group, at 9q34, was the third linkage group identified in the human species [3, 34]. The recombination fraction between the two loci is about 10%, higher in females, and the ABO-NPS1-AK1 linkage group was assigned to 9q34 in 1976; in 1997, analysis of five families placed the gene in a 1–2 cM interval between D9S60 and AK1 [4, 14]. In 1998, Duba and colleagues described a carrier of a balanced translocation t(9;17)(q34.1;q25) with typical NPS, and the breakpoint helped to delimit the region [35]. In the same year, Dreyer and colleagues identified heterozygous de novo variants in LMX1B in three independent patients, one altering specific DNA binding and two causing premature termination; these were the first pathogenic variants described in a LIM-homeodomain protein, and the Lmx1b null mouse, described in parallel, had hypoplastic nails, absent patellae and renal dysplasia [36]. McIntosh and colleagues found 25 variants in 37 of 41 families, consistent with haploinsufficiency, and Vollrath and colleagues identified loss-of-function variants in four families with NPS and open-angle glaucoma [14, 37].

1.4. Isolated renal form and non-coding regions

The expression "nail-patella-like renal disease" was used before the molecular era for glomerular basement membrane changes similar to those of NPS in patients without nail or bone anomalies; Dombros and Katz described in 1982 a 34-year-old woman with microscopic haematuria and deposition of collagen fibres in the mesangial matrix, with no signs of NPS in her or her relatives, and Zuppan and colleagues, in 2003, a 17-year-old boy with chronic haematuria and non-nephrotic proteinuria with the same ultrastructure [13]. Another description, that of Salcedo in 1984, referred to three children of first-cousin parents of Palestinian Arab ancestry with early proteinuria and kidney failure, two of whom died with end-stage kidney disease at 6 and 7 years, and suggested autosomal recessive transmission [13, 38]; the name "Salcedo syndrome" became associated with OMIM entry 256020, created in 1986, which now describes an autosomal dominant disease caused by LMX1B [5, 13]. In 2013, Boyer and colleagues demonstrated by linkage and exome sequencing that the LMX1B variant p.(Arg246Gln) causes hereditary focal segmental glomerulosclerosis without extrarenal involvement [10], a finding confirmed in 2014 in a Japanese child with the same de novo variant and in 2017 in two large North American families [13]. In 2021, Haro and colleagues identified two autoregulatory cis-regulatory modules of Lmx1b in the limb (LARM1 and LARM2) and loss-of-function variants in that region in families with NPS and a normal coding sequence [39]; in 2026, Brunelle and colleagues described regulatory deletions, translocations and a 5′ untranslated region variant, raising the diagnostic yield to close to 100% in a reference laboratory [23].

1.5. Nomenclature

"Nail-patella syndrome" is the most accepted term, although it suggests that the nails and patellae are what matters most clinically; "hereditary onycho-osteodysplasia" (HOOD) is more accurate but little used, and the GeneReviews authors consider that "hereditary onycho-osteodysplasia with nephropathy and glaucoma" would be the most appropriate designation [1]. The 2023 revision of the Nosology of Genetic Skeletal Disorders classifies the entity as "LMX1B-related nail-patella syndrome" in the group of patellar dysostoses [1, 40]. In OMIM, entry 161200 retains the synonyms NPS1, HOOD, Fong disease, Turner-Kieser syndrome, Österreicher syndrome and "pelvic horn syndrome", and entry 256020 is now designated FSGS10, retaining as synonyms NPLRD, "glomerular basement membrane disease, nail-patella syndrome type" and "Salcedo syndrome" [2, 5]. Orphanet distinguishes ORPHA:2614 (NPS) from ORPHA:2613 (renal form); GeneGuidance erroneously associated OMIM 161200 with ORPHA:2613 and with the prevalence of less than 1/1,000,000 of the renal form, a value that does not apply to NPS [9, 16, 17].

2. Molecular Genetics and Pathophysiology

2.1. The LMX1B gene and protein

LMX1B (LIM homeobox transcription factor 1 beta; Gene ID 4010; OMIM 602575; HGNC:6654; UniProt O60663) is located at 9q33.3, spans about 82 kb and has eight exons; intron 2, of about 75 kb, accounts for most of the size of the gene [7, 9, 21]. The protein has two N-terminal cysteine-rich zinc-binding LIM domains (LIM-A, encoded by exon 2, and LIM-B, by exon 3), a 60-amino acid homeodomain (exons 4 to 6) and a C-terminal activation sequence rich in glutamine and serine [4, 21]. Alternative splicing of the last 21 nucleotides of exon 7 gives rise to proteins of 372 or 379 amino acids (395 or 402 if 23 amino acids encoded by a region presumed to be untranslated are included), and the sequence is 99% identical among mammals [4]. In the adult kidney, the gene is expressed only in the podocyte, from the S-shaped body stage of glomerular development [4].

2.2. Functions in development and in adult tissues

LMX1B is a cardinal gene in dorsoventral patterning of the limbs: it specifies dorsal limb identity at the zeugopod and autopod levels, and loss of function causes ventralisation, which explains the nail dysplasia, the absence of the dorsal skin creases of the distal interphalangeal joints and the hypoplasia of the patella [3, 9]. WNT7A is the other main regulator of this axis; LMX1B acts downstream of WNT7A, but the interaction between the two is not a simple unidirectional pathway [41]. The distribution of nail changes follows this biology: in NPS the thumbnail is the most affected and, in each nail, the ulnar side is more affected than the radial side, whereas in syndromes due to loss of WNT7A the gradient is reversed, radioulnar [1, 41].

Outside the limb, LMX1B directs the formation of the anterior segment of the eye and the podocyte differentiation programme [1]. In the mouse, it regulates FOXC1 and FOXC2 in the corneal stroma, a pathway shared with anterior segment dysgenesis, which gives a biological basis to the glaucoma [19]. In the glomerulus, LMX1B binds to a sequence with enhancer function in intron 1 of COL4A4, in mouse and human, and the Lmx1b−/− mouse, which dies soon after birth with massive glomerular vascular leakage, has greatly reduced expression of the α3 and α4 chains of collagen IV, through loss of activation of a COL4A3/COL4A4 enhancer, and reduced CD2AP and podocin (NPHS2), with altered expression of nephrin; the heterozygote has a moderate reduction [4, 15, 42]. The interaction of the LMX1B homeodomain with that of PAX2 led to PAX2 being proposed as a modifier gene [15]. In human NPS biopsies, however, the α3, α4 and α5 chains of collagen IV, podocin, synaptopodin, GLEPP1, CD2AP, α3 integrin and nephrin show normal immunohistochemistry, so the murine model does not translate directly [4]. RNA sequencing of murine podocytes indicates that LMX1B acts mainly as a transcriptional repressor [43].

In the nervous system, Lmx1b is required for the differentiation and migration of dorsal horn neurons of the spinal cord; failure of migration of the neurons that receive sensory afferents is consistent with the reduced sensitivity to pain and temperature observed in patients [44]. The gene is also required for dopaminergic and serotonergic neurons [9]. In heterozygous mouse models with missense variants affecting DNA binding, postnatal maturation of forebrain serotonergic axons (hippocampus and motor cortex) is impaired and there are spatial memory deficits; these data are preclinical [45]. The cardiovascular role of LMX1B is poorly understood [1].

2.3. Molecular mechanism: haploinsufficiency and its exceptions

The main mechanism of NPS is haploinsufficiency. Truncating variants are eliminated by nonsense-mediated messenger RNA decay, total or partial deletions remove one copy, and homeodomain missense variants reduce or abolish DNA binding, while those in the LIM domains disturb the secondary structure of the zinc fingers [1, 21, 46]. In humans the disease is dominant; in the mouse, the NPS-like phenotype (with neonatal lethality) requires homozygosity [4]. In luciferase assays in Cos-1 cells, five variants from patients with severe nephropathy, including two in the homeodomain, had no transcriptional activity and exerted no dominant-negative effect when co-expressed with the normal allele, which supports haploinsufficiency even in severe renal phenotypes [11].

Two sets of data qualify this rule. In knock-in mice with the LIM variants H77L (LIM-A) and C118F (LIM-B) (published designations, in the numbering of the murine Lmx1b protein), heterozygotes are healthy and homozygotes reproduce the null phenotype; the mutant proteins are ubiquitinated and degraded by the proteasome, with a reduced half-life, and bortezomib prolongs that half-life. The homeodomain variant V265D (designation published by the authors, with no human HGVS equivalent given), in contrast, produces a protein more stable than the normal one (half-life of 8.0 h versus 4.8 h), consistent with another mechanism, possibly with dominant action [43]. In a mouse model of glaucoma, homeodomain missense variants had a dominant-negative effect in vivo [21]. The second set is FSGS10: arginine 246 stabilises the interaction of the homeodomain with the phosphate-ribose backbone of DNA, and the substitutions p.(Arg246Gln) and p.(Arg246Pro) cause glomerular disease without a limb phenotype, whereas the stop codon at the same residue, p.(Arg246Ter), causes classic NPS; the authors interpreted this contrast as a residue-specific renal function, which challenges, at least in some cases, the model of pure haploinsufficiency [10]. In later functional studies, p.(Arg246Gln) only partially reduced transcriptional activity, less than the NPS variants and without a global dominant-negative effect, but exerted a dominant-negative effect on some WT1 isoforms in podocyte cell lines, which may explain the renal specificity [13, 15]. Heterozygous deletion of the whole gene, detected by MLPA in two patients, produces a phenotype similar to that of point variants, which confirms haploinsufficiency in NPS [14].

2.4. Variant spectrum

GeneReviews counts more than 170 pathogenic LMX1B variants in NPS, and a 2025 study mentions more than 200 [1, 45]. About 80% are located in the LIM domains and about 20% in the homeodomain, with few in the C-terminus; no pathogenic variant has been described in the carboxy-terminal third of the coding sequence, a region whose alteration probably does not inactivate the protein, which weighs on the interpretation of distal truncating variants [1, 4, 46]. A series of recurrent variants in the homeodomain accounts for about 30% of pathogenic variants [1]. In the French cohort of 55 families, truncating variants occurred in 31 families (four with large deletions), LIM missense variants in five and homeodomain missense variants in 14; there were 38 different alterations, 19 of them novel, and five recurrent in three families each — c.303_304delGT p.(Tyr102LeufsTer45), c.661C>T p.(Arg221Ter), c.668G>A p.(Arg223Gln), c.706G>C p.(Ala236Pro) and c.736C>T p.(Arg246Ter) — with no apparent founder effect because they had different origins; the variant c.317A>C p.(Asp106Ala), found in two unrelated Spanish families, suggests a possible founder effect [21].

Structural and non-coding alterations are a minority but clinically relevant. Balanced translocations that disrupt the gene or separate it from its regulatory elements and an inversion of about 4.2 Mb in 9q, published as g.129385769_133614642 with accession NC_000009.12 (the coordinates correspond to the GRCh37 assembly, because in GRCh38 LMX1B begins at 126.6 Mb), which disrupts LMX1B in intron 2 and ABL1 in intron 1 and generates a hybrid transcript lacking LIM-B and the homeodomain, have been described in families with NPS [23, 35, 47]. Heterozygous deletions of the autoregulatory modules LARM1/LARM2, located about 60 kb upstream of the promoter, a deletion of a conserved upstream sequence bound by LMX1B itself, and the 5′ untranslated region variant NM_001174147.2:c.-226G>A (NC_000009.12:g.126614224G>A), which creates an upstream open reading frame, cause NPS with manifestations limited to the nails and limbs [23, 39, 48]. A consanguineous case with rare homozygous variants in LARM2 showed that regulatory alterations can follow recessive inheritance [23]. A deletion of about 2 Mb in 9q including the whole gene was described in a patient with a complex phenotype, corresponding to the territory of the 9q33.3q34.11 microdeletion syndrome [29, 49].

2.5. Variant nomenclature and transcripts

The MANE Select transcript is NM_001174147.2 (protein NP_001167618.1). Transcript NM_002316.3, used in the Japanese and French series and in the FSGS10 studies, shares the c. numbering with MANE at all positions checked in VariantValidator (c.706, c.737, c.793 and c.819+1), and there is a more recent version, NM_002316.4 [8]. Version NM_002316.2, used in earlier articles, has numbering 69 nucleotides (23 amino acids) lower, so the former c.109C>T p.Gln37* corresponds to c.178C>T p.(Gln60Ter) in the current numbering, a conversion given by the authors themselves [21]. Variants from articles without a declared transcript, such as Gln65Pro, Ala213Pro, Gln59Ter and Arg198Ter in the 2006 Australian series, are kept in the historical nomenclature [19].

Validation was performed in VariantValidator on GRCh38 and ClinVar status was consulted for four variants; the LRG_1014 record for the gene is pending [8, 56]. The classification of p.(Gly117Ser) as a variant of uncertain significance in ClinVar diverges from its presentation in GeneReviews as a cause of isolated FSGS; Gly117 lies in the LIM-B domain and not in the homeodomain, where the other FSGS10 variants cluster [1, 50, 56].

2.6. Genotype-phenotype correlations

For extrarenal manifestations there is no clear correlation between the type or location of the variant and the phenotype [1, 37, 57]. The severity of nail dysplasia was associated with the haplotype of the mutant allele (p=0.024) and not with the variants or variant classes (p>0.5), which suggests a cis element on the affected allele [4, 58]. In 1956, Renwick had found correlations of about 0.5 between affected siblings and close to zero between affected parent and child for nail and patellar dysplasia, and attributed the variation to isoalleles of the normal allele inherited from the unaffected parent; the 2005 study did not confirm this role of the normal allele [14, 58]. For the kidney, the correlation is partial. In the Dutch cohort of 106 individuals from 32 families, homeodomain variants were associated with more frequent and higher proteinuria than LIM domain variants; 53% of the variation in proteinuria was attributable to the family and 30% to the genotype [4, 57]. In the Japanese cohort, the missense variants associated with severe nephropathy were located in helices I (Ala236) and III (Val263, Val265; the recognition helix that contacts the major groove of DNA), whereas FSGS10 variants without an extrarenal phenotype — p.(Arg246Gln), p.(Arg246Pro), p.(Arg249Gln) and p.(Ala278Val) — lie in helices II and IV [11]. The variant p.(Ala236Pro) caused nephropathy in the six affected members of a French family, three of whom had end-stage kidney disease [21].

The genotype does not, however, predict individual progression. In the Pittsburgh study, the variants with most renal involvement were c.819+1G>A (2/2), p.Cys146Tyr (2/3) and p.Leu252Pro (3/3), and those with least were p.Gln60Ter (1/9), p.Arg221Ter (0/4) and p.Arg231Ter (0/6) (χ²=24; p=0.008); because these are variants of different types, the author concluded that there is no "nephropathy locus" [4]. In the Japanese family with p.(Val265Phe), the father and aunt had mild or absent proteinuria and normal kidney function up to 40 years of age, whereas the two children lost function in adolescence [11]. Discordant identical twins, one with rapid kidney failure and the other with proteinuria only, have been described [4]. The presence and severity of proteinuria are the best predictor of progression [1, 11]. Regulatory alterations (LARM1/LARM2) appear to cause a skeletal-only NPS, but the series is small and the authors recommend maintaining renal and ocular surveillance [23].

2.7. Allelic disorders, modifiers and heterogeneity

FSGS10 is the only established allelic disorder (section 3.9). Modifier variants in podocyte genes (NPHS1, NPHS2, CD2AP, ACTN4) have been proposed to explain the 5%–10% of patients with early nephrotic proteinuria, a hypothesis not demonstrated [4]. The French PNDS (French National Diagnosis and Care Protocol) adds that variants in genes encoding LMX1B partners, such as PAX2, may modulate renal severity, based on a single study [20]. The co-occurrence of a second genetic disease can modify the renal phenotype: a likely pathogenic COL4A4 variant coexisted with p.(Arg231Ter) in a patient with an Alport-like glomerular basement membrane (GBM), and a hemizygous OCRL variant explained the tubular proteinuria, hypercalciuria and nephrocalcinosis in two of three siblings with NPS [52, 53]. In five of 55 clinically indistinguishable French families (9%) no LMX1B alteration was found after extensive study, and one family had no linkage to the locus, which led the authors to propose genetic heterogeneity, not yet demonstrated [21]; the subsequent study by the same group, which included regulatory regions and structural variants, resolved almost all the negative cases [23]. In addition to recessive regulatory alterations (section 2.4), the PNDS mentions a Saudi family, published in 2015, with transmission consistent with autosomal recessive inheritance and coding region variants, which makes recessive inheritance a rare exception documented also outside the LARM [20].

3. Clinical Spectrum and Manifestations by System

3.1. Reference cohorts and frequency of manifestations

Frequency data come from referral series, biased towards cases diagnosed by geneticists, and not from population studies. The British cohort of Sweeney and colleagues (2003) brought together 123 patients from 43 families (70 women and 53 men; mean age 32.6 years, from 4 months to 80 years), recruited through clinical genetics services (28 families), the patient group (13) and self-diagnosis (two) [12]. The French cohort of Ghoumid and colleagues (2016) included 94 affected individuals from 55 families, mostly French, with 82 characterised carriers of an LMX1B alteration [21]. The Dutch cohort of Bongers (2005) studied 106 individuals from 32 families [57], and the Japanese cohort of Harita (2020) brought together 13 patients with confirmed nephropathy, recruited through a biopsy registry and a survey of scientific societies, and therefore biased towards young and severe cases [11].

Sources of the table: [1, 12, 21]. The height of British adults was at the 25th centile (170.9 cm in men and 158.5 cm in women), with weight at the 50th centile and normal birth weight [12]; GeneReviews describes average stature, whereas the Swedish family with an inversion of the gene had short stature in all five affected members (z-score from −0.8 to −3.2) [1, 47].

3.2. Nails and hands

Nail changes are the most constant manifestation and are present from birth. The nails may be absent (anonychia), hypoplastic or dystrophic, with longitudinal or horizontal ridges, pitting, discoloration, thinning or, less often, thickening; they may be split into two halves by a longitudinal cleft or a skin ridge, and sometimes the change is limited to triangular lunulae, considered characteristic [1, 59]. The distribution follows a gradient: the thumbs are the most affected, severity decreases from the index finger to the little finger and, in each nail, the ulnar side is more affected [1, 12]. In the British series, the change was limited to the thumbs in 42% (52/123), to the thumbs and index fingers in 26% and was more extensive in 29%; toenails were affected in 67% (82/122), especially that of the fifth toe [1, 12]. In the French series, koilonychia and longitudinal ridges occurred in 50%, anonychia (mainly of the thumbs) in 26%, triangular lunulae in 31 of 72 patients (43%; the article states 29%) and absent lunulae in 13% [21]. Triangular lunulae may be less frequent in children [60].

Loss of the dorsal skin creases over the distal interphalangeal joints, with reduced flexion of those joints, occurred in 96% of British patients and follows the same gradient as the nails; it is the most frequent sign of the syndrome and more sensitive than triangular lunulae [12, 60]. Hyperextension of the proximal interphalangeal joints with flexion of the distal ones (swan-neck deformity) occurred in 58% and clinodactyly of the fifth finger in 35% [12]. A 20-year-old woman with a previous diagnosis of nail lichen planus, treated without improvement with topical halobetasol, had bilateral cubitus valgus, triangular lunulae, split nails, absence of the distal interphalangeal creases and hypoplasia of the thumb with greater dysplasia at the ulnar border; her father and paternal grandfather were affected [60].

3.3. Knee

Knee complaints include pain, instability, locking, clicking, patellar dislocation and inability to extend fully, sometimes with underdevelopment of the vastus medialis [1]. The patellae are small, irregular or absent, sometimes asymmetric, and tend to lie laterally and superiorly even without dislocation; the medial femoral condyles are prominent and the lateral ones hypoplastic, and the tibial tuberosity is prominent, which gives the knee a flattened profile [1, 3]. There may be flexion contractures due to tight hamstrings, osteochondritis dissecans, synovial plicae and absence of the anterior cruciate ligament, and early osteoarthritis is common [1]. On radiographs of 95 skeletally mature Dutch patients, patellar aplasia occurred in 4% and hypoplasia in 86%, with a predominance of Wiberg III, IV and "Hunter's cap" forms; the lateral femoral condyle was shortened in 55%, its anterior surface prominent in 56% and the anterior surface of the medial condyle flat in 92%, the trochlea was Dejour type A1 in 93%, and the "quartet" of patellar aplasia or hypoplasia with the three malformations of the distal femur occurred in 27%; the shape of the patella was not associated with the genotype [61]. Magnetic resonance imaging shows the patellar cartilage, trochlear dysplasia, meniscal anomalies, an anterior sagittal fibrous or synovial septum and synovitis [30]. The French PNDS (French National Diagnosis and Care Protocol) describes the "square" knee, due to absence of the patella in the trochlear groove and hypoplasia of the lateral condyle, and a tense synovial band (plica) between the suprapatellar pouch and the trochlea that divides the joint, prevents centring of the patella and may damage the cartilage; in the infant, before ossification, a lateral dislocation of the patella may be observed that appears at about 30° of flexion and increases with flexion, a pattern different from the acquired patellar instability of the older child, which makes palpation of the patella the essential examination at that age [20]. The same protocol adds exaggerated external tibial torsion to the patellar anomalies and describes the progression of the unstable knee to painful functional disability with early patellofemoral osteoarthritis [20].

The functional impact was measured in a survey of 139 Dutch patients (74% response): the mean KOOS (Knee injury and Osteoarthritis Outcome Score) was 73.04 and the Kujala score 74.01, with great variability; 48.5% had patellofemoral instability, 23 patients had undergone surgery on 31 knees and 12% were considering surgery [62]. Surgical results are given in section 7.6.

3.4. Elbow and upper limb

The elbow shows limited extension, pronation and supination, cubitus valgus, antecubital pterygia and dislocation of the radial head, usually posterior, sometimes asymmetrically [1]. In the British series, the extension deficit was less than 15° in 36% of elbows, 15° to 45° in 27%, 45° to 90° in 5% and greater than 90° in 2% [12]. Radiologically there is dysplasia of the radial head, hypoplasia of the capitulum and lateral epicondyle and prominence of the medial epicondyle [1, 31]. The scapula may have a thickened lateral border and a hypoplastic glenoid (9% in the French series) [21]. The distal radioulnar joint may have flat, dysplastic surfaces, with limited pronation and hypersupination quantified by dynamic radiostereometry [63]. Madelung deformity is among the anomalies described [31]. Elbow pterygium, unilateral or bilateral, was observed in 12% (15/123) of the British series, more than in earlier series; the neurovascular bundles may run superficially in the fold, which makes extension surgery difficult, and the study did not confirm that pterygium predicts kidney disease [12]. The PNDS records elbow anomalies in about two-thirds of patients [20].

Muscle mass of the arms and thighs is reduced, and one British patient had been thought to have muscular dystrophy because of almost complete absence of biceps and triceps [12]. A deltoid biopsy at 2 years, in a patient with upper limb weakness, raised creatine kinase and elbow contractures, showed no primary myopathy, and the authors attributed the weakness to the developmental defect of the limb; the clinical picture has similarities with Emery-Dreifuss dystrophy [64]. Aplasia of pectoralis minor, biceps, triceps or quadriceps has been described as an occasional anomaly [31].

3.5. Pelvis, spine, feet, bone and body habitus

Iliac horns are bilateral bony projections from the posterior surface of the iliac wings, at the insertion of gluteus medius; they are pathognomonic, usually asymptomatic, detectable on radiography, third-trimester ultrasound and bone scintigraphy, palpable when large, and may have an epiphysis at the apex in children [1, 30]. Their frequency on the available radiographs was 68% in the United Kingdom and 76% in France, so their absence does not exclude the diagnosis [9, 12, 21]. Flared iliac wings and prominent anterior superior iliac spines are associated [3]. Clavicles with analogous projections have rarely been described [30].

In the feet, talipes equinovarus, calcaneovarus, calcaneovalgus, equinovalgus, hyperdorsiflexion and flat foot occur, and tight Achilles tendons contribute to equinovarus and toe walking [1]. By definition (non-progressive congenital contractures in more than one joint), many patients have arthrogryposis, a term rarely used in NPS; with that definition, the proportion may reach 75% [1, 65]. Low back pain affected 55% of British patients and scoliosis, usually mild, 23% of those assessed; lumbar hyperlordosis, spondylolysis, spondylolisthesis and pectus excavatum also occur [1, 12]. Congenital hip dislocation is rare [1]. The French PNDS, based on the same series, records flat foot in 64% of British patients, clubfoot in 19% versus 50% in an earlier series, metatarsus adductus, calcaneovalgus foot and convex foot, abnormalities of sagittal spinal balance in 47% and scoliosis in 23%, and pectus excavatum in about one-third; it adds coxa valga and femoral hyperanteversion as hip changes to look for on radiography [20].

In 31 adults with molecularly confirmed NPS, compared with 60 matched controls, bone mineral density measured by dual-energy X-ray absorptiometry (DXA) was 11%–20% lower at the hip (p≤0.001) and 8% lower at the spine (p<0.05); after adjustment for body mass index, the difference persisted at the hip and disappeared at the spine. In 12 children, the z-score was lower only at the femoral neck and trochanter. Fracture risk was higher (odds ratio 30.9; 95% CI 6.4–149.6), especially in girls before puberty and in long bones, in particular the clavicle, as was the risk of scoliosis (odds ratio 16.0; 95% CI 3.3–78.2); the wide intervals reflect the sample size [66].

The habitus is slim, with difficulty gaining weight, especially muscle mass, despite adequate diet and exercise, more evident in adolescence and young adulthood; hyperlordosis makes the buttocks prominent, and the forehead and temporal hairline are high, sometimes resembling male-pattern recession in women [1, 12]. The PNDS considers the muscle hypoplasia secondary to the bone anomalies and not primary, because LMX1B is not expressed in muscle, and also describes breast hypoplasia in some patients and fine, slow-growing hair, findings consistent with the gene's expression territory [20].

3.6. Kidney: natural history

The nephropathy usually manifests as proteinuria, with or without haematuria, which may appear at any age from birth, be intermittent, regress spontaneously, remain asymptomatic for decades or progress to nephrotic syndrome and, occasionally, to end-stage kidney disease, rapidly or after many years of asymptomatic proteinuria [1, 12]. Haematuria was reported in 10%–20% of patients in the three series that documented it [4]. The reported frequency depends on the definition, the method and the recruitment, and the least biased series are the British and the Dutch [4]. In the following table, GFR denotes glomerular filtration rate and CKD chronic kidney disease.

Sources of the table: [4, 11, 12, 21, 57]. The series of Bennett, Looij and Meyrier are cited according to Lemley [4]. Studies before 2003 reported renal involvement in 12%–55% and kidney failure in 5%–14%; in an unselected series by Renwick, with 75 patients from eight families, urinalysis revealed renal involvement in 12% [12]. The estimate of end-stage kidney disease "up to 15%" comes from the series of Meyrier and Looij; the more recent series point to 3% in the United Kingdom and less than 5% in Japan [1, 4, 11]. Reference textbooks give different values (renal involvement in ~25%, 30%–50% or 40%–60%, and kidney failure in 15%), reflecting the series they cite [3, 31, 59].

In the Dutch series, nephropathy was more frequent in females and in patients with a family history of nephropathy, and patients with proteinuria were older (48 versus 36 years, p=0.03) and had lower estimated GFR (78 versus 100 mL/min/1.73 m²) [4, 57]. In the French series, the difference between sexes (19% versus 30%) was not significant after adjustment for age [21]. In the Pittsburgh study, the estimated creatinine clearance of adults was 93 ± 24 versus 113 ± 21 mL/min/1.73 m² in 138 controls (p<0.001), and the annual decline was 1.29 ± 0.28 versus 0.50 mL/min/1.73 m² (p=0.018, excluding an outlier), that is, a loss of filtration with age about twice normal; there was no relationship between age and albuminuria in adults (p=0.997), and the estimated GFR of the 10 children assessed was normal [4]. From these data, Lemley proposed two profiles: 90%–95% of patients with slow loss of filtration and low non-progressive proteinuria, and 5%–10% with nephrotic proteinuria from childhood or young adulthood and progression to kidney failure [4, 31]. The low muscle mass of NPS may lead creatinine-based equations to overestimate kidney function [4].

In the Japanese cohort, most urinary abnormalities were detected in childhood by the urine screening programmes at 3 years and annually at school. The five patients with estimated GFR below 60 mL/min/1.73 m² before 25 years all had moderate to massive proteinuria (protein/creatinine ratio above 1.5 g/g, or more than 1.5 g/day) from childhood [11].

Source: [11]. CKD, chronic kidney disease. Corticosteroids may not be effective in the proteinuria of NPS, and a Japanese patient with an initial diagnosis of focal segmental glomerulosclerosis was treated with corticosteroids and immunosuppressants before the nail anomaly was recognised, six years later [1, 11]. Other variants described with end-stage kidney disease include c.176G>A p.(Cys59Tyr), with kidney failure at 7 and 16 years in two patients, c.706G>C p.(Ala236Pro), c.788T>A p.(Val263Asp) and c.741+1G>A [11]. A Finnish newborn with NPS and transient nephrotic syndrome at birth has been described, as has a death from kidney failure at 8 years [4, 12]. In a family described by Similä in 1970, the kidney disease took the form of congenital nephrosis, with five renal patients among eight NPS carriers, and characteristic glomerular changes were documented at 27 months in a child with proteinuria before 2 years; the familial aggregation of the nephropathy led to the proposal of two distinct genes, a hypothesis not supported by linkage to the ABO locus [14]. The nephropathy may appear or worsen in pregnancy (section 8.5) [1].

3.7. Kidney: histology

The most specific changes are ultrastructural. Electron microscopy shows irregular thickening of the glomerular basement membrane (GBM) with electron-lucent "moth-eaten" areas and bundles of banded type III collagen fibres in the lamina densa and, occasionally, in the mesangium; staining with phosphotungstic acid or tannic acid facilitates visualisation [1, 4, 11]. The foot processes are normal or show focal effacement, and immunofluorescence is negative or shows non-specific IgM, C3 or C1q deposits [4]. Light microscopy is usually normal, apart from variable glomerular sclerosis; in the Japanese series, biopsy of six patients showed minimal changes in most and focal or global sclerosis in three, and one patient with crescents at 9 years had more sclerosed glomeruli at 11 [4, 11]. The typical ultrastructural changes were present in four of five patients studied by electron microscopy, including patients with normal kidney function, and may exist without clinical kidney disease, as in a patient followed from 8 to 11 years without apparent renal involvement [14]; histological severity does not predict prognosis, and a patient with minimal glomerular changes at 14 years reached CKD stage 4 in his early twenties [4, 11]. The histological differential diagnosis includes collagen III glomerulopathy, autosomal recessive, with mesangial and subendothelial deposition of collagen III and a normal lamina densa (section 6) [4].

3.8. Eye

Lester's sign is a zone of darker pigmentation, cloverleaf- or flower-shaped, around the central part of the iris, more visible in blue eyes [1, 31]. Primary open-angle glaucoma and ocular hypertension occur with increased frequency and at younger ages than in the general population, and congenital and normal-tension glaucoma have also been described [1, 33, 57]. The French PNDS (French National Diagnosis and Care Protocol) stresses that ocular involvement, like the rest of the phenotype, varies within the same family [20]. In the two Michigan families identified through glaucoma, six of 13 and seven of 11 patients with NPS had open-angle glaucoma, and all patients with glaucoma had NPS [33]. In the British series, the prevalence of glaucoma was 9.6% (8/83) and that of ocular hypertension 7.2% (6/83); over 40 years of age these rose to 16.7% and 11.9%, and glaucoma or ocular hypertension was present in 29% (12/42) of these patients, with a mean age at detection of 47.9 years (23–78) [12]. In south-eastern Australia, glaucoma affected two of six patients over 40 years (33%), versus 2%–3% of the general population of the same age, and in an additional series of 29 families glaucoma was present in nine (31%) [19]. In the French series, 21% of the 43 patients with measured intraocular pressure had intraocular hypertension, five of them under 40 years [21]. The age-specific relative risk has not been estimated [19].

Other rare ocular manifestations include ptosis, hypertelorism, epicanthus, sclerocornea, microcornea, keratoconus, cataract, microphakia, anisocoria and ectopic pupil [19, 31]. Sensorineural hearing loss, unilateral or bilateral, was identified as a manifestation in the Dutch series [31, 57]. According to the PNDS, in that series 11 of 24 patients assessed had presbycusis-type hearing loss, unilateral in two-thirds, between 17.5 and 69.2 years (median 46.7 years); because other causes of deafness were not investigated, the association may be fortuitous, but the French protocol includes the audiogram in assessment and follow-up (section 11.2) [20, 57].

3.9. Isolated LMX1B glomerulopathy (FSGS10)

FSGS10 is an autosomal dominant kidney disease with glomerulopathy without extrarenal manifestations. Severity and histology vary greatly, even within the same family; most patients develop proteinuria and haematuria in the first decades, but the disease may appear at any age, including late adulthood, and some progress to end-stage kidney disease while others remain stable [5]. In family F described by Boyer, ten affected members over four generations, with p.(Arg246Gln), had nephrotic albuminuria detected at 6 and 26 years in the two probands, focal segmental glomerulosclerosis not otherwise specified on biopsy and normal kidney function at diagnosis; one of the probands reached end-stage kidney disease at 54 years, the father was transplanted at 60 years, and six other relatives had proteinuria detected between 22 and 70 years, three of them with end-stage kidney disease at 36, 40 and 70 years; a proband's son had microalbuminuria of 60 mg/day at 7 years on family screening [10]. Among 73 additional families with dominant podocytopathy, the same variant was found in a family whose proband had nephrotic syndrome at 22 years, and p.(Arg246Pro) in another whose proband had nephrotic syndrome at 5 years with minimal change disease on biopsy [10]. In all probands, nail, patellar or elbow dysplasia, iliac horns and glaucoma were excluded by dermatological and ophthalmological examination and radiographs of the elbows, pelvis and knees [10]. Other descriptions with the same variant include a 6-year-old Japanese girl with mild proteinuria and microscopic haematuria discovered incidentally, a de novo variant and "moth-eaten" GBM with collagen III (Isojima, 2014); 18 affected members of two large North American families (Hall, 2017), with focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy or immune complex glomerulonephritis on light microscopy; and two unrelated families of Hispanic ancestry with proteinuria, microscopic haematuria and hypertension, whose biopsies showed myelin figures and "zebra" bodies in podocytes, without the typical irregular thickening of the GBM (Lei, 2020) [13]. Penetrance is complete and expressivity highly variable [13].

The histology of FSGS10 is heterogeneous: focal segmental glomerulosclerosis, minimal change disease, normal electron microscopy, foot process effacement, and rarely immune complex nephropathy; the GBM changes similar to those of NPS are not always present, and in family F the GBM had normal thickness and structure [5, 6, 10]. Myelin figures and "zebra" bodies in podocytes have been described in several patients with p.(Arg246Gln) and prompted suspicion of Fabry disease, which makes this finding a clue to LMX1B nephropathy [6, 22, 67]. According to Vairo, the renal prognosis of p.(Arg246Gln) is worse than that of the nephropathy of typical NPS [6]. In the Spanish family with p.(Gly117Ser), a 50-year-old woman had nephrotic proteinuria with preserved function, focal segmental glomerulosclerosis and thinning of the GBM, her brother was transplanted after an initial diagnosis of minimal change disease and the paternal uncle had the same disease [50]. LMX1B accounts for 3%–5% of all non-syndromic steroid-resistant nephrotic syndrome, especially with onset in the second decade or later [18]. An apparently isolated renal phenotype may have extrarenal manifestations recognised only after the genetic result, so an LMX1B finding on a renal panel requires examination of the nails, knees, elbows, pelvis and eyes [18].

3.10. Nervous system, digestive tract, circulation and teeth

Peripheral neurological symptoms affected 25% of British patients: intermittent episodes of numbness, tingling and sometimes burning in the hands and sometimes the feet, without a precipitant, in a glove-and-stocking distribution, which may extend to the elbows and calves and last from minutes to hours, without motor weakness [12]. Sensitivity to pain and temperature in the hands and feet is reduced in about a quarter of patients, which exposes them to burns and other injuries; the probable mechanism is the inability of A-delta and C fibres to connect to dorsal horn interneurons [1, 44]. These symptoms rarely result from local orthopaedic problems, the spine or cervical ribs [1]. Epilepsy occurred in 6% (7/123), with a mean age at onset of 29 years (from 17 months to 66 years), versus a lifetime prevalence of 0.4% in the United Kingdom [12]. A five-generation Danish family had early-onset paroxysmal cranial dyskinesia associated with a novel LMX1B variant (LOD 6.54), and the authors proposed a dopaminergic mechanism [68].

In a study of 50 North American adults with NPS, 22% had elevated attention deficit symptoms on the CAARS (Conners' Adult ADHD Rating Scale) and 40% had an elevated score on the Beck Depression Inventory (BDI-II), with no difference by sex, age or education and no association with the predicted effect of the variant [69]. In this sample (38 women and 12 men, mean age 46 years), the CAARS global attention deficit hyperactivity disorder (ADHD) symptom index was elevated in 8 of 50 patients (16%; 16% of women and 17% of men), the inattention scale in 11 of 50 (22%) and the hyperactivity-impulsivity scale in 7 of 50 (14%, all women); these are self-report scores above the normative threshold and not clinical diagnoses of ADHD, although the PNDS presents them as the frequency of the disorder and compares them with the prevalence of 4.4% in North American adults; the elevated depression score (39% of women and 42% of men) was mild in 10 patients, moderate in nine and severe in one, against a prevalence of major depressive disorder of 16.2% in North American adults [20, 69]. A qualitative study of nine adults, cited by the PNDS, describes in childhood distress linked to social rejection because of the visibility of the disability, to school absences for treatment and to exclusion from physical activities, and in adulthood uncertainty about acceptance by a partner and about transmission to children [20]. Intellectual disability, psychosis and schizophrenia are listed as occasional findings [31], and the British authors considered cleft lip and palate, deafness, cancer predisposition, intellectual disability and psychosis probably coincidental [12]. Pain, long underestimated, is according to the PNDS part of the disease: it results from the joint anomalies and their effect on posture and mobility, from osteoporotic fractures and possibly from the role of LMX1B in midbrain dopaminergic neurons and in the development of dorsal horn afferents; it can be very disabling, but is absent in some patients even at an advanced age, and intellectual disability only occurs in microdeletions that include neighbouring genes [20].

Intestinal symptoms affected 31% of British patients: irritable bowel syndrome in 13% and constipation requiring treatment, usually from birth, in 18%, a frequency that did not differ significantly from the general population [12]. Poor peripheral circulation, with very cold hands and feet even in warm weather, was reported by 12 of 22 patients asked, two with a diagnosis of Raynaud phenomenon [12]. Dental problems, mainly weak and brittle teeth, sometimes with thin enamel, affected 23% [12].

3.11. Vascular and cardiac findings described in isolated cases

Congenital aplasia of the internal carotid artery in a patient with confirmed NPS and spontaneous coronary artery dissection in a 35-year-old multigravida during labour have been described, with the hypothesis of a contribution of abnormal collagen formation [70, 71]. A polyarteritis-like vasculitis is listed among the occasional anomalies [31]. A 2026 Portuguese report, from the Unidade Local de Saúde de Coimbra, describes vascular involvement in NPS, with stroke and haemorrhage among the keywords, but the text was not accessible and the clinical details are not known [72]. The occurrence of Goodpasture syndrome in a patient with NPS was described in 1976; the Goodpasture antigen lies in the α3 chain of collagen IV, whose expression depends on LMX1B in the mouse, but a causal relationship has not been established [14]. GeneReviews considers it premature to state that these vascular anomalies are part of the phenotype [1]. The PNDS also mentions a second case of spontaneous coronary dissection and a spontaneous renal artery dissection, and likewise concludes that the small number of events does not allow coincidence to be excluded [20]. NPS appears in a table of syndromes associated with left ventricular non-compaction, based on a single report of a patient with concomitant mitochondrial myopathy; the same patient, a 47-year-old man with a 17-bp deletion in exon 5 of LMX1B and the mitochondrial variant m.3243A>G, had complete atrioventricular block attributed mainly to the mitochondrial myopathy, so the association has not been established [73–75].

3.12. Natural history by age

In the prenatal period, ultrasound may show clubfoot, other limb anomalies, iliac horns and absent patella, between 18 and 36 weeks, usually in the context of a family history [1, 30, 76]. In the newborn and infant, the nail changes are already present and the iliac horns may be seen on radiography, but they rarely attract attention; proteinuria may be present from birth [1, 3]. The ossification centres of the patella appear between 3 and 6 years and ossification is only completed in adolescence, so patellar dysplasia is more evident in adults and an early radiograph may not show the patella [1, 30]. The PNDS places the appearance of the ossification centre after 4 years and recommends, until then, palpation and ultrasound by an experienced paediatric radiologist [20]. The manifestations become more apparent at the end of childhood, when patellar dislocations, elbow limitations and urinary abnormalities detected on screening often lead to the diagnosis [3, 11]. In adolescence and young adulthood most orthopaedic interventions take place, the slim habitus is more evident and the small group with nephrotic proteinuria and loss of function emerges [1, 11]. After 40 years of age, clinically evident nephropathy affects one-third of patients, glaucoma and ocular hypertension about 29%, and secondary osteoarthritis progressively limits the function of the knees and elbows [3, 12, 31].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion rests on the combination of nail, joint and radiological findings, with or without a dominant family history; the absence of a family history does not exclude the diagnosis, because about 12.5% of cases are de novo and the mild forms in parents often go unnoticed [1, 12]. GeneReviews lists as suggestive findings the nail anomalies, including triangular lunulae; a small, irregular or absent patella on palpation or radiography, with recurrent subluxation or dislocation; limited elbow extension, pronation and supination, cubitus valgus and antecubital pterygia; and, on radiography, dysplasia of the radial head, hypoplasia of the lateral epicondyle and capitulum, prominence of the medial epicondyle and iliac horns [1]. In the dermatology or genetics clinic, in the presence of severe nail dysplasia with normal teeth, skin and hair, the Oxford Desk Reference recommends palpating the patellae, examining elbow extension and pronation-supination, requesting radiographs of the hands, elbows, pelvis and knees, and performing urine dipstick testing and plasma creatinine measurement [59]. Absence of the skin creases over the distal interphalangeal joints, present in 96% of patients, is a quick examination sign and more sensitive than triangular lunulae [12, 60]. The French PNDS (French National Diagnosis and Care Protocol) insists on early diagnosis: before 3 years of age there are no functional complaints or specific signs, but recognition at that age allows orthopaedic treatment to start early, with better functional results; without a family history, suspicion rests on nail dysplasia associated with joint signs (patellae, elbows, iliac horns); with a family history, the diagnosis is made in early childhood in the presence of nail dysplasia or another sign in the child of an affected person; and, more rarely, the disease is revealed by proteinuria on dipstick or by ocular hypertension in a patient whose nails and joints had not attracted attention [20].

4.2. Described diagnostic delays

Several reports illustrate how the diagnosis is missed when the presentation is renal. In the Japanese cohort, a boy with urinary abnormalities on school screening at 9 years only had the elbow deformity and nail hypoplasia noticed by an orthopaedic surgeon five years later, and a girl with focal segmental glomerulosclerosis was treated with corticosteroids and immunosuppressants until the nail anomaly was identified [11]. This latter patient, with nephrotic syndrome at 7 years, was only diagnosed at 24 years when she was referred for knee pain [51]. A woman from Hong Kong with haematuria and proteinuria since her first pregnancy was diagnosed with Alport syndrome on biopsy and only years later were the dystrophic nails and cubitus valgus recognised [52]. An Indian female proband with kidney failure had NPS recognised through her son's deformities [79]. A review of 15 English-language patient information websites found accurate renal information in only 10 and omission of glaucoma in one [80].

4.3. Warning and emergency signs

The signs requiring rapid referral are renal, ocular and neurological. In the renal sphere, they include the appearance of proteinuria, its progression to moderate or nephrotic values (protein/creatinine ratio above 1.5 g/g in the Japanese series), nephrotic syndrome with oedema, arterial hypertension and a fall in estimated GFR; moderate or severe proteinuria in childhood or adolescence, especially with a homeodomain variant, identifies the group at risk of progression [1, 11]. Severe nephrotic syndrome exposes patients to thromboembolic complications, as illustrated by renal vein and inferior vena cava thrombosis in a pregnant woman with NPS [78]. In the ocular sphere, an abnormal or absent red reflex in an infant or young child requires immediate referral to ophthalmology, and any visual field loss or raised intraocular pressure requires specialist assessment [1]. In pregnancy, a rise in blood pressure or proteinuria may correspond to pre-eclampsia or worsening of the nephropathy [1, 30]. Reduced sensitivity to pain and temperature justifies education to prevent burns, and epileptic seizures require neurological assessment [1].

4.4. Newborn screening

There is no newborn screening for NPS. The birth prevalence recorded by EUROCAT (0.2/1,000,000) is much lower than the prevalence estimates, which reflects the fact that most findings are not recognised at birth [16]. The Japanese urine screening programmes at 3 years and at school age detected most of the urinary abnormalities in the Harita cohort, but they are not programmes targeted at NPS [11].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal published clinical criteria for NPS, a point on which GeneReviews and the French PNDS (French National Diagnosis and Care Protocol) agree [1, 20]. The diagnosis is established in a proband with suggestive clinical and radiological findings and/or a heterozygous pathogenic or likely pathogenic LMX1B variant; a variant of uncertain significance neither establishes nor excludes the diagnosis [1]. Iliac horns are considered pathognomonic, but are absent on 24%–32% of pelvic radiographs, and no biochemical test confirms the disease [1, 9, 12, 21]. In the British series, a patient without a family history and without iliac horns, with only non-specific lateral flaring of the ilia, was excluded for not meeting the clinical diagnosis [12]. For FSGS10, the diagnosis is molecular: a pathogenic LMX1B variant in a patient with glomerulopathy and active exclusion of nail, skeletal and ocular findings [5, 10].

5.2. Imaging

The pelvic radiograph looks for iliac horns, flared iliac wings and prominent anterior superior iliac spines; the knee radiograph, for hypoplasia or absence of the patella, its lateral and superior position and hypoplasia of the lateral femoral condyle; the elbow radiograph, for hypoplasia of the capitulum and lateral condyle of the distal humerus and hypoplasia of the radial head, sometimes with dislocation [3]. In a classic atlas, the hypoplastic capitulum with a small radial head, the mid-posterior iliac spur and the hypoplastic scapula with a convex, thickened lateral border are given frequencies of 90%, 71% and 44%, with no denominator or population declared; delayed ossification of secondary centres, valgus femoral neck, small fibular head and prominent tibial tuberosity are also described [31]. Figures 20.7.1 to 20.7.3 of Spranger's atlas show, in an 11-year-old girl and an adult man, bilateral iliac horns with flared iliac wings, small flattened lateral femoral condyles, small laterally dislocated patellae, a subluxed radial head and antecubital pterygium [3].

Magnetic resonance imaging assesses the unossified patellar cartilage, trochlear dysplasia, the menisci, the anterior sagittal synovial septum and synovitis, and should precede any surgery or intensive physiotherapy, because bone and soft tissue anatomy is abnormal; computed tomography helps in planning complex anatomies of the pelvis, knee and spine [1, 30]. Renal ultrasound is not used routinely in surveillance, which relies on urine and blood tests [30]. Ultrasound can detect absent patellar ossification centres in the young child [77].

5.3. Renal assessment and biomarkers

Initial assessment includes blood pressure, urinalysis and albumin/creatinine ratio in the first morning urine, which is more sensitive than urinalysis because it corrects for urinary concentration [1, 12]. The dipstick is only reliably positive when the albumin/creatinine ratio exceeds about 300 µg/mg (normal value below 30 µg/mg), so it does not detect low-grade albuminuria [4]. Creatinine-based estimated GFR may overestimate function in patients with low muscle mass [4]. In the Japanese series, nephropathy was defined by haematuria of any grade, proteinuria of 0.15 g/g creatinine or more or estimated GFR below 60 mL/min/1.73 m², and in the French series by proteinuria above 0.1 g/L (or 0.300 g/24 h) or kidney failure [11, 21].

Kidney biopsy is discouraged in NPS with a classic clinical picture and is only justified in the presence of signs of another nephropathy, such as lupus or diabetic nephropathy; the clinical-radiological diagnosis can avoid it, as in the pregnant woman with nephrotic syndrome described by Aboobacker [4, 78]. When the presentation is undiagnosed steroid-resistant nephrotic syndrome, biopsy retains its role, but the paediatric recommendations exclude potentially familial, syndromic or genetic forms from systematic biopsy and suggest performing genetic testing before biopsy when the result is rapid [24]. If a biopsy is performed, electron microscopy and collagen stains are essential (section 3.7), and myelin figures in podocytes with normal alpha-galactosidase A activity and lyso-Gb3 should prompt consideration of LMX1B [6, 22].

5.4. Genetic testing

GeneReviews proposes two routes. When the phenotype suggests NPS, single-gene testing is performed: sequencing of LMX1B (missense, nonsense, splicing variants and small insertions and deletions) and, if negative, targeted deletion and duplication analysis; a multigene panel including LMX1B and the genes of the differential diagnosis, with deletion and duplication analysis, is preferable when kidney disease or glaucoma dominates the presentation [1]. When the phenotype is atypical, the exome is the most used technique and the genome is an alternative; karyotyping may be considered if the tests are negative and there is clinical suspicion with a dominant pattern, to detect translocations or inversions [1]. In cases with clinical and radiological NPS without a coding variant, the upstream enhancer, the 5′ untranslated region and rearrangements should be studied [1, 23].

Source: GeneReviews table 1 [1]. MLPA, multiplex ligation-dependent probe amplification. Exome and genome sequencing can detect deletions and duplications through breakpoints or read depth, with lower sensitivity than targeted methods [1]. These proportions describe the distribution of the variants found and not the clinical sensitivity of the test: 5%–10% of individuals with clinical and radiological findings of NPS have no detectable variant in the coding region [1, 48].

The proportion of families with an identified variant varied with the period and the method: 37 of 41 (90%) in 1998, 38 of 43 (88%) in 2003 by SSCP (single-strand conformation polymorphism) and sequencing, 17 of 20 (85%) in an Italian series from 2010, five of eight (62.5%) in an Australian series that sequenced only the exons, and 50 of 55 (91%) with Sanger sequencing and MLPA in the 2016 French series [12, 19, 21, 37, 49]. In the French series, negative cases were studied by 244K array-CGH and sequencing of the whole gene by 15 long-range PCRs of about 10 kb, with about 450 variants per patient, mainly in intron 2 [21]. In 2026, the same reference laboratory studied four patients with a negative coding panel, one by targeted sequencing including LARM1 and LARM2 and three by trio genome sequencing, and found a 47-kb non-coding deletion (NC_000009.12:g.126528370_126575687delinsGTG) removing LARM1 and LARM2 without affecting the gene, two de novo translocations with breakpoints at 9q33.3 between LMX1B and the LARM, and the de novo 5′ untranslated region variant c.-226G>A; the group estimates a yield of about 95% for coding or flanking intronic variants and close to 100% with analysis of the regulatory regions, in patients with a typical clinical diagnosis [23]. These values are yields in selected patients at a reference centre and not population sensitivity.

5.5. Limitations of the tests

A negative result of coding sequencing does not exclude NPS. Upstream regulatory deletions, 5′ untranslated region variants, inversions and balanced translocations escape exon sequencing and MLPA, and an inversion with intronic breakpoints may also escape automated genome analysis if structural variants are not searched for systematically [23, 47]. The title of the report by Sabir and colleagues highlights the risk of a negative whole genome in a child with arthrogryposis as the presentation of NPS [65]. Expression of LMX1B in blood, lymphoblasts, fibroblasts and skin is too low for RNA studies, which limits the functional assessment of splicing variants and rearrangements [21, 47]. Parental somatic mosaicism may not be detected in leucocyte DNA, and exclusively gonadal mosaicism is not detectable (section 8.3) [1, 49]. Truncating variants in the carboxy-terminal third require caution, because no pathogenic variant has been described in that region [46].

Variants of uncertain significance are frequent in non-coding regions: ClinVar records one pathogenic variant and about 100 of uncertain significance in the untranslated regions of LMX1B [23]. Two deep intronic variants in intron 2 found in negative families were considered probably not pathogenic [21]. In a Belgian infant with nephrotic syndrome that remitted spontaneously at 12 months without corticosteroids, a panel identified variants of uncertain significance in LMX1B and TTC21B, inherited from the mother, and the authors considered the evidence insufficient for an oligogenic mechanism [81]. The p.(Gly117Ser) of the Spanish family with FSGS is classified as of uncertain significance in ClinVar [56]. Segregation in affected and unaffected relatives, targeted examination for extrarenal findings and periodic reassessment are the tools for reclassifying these variants.

5.6. Content of the report

The report should state the gene, the transcript with version (the MANE Select is NM_001174147.2), the HGVS description at DNA and protein level, the genomic coordinate with the assembly, the zygosity, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the method, including whether deletions, duplications, regulatory regions and structural variants were analysed [8, 24]. The paediatric recommendations for steroid-resistant nephrotic syndrome call for ACMG classification, Sanger confirmation, exome or genome if the panel is negative with high suspicion, and genetic counselling [24]. When the variant comes from an article using another transcript, the correspondence with MANE should be checked in VariantValidator, especially for NM_002316.2 numbering, shifted by 69 nucleotides [8, 21].

5.7. Recommendations for steroid-resistant nephrotic syndrome

Isolated renal presentation places NPS and FSGS10 within steroid-resistant nephrotic syndrome (SRNS), defined by the absence of complete remission after 4 to 6 weeks of glucocorticoids [18, 24]. About 30% of paediatric-onset SRNS and 10%–15% of adult-onset SRNS have a monogenic cause in one of about 60 genes, and LMX1B appears in the tables of syndromic and non-syndromic SRNS [18]. KDIGO 2025 (Kidney Disease: Improving Global Outcomes) defines SRNS by the absence of complete remission at 4 weeks, with a confirmation period up to 6 weeks, and recommends immediately considering a genetic cause and genetic testing by experts [25].

Source: [24]. IPNA, International Pediatric Nephrology Association; NGS, next-generation sequencing. KDIGO 2025 adds that genetic testing is recommended in all patients with SRNS, with a comprehensive panel, because identification of a podocyte variant avoids unnecessary exposure to immunosuppressants [25]. Prenatal and preimplantation diagnosis is covered in section 8.4.

5.8. Practical algorithm

5.9. Initial assessment according to the French national protocol

The 2020 HAS PNDS (French National Diagnosis and Care Protocol) defines a more extensive initial work-up than that of GeneReviews, which serves as the baseline for follow-up [20].

PRM, physical and rehabilitation medicine. GeneReviews does not include pachymetry, gonioscopy, bone biochemistry, EOS radiography or the audiogram in the initial assessment and proposes DXA above 18 years or in the presence of unexplained fractures or skeletal pain, a criterion close to that of the PNDS [1, 20].

6. Differential Diagnosis

6.1. Skeletal and syndromic differential diagnosis

The differential diagnosis of NPS has three fronts: patellar dysostoses and syndromes with absent or hypoplastic patella, diseases with nail dysplasia, and genetic nephropathies and glaucomas. Iliac horns and elbow anomalies distinguish NPS from most other causes of patellar hypoplasia [3, 82].

Ischiopatellar dysplasia is the closest differential diagnosis. In the TBX4 form, the course is benign, except for patellar instability, and ossification of the ischiopubic synchondroses may be completed in adulthood, which makes the diagnosis difficult after childhood; magnetic resonance imaging shows thin, eccentric unossified patellar cartilage, an elongated patellofemoral ligament and hypoplasia of the medial femoral condyle and trochlea [82]. The SOX9 forms are associated with developmental delay, and mild campomelic dysplasia may present as ischiopatellar dysplasia [82]. Cleidocranial dysplasia (wide synchondroses, absent or hypoplastic clavicles and Wormian bones), spondylo-megaepiphyseal-metaphyseal dysplasia and ischiospinal dysostosis are part of the radiological differential diagnosis of ischiopatellar dysplasia [82]. Coffin-Siris syndrome, Alport syndrome and Fabry disease are part of the differential diagnosis.

6.2. Nail differential diagnosis

Pachyonychia congenita, of autosomal dominant inheritance due to variants in keratins K6, K16 and K17, causes symmetrical hypertrophic dystrophy of all nails from the neonatal period, with thickened yellowish-brown nails, different from the hypoplasia with an ulnar gradient of NPS [59]. A mid-nail defect also occurs in Ellis-van Creveld syndrome and popliteal pterygium syndrome [59]. The nail dystrophy of NPS may be confused with an acquired dermatological disease, such as nail lichen planus, and looking for the distal interphalangeal creases, the gradient from thumb to little finger and the elbow resolves the differential diagnosis [60]. The PNDS (French National Diagnosis and Care Protocol) stresses that the nail changes of NPS differ from those of the ectodermal dysplasias [20].

6.3. Renal and histological differential diagnosis

Myelin figures are not pathognomonic of Fabry disease, and three reports with LMX1B variants show "zebra" bodies in podocytes, so a negative Fabry work-up should lead to LMX1B being included in the investigation [6, 22, 67]. In the Mayo Clinic patient, leucocyte alpha-galactosidase A activity was 35.3 nmol/h/mg (normal above 23.1) and plasma lyso-Gb3 0.4 ng/mL (normal below 1.8), and exome sequencing of kidney tissue identified the LMX1B variant [6]. The histological overlap with Alport syndrome has a biological basis, because both involve the GBM and collagen IV, and the two diseases coexisted in a patient with a truncating LMX1B variant and a COL4A4 splicing variant [52]. An atypical renal phenotype in NPS, such as tubular proteinuria or nephrocalcinosis, should prompt a search for a second diagnosis [53]. The glomerulopathy of NPS and FSGS10 are corrected by transplantation, without recurrence of the primary disease, unlike many non-genetic forms of SRNS [4, 18].

6.4. Ophthalmological differential diagnosis

Juvenile open-angle glaucoma, with onset between 4 and 35 years and an estimated prevalence of 1/50,000, is associated with myopia and with MYOC and CYP1B1; the Mendelian forms of adult primary open-angle glaucoma are most often caused by MYOC (2%–4% of the total and 16%–40% of early-onset forms with high pressure and a strong family history) [86]. NPS is among the syndromic causes of secondary juvenile or adult glaucoma, together with nanophthalmos, Marfan syndrome and ectopia lentis, homocystinuria, Norrie disease, anterior segment anomalies, neurofibromatosis type 1 and Sturge-Weber syndrome; when NPS is found in a patient with glaucoma, surveillance for nephropathy should be offered [42]. In early-onset glaucoma, examination of the nails and elbows distinguishes NPS from MYOC forms.

7. Treatments and Risk Management Strategies

7.1. Principles and applicable guidelines

The only national protocol specific to NPS is the 2020 French PNDS (French National Diagnosis and Care Protocol) of the Haute Autorité de Santé (HAS), prepared by the reference centres for developmental anomalies (Lille) and constitutional bone diseases (Imagine Institute, Paris) on the basis of the literature and, where evidence is lacking, expert consensus, especially regarding the frequency of surveillance; the GeneReviews recommendations rest on the authors' experience, and there is no treatment directed at the genetic defect nor any randomised trial in the disease [1, 9, 20]. Treatment is supportive and multidisciplinary, directed at quality of life, function and prevention of complications, and renal and ophthalmological decisions rely on guidelines for broader conditions: the 2020 IPNA recommendations for paediatric SRNS, the 2025 KDIGO guideline for nephrotic syndrome in children, the 2024 KDIGO guideline for chronic kidney disease (CKD) and the 6th edition of the European Glaucoma Society (EGS) guidelines, of 2025 [1, 24, 25, 86, 87].

ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; NSAID, non-steroidal anti-inflammatory drug; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose cotransporter 2; ACR, albumin/creatinine ratio.

The main divergence between sources concerns immunosuppression. IPNA recommends stopping prednisolone and not starting calcineurin inhibitors when there is a monogenic form (grade B, moderate), based on complete remission of 2.7%–3.0% and partial remission of 10.8%–16% under immunosuppression in genetic forms [24]. KDIGO 2025 maintains conservative treatment of genetic forms, but accepts that some variants, especially of WT1 and PLCE1, respond to calcineurin inhibitors, and does not mention LMX1B [25]. In 2009, Lemley suggested ciclosporin in patients with NPS resistant to ACE inhibitors, by analogy with Alport syndrome, an opinion predating current recommendations [4]; in 2025 a response to ciclosporin was described in a single patient (section 7.10) [54].

The PNDS diverges from the other sources on several points. On NSAIDs, GeneReviews advises against chronic use, whereas the PNDS proscribes them in the presence of renal involvement and, without it, only allows them after nephrological advice, in a short course, without nephrotic syndrome or dehydration and without combination with another nephrotoxic drug or with an ACE inhibitor or ARB [1, 20]. On the timing of RAAS inhibition, the PNDS proposes an ACE inhibitor or ARB "at a more advanced stage", without defining a threshold, whereas IPNA starts them at the diagnosis of SRNS and KDIGO 2024 recommends them from albuminuria A3 and suggests them in A2; this article follows the KDIGO and IPNA thresholds, which are more explicit [20, 24, 87]. In glaucoma, the PNDS reserves laser trabeculoplasty and surgery for uncontrolled glaucoma or intolerance to eye drops, whereas EGS 2025 accepts trabeculoplasty as first line [20, 86]. In follow-up, the PNDS is the only source to recommend periodic audiograms, baseline DXA at transition and at defined intervals and three-yearly creatinine in adults; annual ophthalmological surveillance coincides with that of GeneReviews and departs from the two-yearly interval of the British and French series (section 11.2) [1, 12, 20, 21]. In forms due to LARM alterations, the PNDS states that there is no renal or ocular risk, whereas the 2026 study from the same laboratory recommends maintaining surveillance until more cases are available, a position this article adopts [20, 23].

7.2. Assessment after diagnosis

Source: GeneReviews tables 4 and 5 [1].

7.3. Nephroprotection

RAAS inhibition is the basis of treatment of proteinuric nephropathy. GeneReviews indicates that ACE inhibitors can control blood pressure and slow the progression of proteinuria, with carefully monitored use in children [1]. The rationale comes from the renoprotective effect demonstrated in non-diabetic proteinuric glomerulopathies, extrapolated to NPS; in an 8-year-old child, a low-dose ACE inhibitor reduced the protein/creatinine ratio from 2.2–2.8 to 0.4–0.8 mg/mg, in an isolated report with no dose described [4]. In the microalbuminuria phase, the benefit of intervention has not been demonstrated in NPS [4]. KDIGO 2024 recommends starting an ACE inhibitor or ARB in CKD with severely increased albuminuria (A3) without diabetes (1B) and suggests it in moderately increased albuminuria (A2) (2C), titrating to the maximum approved tolerated dose, checking blood pressure, creatinine and potassium 2 to 4 weeks after starting or after each dose increase, continuing the drug unless creatinine rises by more than 30% within 4 weeks and continuing it even with estimated GFR below 30 mL/min/1.73 m² [87]. The KDIGO recommendation is the reference; the labels, by comparison, differ below that threshold: in children, the labels and SmPCs of enalapril, lisinopril and losartan do not recommend use with GFR below 30 mL/min/1.73 m², so continuation as proposed by KDIGO is, in children, outside the label conditions, and in adults lisinopril requires a reduced starting dose (2.5–5 mg with clearance of 10–30 mL/min and 2.5 mg below 10), an adjustment that applies to titration [88–93]. IPNA recommends, in children with SRNS, starting an ACE inhibitor or ARB at diagnosis (grade B, moderate), quantifying the change in proteinuria in the first morning urine (grade D) and aiming for the maximum approved tolerated doses (grade C), with a dose-dependent antiproteinuric reduction of about 30% with ACE inhibitors [24]. The French PNDS adds, from diagnosis, non-pharmacological nephroprotective measures (normalisation of dietary salt and protein, control of excess weight and prohibition of smoking), reserves ACE inhibitors or ARBs, with an antiproteinuric and nephroprotective aim, for a more advanced stage and institutes conservative treatment of CKD according to estimated GFR, in particular below 60 mL/min/1.73 m² [20].

The precautions are the same in the two guidelines. The combination of ACE inhibitor, ARB and direct renin inhibitor should be avoided (1B), because it increases acute kidney injury and mortality [24, 87]. In CKD stage 4 use requires caution, and the drug should not be started or continued in the presence of volume depletion, acute kidney injury, hyperkalaemia, or frequent vomiting or diarrhoea (grade X, strong); IPNA prefers drugs without exclusively renal elimination, such as ramipril and ARBs, which do not accumulate in kidney failure (grade D) [24]; because the US and Portuguese labels do not establish the safety or the paediatric dose of ramipril, its use in children is off-label, and among ARBs only losartan has a paediatric dose on the label (from 6 years) [92–95]. In adolescent girls, contraception is mandatory because of the teratogenicity of RAAS inhibitors (grade X, strong) [24]. Excessive salt intake should be avoided (grade C), with dietitian support (grade D), and vaccination should be reviewed and completed, especially against encapsulated bacteria and varicella [24]. In monogenic forms, ineffective immunosuppression should be stopped, maintaining the ACE inhibitor or ARB and supportive measures (grade X, strong); corticosteroids may not be effective in the proteinuria of NPS [1, 24, 51]. Blood pressure should be controlled to the KDIGO 2024 targets (section 11.2), and hypertension is treated by nephrology according to standard practice [1, 87].

None of these drugs has an approved indication for NPS or FSGS10; their use for nephroprotection is, as a rule, off-label, with doses extrapolated from hypertension (approved paediatric indication) or CKD. The exception is ramipril in Portugal: the SmPC of Triatec® includes clinically manifest non-diabetic glomerular nephropathy with macroproteinuria of 3 g/day or more, so an adult with NPS or FSGS10 nephropathy with that degree of proteinuria falls within the approved indication [95].

In Brazil, enalapril (Renitec®), losartan (Cozaar®) and dapagliflozin (Forxiga®) have active registration with ANVISA, with numerous generics and similar products, but the professional package leaflets were not accessible, so Brazilian doses are not included in the table [98]. The FDA and the Portuguese SmPCs use different paediatric schedules for enalapril and lisinopril: the FDA defines the starting dose per kilogram (0.08 mg/kg up to 5 mg), whereas the Portuguese SmPCs of Renitec® and Zestril® use fixed doses by weight band (2.5 or 5 mg initially), with maximums of 20 and 40 mg; the Renitec® SmPC states that the maximum dose studied was 0.58 mg/kg (up to 40 mg) in a study of 110 children aged 6 to 16 years [88–91]. For ramipril, the maximum in hypertension is 10 mg/day in the Portuguese SmPC and 20 mg/day in the US label, and paediatric losartan starts at 0.7 mg/kg (up to 50 mg) in the USA and at 25 or 50 mg according to weight in Portugal [92–95]. The maximum paediatric doses of ACE inhibitors and ARBs in IPNA supplementary table S8 were not accessible, and the values presented are those of the labels.

In KDIGO 2024, SGLT2 inhibitors have a strong recommendation in adults with CKD and estimated GFR of 20 mL/min/1.73 m² or more with an ACR of 200 mg/g or more (1A), a suggestion with GFR of 20 to 45 and ACR below 200 mg/g (2B), continuation below 20 unless there is intolerance or kidney replacement therapy is started, and suspension during prolonged fasting, surgery or severe acute illness [87]. The recommended dose is 10 mg once daily, the same in KDIGO and on the labels. By comparison, the dapagliflozin labels do not recommend starting the drug with GFR below 25 mL/min/1.73 m² and do not establish it in CKD below 18 years of age, so initiation between 20 and 25 mL/min/1.73 m² as recommended by KDIGO falls outside the label conditions [87, 96, 97]. The European SmPC states that there is no experience in CKD without diabetes and without albuminuria and that patients with albuminuria may benefit more [97]. In NPS there are no specific data; a Korean patient with FSGS10 treated with an ARB and an SGLT2 inhibitor (drugs and doses not specified) had normal function and a protein/creatinine ratio of 2.0 g/g at 6 months, versus 4.6 g/g at diagnosis, and a Chinese boy with NPS maintained nephrotic proteinuria on a RAAS inhibitor and an SGLT2 inhibitor [22, 54].

7.4. Advanced kidney disease, dialysis and transplantation

In end-stage kidney disease, kidney replacement therapy includes consideration of transplantation, the results of which are usually favourable [1]. The PNDS (French National Diagnosis and Care Protocol) considers progression to dialysis or transplantation rare and confirms that the disease does not recur in the graft [20]. Numerous successful transplants have been described, without de novo anti-GBM disease, because the distribution of collagen IV is normal, and patients with NPS are considered good candidates [4]. Genetic SRNS does not recur in the graft, unlike non-genetic SRNS, which recurs rapidly in about 70% [18]. IPNA recommends genetic testing before transplantation to estimate the risk of recurrence (grade B), with recurrence of 0% in a Brazilian cohort and 7% in a European one in monogenic forms, versus 24% and 50% in non-genetic forms, and recommends offering transplantation to children with end-stage kidney disease due to SRNS regardless of the cause (grade B) [24]. The North American patient with FSGS10 received a deceased-donor kidney two years after referral [6].

The choice of a living donor requires genetic testing in genetic SRNS (grade X, strong). A candidate with a pathogenic or likely pathogenic variant in a dominant gene should be excluded, with or without symptoms (grade X, strong), which applies to all relatives carrying the family's LMX1B variant, given the complete penetrance and variable expressivity; in dominant forms, donation by relatives on the affected side is discouraged, and an asymptomatic carrier of a variant of uncertain significance should only be considered after extensive assessment and in the absence of an alternative (grade C, weak) [4, 18, 24]. Relatives without the familial variant can be discharged from surveillance [18].

7.5. Glaucoma and ocular hypertension

The glaucoma of NPS is treated according to standard ophthalmological practice [1]. According to EGS 2025, the initial treatment of primary open-angle glaucoma is pressure-lowering monotherapy or laser trabeculoplasty as first line, with more intensive initial therapy if the pressure is in the upper half of the 20s mmHg or the disease is severe (high evidence, strong recommendation); prostaglandin analogues are the most effective drugs and the first medical choice (high evidence, strong), with no difference in pressure reduction between formulations with and without preservatives; trabeculectomy with antifibrotics is the recommended surgery [86]. In juvenile open-angle glaucoma, medical treatment is more effective than in congenital glaucoma, but surgery is often necessary (40%–70%) [86]. In an Australian series, a patient with normal-tension glaucoma diagnosed at 63 years, already with advanced cupping, progressed with involvement of central vision and underwent bilateral trabeculectomy and topical pressure-lowering drugs, with stable fields since then; another patient, with a maximum pressure of 27 mmHg at 33 years, was controlled with 0.5% timolol [19].

COPD, chronic obstructive pulmonary disease. Neither drug has a specific indication for NPS; the approved indication is open-angle glaucoma and ocular hypertension. The choice, combination and surgery are decisions for the ophthalmologist according to the EGS. The French PNDS treats the ocular hypertension and glaucoma of NPS like those of primary open-angle glaucoma, with pressure-lowering eye drops and laser trabeculoplasty or surgery if the pressure is not controlled or there is intolerance [20]. Because the same protocol strongly advises against beta blockers in patients with Raynaud phenomenon, the presence of vasomotor symptoms, frequent in NPS, is an argument to weigh in favour of a prostaglandin analogue, already the first medical choice of the EGS, instead of timolol; the EGS also states that glaucoma with lower pressures may be more common in women with vascular dysregulation, such as Raynaud phenomenon, an association not studied in NPS [20, 86].

7.6. Orthopaedics and rehabilitation

Joint symptoms without a limiting anatomical anomaly (pain, instability, locking, clicking, dislocation or reduced range) are treated with analgesics, physiotherapy, splints and orthoses; anatomical anomalies, such as contractures and pterygia, receive standard orthopaedic treatment, including surgical correction, preceded by magnetic resonance imaging to plan the intervention; the spine and chest wall are managed by orthopaedics [1]. A 2026 narrative review, with publication bias acknowledged by the authors and short follow-up, states that the surgical decision is guided by symptoms and by functional impact measured by scales such as the KOOS and Kujala, that the literature favours early intervention in children with patellar instability and that surgery was performed in 23%–63% of cases in the series [30]. The main indication is recurrent lateral patellar dislocation, with or without pain. The techniques described include soft tissue realignment, reconstruction of the medial patellofemoral ligament (with a double-bundle gracilis graft suggested for small patellae), the Leeds-Keio ligament, the Krogius-Lecène procedure (with good results at 26 years), quadricepsplasty for extension contracture, capsular release for flexion deformity and, in advanced cases, partial or total arthroplasty, with a custom patellar component because of insufficient thickness; initial arthroscopy allows resection of the sagittal synovial septum, which may re-form [30]. The complications described include patellar tendon rupture, including after anteriorisation of the tibial tuberosity, persistent pain, recurrent instability and recurrent meniscal tears after isolated septum resection, and the worst results were associated with isolated lateral release, tuberosity transfer and bilateral Judet quadricepsplasty [30].

In the Dutch survey, surgery on 31 knees improved pain in 87% and function in 30%, with satisfaction of 61% and dissatisfaction of 10%; after patellar realignment, instability persisted in 40% of knees, a proportion that did not differ from that of non-operated knees, in a level IV evidence study [62]. In the Swedish family, two children underwent patellar stabilisation at 11 and 13 years [47]. In the foot, clubfoot, pes cavus, calcaneovalgus, congenital vertical talus and equinus may require early posteromedial release to obtain a plantigrade foot [30]. An Indian child with bilateral clubfoot was corrected by the Ponseti method started at 2 months, with five casts and bilateral percutaneous Achilles tenotomy, without recurrence at 6 months [77]. In the upper limb, soft tissue releases and radial head excision, sometimes bilateral, are described [30]. Upper limb weakness, possibly due to disuse secondary to elbow contracture, benefits from physiotherapy and not from treatment for myopathy [1, 64]. Adapted sport is an option to consider [1].

The French PNDS proposes starting joint management at diagnosis, even before 3 years of age and without complaints, because early intervention improves functional results, with active physiotherapy and occupational therapy from early childhood to strengthen muscles, limit instability and compensate for limitations, continued in adulthood to avoid deconditioning [20]. At the knee, it recommends realignment of the patella between 2 and 3 years of age, because in late cases the interventions are more extensive and joint remodelling less, with early ultrasound or magnetic resonance imaging if examination does not allow the patella to be assessed; there is no consensus on the most effective technique, and surgery is performed "à la carte", in stages: lateral release of the retinaculum and capsule; release of the quadriceps, proximal, distal or bipolar, to centre or lengthen it in extension stiffness; hamstring lengthening and posterior capsulotomy for flexion deformity; longitudinal splitting of the patellar tendon with medial transfer or anteromedialisation of the tibial tuberosity; vastus medialis plasty combined with physis-sparing medial patellofemoral ligament reconstruction; and femoral osteotomy or guided growth for residual or rotational deviations. Early resection of the plica may, in theory, be sufficient [20]. At the elbow, most patients have good function without surgery; radial head resection at the end of growth may improve pain and deformity, but not mobility, and reconstruction is reserved for bilateral flexion deformity greater than 45° affecting independence as confirmed by occupational therapy assessment, a situation in which an anterior release may reduce the flexion deformity [20]. In the foot, the aim is a plantigrade foot that allows walking and footwear, with relatively early surgery limited to soft tissues and tendon transfers to avoid osteotomies and arthrodeses [20]. Iliac horns require no treatment; coxa valga, external femoral rotation and hip dislocation require early treatment, thoracolumbar scoliosis surveillance and adapted treatment, and the shoulder, as a rule, only rehabilitation [20].

7.7. Other systems

Reduced bone mineral density, with osteoporosis or frequent fractures, has no NPS-specific treatment and follows the standard treatment of paediatric or adult endocrinology, with the drug and dose defined by the label of the chosen medicinal product [1]. Constipation and inflammatory bowel disease receive standard treatment, the latter by gastroenterology [1]. For epileptic seizures, many antiepileptic drugs may be effective and none has been demonstrated specifically in NPS; the choice rests with an experienced neurologist, according to seizure type, with education of parents and caregivers [1]. Reduced sensitivity to pain and temperature requires education to avoid burns and other injuries, and dental anomalies require follow-up by a dentist [1]. Social services support the coordination of appointments, equipment and medication [1].

The French PNDS details the management of these systems. The nail changes have no treatment or surgical indication; nail prostheses may serve cosmetic purposes, and the psychological impact, sometimes considerable in adolescence, should be considered [20]. Pain is assessed from diagnosis in a pain clinic working with paediatric or adult PRM, with preventive measures (analgesics before exertion or physical activity, physiotherapy, occupational therapy, orthoses, hypnosis); paracetamol is the analgesic for occasional use, NSAIDs follow the restrictions in section 7.8, and other molecules with possible analgesic action, including the cannabinoids discussed in the protocol's references, are only considered by decision and with follow-up of a physician from a pain centre familiar with NPS [20]. A suspected neuropathy is investigated and followed by paediatric or adult neurology [20]. Raynaud phenomenon is treated as usual, with protection against cold and damp (silk gloves, mittens, warm socks), avoidance of contact with cold objects, sudden temperature changes and local trauma, and abstention from tobacco and beta blockers [20].

For bone, the PNDS proposes vitamin D supplementation according to the 25-hydroxyvitamin D level of the initial work-up and, in the presence of densitometric osteoporosis, especially with spontaneous or low-energy fractures, the opinion of a bone disease expert to decide case by case on antiosteoporotic treatment, with no specific data in NPS [20]. For the teeth, it recommends oral hygiene from early childhood, with brushing by the parents and later supervised, fluoride toothpaste, fluoride varnish and fissure sealants, and dental appointments two to four times a year from the eruption of the first teeth, with hospital referral if necessary [20]. Psychological support accompanies transition stages (school entry, adolescence, career guidance, life as a couple, parenthood plans), addresses the experience of social rejection in childhood and the parents' feelings of guilt, includes regular assessments and referral to child or adult psychiatry if there are signs of ADHD or depression, and may be complemented by therapeutic education sessions dedicated to limb malformations or to "the gaze of others" [20]. Digestive and hearing symptoms are referred to gastroenterology and otorhinolaryngology [20].

The PNDS gives no doses; the following schedules are those of the Portuguese SmPCs, applied by extrapolation from the general indication of each medicinal product.

7.8. Agents and situations to avoid

Chronic use of NSAIDs should be avoided because of their deleterious effect on kidney function [1]. The PNDS is more restrictive: it proscribes NSAIDs and other nephrotoxic drugs in the presence of renal involvement and, without it, only allows them after the advice of paediatric or adult nephrology, as a short course, in the absence of nephrotic syndrome and dehydration and without combination with another nephrotoxic drug or with vasoactive drugs such as ACE inhibitors and ARBs; it also advises against tobacco and beta blockers in patients with Raynaud phenomenon [20]. In established monogenic forms, ineffective prednisolone and prednisone should be avoided and calcineurin inhibitors should not be started (section 7.1) [18, 24]. The combination of ACE inhibitor, ARB and direct renin inhibitor should be avoided, and RAAS inhibitors should be suspended in the presence of volume depletion, acute kidney injury, hyperkalaemia or frequent vomiting and diarrhoea [24, 87]. Ophthalmic timolol is contraindicated in asthma and in the other situations described in section 7.5 [100]. Cautious use of diuretics, vitamin D and thyroid hormone is part of the general recommendations for genetic SRNS [18].

7.9. Perioperative care and transition

Before any orthopaedic surgery or intensive physiotherapy, magnetic resonance imaging of the joints identifies the bone and soft tissue anomalies and allows the technique to be planned [1, 30]. Dapagliflozin should be stopped at least 3 days before surgery or prolonged fasting [96], and KDIGO 2024 recommends suspending SGLT2 inhibitors during surgery and severe acute illness [87]. Transition from paediatric to adult services should maintain annual renal and ophthalmological surveillance, contraception in women on RAAS inhibitors and genetic counselling of affected or at-risk young adults [1, 24]. The PNDS provides, at the end of adolescence, for a transition consultation at the reference or competence centre, with career guidance, baseline DXA and audiogram, to avoid interruption of follow-up [20]. In an emergency, the team should be informed of the diagnosis, the malformations and any renal or ocular involvement, as well as of all ongoing therapies (renal, ocular, analgesic), with attention to pain control; the health record booklet or the electronic medical record serves as the liaison document and should accompany the patient, and the PNDS does not define a specific emergency card [20].

7.10. Comparative regulatory status

No medicinal product has an approved indication for NPS or FSGS10 in the USA, the European Union or Portugal. The only recent regulatory change with potential application is the approval by the Food and Drug Administration (FDA), on 13 April 2026, of an extension of indication of sparsentan (Filspari®), a dual endothelin receptor and angiotensin receptor antagonist, for focal segmental glomerulosclerosis [104]. The initial PDUFA (Prescription Drug User Fee Act) date of 13 January 2026 was extended to 13 April 2026 because of a major amendment to the application, according to the sponsor; the approval date is confirmed in the official Drugs@FDA database [104].

UPCR, urine protein/creatinine ratio; REMS, Risk Evaluation and Mitigation Strategy. For focal segmental glomerulosclerosis, the US label provides, above 50 kg, 400 mg orally once daily, increased to 800 mg after 14 days according to tolerance, and, up to 50 kg, 200 mg increased to 400 mg; RAAS inhibitors and endothelin antagonists should be stopped before initiation, aminotransferases and bilirubin measured before and every 3 months, the drug not started with aminotransferases more than 3 times the upper limit of normal, pregnancy excluded before initiation, and strong CYP3A inhibitors avoided; after interruption, it can be resumed at 50% of the dose and titrated after 14 days [104]. The tablets are swallowed whole with water before the morning or evening meal, and may be crushed in water; hypotension, acute kidney injury, hyperkalaemia and fluid retention are label warnings, and ALT or AST elevations of at least 3 times the upper limit occurred in up to 3.5% of patients [104].

7.11. Clinical trials

There is no interventional trial registered for NPS or LMX1B in ClinicalTrials.gov; a search by condition returned two observational studies, an NIH study of hereditary connective tissue disorders (NCT00001641, completed) and the British RaDaR registry of rare kidney diseases (NCT06065852, recruiting, which includes NPS and focal segmental glomerulosclerosis) [106]. A negative search in a registry does not prove that no studies exist outside it.

The DUPLEX doses were, above 50 kg, sparsentan 400 mg increased to 800 mg or irbesartan 150 mg increased to 300 mg, and, up to 50 kg, 200 to 400 mg or 75 to 150 mg; the mean age was 42 years, baseline estimated GFR about 63 mL/min/1.73 m² and baseline geometric UPCR about 3.1 g/g [104]. The trial missed the primary kidney function outcome and showed only an antiproteinuric effect, lost after discontinuation; a relative reduction of 22% in proteinuria should be read against a baseline value of 3.1 g/g and is not equivalent to a demonstrated benefit in renal survival. Genetic testing was not performed routinely, the label does not present results by gene and there are no published data on patients with LMX1B in the trial, so any application to NPS is an extrapolation; results of different trials should not be compared indirectly.

7.12. Developments in the last 12 months and research

In the Regensburg study, bortezomib, a proteasome inhibitor approved in multiple myeloma, prolonged in vitro (10 µM) the half-life of the mutant LIM proteins and, given on alternate days to mice with inducible podocyte inactivation of one allele and the LIM variant on the other allele, markedly reduced proteinuria by day 7, without observed renal toxicity; the authors propose studying proteasome inhibitors, ideally with podocyte-targeted delivery, and there is no human study [43]. In the Chinese report, the biopsy showed focal glomerular immaturity, foam cells, diffuse foot process effacement and a heterogeneous GBM with an Alport-like pattern; albumin rose from 28.8 to 39.4 g/L and creatinine remained between 54 and 63 µmol/L, and the ciclosporin dose is not given in the abstract [54]. This result, in a single uncontrolled patient, diverges from the IPNA recommendation and does not justify routine use. If it is considered in a specific patient, the reference dose in children is that of KDIGO 2025 for SRNS, applied by extrapolation: 5 mg/kg/day in two oral doses, with a 12-hour trough level of 60–150 ng/mL, discontinuation without partial response at 6 months and maintenance for at least 12 months if there is a response [25]. The SmPC of ciclosporin (Neoral®, Sandimmun Neoral® in other European countries), cited for comparison, includes steroid-dependent and steroid-resistant nephrotic syndrome due to primary glomerulopathy, including focal segmental glomerulosclerosis, and differs from KDIGO in children: for induction, with normal kidney function apart from proteinuria, 6 mg/kg/day in children (5 mg/kg/day in adults, the dose used in adults in the absence of a guideline dose consulted), in two oral doses, without exceeding these values; level measurements only occasionally, in specific situations, with no trough target; with reduced kidney function, starting dose not exceeding 2.5 mg/kg/day; combination with low-dose corticosteroid if the effect is insufficient; discontinuation if there is no improvement after 3 to 6 months; and slow reduction to the minimum effective dose for maintenance [25, 108]. The label indication refers to primary glomerulopathies; in a monogenic form such as NPS or FSGS10, use contradicts the IPNA recommendation and is an extrapolation, and IPNA recommends, if there is remission under immunosuppression in a genetic form, reviewing the pathogenicity of the variant [24]. The SmPC warns of the difficulty of detecting ciclosporin nephrotoxicity in nephrotic syndrome, with structural renal changes described without a rise in creatinine [108]. The demonstration of tissue-specific manifestations of a patient variant in the mouse and the association of lmx1ba loss in zebrafish with early osteoarthritis were published as bioRxiv preprints in 2026 (Amano and colleagues; Moss and colleagues), without peer review; they do not constitute clinical evidence.

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

NPS and FSGS10 are transmitted in an autosomal dominant manner [1, 5]. In the British cohort, the disease was inherited in 87.5% (105/120) of patients and sporadic in 12.5% (15/120), and no cases of non-penetrance or germline mosaicism were observed [12]; in south-eastern Australia, 9 of 52 cases (17%) were sporadic [19]. Each child of an affected person has a 50% risk of inheriting the variant [1]. Penetrance in heterozygotes is complete, but expressivity is so variable between relatives that neither the family history nor the presence of the variant allows severity to be predicted, including renal risk [1, 11].

8.2. Assessment of the parents and mosaicism

If the proband has a molecular diagnosis and appears to be an isolated case, the parents should be tested for the variant, both to estimate the recurrence risk and to start their own renal and ocular surveillance; if the variant is not known, the parents should be examined, because mild manifestations easily go unnoticed, and an apparently negative family history can only be confirmed by clinical and/or molecular assessment of the parents [1]. If the variant is not found in either parent, the explanation is a de novo variant or parental gonadal or somatic and gonadal mosaicism [1]. In an Italian series of 20 patients, somatic mosaicism was demonstrated in two clinically unaffected parents, the first described cases of transmission of a mutant LMX1B allele from a mosaic parent [49]. Leucocyte DNA may not detect somatic mosaicism and does not detect exclusively gonadal mosaicism, and a parent with somatic mosaicism may have a mild or minimal phenotype [1]. If the proband has a translocation disrupting the gene, the parents should be karyotyped [1]. The PNDS (French National Diagnosis and Care Protocol) points out that parental testing should be preceded by a clinical examination targeted at minimal signs and that, because of the possibility of germline mosaicism, the siblings of a patient should at least be examined even when the variant appears de novo; in the British series, 87.5% (105/120) of patients had inherited the disease [12, 20].

8.3. Cascade testing and assessment of minors

GeneReviews considers it appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives, older and younger, in order to start renal and ophthalmological surveillance early: molecular testing if the familial variant is known and, if not, blood pressure, urinalysis, albumin/creatinine ratio in the first morning urine and glaucoma screening [1]. In children, testing is justified because there is a medical benefit in childhood, since renal surveillance begins at birth [1, 12]. IPNA recommends screening the siblings of children with SRNS for proteinuria even before genetic testing (grade C), and the GeneReviews chapter on genetic SRNS advises offering proteinuria screening to first-degree relatives without waiting for molecular confirmation [18, 24]. Relatives without the familial variant can be discharged from surveillance [18]. In FSGS10, family screening identified microalbuminuria of 60 mg/day in a 7-year-old child [10]. The implications for kidney donation are covered in section 7.4.

8.4. Prenatal diagnosis and preimplantation genetic testing

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible; the manifestations in the fetus cannot be predicted either from the family history or from the presence of the variant, and perspectives on the use of these tests differ between people and families, so the decision is personal [1]. Chorionic villus sampling allows diagnosis in the first trimester, by haplotypes or by the familial variant [4]; the first molecular prenatal diagnosis, published in 1999, used five DNA markers flanking LMX1B [14]. According to the OMIM entry, most families request prenatal diagnosis in the hope of predicting severity, which no test allows [14]. Ultrasound may detect clubfoot, other limb anomalies, large iliac horns or absent patella, especially in the third trimester, and the first ultrasound prenatal diagnosis of NPS was based on the iliac horns [1, 30, 76]. When the molecular diagnosis has not been confirmed in an affected person, GeneReviews suggests DNA banking [1]. In families with regulatory alterations, prenatal testing requires the same method that identified the alteration in the proband (genome, targeted sequencing of the LARM or rearrangement analysis) [23]. In France, termination of pregnancy for medical reasons after prenatal diagnosis and preimplantation genetic testing are only authorised, after the opinion of a multidisciplinary prenatal diagnosis centre, for a particularly severe and incurable disease, so the PNDS recommends responding case by case, according to the request, the personal situation and the severity of the complications; because the most frequent signs are not visible on ultrasound or only very late, prenatal diagnosis depends on molecular analysis of the previously identified familial variant, in a sample obtained by chorionic villus sampling (or by amniocentesis, a technique also presented at the preconception consultation) [20].

8.5. Pregnancy and lactation

Abnormal kidney function may appear or worsen in pregnancy [1]. In the British series, 29% (14/48) of women who had been pregnant developed pre-eclampsia, an incidence the authors consider higher than that of the general population, and renal involvement limited to pregnancy explained the difference between the 37.5% and the 25% renal involvement [4, 12]. A 31-year-old Indian primigravida, without a previous diagnosis, had proteinuria at 16 weeks and anasarca at 20 weeks, with proteinuria of 11 g/day; she had a fetal death at 22 weeks and thrombosis of the left renal vein and inferior vena cava four days later, treated with anticoagulation; on an ARB and without immunosuppression, proteinuria fell to 700 mg/day at 2 years [78]. A 35-year-old multigravida had spontaneous coronary artery dissection during labour [71]. Most pregnant women with NPS reach term without major complications, and early kidney injury may mimic pre-eclampsia [30].

The French PNDS organises pregnancy in three stages. Before conception, the patient should be seen by nephrology (renal work-up and close surveillance plan), ophthalmology (intraocular pressure), genetics, with her partner, and, after these, by a maternal medicine obstetrician, who discusses follow-up, looks for other risk factors for pre-eclampsia and explains prenatal diagnosis techniques if this has been proposed [20]. From the beginning of pregnancy, follow-up takes place in a level 2 or 3 maternity unit, with the nephrologist and ophthalmologist informed, a new genetics consultation and, if the couple so wishes, discussion of prenatal diagnosis with the prenatal diagnosis centre; the obstetrician monitors blood pressure and proteinuria and haematuria from the start, refers to nephrology as soon as proteinuria appears and looks for the other factors for pre-eclampsia (nulliparity, oocyte donation, multiple pregnancy, age over 35 years, diabetes, obesity, family history). The PNDS cites pre-eclampsia in 14 of 48 British women (29%, versus 5% in the general population) and pelvic narrowing that led to caesarean section in 7 of 48, a finding not described in other series [20]. The original article mentions seven women with caesarean section for a narrow pelvis without giving the denominator, so the fraction of 7 in 48 results from the PNDS reading [12]. Ultrasound, performed by a reference sonographer, looks for elbow pterygia, clubfoot and iliac horns in the fetus; if the mother has nephropathy, because of the risk of fetal growth restriction, an additional ultrasound at around 26 weeks with uterine Doppler is proposed, then adapting surveillance to growth [20]. At the end of pregnancy, the maternity paediatric team is alerted for a careful examination of the newborn in the delivery room and on the ward, and psychological support is offered to the future parents [20].

Frequent urinalysis and blood pressure measurement are recommended during pregnancy [1]. ACE inhibitors should be reviewed ideally before conception, or as soon as pregnancy is recognised, for a switch to an alternative, given the adverse fetal effects [1]. All RAAS inhibitors in section 7.3 carry a boxed warning for fetal toxicity on the FDA label, and the Portuguese SmPC of enalapril contraindicates it in the 2nd and 3rd trimesters and requires it to be stopped immediately when pregnancy is diagnosed [88–90, 92]. Sparsentan has embryo-fetal toxicity with exclusion of pregnancy before initiation, and dapagliflozin is not recommended in the 2nd and 3rd trimesters [97, 104]. In lactation, the Portuguese SmPC does not recommend enalapril when breastfeeding preterm infants and in the first weeks after birth, and allows it with an older infant if the therapy is necessary and the infant is monitored [89]; the US labels of lisinopril and sparsentan advise against breastfeeding, as does that of dapagliflozin [90, 96, 104]. The MotherToBaby service, referred to by GeneReviews, provides information on medication in pregnancy [1].

8.6. Content of counselling

Counselling should be provided by genetics professionals and include the pedigree, the nature of the disease, the mode of inheritance and its implications [1]. The ideal time to discuss risks and reproductive options is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. The points specific to NPS are the unpredictability of severity in each child, the renal and ocular risk that justifies surveillance of all carriers regardless of skeletal severity, the renal and hypertensive obstetric risk, the teratogenicity of nephroprotective drugs, the exclusion of carriers as kidney donors and, in families with regulatory alterations, the uncertainty about renal and ocular risk, which maintains the indication for surveillance [1, 23, 24]. The French PNDS recommends that the diagnosis be disclosed in a dedicated consultation, jointly with a geneticist when the test was requested by another specialist, preferably with a psychologist, covering the characteristics of the disease, the need for an extra-ungual and extra-skeletal work-up, the follow-up plan, the professionals involved, the mode of transmission, the patient association and social support; this is followed by a summary letter to the general practitioner, the correspondents and the patient or parents, and a second consultation a few weeks later to revisit the information and introduce the team [20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The estimate of 1/50,000 would imply about 6000 affected individuals in the USA, a number much higher than that of identified patients, which may reflect underdiagnosis, with families undiagnosed for generations, or a lower true frequency [4]. The value of 2/100,000 presented by GeneGuidance is the direct conversion of the GeneReviews estimate and does not cover FSGS10, for which there is no population frequency estimate [9]. None of the sources measures birth incidence with genetic verification.

9.2. Cohorts by region and founder effect

Clinical data come mainly from Europe, the USA, Australia and Japan: the British cohort of 123 patients [12], the French cohort of 55 families, with patients from Belgium, Switzerland, Spain, Australia and the USA [21], the Dutch cohorts of 106 individuals, 95 knee radiographs and 139 surveys [57, 61, 62], the Italian cohort of 20 patients [49], the Swedish family with an inversion [47], the Danish family with dyskinesia [68], the North American cohorts from Pittsburgh, Baltimore and Michigan [4, 33, 66, 69], the Australian [19] and the Japanese [11]. Case reports from South Korea, China, Hong Kong, India, Malaysia, Canada and Belgium broaden the diversity of origins, but do not allow frequencies to be estimated [22, 52–55, 78, 81, 85].

The recurrent variants of the French series had different origins and did not suggest a founder effect, with the exception of p.(Asp106Ala), present in two unrelated Spanish families [21]. The sources consulted do not describe founder populations with an increased frequency of NPS. In FSGS10, p.(Arg246Gln) has been described in two families of the Paris international cohort, in a North American patient and in a Korean family, a distribution consistent with mutational recurrence at the residue; the absence of a founder haplotype has not been studied [6, 10, 22]. The frequency of glaucoma in the general population varies with ancestry, non-Caucasian, especially Black, ethnicity being a risk factor, but the NPS series do not estimate glaucoma risk by ancestry [19, 86].

9.3. Portugal and Brazil

The sources consulted do not include prevalence estimates for NPS in Portugal or Brazil, which does not demonstrate that such data do not exist. Two Portuguese reports from 2026 were identified. The first, from the Unidade Local de Saúde de São João (Porto) and the Hospital do Divino Espírito Santo in Ponta Delgada, describes a 59-year-old woman with NPS and the LMX1B variant c.178C>T p.(Gln60Ter) (section 10.3) [110]. The second, from the Unidade Local de Saúde de Coimbra, a member of ERN BOND, describes vascular involvement, but only the metadata were accessible [72]. From Brazil, Richieri-Costa described in 1991 a three-generation family with four affected members, three with antecubital pterygium, two with proteinuria and one with cleft lip and palate [14]; IPNA also cites a Brazilian paediatric transplant cohort for SRNS with 0% recurrence in the graft in monogenic forms, a finding for SRNS in general and not specific to LMX1B [24]. In Brazil, the ACE inhibitors, ARBs and dapagliflozin used for nephroprotection have active registration with ANVISA (section 7.3) [98].

9.4. Special populations

In children, renal surveillance begins at birth and ophthalmological surveillance as soon as the child cooperates with the examination, and the Japanese urine screening programmes show that nephropathy can be detected at 3 years [1, 11]. In pregnant women, the risk of pre-eclampsia and worsening proteinuria requires obstetric and nephrological surveillance (section 8.5) [12]. After 40 years of age, clinically evident nephropathy and glaucoma become more frequent [12]. In FSGS10, the disease may appear in late adulthood, as in the patients aged 52 and 65 years with p.(Arg246Gln) [5, 6, 22]. Low muscle mass requires creatinine to be interpreted with caution at all ages [4].

9.5. European Reference Networks and patient associations

Three European Reference Networks cover the disease: ERN BOND, for rare bone diseases; ERKNet, for rare kidney diseases, including hereditary glomerulopathies and SRNS; and ERN-EYE, for rare eye diseases [26–28]. Nail Patella Syndrome Worldwide, a US-based patient association with members from several countries, publishes a newsletter and a medical brochure, and Nail-Patella Syndrome (UK) serves the United Kingdom; both are listed by the National Organization for Rare Disorders (NORD) [111, 112]. The former domain of the North American association, cited in 2009 articles, no longer belongs to it and should not be used as a source of information [111]. The British RaDaR registry of rare kidney diseases includes NPS and focal segmental glomerulosclerosis [106]. The LMX1B LOVD variant database, HGMD and ClinVar are the locus-specific and general variant databases [1].

In France, the 2020 HAS PNDS places follow-up in a rare disease reference or competence centre for developmental anomalies and malformation syndromes (AnDDI-Rares network) or for constitutional bone diseases (OSCAR network), usually coordinated by the clinical geneticist, in liaison with the general practitioner, who confirms the diagnosis at the centre, participates in coordination and ensures surveillance for complications; dental involvement may be followed in the network of rare oral and dental disease centres O-Rares (TETECOU network) [20]. The centre provides the general practitioner with the elements for the long-term condition (ALD) care protocol, and social workers support applications to the Maison Départementale des Personnes Handicapées (MDPH): at school, a support worker for pupils with disabilities (AESH), the education allowance for a child with a disability (AEEH), an individualised reception plan (PAI), a personalised schooling plan (PPS) or a localised school inclusion unit (ULIS), without defining the child by the disease; in adults, workplace adaptation by occupational medicine, recognition of disabled worker status (RQTH), mobility-inclusion cards, the disabled adult allowance (AAH), the disability compensation benefit (PCH) and, in complex situations, the liaison team for rare disabilities (ERHR) [20]. The French patient association, Association du syndrome Nail-Patella, took part in the review of the PNDS and is suggested to all families from diagnosis, with the decision left to the patient and parents [20]. In childhood, the maternal and child protection physician and the school physician help to resolve medico-social difficulties, and follow-up includes a physiotherapist and occupational therapist, a PRM physician or rheumatologist familiar with the disease and a referring physician at a pain centre [20].

10. Illustrative Clinical Case

10.1. Steroid-resistant nephrotic syndrome as the first manifestation of de novo NPS

Nakata and colleagues described in 2017 a 24-year-old Japanese woman referred for knee pain of 12 months' duration [51]. At 7 years of age she had had nephrotic syndrome, and kidney biopsy led to a diagnosis of primary focal segmental glomerulosclerosis: light microscopy showed focal glomerular lesions, immunofluorescence weakly positive IgM and C3 in the segmental lesions, and electron microscopy mild irregular thickening of the GBM and swollen podocytes with partial foot process effacement, without electron-lucent areas or dense deposits (figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC5363042/figure/Fig1/). The nephrotic syndrome worsened progressively without oedema. From 18 years of age she received corticosteroids, without response; ciclosporin was stopped after one week because of fatigue, and the corticosteroids were tapered with proteinuria of 4–6 g/24 h [51].

At 24 years, examination showed poorly developed nails and small corneas, with normal intraocular pressure, and radiography and computed tomography revealed hypoplastic patellae, dislocation of the elbows and iliac horns (figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC5363042/figure/Fig2/). Tests showed total protein of 4.8 g/dL, albumin of 2.8 g/dL, creatinine of 1.01 mg/dL, estimated GFR of 45 mL/min/1.73 m² and proteinuria of 7.67 g/g creatinine, without haematuria, with negative serology for secondary causes. Genetic testing identified the heterozygous LMX1B splicing variant c.819+1G>A, at the first nucleotide of intron 5, absent in both parents, that is, de novo (figure 3, https://pmc.ncbi.nlm.nih.gov/articles/PMC5363042/figure/Fig3/); the article does not state the transcript, but the same variant corresponds to NM_001174147.2:c.819+1G>A, classified as pathogenic in ClinVar [8, 51, 56]. The biopsy was not repeated, because of renal atrophy (9-cm kidney with parenchymal thinning), and the corticosteroids were gradually withdrawn without worsening of the nephrotic syndrome [51]. The patient corresponds to case 13 of Harita's Japanese series, with chronic kidney disease stage 4 at 25 years at the last follow-up [11].

The authors attributed the 17-year diagnostic delay to three factors: the nephrotic syndrome preceded obvious orthopaedic signs, there was no family history, and the histology of the initial phase was non-specific [51]. The case illustrates the current recommendation to look for extrarenal manifestations and perform genetic testing in all paediatric SRNS before prolonging immunosuppression [24, 25]. The corticosteroid therapy and ciclosporin the patient received before diagnosis do not correspond to the recommended management of a monogenic form, which is withdrawal of immunosuppression and continuation of RAAS inhibition; the only therapy the authors mention as indicated is an ACE inhibitor to reduce proteinuria [24, 51].

10.2. Complementary case: FSGS10 mimicking Fabry disease

Pinto e Vairo and colleagues described in 2020 a 65-year-old North American woman with hypertension since 58 years of age, on an ARB, with oedema and chronic kidney disease, creatinine of 1.1–1.2 mg/dL and marked proteinuria [6]. The first biopsy showed focal segmental glomerulosclerosis and focal myelin figures in podocytes, but GLA sequencing was negative and there was no exposure to silica, amiodarone or hydroxychloroquine; her mother had had focal segmental glomerulosclerosis at 69 years and kidney failure two years later. Four years later, at the Mayo Clinic, there were no signs of Fabry disease, cardiac and brain magnetic resonance imaging were normal, leucocyte alpha-galactosidase A activity was 35.3 nmol/h/mg and lyso-Gb3 0.4 ng/mL, creatinine had risen to 1.9 mg/dL and proteinuria was 6162 mg/24 h. The second biopsy showed global sclerosis in 30% of glomeruli, segmental sclerosis with podocyte capping, focal GBM duplication, tubular atrophy and interstitial fibrosis of about 25%, and, on electron microscopy, myelin figures only in podocytes, foot process effacement of about 30% and absence of collagen fibrils in the GBM (figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC7424659/figure/Fig1/). Exome sequencing of kidney tissue identified NM_002316.3:c.737G>A p.(Arg246Gln) (= NM_001174147.2:c.737G>A on the MANE transcript), confirmed as germline in blood, and the patient received a deceased-donor transplant two years after referral [6]. The case shows that, in FSGS10, the absence of the typical GBM changes does not rule out LMX1B and that myelin figures are not specific to Fabry disease.

10.3. Portuguese case: diagnosis in adulthood in a rheumatology clinic

Sebastião, Rato and Costa described in 2026 a 59-year-old Portuguese woman referred to the rheumatology clinic for bilateral mechanical knee pain, without relevant personal or family history [110]. The patellae were impalpable bilaterally, with preserved knee range of motion; there was bilateral camptodactyly of the fifth finger and hypoplasia of the thumbnails, and the elbow had an extension deficit of about 20° and bilateral limitation of pronation-supination, changes the patient reported since early childhood. Biochemistry, including inflammatory markers and kidney function, the spot urine protein/creatinine ratio and the urinary sediment were normal. Radiographs showed severe bilateral patellar hypoplasia with prominent tibial tuberosities and osteophytosis of the lateral compartment, bilateral hypoplasia and subluxation of the radial head, and flared iliac crests with prominent anterior iliac spines (figure 1 of the article, panels A to F, in the published legend: https://doi.org/10.1007/s10067-026-08102-1; the image was not viewed directly). Molecular testing identified the heterozygous pathogenic variant c.178C>T p.(Gln60Ter) in exon 2 of LMX1B, with no transcript stated; in the NM_002316.3 numbering of the French series, the same description corresponds to the truncating variant p.(Gln60Ter), which in the Pittsburgh study was associated with renal involvement in only one of nine carriers [4, 21, 110]. Ophthalmological screening was recommended [110].

The case shows that NPS can reach adulthood undiagnosed when the family history is negative and the complaints are only articular, and that examination of the nails and elbows in knee pain with impalpable patellae is sufficient to raise suspicion. The figures cited in the article's discussion (nephropathy in 40%–60%, glaucoma or ocular hypertension in about 50%) come from reviews and are higher than those of the primary series in section 3; the recommended surveillance is that of section 11, with annual urine and blood pressure checks in addition to ophthalmological screening [1, 12].

11. Prognosis and Long-term Follow-up

11.1. Prognosis

The vital and functional prognosis depends mainly on the kidney, the eye and the joints. The nephropathy is rarely significant before the fourth decade and, from then on, contributes to increased mortality [3]. The proportion of patients reaching end-stage kidney disease ranges from 3% (3/123) in the British series, 1 in 108 in the Dutch series and less than 5% in the Japanese series to about 15% in the older series of Meyrier and Looij; the Pittsburgh study found no case among 57 patients [4, 11, 12]. Most patients have a slow decline in filtration, about twice that expected for age, with low non-progressive proteinuria, whereas 5%–10% have nephrotic proteinuria from childhood or young adulthood and progress to kidney failure [4, 31]. The predictors of progression are the presence and severity of proteinuria, especially moderate to massive in childhood, and homeodomain variants; early histology does not predict prognosis [1, 11]. In paediatric genetic SRNS in general, end-stage kidney disease occurred in 71%–74%, versus 4%–29% in non-genetic SRNS, with median renal survival of 45–48 months versus 58–205 months, values from SRNS cohorts and not from NPS, in which progression is less frequent [24]. In FSGS10, progression to end-stage kidney disease is frequent in the families described, at ages from 36 to 70 years in family F, and the renal prognosis of p.(Arg246Gln) is described as worse than that of the nephropathy of typical NPS [6, 10]. Transplantation has good results and the disease does not recur in the graft [1, 18].

Glaucoma and ocular hypertension affect about 29% of patients over 40 years of age and are treatable, which justifies screening [12]. Early osteoarthritis of the knee and elbow progressively limits function, and patellar instability persists in about 40% of knees after realignment [1, 31, 62]. Fracture risk is increased, with lower bone mineral density at the hip [66]. In the Swedish family followed for 9 years with annual clinical examination, urine testing and ophthalmological examination, none of the five affected members developed nephropathy or ocular involvement, and all had short stature of variable degree [47].

11.2. Surveillance

The renal surveillance intervals agree between sources: GeneReviews, Sweeney and colleagues, Lemley and Ghoumid and colleagues recommend annual screening from birth, with blood pressure and urine, and Ghoumid stresses this especially for homeodomain variants [1, 4, 12, 21]. Ophthalmological surveillance diverges. The 2026 GeneReviews recommends at least annual screening as soon as the child cooperates; the recommendations table of Sweeney and colleagues and the French series propose screening every 2 years in adults, and a classic atlas suggested renal and ophthalmological examination every 2 years in adults [1, 12, 21, 31]. The attribution to Sweeney, in an Australian series, of a recommendation for annual examination as soon as the child cooperates does not correspond to the table in the original article [12, 19]. The 2020 French PNDS (French National Diagnosis and Care Protocol), coordinated by the Lille centre, from which the 2016 French series comes, recommends ophthalmological examination with intraocular pressure at least annually in children and adults, in agreement with GeneReviews [1, 20]. The annual interval is the most recent and the most conservative, and is the one this article adopts; once ocular hypertension or glaucoma has been identified, the intervals become those of the EGS [1, 86]. In patients with regulatory alterations (LARM1/LARM2), possibly without renal and ocular risk, the authors recommend maintaining surveillance until more cases are available [23]. The PNDS, which predates that study, stated that there was no renal or ocular risk in these forms; this article maintains surveillance [20, 23]. The PNDS adds to the GeneReviews surveillance the audiogram, three-yearly creatinine, DXA at defined intervals and three-yearly assessment, in adults, of pain, orthopaedics and psychological status [1, 20].

12. Summary and Final Considerations

Nail-patella syndrome results from loss of function of one allele of LMX1B, a LIM-homeodomain transcription factor that specifies the dorsal aspect of the limbs, the anterior segment of the eye and the podocyte programme. The tetrad of nail dysplasia with an ulnar gradient, small and unstable patellae, limited elbow movement and iliac horns allows a clinical diagnosis, but none of the four is present in all patients; loss of the creases over the distal interphalangeal joints, present in 96%, is the most sensitive examination sign. Inheritance is dominant, with complete penetrance and unpredictable expressivity within each family, and about one in eight cases is de novo.

The kidney determines most of the prognosis. Proteinuria affects a quarter to a half of patients, but end-stage kidney disease is rare in recent series (3% in the United Kingdom) and is concentrated in a small group with moderate to nephrotic proteinuria from childhood, especially with homeodomain variants. Annual surveillance of blood pressure and albumin/creatinine ratio from birth, renin-angiotensin-aldosterone system inhibition for proteinuria, avoidance of corticosteroids and calcineurin inhibitors in monogenic forms, contraception in treated women and exclusion of carrier relatives as kidney donors are the central renal measures. Transplantation has good results and the disease does not recur in the graft.

Open-angle glaucoma and ocular hypertension affect about three in ten patients after 40 years of age, sometimes with normal pressure, and justify screening with intraocular pressure, optic disc and visual fields as soon as the child cooperates. Orthopaedic complaints, especially patellar instability, require magnetic resonance imaging before any surgery, and surgical results are variable. Reduced bone mineral density, constipation, reduced pain sensitivity and dental changes complete the multidisciplinary follow-up. The 2020 French PNDS, the only specific national protocol, extends that follow-up to the audiogram, periodic DXA, the pain clinic and psychological and social support, and recommends early patellar realignment, between 2 and 3 years of age.

Isolated LMX1B glomerulopathy (FSGS10), caused by variants such as p.(Arg246Gln) in helices II and IV of the homeodomain, presents as focal segmental glomerulosclerosis or nephrotic syndrome without nail or skeletal findings and may mimic Fabry disease through myelin figures in podocytes; it justifies the inclusion of LMX1B in all glomerular disease panels. Molecular diagnosis reaches close to 100% in reference centres when sequencing is combined with analysis of deletions, the LARM1/LARM2 regulatory regions, the 5′ untranslated region and structural variants. There is no targeted treatment; proteasome inhibition is a preclinical hypothesis, and the US approval of sparsentan for focal segmental glomerulosclerosis without nephrotic syndrome rests on a trial without results by gene and without demonstrated benefit on kidney function.

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