Anterior Segment Dysgenesis (Axenfeld-Rieger and Peters Anomaly)

Literature and regulatory information updated: 10 October 2026.

PITX2- and FOXC1-related Axenfeld-Rieger syndrome and anomaly, isolated Peters anomaly (PAX6, PITX2, FOXC1, CYP1B1, FOXE3, SOX2 and other genes) and Peters-plus syndrome (B3GLCT). Aniridia and the PAX6 spectrum, primary congenital and juvenile glaucoma, and microphthalmia, anophthalmia and coloboma are part of the differential diagnosis.

0. Initial Reference Table

OMIM: Online Mendelian Inheritance in Man; ORPHA: Orphanet code; HGNC: HUGO Gene Nomenclature Committee, the international committee for human gene nomenclature; MANE: Matched Annotation from NCBI and EMBL-EBI, common reference transcript; PTRPLS: Peters-plus syndrome; ERN: European Reference Network.

OMIM entry 601499 (Axenfeld-Rieger syndrome type 2, RIEG2) corresponds to a locus at 13q14 defined by large 13q deletions and by one family with linkage to that region, with no gene identified, and its existence as a distinct entity is uncertain [1, 3]. The autosomal recessive form of anterior segment dysgenesis without extraocular manifestations (ORPHA:519388; OMIM 617319, ASGD8) is associated with CPAMD8, and ASGD7 (OMIM 269400) with PXDN [1, 26].

1. Introduction

1.1. Definition and Scope

Anterior segment dysgenesis (ASD) comprises congenital malformations of the cornea, iris, lens and iridocorneal angle, including the trabecular meshwork and Schlemm canal, that result from disturbed development of these interdependent structures: a primary abnormality in one of them alters the formation of the others, even when the responsible gene is expressed in a localised tissue [15]. The corresponding Orphanet group (ORPHA:88632, developmental anomaly of the anterior segment) brings together Axenfeld-Rieger syndrome, the Axenfeld and Rieger anomalies, Peters anomaly and Peters-plus syndrome, among other entities [2, 5, 7]. The classic clinical phenotypes do not correspond to distinct genetic entities: the same gene can produce Axenfeld-Rieger, Peters or aniridia presentations, and the same clinical picture can result from different genes, reflecting allelic and locus heterogeneity [15, 17].

Axenfeld-Rieger syndrome (ARS) is defined by Orphanet as an umbrella term for overlapping genetic disorders whose main feature is anterior segment dysgenesis, with variable extraocular congenital anomalies, autosomal dominant inheritance and neonatal onset [2]. Axenfeld anomaly consists of anterior displacement of Schwalbe line (posterior embryotoxon) with iris strands inserting into it; Rieger anomaly adds deformation of the anterior chamber with marked atrophy of the iris stroma, iris holes or pseudoholes and corectopia [4, 18]. The term “syndrome” is reserved for patients with extraocular manifestations, mainly dental, craniofacial and umbilical, and the term “anomaly” for the purely ocular picture [12, 27].

Peters anomaly is a congenital central corneal opacity with absence of the posterior stroma, Descemet membrane and endothelium in the opaque area, accompanied by adhesions between the posterior corneal surface and the iris or lens [5, 15]. Peters-plus syndrome (PTRPLS) is the constellation caused by biallelic variants in B3GLCT: Peters anomaly or another anterior segment anomaly, short stature with rhizomelia, brachydactyly, characteristic facies, cleft lip or palate and developmental delay of variable degree [6].

Outside the scope of this article, except in the differential diagnosis, are aniridia and the PAX6 spectrum, including WAGR spectrum disorder (Wilms tumour, aniridia, genitourinary anomalies and developmental delay), primary congenital and juvenile glaucoma, including CYP1B1, LTBP2, TEK and MYOC, and microphthalmia, anophthalmia and coloboma, including SOX2 and FOXE3. Peters anomaly associated with these genes is described here insofar as it has specific features.

1.2. Historical Overview

Axenfeld described posterior embryotoxon with corectopia in 1920, and Rieger published in 1935 a series of patients with what he called “mesodermal dysgenesis” of the cornea and iris [27]. Rieger (1898–1986) recognised in 1935 and 1941 the association of hypodontia with malformation of the anterior chamber as a dominantly transmitted disorder, and Alkemade's 1969 review confirmed autosomal dominant inheritance and described the characteristic facies, with a broad nasal root, telecanthus and maxillary hypoplasia with a prominent lower lip [28]. Jorgenson and colleagues stressed in 1978 that failure of involution of the periumbilical skin is a cardinal feature, and De Hauwere and colleagues delineated in 1973 Rieger anomaly with hypertelorism and psychomotor delay (OMIM 109120) [28]. The Axenfeld and Rieger anomalies were described as separate entities in the 1920s and 1930s, and the unifying term “Axenfeld-Rieger syndrome” was proposed in 1983, on the basis of overlapping phenotypes and intrafamilial variability [3]. In 2000, Alward argued that the Axenfeld and Rieger anomalies, Rieger syndrome, iridogoniodysgenesis anomaly and syndrome, iris hypoplasia and familial iridogoniodysplasia with glaucoma should be considered a single entity, whose most important clinical feature is a glaucoma risk of at least 50% [29]. The Oxford Desk Reference adopts the designation “Axenfeld-Rieger malformations” to eliminate arbitrary subclassifications, keeping the historical terminology as a key to reading the literature [15].

Peters-plus syndrome was delineated by van Schooneveld and colleagues in 1984, in a series of 11 patients with Peters anomaly, short stature, brachymorphism mainly of the hands and abnormal ears, which included opposite-sex twins and affected sisters; according to those authors, Peters had described in 1906 three siblings with the anomaly that bears his name, and Kivlin and colleagues argued in 1986 that Peters anomaly is a morphological rather than a causal entity, because it occurs in many genetic and non-genetic syndromes [30]. The eponyms Krause and Kivlin persist in the synonyms Krause-Kivlin and Krause-van Schooneveld-Kivlin [7, 31]. Townsend's 1974 classification distinguished isolated central leucoma, leucoma with corneolenticular touch and leucoma with Rieger dysgenesis; the current classification separates type I, with iridocorneal adhesions and central opacity, usually unilateral and rarely syndromic, from type II, with corneolenticular touch or cataract, usually bilateral and more often associated with systemic anomalies [13]. GeneReviews now regards the two types as points on a spectrum [6].

1.3. Milestones of Molecular Discovery

In 1994, Hanson and colleagues found a deletion of one copy of PAX6 in a child with Peters anomaly and a missense variant in the paired domain in an autosomal dominant family with anterior segment anomalies, noting that heterozygous Sey mice had a Peters-like phenotype [32]. In 1996, Semina and colleagues cloned the RIEG gene (now PITX2) at 4q25, a bicoid-class homeodomain transcription factor, and identified six variants in patients with Rieger syndrome; in the mouse, the gene is expressed in the periocular mesenchyme, the maxillary and mandibular epithelia, the umbilicus, Rathke pouch, the vitelline vessels and the limb mesenchyme, which explains the distribution of the extraocular manifestations [33].

In 1998, two groups identified the second gene. Nishimura and colleagues located FKHL7 (now FOXC1), a forkhead transcription factor at 6p25, from the breakpoint of a balanced translocation t(6;13)(p25;q22) and from a 6p deletion in patients with congenital glaucoma, and found variants in patients with Rieger and Axenfeld anomalies and with iris hypoplasia [34]. Mears and colleagues described, in five families with iridogoniodysgenesis type 1 and 16 sporadic patients, a 10 bp frameshift deletion and two missense variants in the forkhead domain [35]. In 1999, Doward and colleagues associated a PITX2 variant with unilateral Peters anomaly for the first time [36], and Vincent and colleagues reported CYP1B1 variants in Peters anomaly in 2001 and, in 2006, in a series of 15 patients, in 3/15 (20%) versus 1/140 (0.7%) controls [37, 38].

In 2006, Lesnik Oberstein and colleagues identified by array comparative genomic hybridisation a microdeletion and, subsequently, biallelic truncating variants in B3GALTL (now B3GLCT) in all 20 patients with Peters-plus tested, establishing a monogenic syndrome with a predominant variant [39]. In 2008, Hess and colleagues showed that the encoded enzyme synthesises the disaccharide glucose-β1,3-fucose O-linked to thrombospondin type 1 repeats and that, in patients' properdin, only O-linked fucose is present, without the disaccharide, which classified the syndrome as a congenital disorder of glycosylation [40].

1.4. Current Nomenclature and Reclassifications

OMIM maintains three ARS types: type 1 (180500, PITX2), type 2 (601499, 13q14 locus without a gene) and type 3 (602482, FOXC1), and a series of anterior segment dysgeneses with an associated gene: ASGD1 (PITX3), ASGD2 (FOXE3), ASGD3 (FOXC1), ASGD4 (PITX2), ASGD5 (PAX6), ASGD6 (CYP1B1), ASGD7 (PXDN) and ASGD8 (CPAMD8) [1]. Reis and colleagues proposed in 2023 replacing numbering by type with gene-based designation, “PITX2-related ARS” and “FOXC1-related ARS”, because extraocular manifestations, risks and surveillance depend on the gene and not on the clinical subtype [3].

As regards Peters-plus syndrome, the diagnosis requires the typical constellation with biallelic variants in B3GLCT; patients with Peters anomaly and systemic manifestations without alterations in this gene are designated “atypical Peters-plus” or “Peters plus-like” [6]. Weh and colleagues found no B3GLCT variants in 55 patients with a Peters plus-like phenotype or with isolated Peters anomaly, which confirmed that the strong association is limited to the classic form [41]. The symbol B3GALTL (“beta-1,3-galactosyltransferase-like”) was replaced by B3GLCT (beta-1,3-glucosyltransferase), and Saudubray classifies the disorder as B3GLCT-CDG, a defect of O-glycosylation [6, 8].

2. Molecular Genetics and Pathophysiology

2.1. Development of the Anterior Segment and the Neural Crest

The anterior segment forms through the interaction of the surface ectoderm, which gives rise to the corneal epithelium and the lens, with the neural crest-derived periocular mesenchyme, which migrates in successive waves and gives rise to the corneal endothelium, the stromal keratocytes, the stroma of the iris and ciliary body and the trabecular meshwork [13]. The transcription factors PITX2 and FOXC1 act in this mesenchyme: their haploinsufficiency disturbs the migration and differentiation of neural crest cells, which produces iridogoniodysgenesis and impairs aqueous humour outflow [9, 11]. Glaucoma in ARS results from late arrest of angle development, with reduced intertrabecular spaces and a compacted trabecular meshwork, and not only from the strands visible on gonioscopy [27]. PITX2 negatively regulates FOXC1, which helps to explain the overlap between the phenotypes caused by the two genes [27].

In Peters anomaly, the proposed mechanisms are failure of separation of the lens vesicle from the surface ectoderm, abnormal migration of neural crest cells and, in sporadic cases, intrauterine inflammation [13]. Histopathology shows abnormal or absent Descemet membrane and endothelium in the opaque zone, absent at the point of iris adhesion, a disorganised and oedematous epithelium, Bowman membrane replaced by pannus and lamellar disorganisation of the posterior stroma [13]. Migration of endothelium from the periphery to the centre, described as self-repair, is the proposed basis for spontaneous improvement of the opacity in some infants and for the technique of selective endothelial removal [13]. Exposure to isotretinoin in the first trimester can produce similar lenticulo-irido-corneal adhesions [13]. In Peters-plus syndrome, incomplete separation of the lens secondarily obstructs neural crest migration, leading to goniodysgenesis, glaucoma and iridocorneal adhesions [6].

2.2. PITX2

PITX2 (4q25; OMIM 601542; HGNC:9005) encodes a homeodomain transcription factor of the RIEG/PITX family that directs the development of the anterior segment, teeth and abdominal organs, the differentiation of pituitary somatotrophs and lactotrophs, and left-right asymmetry [9]. The gene has three main isoforms, PITX2A, PITX2B and PITX2C, with distinct N-termini and a common homeodomain and C-terminal region [12]. The MANE Select transcript is NM_000325.6, which encodes the PITX2C isoform, whereas the ARS literature, including the Reis 2023 cohort, uses NM_153427.2 (PITX2A); with this reference, the homeodomain corresponds to amino acids 38–98 and the OAR domain to amino acids 233–246, and all known pathogenic variants lie in the region common to the three isoforms [3, 10]. In the examples checked in VariantValidator, numbering in NM_000325.6 differs by 159 nucleotides in c. notation and by 53 amino acids in p. notation from NM_153427.2; conversion should always be performed with a tool and not by manual addition [10].

The predominant mechanism is haploinsufficiency through loss of function, and ClinGen assigns PITX2 a haploinsufficiency score of 3 and a triplosensitivity score of 0, which gives deletions the same diagnostic weight as sequence variants [9]. There are, however, alleles with increased transcriptional activity and dominant-negative or gain-of-function effects, and Orphanet lists both mechanisms [2, 3]. Saadi and colleagues demonstrated in 2001 a dominant-negative effect of the p.Lys88Glu variant, a designation published on the PITX2A isoform (NM_153427.2:c.262A>G p.(Lys88Glu); MANE NM_000325.6:c.421A>G p.(Lys141Glu)) [10], in an infant with complete Rieger syndrome, and Espinoza and colleagues showed in 2002 that PITX2 activates the DLX2 promoter, required for dental development: an allele associated with iris hypoplasia without dental anomalies retained DLX2 activation, unlike an allele associated with the full picture, which offers a molecular explanation for the presence or absence of dental changes [28]. In the Reis 2023 cohort (59 individuals with PITX2 variants), there were 8 deletions including the coding region, 2 deletions of the upstream regulatory region, 34 variants with a premature termination codon (nonsense, splicing or frameshift) and 15 missense variants clustered in the homeodomain [3]. In the same authors' compilation, the literature contained 106 heterozygous intragenic PITX2 variants (40 missense, 33 of them in the homeodomain, 2 in-frame and 64 truncating), mostly private [3]. In Zhou 2023's review of 593 families, PITX2 variants were distributed as 32.00% missense or in-frame, 42.67% truncating and 25.33% large deletions, with 87.50% of missense variants in the homeodomain [42].

The non-coding upstream regulatory region of PITX2 contains conserved elements whose loss causes ARS with an intact gene. Reis 2023 identified deletions of this region in five independent families and defined conserved elements 5 to 7, chr4:111848106–112037113 in GRCh37 coordinates, as the minimal region, recommending its inclusion in clinical copy-number analysis [3]. In 2026, Mitchell and colleagues described by genome sequencing two families with typical PITX2 ARS and an intact gene: a 450 kb deletion removing the distal conserved enhancers and a 12.54 Mb inversion that separates PITX2 from those enhancers, a mechanism not detected by coding sequencing or by microarray [43]. Liu and colleagues described in 2026 four Han Chinese families with three novel microdeletions (from 206 bp to 449.97 kb) and one nonsense variant, all with dental and umbilical anomalies, and secondary glaucoma in seven patients [44].

2.3. FOXC1

FOXC1 (6p25.3; OMIM 601090; HGNC:3800) is a single-exon gene encoding an isoform with a forkhead DNA-binding domain; the MANE Select transcript is NM_001453.3, and variant numbering does not differ from that of NM_001453.2, used in the literature [10, 12]. With that reference, the forkhead domain corresponds to amino acids 77–168, the nuclear localisation signal to amino acids 168–176, the activation domains to amino acids 1–51 and 435–553 and the inhibitory domain to amino acids 215–365 [3]. FOXC1 regulates FOXO1, involved in cell viability and resistance to oxidative stress in the eye [11].

FOXC1 is dosage-sensitive in both directions. Haploinsufficiency (ClinGen score 3) is the main mechanism, and whole-gene deletions accounted for 32% of FOXC1 variants in the Reis 2023 cohort, versus 17% for PITX2 [3, 11]. Duplications including FOXC1 are also pathogenic and are associated with more severe glaucoma [11, 27]. Maxwell and colleagues described in 2026 20 individuals from 10 families with FOXC1 duplications in the ANZRAG (Australian and New Zealand Registry of Advanced Glaucoma) and Massachusetts Eye and Ear registries, between 2008 and 2025: all those tested had glaucoma, 17 had been referred as juvenile open-angle glaucoma (JOAG), and only 2 (10.5%) had subtle systemic manifestations; duplications accounted for 13.5% (95% confidence interval, 95% CI, 6.7–25.3) of probands with JOAG and a genetic diagnosis in ANZRAG, second only to MYOC (53.8%), and 9.5% (95% CI 2.7–28.9) at Massachusetts Eye and Ear [22]. The authors suggest routine copy-number analysis in JOAG [22].

In the Reis 2023 cohort (69 individuals with FOXC1 variants) there were 22 deletions, 27 truncating variants and 20 missense variants, the latter in the forkhead domain; the literature contained 126 intragenic variants (52 missense, 49 in the forkhead domain, 3 in-frame and 71 truncating), with the recurrent variant c.482T>A p.(Met161Lys) in four families [3]. In Zhou 2023's review, FOXC1 variants were 34.49% missense or in-frame, 35.13% truncating and 30.38% large deletions, with 76.14% of missense variants in the forkhead domain [42]. The 6p25 microduplication including FOXC1 has also been described as a cause of brachydactyly type E, based on the gene's expression during osteoblast differentiation [45].

2.4. Normalisation of the Cited Variants

The following conversions were obtained in VariantValidator (GRCh38) and not by manual calculation [10].

The recurrent PITX2 variant NM_153427.2:c.475_476del p.(Leu159Valfs*39) (MANE NM_000325.6:c.634_635del p.(Leu212ValfsTer39)) was described in four families [3, 10]. The MANE Select transcript of PAX6 is NM_001368894.2 [10]. The Peters variants described by exome sequencing in Weh 2014 (PAX6 c.155G>A p.(Cys52Tyr), TFAP2A c.1025+2T>A, HCCS c.715C>T p.(Gln239*), NDP c.385G>A p.(Glu129Lys), FLNA c.3446C>T p.(Pro1149Leu) and SLC4A11 c.1422T>A p.(Tyr474*) with c.2544G>A p.(Met848Ile)) are cited without a transcript in the source abstract and were not normalised [47].

2.5. Genotype-Phenotype Correlations in ARS

The distinction between PITX2 and FOXC1 is the most clinically useful correlation. In the Reis 2023 cohort (128 individuals from 91 families), PITX2 was identified in 37/41 (90%) of probands with dental and umbilical anomalies, and FOXC1 in 16/25 (64%) of probands with congenital heart disease or hearing loss; of the 17 families referred with diagnoses other than ARS, 94% had FOXC1 variants [3]. Variant type was not associated with the main phenotypes or with the glaucoma rate, but PITX2 deletions larger than 3 Mb were associated with intellectual disability (p=0.025) and heart disease (p=0.0025), reflecting involvement of contiguous genes [3]. In FOXC1, aniridia was more frequent with missense variants and deletions than with truncating variants (p=0.017 and p=0.010), hearing loss was more frequent with deletions (p=0.005) and less frequent with missense variants (p=0.016), enamel hypoplasia occurred only with deletions or truncating variants (p=0.004), and intellectual disability and cleft palate or bifid uvula occurred only with deletions larger than 2 Mb [3].

In Zhou 2023's review, systemic manifestations were present in 89.16% of families with PITX2 and in 58.77% of families with FOXC1 (p=5.44×10⁻¹⁷), and there were differences between genes in the frequency of glaucoma (p=0.03), corectopia (p=3.05×10⁻⁶), polycoria (p=5.21×10⁻⁸) and best-corrected visual acuity (p=0.038); the proportion of patients of European ancestry was higher with FOXC1 (p=0.02), and macular retinoschisis was described with a PITX2 variant [42]. In the full text of Zhou 2023, which pools mostly literature data, glaucoma was described in 44.06% of affected relatives with PITX2 and in 54.55% of those with FOXC1, corectopia in 35.81% and 18.57% and polycoria in 18.60% and 2.95%, respectively; 73.54% of families had a diagnosis of ARS and 20.46% other ocular diagnoses, including aniridia, isolated glaucoma and Peters anomaly [42]. Strungaru and colleagues studied 126 patients from 20 probands from their laboratory (91 with FOXC1 alterations, 57 of them from two families with a duplication, and 35 with PITX2 alterations): non-ocular findings were more frequent with PITX2 (p=0.006), FOXC1 duplications were associated with glaucoma in all 29 assessed and with onset in childhood, and PITX2 carriers had worse visual acuity, more bilateral visual loss and needed more surgery, so the authors attributed the more severe prognosis to PITX2 and to FOXC1 duplications [48]; this conclusion differs from that of Reis 2023 and Souzeau 2017, in which glaucoma appears earlier with FOXC1 [3, 21]. Intrafamilial variability, greater with FOXC1, suggests the action of modifier genes [3].

2.6. Other Genes of ARS and Anterior Segment Dysgenesis

The French national protocol (PNDS, Protocole National de Diagnostic et de Soins) states that PITX2 and FOXC1 account for about half of ARS cases and lists other genes each described in one or two families, with dominant or recessive inheritance: CYP1B1, COL4A1, PAX6, FOXE3, CPAMD8, PXDN, PIK3R1, BMP4, ADAMTS17, FOXC2 and PRDM5 [12]. Isolated posterior embryotoxon is the most frequent anterior segment anomaly in Alagille syndrome, so JAG1 should be included in the panel [12]. In Zhou 2023's review, 13 families had variants in two genes, 7 had biallelic FOXC1 variants and 6 had variants in ADAMTS17, PRDM5, COL4A1 or CYP1B1 [42].

Ma and colleagues studied 41 patients with ASD, mostly sporadic, by microarray, exome and genome sequencing with trio structural variant analysis, and obtained a probable cause in 54% (22/41): 51% (19/37) of sporadic and 75% (3/4) of familial cases; two thirds of sporadic cases had heterozygous variants, mostly de novo, and about one third (7/22) of the causes lay in rare or recently associated genes (PXDN, GJA8, COL4A1, ITPR1, CPAMD8), including a new association between Axenfeld-Rieger and homozygous ADAMTS17 [49]. In the Japanese multicentre study by Nishina 2026 (111 patients with bilateral lesions), de novo variants in PAX6, PITX2 and GJA8 and inherited variants in FOXC1 and CYP1B1 were the main causes of ASD and aniridia; glaucoma was frequent with CYP1B1 and FOXC1, systemic anomalies with FOXC1 and PITX2, and BMP4 and RARB were associated with neurological anomalies [17].

2.7. Genetics of Peters Anomaly

Isolated Peters anomaly has an identified genetic cause in a minority of patients. Chesneau and colleagues studied 95 French and Spanish patients by microarray, genome, exome and a panel of 119 ocular genes and identified a cause in about one third, distributed across 12 genes and copy-number variants: B3GLCT was the most frequent gene in the syndromic form and PAX6 in the isolated form, and SOX2 emerged as the third gene, in four unrelated patients with isolated Peters or with microphthalmia, the first association between SOX2 and Peters [14]. Weh and colleagues, using exome sequencing in 27 patients, found a variant in only one of the eight known genes (de novo PAX6) and proposed TFAP2A and FLNA in the syndromic form and HCCS, NDP and SLC4A11 in the isolated form [47].

Reviews and reference books list PAX6, PITX2, CYP1B1, FOXC1, COL6A3, B3GLCT, SOX2, PITX3, FOXE3, COL4A1 and MAF as Peters genes, as well as NDP, SLC4A11 and HCCS, and describe chromosomal anomalies of chromosomes 4, 11, 13 and 20 [13, 15, 31]. Orphanet considers CYP1B1, FOXC1, FOXE3 and PAX6 assessed and lists PITX2 as a tested candidate gene [5]. In the case of PAX6, truncating variants cause aniridia, whereas some missense variants in the paired domain (residues 4–130) produce milder phenotypes, including Peters anomaly, described as “atypical aniridia” [15, 50]. In three Japanese families and one sporadic case, the PAX6 variant p.Val54Asp (published designation; NM_001368894.2:c.161T>A p.(Val54Asp)) [10] produced Peters anomaly, congenital cataract, Axenfeld anomaly or foveal hypoplasia, and the family described by Hanson in 1994 included Peters anomaly and Rieger anomaly [51]. In CYP1B1-related Peters anomaly, the central opacity is associated with stromal thinning, absence of segments of the central Descemet membrane and iridocorneal or keratolenticular adhesions, with refractory glaucoma [52]. Edward and colleagues found biallelic CYP1B1 variants in 6 of 11 Saudi patients with Peters anomaly from consanguineous families, 5 of them homozygous for p.(Gly61Glu), some from families previously described as primary congenital glaucoma; as the same genotype was observed in relatives without disease, with primary congenital glaucoma or with Peters anomaly, the authors proposed modifiers of the ocular phenotype [53]. The model proposed for CYP1B1 is the production of a signalling metabolite, steroid or retinoid, required for development of the trabecular meshwork [46].

Recent preclinical studies add candidate pathways without clinical application: in the mouse, loss of ABL kinases induces Peters anomaly type II through failure of lens vesicle separation, via an ABL–PTPN12–p130CAS pathway, and the phenotype is attenuated by RAC1 inhibition [54]; loss of ephrin-A5 produces signs of Peters anomaly in another murine model [55].

2.8. B3GLCT and Peters-plus Syndrome

B3GLCT (13q12.3; OMIM 610308; HGNC:20207) encodes a type II endoplasmic reticulum glucosyltransferase that transfers glucose to O-linked fucose (previously added by POFUT2) on thrombospondin type 1 repeats [6, 16]. These repeats are present in extracellular matrix proteins of the ADAMTS family that require this O-glycosylation for secretion and function, and pathogenic variants cause loss of function [6, 40]. Loss-of-function variants and large deletions result in absent or truncated protein lacking the catalytic domain [31].

The variant NM_194318.4:c.660+1G>A, at the canonical splice donor site of intron 8, is the most frequent: in the founding study, it was found in 80% of families and 67% of probands; Weh 2014 found it in 8 of 9 patients, corresponding to 55% of alleles in that study and 69% of all alleles published up to then, with 2 homozygotes and the remainder compound heterozygotes [6, 41]. Smith's textbook states that about 70% of those tested are homozygous for this variant; this figure corresponds to the founding study, in which 16 of the 18 additional patients from 15 families, mostly Dutch, were homozygous, and it differs from that of Weh 2014 because of differences in population and period [30, 31, 41]. In the founding study, the microdeletion of about 1.5 Mb at 13q12.3-q13.1 detected in two siblings (with c.660+1G>A on the other allele) encompassed B3GLCT, BRCA2 and LGR8, and was associated with breast cancer in the maternal family [30]. In gnomAD v4, the variant has 1521 alleles in 1 436 492 in exomes (allele frequency of about 0.106%), 1364 in 1 089 560 in non-Finnish Europeans, 122 in 152 194 in genomes and no homozygotes [56]. Weh 2014 described the novel variants c.168dup p.(Gly57Argfs*11), c.1234C>T p.(Arg412*), c.1045G>A p.(Asp349Asn), c.1181G>A p.(Gly394Glu) and c.347+5G>T [41]. Deletion of exon 15, the last exon, is a founder variant identified in 11 homozygotes from six families in a village in Turkey [6]. GeneReviews recognises no clinically relevant genotype-phenotype correlation [6].

2.9. Allelic Disorders, Penetrance and Expressivity

PITX2 variants also cause ring dermoid of the cornea (OMIM 180550), and the gene contributes to susceptibility to familial atrial fibrillation (ORPHA:334); in the Icelandic genome-wide association study (550 patients with atrial fibrillation or flutter and 4476 controls), the rs2200733 polymorphism at 4q25, in a haplotype block with no known gene adjacent to the one containing PITX2, was associated with atrial fibrillation with an odds ratio of 1.84 (95% CI 1.54–2.21) and of 1.72 (1.59–1.86) in the combined European replications [57]; loss-of-function PITX2 variants have been described with isolated congenital heart disease, including tetralogy of Fallot [9, 27]. FOXC1 duplications produce JOAG without evident ARS, and 6p25 deletions including FOXC1 produce 6p25 deletion syndrome and De Hauwere syndrome, discussed in the differential diagnosis [3, 22].

The French PNDS describes ARS as having complete penetrance and highly variable expressivity and, elsewhere, as having high penetrance [12]. Molecular cohorts show high but incomplete penetrance of the cardinal features: in the Reis 2023 cohort, 6 of the 68 FOXC1 variant carriers assessed had a normal anterior segment, and glaucoma penetrance increased with age [3, 21]. A parent may have only subtle posterior embryotoxon, detectable only on slit-lamp examination [9, 15]. In Peters anomaly, apparently normal carriers may have posterior embryotoxon or Axenfeld anomaly [15].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Axenfeld-Rieger Syndrome: Ocular Manifestations

The ocular manifestations of ARS are always bilateral, although they may be highly asymmetric [52]. The French PNDS groups them into five categories: iris anomalies (progressive corectopia and polycoria, iris hypoplasia and, rarely, aniridia), posterior embryotoxon, congenital or, more often, juvenile glaucoma, angle dysgenesis with iridocorneal adhesions and, in two cases, agenesis of an extraocular muscle [12]. Heterochromia, iris coloboma, corneal opacities, cataract, lens subluxation or coloboma and ectropion uveae have also been described [12, 52]. Vision may be almost normal in the absence of glaucoma [27].

Posterior embryotoxon is a prominent, anteriorly displaced Schwalbe line, visible as a white peripheral ring on the posterior corneal surface; in Axenfeld anomaly, iris strands insert into this line; in Rieger anomaly, iris stromal atrophy, corectopia and pseudopolycoria are added [24, 58]. On gonioscopy, numerous and prominent iris processes may represent a form of ARS and are distinguished from goniosynechiae, which are thicker and extend beyond the scleral spur [23].

In the Reis 2023 cohort, all PITX2 variant carriers had an anterior segment phenotype (typical ARS anomalies in 93%), versus 91% of FOXC1 variant carriers (typical in 72%); corneal opacity occurred in 15% and 24% and aniridia in 8% and 13%, respectively [3]. The ocular spectrum was broader with FOXC1 (19/68 with a phenotype other than the typical one versus 4/59; p=0.002): aniridia in 4, corneal opacity in 3, aniridia with opacity in 3, primary congenital glaucoma in 2, iris or retinal coloboma in 1 and a normal anterior segment in 6 [3]. In the Australian and New Zealand cohort of Prem Senthil 2022 (61 individuals from 32 families, median age 39 years), corneal anomalies were more frequent with FOXC1 (18/36, 50%) than with PITX2 (4/25, 16%; p=0.007), and iris hypoplasia (p=0.008) and pseudopolycoria (p=0.001) were more frequent with PITX2; glaucoma was present in 72%, and corneal decompensation was associated with corneal anomalies, glaucoma surgery and cataract surgery [59].

3.2. Glaucoma in ARS: Frequency, Age and Severity

Glaucoma is the manifestation that determines the visual prognosis. Classic estimates point to a risk of 50–60%, usually in the second or third decade and occasionally congenital [27, 29, 60]. Molecularly confirmed cohorts show higher frequencies and differences in age between genes; risk factors are expressed as adjusted odds ratios (OR).

In the Reis 2023 cohort, more than half of FOXC1 variant carriers with glaucoma were diagnosed in the first one or two years of life (25/38) and 8/38 between 2 and 10 years; among those aged at least 10, 20 and 49 years, the proportion with glaucoma reached 61% (14/23), 61% (11/18) and 50% (3/6) at those ages, and 27 of 34 patients with data underwent surgery [3]. The authors stress that the overall frequency, 72% with PITX2 and 66% with FOXC1, exceeds the commonly cited lifetime risk of 50%, and that recent cohorts describe 70–75% glaucoma with surgery in 86% [3]. The differences between Strungaru 2007, which attributes the worse prognosis to PITX2, and Reis 2023 and Souzeau 2017, in which FOXC1 is associated with earlier onset, result from different ascertainment populations: the Strungaru series concentrates many patients in few families, with a high proportion of FOXC1 duplications, and the authors themselves point out this limitation, whereas Souzeau 2017 shows that the age of unaffected carriers biases the comparison between genes, because young people without glaucoma may still develop it [3, 21, 48]. In Zhou 2023's literature compilation, with non-uniform assessment, glaucoma frequencies are lower (44–55%) than in clinical cohorts [42]. The Japanese guideline states that ASD predisposes to secondary glaucoma from school age to adolescence and to secondary cataract [24].

3.3. PITX2-Related ARS: Extraocular Manifestations

Dentition is the most characteristic extraocular manifestation: hypodontia or oligodontia, mainly of the maxillary incisors (primary and permanent) and second premolars, microdontia, conical crowns, short roots, taurodontism, hypoplastic enamel and a thickened labial frenulum [12, 27]. Teeth are not visible at birth, and dental assessment takes place with eruption [12]. The face shows midface and maxillary hypoplasia, a broad flat nasal root, a short philtrum, a thin upper lip and an everted lower lip, with a prognathic appearance; hypomaxilla develops progressively and gives rise to a skeletal class III [12, 27]. Redundant periumbilical skin, without involution, is present in more than 50% of patients and is visible at birth, and may be associated with umbilical hernia or omphalocele [12, 27]. Failure of involution of the periumbilical skin is often mistaken for umbilical hernia and operated on in the neonatal period; Toppare and colleagues measured the periumbilical skin in 304 Turkish newborns (mean of 12.36 mm on the cranial side) and proposed considering ARS when the cranial measurement exceeds 18.82 mm (more than 2 standard deviations) [28, 64].

In the Reis 2023 cohort, PITX2 variant carriers had systemic anomalies in 57/57, facial dysmorphism in 37/40, dental anomalies in 40/44 (microdontia or hypodontia in 91%), umbilical anomalies in 49/52 (redundant skin 42%, hernia 33%, omphalocele 15%), Meckel diverticulum in 15/57 (26%), including one case of intestinal obstruction and one of diverticulitis, and imperforate or anteriorly placed anus in 3/57 [3]. The findings specific to PITX2 were dental anomalies (p=6×10⁻¹⁹), umbilical anomalies (p=3×10⁻¹⁹) and Meckel diverticulum (p=1×10⁻⁵); in the mouse with conditional mesenchymal deletion of Pitx2, Meckel diverticulum occurs in 65% [3]. Hypospadias (7%), anal stenosis, growth hormone deficiency and sella turcica anomalies, congenital heart disease (7%), hearing loss (2%) and intellectual disability (11%) have also been described [3, 15, 27]. One family has been described with autosomal dominant isolated growth hormone deficiency associated with ARS [28]. In iris hypoplasia with early-onset glaucoma (iridogoniodysgenesis), the iris colour is characteristic, slate grey or chocolate brown, because the pigment epithelium is visible through the hypoplastic stroma, and this sign allows affected individuals to be recognised at birth; glaucoma usually appears in the second decade and is resistant to medical treatment [64].

3.4. FOXC1-Related ARS: Extraocular Manifestations

The systemic profile of FOXC1 is different. In the Reis 2023 cohort, carriers had systemic anomalies in 45/65, facial dysmorphism in 42/54 (mainly widely spaced eyes and ear anomalies), congenital heart disease in 21/65 (septal and valvular defects, stenoses and anomalous vascular courses) and hearing loss in 21/65 [3]. Hearing loss, mixed or sensorineural, appeared at any age (by 2 years in 4, in childhood in 4, in adolescence in 4 and in adulthood in 7), was progressive and included two cases of Ménière disease; it affected 30% (8/27) by age 10, 60% (12/20) by 30 and 67% (8/12) by 40 [3]. There were skeletal or joint anomalies in 16/65 (hip in 7, with dysplasia or dislocation in 5, scoliosis in 2, pectus in 2, hypermobility or joint pain in 11), growth or feeding disorders in 16/65 (gastrostomy in some, tracheo-oesophageal fistula, oesophageal stenosis and narrow pylorus in one patient each), congenital anomalies of the kidney and urinary tract (CAKUT) in 5/65, developmental delay in 19/65, resolved in most, with intellectual disability in 6, and dental changes in 21/50 (enamel hypoplasia or caries in 15/50 and crowding in 8/50) [3]. The findings specific to FOXC1 were widely spaced eyes, enamel hypoplasia (p=7×10⁻⁵), dental crowding (p=0.006), hearing loss (p=1×10⁻⁵) and hip disease (p=0.01) [3].

Brain magnetic resonance imaging (MRI) in 16 FOXC1 variant carriers showed periventricular, subcortical and deep white matter hyperintensities in all but one, colpocephaly or ventriculomegaly in all but three, arachnoid cysts in five, Dandy-Walker variant with corpus callosum dysgenesis in one and low-lying cerebellar tonsils in two; MR angiography showed vascular anomalies in the two patients studied, and there was no relationship between MRI severity and developmental delay [3]. A systematic review of 63 ARS studies found white matter changes in 41.3% of studies, Dandy-Walker malformation in 19% and agenesis of the corpus callosum in 17%; six studies assessed neurovascular findings (stroke, small vessel disease, arterial tortuosity and dolichoectasia, without moyamoya), and the authors concluded that structural findings are frequent but generally benign, which limits the usefulness of screening MRI [65]. In carriers of FOXC1 missense variants, Aldinger and colleagues described mild hypoplasia of the cerebellar vermis and abnormal white matter signal corresponding to prominent perivascular spaces [66]. In the first families described with FOXC1, ARS was associated with atrial septal defect and sensorineural hearing loss without craniofacial or dental changes, and in families with truncating variants one member had Peters anomaly [66].

In a blinded assessment of 34 individuals from 18 families by five geneticists, a thin upper lip (55.9%) and a prominent forehead (41.2%) were common to both genes, whereas hypertelorism or telecanthus (81.8% with FOXC1 versus 25.0% with PITX2; p=0.002) and low-set ears (31.8% versus 0%; p=0.036) were specific to FOXC1 [67]. In the ANZRAG cohort of Souzeau 2017, recruited from an advanced glaucoma registry, all PITX2 carriers had dental and umbilical anomalies, but 70% of FOXC1 carriers had no systemic manifestations, versus 69% with manifestations in the Reis 2023 cohort, a difference reflecting the ocular recruitment bias of the former [3, 21].

3.5. Frequencies Compared by Gene

Source: Reis 2023, table 1; denominators vary by feature (for example, glaucoma assessed in 32 and 58 individuals, teeth in 44 and 50, umbilicus in 52 and 65) [3].

3.6. Contiguous 6p25 and 4q25 Deletions

The recurrent subtelomeric 6p25 deletion, which includes FOXC1, combines ASD with hearing loss, heart disease, central nervous system (CNS) malformations, hydrocephalus, developmental delay, hypertelorism and downslanting palpebral fissures [27]. In the Reis 2023 series, hydrocephalus occurred in 39% of 6p25 deletions including FOXC1, and the 1.3 Mb deletion including FOXC1, FOXF2 and FOXQ1 defines the critical region of De Hauwere syndrome, which the authors propose to integrate as a “FOXC1opathy” [3, 68]. Large 4q25 deletions including PITX2 give rise to more complex phenotypes, with more frequent intellectual disability and heart disease [3, 27]. Intellectual disability is rare in ARS due to intragenic variants and, when present, is usually secondary to visual or hearing deficits, and may be severe in contiguous gene deletions [27].

3.7. Peters Anomaly

Peters anomaly is bilateral in about 80% of patients according to the Oxford Desk Reference, often asymmetrically, is frequently associated with lens anomalies and microphthalmia and is usually an isolated defect in an otherwise normal child [15, 31]. The proportion of bilateral cases varies with the series: in the Toronto cohort (SickKids, 2000–2013; 80 eyes of 54 patients), 51.9% were unilateral, 71.2% of eyes had type I and 28.8% type II [69]; in Japan, about 75% of ASD cases are bilateral and, when one eye has Peters anomaly, the other has Peters in half of cases and another dysgenesis (sclerocornea, anterior staphyloma) in 20–30% [24]. Khasnavis's review stages the disease as mild (opacity with normal iris and lens), moderate (central iridocorneal adhesions, iris atrophy, sclerocornea, microphthalmia, aniridia or coloboma) and severe (corneolenticular adhesion or corneal staphyloma) [13].

Ocular associations include glaucoma, microphthalmia, coloboma and, more rarely, sclerocornea, corectopia, iris hypoplasia, aniridia and persistent fetal vasculature; the same review cites, for one series, glaucoma in 20%, microphthalmia in 18% and coloboma in 6%, and elsewhere congenital glaucoma in 50–70%, figures that come from different populations and denominators [13]. GeneReviews reports glaucoma in up to 50% of individuals with Peters anomaly, with or without surgery [6]. In Héon's 1992 Montreal series, associated ocular anomalies occurred in 50% and systemic defects in 60% [70]; in the Toronto cohort, 37.0% of patients had systemic anomalies, mainly congenital heart disease (18.5%) [69]; the Japanese guideline estimates systemic anomalies in 20–30% of patients with ASD, more frequent in bilateral cases [24].

The natural history of the opacity is variable. In Kyoto, 15 eyes of 9 infants with unoperated Peters anomaly, followed for at least 6 years (mean 7.9), showed glaucoma in 13 eyes of 7 patients and gradual reduction of the opacity in 4 eyes; in one unilateral child with intensively treated amblyopia, acuity improved with regression of the opacity [71]. The Japanese guideline states that the opacity often improves with growth in Peters anomaly, but not in sclerocornea or anterior staphyloma [24]. In bilateral Peters anomaly (25 consecutive patients, 1995–2005, mean follow-up of 5.1 years), strabismus occurred in 13/18 (72%), in all when visual asymmetry exceeded 1.5 octaves, the only predictor identified (p=0.002) [72]. Opacity and irregular astigmatism reduce contrast sensitivity and cause photophobia [24].

3.8. Peters-plus Syndrome

Eyes. Almost all patients have ocular developmental anomalies, mainly Peters anomaly, with central or eccentric opacity or with a relatively clear central cornea; an extensive defect with a thin cornea may present at birth as ectasia or descemetocele [6]. The lens may be adherent to the cornea, intracorneal or in the anterior chamber, clear or with cataract; there are iridocorneal adhesions with pupillary changes, frequent microphthalmia, persistent fetal vasculature, retinal or optic nerve coloboma and retinal atrophy, and posterior corneal excavation (von Hippel posterior ulcer) is a characteristic finding on anterior segment optical coherence tomography (AS-OCT) or ultrasound biomicroscopy (UBM) [6]. Variability is great between families, between the two eyes of a patient and within families [6]. Opacities may decrease in the first six months, but never allow normal vision; cataract and glaucoma may be present at birth, but usually appear later [31]. The glaucoma rate in PTRPLS is not specified [6].

Growth and skeleton. Growth deficiency is present in all reported patients, with rhizomelia, broad hands and feet and brachydactyly and, occasionally, vertebral anomalies, tethered cord and scoliosis [6]. It may begin prenatally, but birth length is not always below the 3rd centile (below in 82% according to Smith's textbook); adult height ranges from 128 to 151 cm in women and from 141 to 155 cm in men [6, 31]. Elbow range of motion is reduced, the other joints are hypermobile, and there is fifth-finger clinodactyly [31]. Growth hormone deficiency with a good response to replacement therapy has been described in some children [6].

Development. Developmental delay occurs in about 80% according to GeneReviews; Smith's textbook reports intellectual disability in 83% (mild in 34%, moderate in 20%, severe in 26%), autism spectrum disorder, and acquisition of speech and simple skills in all; adults with normal cognition have been described [6, 31].

Face and clefts. Prominent forehead, short palpebral fissures, hypertelorism, long philtrum, thin or accentuated Cupid's bow, broad neck, small or low-set ears and preauricular pits, with a round face in childhood and micrognathia; the facial phenotype does not change significantly with age [6, 31]. Cleft lip and/or palate occurs in about one third according to GeneReviews; Smith's textbook reports cleft lip in 45% and cleft palate in 33% [6, 31].

Other systems. Gastrointestinal anomalies occur in about 50%, structural (anteriorly placed anus or anal atresia) or functional (feeding difficulties without a cleft), with frequent prolonged tube feeding [6, 31]. Congenital heart disease occurs in up to 40% according to GeneReviews and in fewer than 30% according to Smith's textbook (atrial or ventricular septal defect, subvalvular aortic stenosis, pulmonary stenosis, bicuspid pulmonary valve); Orphanet adds hypoplastic left heart and absent right pulmonary vein [6, 7, 31]. Cryptorchidism affects about one third of boys, and CAKUT about 25% (duplex kidney, small hyperechogenic kidney, oligomeganephronia, multicystic dysplastic kidney, glomerulocystic kidneys, hydronephrosis and vesicoureteric reflux) [6]. Central nervous system anomalies are present in 60% of those assessed (hypoplasia or agenesis of the corpus callosum, hydrocephalus or ventriculomegaly, occasional encephalocele) [6]. Microcephaly, macrocephaly, cerebellar hypoplasia, myelomeningocele, iris coloboma, seizures, spastic diplegia, hypoplasia of the labia or clitoris, hypospadias, pectus excavatum and congenital hypothyroidism have occasionally been described [7, 31].

Prenatal period. The spectrum includes non-viable conceptions: 37% of couples with an affected child have recurrent miscarriages or stillbirths, with very low pregnancy-associated plasma protein A (PAPP-A) in the losses; polyhydramnios occurs in about 20%, and ultrasound findings include intrauterine growth restriction (IUGR), short long bones and brain anomalies [6, 31]. Ocular findings are rarely visible on prenatal ultrasound [73].

4. Clinical Recognition and Warning Signs

4.1. Prenatal Period

Prenatal suspicion of Peters-plus syndrome arises from extraocular findings, because Peters anomaly is rarely visible on ultrasound: early IUGR, rhizomelic shortening of the long bones, craniofacial dysmorphism, mild central nervous system anomalies, polyhydramnios, low PAPP-A and a history of recurrent pregnancy loss [6, 31, 73]. Second-trimester ultrasound allows visualisation of the globe and lens, but has low sensitivity for detecting recurrence of ASD [15]. In ARS, fetal MRI or ultrasound may show non-specific posterior fossa or renal changes, as in the case described in section 10 [74].

4.2. Newborn and Infant

There is no newborn screening targeting these entities. The signs that raise suspicion in the newborn and infant are corneal opacity, total or partial, unilateral or bilateral, with strands between the posterior corneal surface and the iris or with a posterior corneal defect; an irregular or displaced pupil; redundant periumbilical skin, umbilical hernia or omphalocele; and signs of childhood glaucoma [12, 24]. The French PNDS summarises that the combination of umbilical anomalies and iris anomalies strongly suggests ARS, that dental anomalies reinforce the suspicion and that genetics confirms it [12]. Faced with congenital corneal opacity, the Oxford Desk Reference recommends always excluding congenital glaucoma, Peters anomaly and congenital aphakia due to FOXE3, and recalls that many causes are progressive metabolic diseases [75].

Peters-plus syndrome should be considered in bilateral Peters anomaly with rhizomelic short stature, brachydactyly, typical facies and, with or without, cleft lip or palate [6]. Peters anomaly with heart disease or other systemic findings without these features points to different causes, discussed in the differential diagnosis [6].

4.3. Child, Adolescent and Adult

In the child, the warning signs of ARS are hypodontia or microdontia with conical teeth at eruption, midface hypoplasia, progressive corectopia or polycoria, and hearing loss and congenital heart disease in FOXC1 carriers [3, 12]. Cases with mild extraocular expression are sometimes classified and treated as primary congenital glaucoma, so ARS and FOXC1 should be considered in all childhood glaucoma [3, 27]. In the adolescent and young adult, juvenile open-angle glaucoma may be the only manifestation of a FOXC1 duplication, and one family referred as ectropion uveae was reclassified as ASD due to a FOXC1 duplication [22]. The family history should cover at least three generations, consanguinity and visual difficulties in relatives, because minimal expression may go unnoticed [15].

4.4. Urgent Signs

Signs of glaucoma in childhood require urgent ophthalmological assessment: photophobia, tearing and blepharospasm; corneal diameter greater than 10.5 mm at birth or 12 mm in the first year; axial length greater than 20 mm at birth or 22 mm after the first year; corneal oedema; and Haab striae [23]. The Japanese guideline uses slightly different thresholds for corneal diameter (11 mm or more in the newborn, 12 mm or more before age 1 year and 13 mm or more at any age) and considers glaucoma suspected with an intraocular pressure (IOP) greater than 21 mmHg on two or more measurements or a cup-to-disc ratio greater than 0.3 in the child [24]. A dense central corneal opacity, especially if bilateral, is a functional emergency because it produces deprivation amblyopia and requires intervention in the first year of life [13]. Corneal ectasia or descemetocele at birth, possible in Peters-plus syndrome, may require a tectonic graft [6]. In PITX2 variant carriers, unexplained anaemia or abdominal pain should prompt a search for Meckel diverticulum [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Ophthalmological Examination

The initial assessment includes age-appropriate visual acuity, slit-lamp biomicroscopy of the iris and limbus (posterior embryotoxon), IOP, systematic fundoscopy, orthoptic examination and refraction, supplemented by AS-OCT, pachymetry, specular microscopy and gonioscopy [12]. In young children, examination under general anaesthesia allows gonioscopy, AS-OCT, fundoscopy, OCT of the optic nerve head, objective refraction, measurement of corneal diameters, axial length and UBM [12]. IOP measured under general anaesthesia is artificially low, and crying raises it; the rebound tonometer allows IOP to be measured without anaesthesia or sedation with a high success rate, and IOP alone is not sufficient to diagnose glaucoma in the child [23, 24]. Corneal irregularity justifies measuring IOP with several devices (rebound, Perkins tonometer, Tono-Pen®, palpation) [24]. The WGA consensus adds that all inhaled anaesthetics lower IOP, sometimes rapidly and markedly, whereas chloral hydrate, ketamine and midazolam appear not to lower it, and recommends using the same anaesthetic in serial examinations; increased corneal diameter, which usually occurs before age 3 years, axial length outside normal limits and progressive myopia are signs of glaucoma, central corneal thickness should not be used to correct IOP in the child, and gonioscopy should be performed at least once [76].

In Peters anomaly, examination under anaesthesia with a portable slit lamp records the diameter of the opacity and its relationship to the undilated pupil, the transparency of the peripheral cornea and the irido- and lenticulo-corneal adhesions; B-mode ultrasound assesses the posterior segment when the opacity prevents fundoscopy [13, 24]. UBM correlates with histopathology and changed the clinical diagnosis in about one third of cases; the UBM classification distinguishes type I (defect of Descemet membrane and endothelium, good outcome after keratoplasty), type II (with iridocorneal adhesions, variable outcome) and type III (with keratolenticular involvement, generally poor outcome, possibly requiring cataract surgery combined with keratoplasty) [13]. AS-OCT, possible from two days of life or under anaesthesia, changed the surgical plan in 21% and can be used intraoperatively in lamellar keratoplasty [13].

The Japanese guideline, in clinical question 1, suggests UBM and AS-OCT to identify the type of ASD when there is clinical suspicion (weak recommendation in favour, evidence C), based on 7 case reports, 6 series and 1 cohort, with no adverse events reported; UBM is a contact examination, requiring topical anaesthesia with 0.4% oxybuprocaine in the cooperative child, sedation or general anaesthesia, and AS-OCT is non-contact [24].

5.2. Diagnostic Criteria

There are no international consensus clinical criteria for ARS or for Peters-plus syndrome; the diagnosis of PTRPLS requires suggestive findings and biallelic pathogenic or likely pathogenic variants in B3GLCT, or one variant with a contiguous 13q12.3 deletion in trans [6]. The Japanese guideline published criteria for ASD with corneal opacity, whose main targets are Peters anomaly, sclerocornea and anterior staphyloma; posterior embryotoxon, the Axenfeld and Rieger anomalies and posterior keratoconus are included only when associated with glaucoma [24].

Source: [24].

The same guideline defines four severity grades: grade I, unilateral with the other eye normal; grade II, bilateral with corrected visual acuity in the better eye of 0.3 or more; grade III, bilateral with the better eye between 0.1 and 0.3; grade IV, bilateral with the better eye below 0.1 (decimal scale) [24]. In grades I to III, secondary glaucoma with a residual central field of 20° or less in the better eye (Goldmann perimeter, I/4 stimulus) raises the grade by one, and in Japan support as a designated intractable disease requires grade III or higher, or a score of 3 or more on the modified Rankin scale or on the nutrition or respiratory scales [24].

5.3. Systemic Assessment

In ARS, systemic assessment includes the umbilicus at birth, dysmorphism, dentition (paediatrician, dentist or paediatric dentist, with orthopantomography), hearing (mixed and sensorineural losses appear at all ages), the heart, paediatric neurology with MRI if indicated, a search for hypospadias and anal stenosis, and pituitary and growth hormone assessment [9, 12]. Examination of apparently unaffected relatives looks for posterior embryotoxon [9, 15]. In Peters anomaly, Khasnavis's review recommends cardiac assessment, abdominal ultrasound, neuroimaging and hearing assessment, and the Toronto cohort recommends always excluding systemic anomalies [13, 69].

For Peters-plus syndrome, GeneReviews recommends the following assessments after diagnosis [6].

Faced with congenital corneal opacity of uncertain cause, the Oxford Desk Reference proposes a baseline investigation: thyroid function; urine metabolic screen (mucopolysaccharides, oligosaccharides, amino acids, organic acids); plasma amino acids; general biochemistry; search for vacuolated lymphocytes, ammonia and lactate; congenital infection serology; leucocyte enzymes, with the sample reaching the laboratory within a few hours; skeletal radiographs; very-long-chain fatty acids; abdominal ultrasound; genomic analysis; and, if necessary, skin or muscle biopsy [75]. The examination includes biomicroscopy, fundoscopy, looking for a cherry-red spot, and ocular ultrasound [75].

5.4. Genetic Strategy

The European Glaucoma Society (EGS) strongly recommends genetic testing in glaucoma associated with ARS or Peters anomaly, because of the extensive phenotypic overlap [23]. Testing is decisive because extraocular manifestations and surveillance depend on the gene [3]. The French PNDS proposes a two-step strategy: first, a next-generation sequencing (NGS) panel of known genes with copy-number analysis (exon or whole-gene deletions and duplications, heterozygous or homozygous), which identifies the causal variant in 50–60% of cases, classified according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and supplemented by chromosomal microarray, fluorescence in situ hybridisation (FISH) or high-resolution karyotype for structural variants; second, if the panel is negative, trio genome sequencing, which in France is part of the France Genomic Medicine Plan 2025, in which ocular malformations are a pre-indication [12]. Genome sequencing identified structural variants in the non-coding regions upstream of PITX2 that had escaped initial analyses [43, 77].

Most earlier articles cited a yield of 40–60% for PITX2 and FOXC1 in ARS, and reference books give 40–55% for PITX2 (about 80% when there are dental or umbilical anomalies) and 8–25% for FOXC1; those studies had incomplete screening for deletions and the regulatory region, and the Reis 2023 cohort, with complete analysis, supersedes them [3, 27]. The combined yield of PITX2 and FOXC1 in isolated ASD is 5–10% [27].

Limits of testing. A negative result does not exclude the diagnosis: variants in deep introns, in non-coding regulatory regions, in genes outside the panel or still unknown are not detected by panels or exomes [12]. Coding sequencing of PITX2 alone does not detect deletions of the upstream regulatory region, and microarray does not detect balanced inversions that separate the gene from its enhancers [3, 43]. PITX2 and FOXC1 deletions and FOXC1 duplications require copy-number analysis, because they carry the same diagnostic weight as sequence variants [9, 11]. The sensitivity of copy-number variant detection by exome or genome may be lower than that of targeted methods [6]. The report should state the gene, the versioned transcript (MANE Select: PITX2 NM_000325.6, FOXC1 NM_001453.3, B3GLCT NM_194318.4), the Human Genome Variation Society (HGVS) notation, zygosity and the ACMG/AMP class; when the literature uses NM_153427.2 for PITX2, both notations should be given [3, 10].

Variants of uncertain significance. A class 3 variant neither establishes nor excludes the diagnosis; extended family study (segregation), population and variant databases, in silico predictions and functional tests on fibroblasts or RNA allow reclassification [6, 12]. For FOXC1, rescue of the zebrafish foxc1a knockdown phenotype by wild-type human mRNA, but not by mRNA carrying the variant, has been used as functional validation in a research setting [62].

5.5. Peters-plus Syndrome: Molecular Algorithm

GeneReviews proposes two approaches. In the first, phenotype-driven, B3GLCT is sequenced and, if zero or one variant is found, targeted deletion/duplication analysis follows (quantitative polymerase chain reaction, or PCR, long-range PCR, multiplex ligation-dependent probe amplification, or MLPA, or targeted microarray) or chromosomal microarray; alternatively, a multigene panel is used [6]. In the second, comprehensive approach, chromosomal microarray is performed followed by exome or genome sequencing with copy-number analysis, in line with recommendations proposing exome or genome sequencing as a first- or second-tier test in developmental delay, intellectual disability and multiple congenital anomalies [6]. Sequencing detects 93% of known pathogenic variants and deletion/duplication analysis 7%; these figures are proportions of variants detectable by each method, not the clinical sensitivity of the test [6].

There are three pitfalls in interpretation: detection of a single variant means that the patient may not have PTRPLS or has a second undetectable variant; apparent homozygosity may result from an undetected deletion on the other allele (false homozygosity) or from uniparental isodisomy; and presence of the variant in only one parent suggests a de novo variant or parental mosaicism [6].

5.6. Practical Algorithm

5.7. Prenatal Diagnosis

In Peters-plus syndrome, the case of Fortún Agud 2026 illustrates diagnosis by prenatal exome after a normal karyotype and microarray, in a pregnancy with early IUGR and rhizomelia [73]. When the familial variant is known, prenatal or preimplantation diagnosis is possible in any of the entities, as described in section 8 [6, 12]. Second-trimester ultrasound has low sensitivity for anterior segment anomalies [15].

6. Differential Diagnosis

6.1. Differential Diagnosis of ARS and Dysgeneses with Glaucoma

AD: autosomal dominant; AR: autosomal recessive; CNS: central nervous system.

The distinction between ARS and primary congenital glaucoma has practical consequences: glaucoma in ARS is mostly juvenile, but may be early and mimic congenital glaucoma, and cases with mild extraocular expression are sometimes classified as primary congenital glaucoma [12, 27]. In the Reis 2023 cohort, 2 of the 69 FOXC1 variant carriers had been diagnosed with primary congenital glaucoma, and in the Souzeau 2017 cohort, one with primary congenital glaucoma and five with primary open-angle glaucoma [3, 21]. Severe, advanced congenital glaucoma can be difficult to distinguish from Peters anomaly, because corneal oedema and opacification prevent observation of the angle [52].

Aniridia and ARS share iris hypoplasia, corectopia and glaucoma, and PAX6 accounts for about 90% of congenital aniridia, but may also produce ARS pictures; conversely, 8–13% of PITX2 or FOXC1 variant carriers have aniridia [3, 12]. SHORT syndrome combines Rieger anomaly with short stature, lipoatrophy and normal intelligence; growth hormone should be used with caution because it worsens insulin resistance [78]. In Alagille syndrome, isolated posterior embryotoxon is the most frequent anterior segment anomaly, which justifies including JAG1 in the panel [12, 79].

6.2. Differential Diagnosis of Congenital Corneal Opacity

The classic mnemonic STUMPED (sclerocornea, trauma, ulcer, mucopolysaccharidoses, Peters, congenital hereditary endothelial dystrophy, dermoid) is little used today; Nischal's classification distinguishes primary opacities (congenital hereditary endothelial dystrophy, posterior polymorphous dystrophy, congenital hereditary stromal dystrophy, X-linked endothelial dystrophy, limbal or central dermoid, isolated peripheral sclerocornea) from secondary congenital ones (kerato-irido-lenticular dysgenesis, such as Peters anomaly) and acquired ones (infection, trauma, mucopolysaccharidoses, cystinosis) [13].

6.3. Differential Diagnosis of Peters-plus Syndrome

GeneReviews compares PTRPLS with the following entities, which share corneal opacity or ASD and systemic manifestations [6].

Peters anomaly with heart disease or other systemic signs without B3GLCT variants is not PTRPLS and should be studied by exome or genome sequencing [6, 41]. In the Chesneau series, B3GLCT was the most frequent gene in syndromic Peters anomaly, but two thirds of patients remained without a diagnosis [14].

7. Treatments and Risk Management Strategies

7.1. Principles and Guidelines

There is no disease-modifying treatment or medicine authorised specifically for ARS, Peters anomaly or Peters-plus syndrome [6, 12]. Treatment is directed at the complications: glaucoma, corneal opacity, amblyopia, cataract and extraocular manifestations. The EGS classifies glaucoma associated with ARS and Peters anomaly as childhood secondary glaucoma associated with non-acquired ocular anomalies (“syndrome” when there are systemic associations) and recommends treating it according to the principles of primary congenital glaucoma, adapted to the primary anomaly, the mechanism of IOP elevation and quality of life, in tertiary centres with highly specialised care [23].

No American guideline or ERN-EYE European Reference Network guideline specific to ARS or Peters anomaly was identified in the sources consulted.

7.2. Medical Treatment of Glaucoma

The French PNDS recommends starting, in general, with conventional topical IOP-lowering drugs, favouring preservative-free eye drops; it considers that drugs that reduce aqueous humour production (beta-blockers, prostaglandin analogues and carbonic anhydrase inhibitors, in the PNDS's wording) are more effective than those acting on outflow, that oral carbonic anhydrase inhibitors may be useful and that alpha-2 agonists are contraindicated before age 12 years because of their central depressant effects [12]. The EGS considers that, in primary congenital glaucoma, initial surgery is almost always necessary and medical treatment is rarely effective in the long term, serving, including oral carbonic anhydrase inhibitors, as a bridge to surgery or after its failure; beta-blockers and carbonic anhydrase inhibitors are first-line choices in the infant when medical treatment is considered [23]. The World Glaucoma Association (WGA) consensus on childhood glaucoma considers that medicines alone rarely have sustained efficacy as primary treatment in the infant and young child, serving as a bridge to surgery, to reduce corneal oedema before it or as an adjunct after partially effective surgery; in non-acquired ocular anomalies, medical treatment is usually first-line, but surgery is often needed early in infantile presentations and should not be delayed, and ocular hypertension should be treated before glaucoma appears [76]. The same consensus recommends using the minimum frequency and concentration that achieve the target IOP, reducing systemic absorption with eyelid closure, removal of excess drops and nasolacrimal occlusion, avoiding brimonidine in young children and informing parents that adverse effects may be atypical, such as nocturnal cough with beta-blockers instead of wheeze [76]. In the trials supporting the European SmPCs, latanoprost once daily and timolol 0.5% (or 0.25% before age 3 years) twice daily lowered IOP similarly at 12 weeks in 107 patients up to 18 years with paediatric glaucoma (−7.18 versus −5.72 mmHg; p=0.2056), although with only 13 children treated with latanoprost before age 3 years and without relevant efficacy in the 4 infants under 1 year [83]; in the dorzolamide trial, about half of the children had congenital glaucoma and others had iridocorneal mesenchymal dysgenesis, and 20% of those treated with dorzolamide monotherapy had adverse effects, mainly local [84]; in the trial of brimonidine 0.2% as an adjunct in children aged 2–7 years, somnolence reached 55% (severe in 8%, with discontinuation in 13%), 63% in children weighing ≤20 kg and 25% in those over 20 kg [85]. In the Reis 2023 cohort, only 30% of PITX2 carriers and 21% of FOXC1 carriers with glaucoma were treated with eye drops alone, and in the Strungaru 2007 series medical or surgical treatment was successful in 18% (7/39), and 57% of treated patients needed both medicines and surgery [3, 48]. No IOP-lowering drug has a specific indication for these diseases; their use is that of secondary paediatric glaucoma, and the doses in the following table are those of the FDA labels, established for adults with open-angle glaucoma or ocular hypertension.

The FDA labels and European SmPCs consulted (UK versions published on the eMC and Portuguese versions from INFARMED's Infomed database) do not give weight-based paediatric doses for topical IOP-lowering drugs. For oral acetazolamide, marketed in Portugal as Carbinib® (250 mg tablets), the Portuguese SmPC indicates for glaucoma, as an adjunct in chronic simple glaucoma and secondary glaucoma, 250–1000 mg per day in the adult and 125–750 mg per day (half to three tablets) in the child, without a per-kilogram dose for this indication, and contraindicates it in hyponatraemia or hypokalaemia, marked hepatic or renal disease, adrenal insufficiency, hyperchloraemic acidosis, cirrhosis and hypersensitivity to sulphonamides [91]; none of the sources gives a specific dose for ARS or Peters anomaly. The GeneReviews chapter on primary congenital glaucoma, withdrawn in 2017 and used only as a historical reference, advised against alpha-2 agonists in children because of the risk of apnoea and bradycardia [52].

7.3. Comparative Regulatory Status

The Portuguese SmPCs (Infomed, consulted on 10 October 2026) match the UK versions on minimum age and paediatric dosage for Xalatan® (paediatric indication with the adult dosage; limited data before 1 year), Alphagan® 2 mg/ml (contraindicated before 2 years, not recommended before 12 years, caution between 2 and 7 years and with weight ≤20 kg) and Timoptol® (transient paediatric use in primary congenital and primary juvenile glaucoma, lowest concentration once daily up to a maximum of 2 drops per day per eye, monitoring for 1–2 hours after the first instillation and until surgery, 1 mg/ml concentration possibly sufficient; version approved on 25 March 2022) [93–95]. The Portuguese SmPC for Trusopt® (revised on 29 January 2026) differs from the UK one in two respects: it describes the paediatric trial in patients “between 1 and <6 years”, whereas the UK version states 1 week to under 6 years, and it adds severe renal impairment (creatinine clearance <30 ml/min) and hyperchloraemic acidosis as contraindications; both report limited paediatric data with three-times-daily administration and the inclusion of children with iridocorneal mesenchymal malformation in the trial [84, 96]. In practice, the Portuguese reference for the infant is the SmPC, and the minimum age in the dorzolamide trial should be read in the UK version, which is more precise.

No regulatory procedure, orphan medicinal product designation or specific authorisation for these diseases was found in the sources consulted (ClinicalTrials.gov and Europe PMC, October 2026); this negative search does not demonstrate the absence of procedures in other databases [97]. National access in Portugal and Brazil was not searched.

7.4. Glaucoma Surgery in ARS

The PNDS recommends surgery when medical treatment does not control IOP: goniotomy, trabeculotomy or implantation of a glaucoma drainage device (GDD), which has become the mainstay of angle bypass surgery in the child and may be combined with partial diode laser cyclophotocoagulation; trabeculectomy is also possible [12]. The EGS recommends goniotomy, trabeculotomy or filtering surgery as primary surgery in congenital glaucoma, with long drainage tubes if these fail, and notes that reoperation is frequent; goniotomy is possible only with a clear cornea, which excludes it in many eyes with Peters anomaly or opacity [23]. Michels and Bohnsack stress that angle bypass surgery (GDD or trabeculectomy) is often necessary [58]. The WGA consensus adds that childhood glaucoma surgery should be performed by trained surgeons in centres with sufficient volume and safe anaesthesia, that the first operation is often the best opportunity, that angle surgery in secondary glaucomas usually has results inferior to those in primary congenital glaucoma, that in non-acquired ocular anomalies trabeculectomy with antifibrotics or primary tube implantation are often necessary, that GDDs may offer the most effective long-term control in refractory cases and that diode laser cyclophotocoagulation has limited long-term success, often requiring repetition and continued medication [76].

These studies are retrospective, with techniques chosen by the surgeon, different definitions of success and small numbers of eyes per technique, which precludes direct comparisons between procedures. The results of Seresirikachorn 2026 suggest that GDD may be preferable as primary surgery, whereas the Indian single-surgeon series of Mandal 2016 obtained durable results with combined trabeculotomy-trabeculectomy in early-onset glaucoma [63, 98].

7.5. Treatment of Corneal Opacity in Peters Anomaly

Peters anomaly with dense central opacity produces deprivation amblyopia, so the treatment decision should be made in the first year of life [13]. While awaiting surgery, mydriasis with phenylephrine can widen the visual axis through the clear peripheral cornea, and occlusion of the better eye is adjusted to the density and laterality of the opacity [13]. In the Toronto cohort, the strategy was adapted to the phenotype: observation in 11.3% of eyes, pupillary dilation in 30%, penetrating keratoplasty (PK) in 53.8% for large, dense central opacity, and abstention in 5.0% because of poor prognosis [69].

Penetrating keratoplasty. GeneReviews suggests considering PK at 3–6 months of age in severe opacification and, in mild opacification, simple separation of iridocorneal adhesions with or without scraping or aspiration of the posterior cornea [6]. Peters anomaly is the most frequent indication for paediatric keratoplasty, and the best results are obtained in mild to moderate disease, with surgery between 2 and 12 months, adherence to intensive postoperative care and early suture removal [13]. The ideal timing is not defined: early surgery prevents amblyopia, but anaesthetic safety favours postponement, and results for age under 6 months are conflicting [99].

The factors for graft failure in Yang 1999 were disease severity, larger donor graft size, central nervous system anomalies, the number of quadrants with anterior synechiae, stromal vessels, total limbal opacification and preoperative glaucoma; rejection was the most frequent cause of failure, and major complications included phthisis, retinal detachment, cataract and glaucoma [100]. In Dana 1997, failure was associated with postoperative ulcer or epithelial defect (p=0.03) and with additional non-corneal surgery (p=0.05), and use of postoperative optical aids was associated with better acuity (p=0.01) [101]. The Wowra 2024 review reports graft survival between 35% and 90%, clarity of 87.5% in type I versus 14.2% in type II in a series of 15 eyes, and failure of 30%, 39%, 70% and 77% at 1, 3, 5 and 10 years in a series of 22 patients; about half of children operated on for congenital opacity achieve functional vision (counting fingers, orientation, independence in feeding, recognising people) [99]. Rejection causes 65% of failures, is reversible in only 27–28% of children versus 50–78% of adults and occurs in more than 90% of cases in the first year, which requires parents trained in daily surveillance; graft infection occurs in 10–50%, and glaucoma is an independent predictor of failure [99]. Khasnavis's review brings together series with graft clarity between 39% and 90% (Zaidman, 30 eyes, 90% in type I; Rao, 40 eyes, 43% at 2 years; Yang, 72 eyes, 39%; Basdekidou, 14 unilateral eyes, 78.6%; Chang, 22 eyes, 48%; Lin, 37 eyes, 73%; Donoso Rojas, 27 eyes, 45.5%; Elbaz, 36 eyes, 67.6%) [13].

Divergence between sources. The Japanese guideline suggests not performing PK for corneal opacity in ASD (weak recommendation against, evidence C), because no study compares PK with natural history, the clarity benefit is short-term and the long-term prognosis is unknown, with risks of intraoperative vitrectomy and lensectomy and of secondary glaucoma; the supporting systematic review included 16 case series, one review and one report, with probable publication bias, and in Japan PK is rarely performed [24]. American series (Dana 1997; Zaidman 2007) conclude that PK in Peters anomaly type I can provide functional vision, and Yang 1999 advises careful consideration, especially after a previous failure [100–102]. The synthesis in the Japanese guideline adds that clarity is relatively maintained in type I and poor in type II, that postoperative acuity is better in bilateral than in unilateral opacity, that the mean duration of clarity is about 11 years in Peters anomaly versus about 3 years in sclerocornea, and that rejection reaches about 40% with simultaneous cataract surgery versus about 30% without it [24]. In practice, the decision is individual, made in a centre experienced in paediatric keratoplasty and based on the type (I or II), laterality, the presence of glaucoma and the family's ability to comply with intensive follow-up.

Alternatives to PK. Sectoral optical iridectomy is an alternative when the peripheral cornea is clear, especially if keratoplasty is unavailable or contraindicated [6]. In a series of 29 eyes of 22 patients (2002–2014; mean age 15.6 months; 81.8% bilateral), there was a red reflex in 96.6% and logMAR acuity went from 2.5 to 1.8 (p<0.001), with improvement in 72.4% of eyes, significant only in bilateral cases; over a mean follow-up of 41.6 months, 17.2% developed glaucoma and 6.9% needed PK [103]. Selective endothelial removal (SEPA) removes the abnormal endothelium in the area of the defect while preserving Descemet membrane, which allows re-endothelialisation from the periphery: in 34 eyes of 28 children in India (2012–2019), with central opacity smaller than 7 mm, the cornea cleared in 85.3%, logMAR acuity went from 2.55 to 1.78 (p<0.0001), and severity (type II) was the only risk factor for failure in multivariate analysis, with no serious complications over a mean follow-up of 0.96 years [104]. Descemet stripping automated endothelial keratoplasty (DSAEK) avoids sutures and allows recovery in 6–12 weeks, versus 6–12 months with PK, but does not resolve stromal opacity and is limited by the small anterior chamber; corneal autorotation is another option, and paediatric keratoprosthesis is reserved for repeated failures, with lifelong care, a therapeutic contact lens and a risk of retroprosthetic membrane and glaucoma [13, 99]. Anterior staphyloma may require enucleation or evisceration because of proptosis or perforation [24].

Peters-plus syndrome. The same principles apply: surgery at 3–6 months to clear the visual axis in severe opacity, separation of adhesions in mild opacity and sectoral iridectomy with a clear peripheral cornea [6]. Isolated cataract surgery is only possible if the cornea allows a surgical view; more often, the lens is removed during PK, intentionally or spontaneously, and the aphakia requires correction with contact lenses or spectacles [6]. The PK results of Zaidman 2007 are not directly applicable, and Reichl 2018 reported much worse results; there are no PTRPLS-specific surgical data, and in neonatal ectasia the tectonic graft is performed without visual expectation [6]. In a series of 19 patients with Peters anomaly described by Yang and colleagues in 2004, severe glaucoma was frequent and was controlled in only 32% of affected eyes, despite combined medical and surgical treatment, and visual outcomes were poor because of uncontrolled glaucoma, amblyopia, neurological changes and postoperative complications; the same figure is cited by Fortún Agud 2026 [51, 73]. In Peters anomaly, the WGA consensus notes that IOP measurement over the central cornea may be inaccurate and recommends measuring it over a clear area of the cornea when possible [76].

7.6. Cataract, Amblyopia, Strabismus, Refraction and Low Vision

Amblyopia should be treated by a paediatric ophthalmologist to optimise the visual outcome; in bilateral Peters anomaly, amblyopia treatment improved vision in 3 of 5 treated children [6, 72]. In ARS, optical or contact lens correction prevents amblyopia and strabismus; filter spectacles and, more rarely, contact lenses that recreate a single, centred pupil relieve photophobia in patients with corectopia or polycoria [12]. Opacity and irregular astigmatism reduce contrast sensitivity, so refractive correction, attention to lighting and low-vision rehabilitation are part of treatment [24]. In an Indian series of phacoemulsification with intraocular lens in 12 eyes of 11 adults with ARS (mean age 45.3 years), logMAR acuity went from 0.9 to 0.4 (p=0.0043) without intraoperative complications, but 11 had secondary glaucoma, 6 eyes needed glaucoma surgery and 2 needed DSAEK for corneal decompensation after cataract surgery [105].

7.7. Systemic Management of ARS

The PNDS recommends maxillofacial surgery and orthodontic consultation according to age, with long-term prosthetic and implant rehabilitation for dental agenesis, neurodevelopmental assessment, screening echocardiogram, brain imaging and hearing assessment, including brainstem auditory evoked potentials [12]. Obstructive sleep apnoea, more frequent in class III dysmorphism due to hypomaxilla, should be sought [12]. Reis 2023 proposes gene-specific plans: with PITX2, treatment of umbilical anomalies, early dental assessment, a low threshold for seeking Meckel diverticulum in the presence of unexplained anaemia or abdominal pain, growth surveillance with pituitary assessment and screening for hypospadias and anal, cardiac and renal anomalies; with FOXC1, repeated audiometry throughout life, echocardiogram, dentist (enamel, crowding), surveillance of feeding, hypotonia and development, assessment of the hip and joints and screening for pectus, oesophageal and renal anomalies [3]. Brain MRI may be useful for both genes, but findings are often benign [3, 65]. The sources consulted do not give the somatropin dose in patients with ARS and growth hormone deficiency; standard treatment of confirmed deficiency applies.

7.8. Systemic Management of Peters-plus Syndrome

GeneReviews recommends multidisciplinary supportive care [6]. Developmental delay justifies early intervention (occupational therapy, physiotherapy, speech and feeding therapy), individualised educational programmes with vision and hearing consultants and, in autism spectrum disorder, behavioural interventions such as applied behaviour analysis [6]. Oromotor dysfunction should be assessed at each visit, with swallowing studies if there is choking, poor weight gain or frequent respiratory infections; measures include thickening or chilling food and, in severe cases, nasogastric tube or gastrostomy; augmentative and alternative communication is indicated when expressive or receptive language is impaired [6]. Physiotherapy aims to maximise mobility and reduce contractures, scoliosis and hip dislocation, with assistive devices as needed [6]. The cleft team, cardiology, nephrology and urology intervene according to findings; growth hormone is indicated only when deficiency is confirmed, and GeneReviews does not give a dose [6, 31]. Low-vision services are provided by early intervention and school in the child and by low-vision clinics and mobility services in the adult [6].

7.9. Interventional Studies and Limits of the Evidence

There are no randomised clinical trials of therapeutic interventions in ARS, Peters anomaly or Peters-plus syndrome in the sources consulted, and the ClinicalTrials.gov search in October 2026 identified only observational or genetic studies [97]. The available efficacy data come from retrospective series and from the paediatric trials supporting the labels of IOP-lowering drugs.

These series are not comparable with one another: the populations differ in age, type of anomaly, laterality, presence of glaucoma and period, the techniques were chosen by the surgeon, and the outcomes (graft clarity, surgical survival, acuity) have different definitions. Success percentages should be read together with the number of eyes and the reoperation rate; the absence of control groups prevents estimation of the absolute benefit over natural history, which may include spontaneous regression of the opacity in Peters anomaly [71]. Negative results, such as the absence of procedures with complete success above 25% at 3 years in Seresirikachorn 2026, are part of the evidence [63].

7.10. Agents to Avoid, Anaesthesia, Pregnancy and Transition

Medicines that increase the risk of glaucoma, such as corticosteroids, should be avoided, and pilocarpine and ecothiopate iodide are relatively contraindicated because they make the anterior chamber shallower and may precipitate glaucoma [6]. Ecothiopate should be stopped before general anaesthesia because of the risk of prolonged apnoea [52]. Alpha-2 agonists are contraindicated before age 2 years according to the FDA and before age 12 years according to the PNDS [12, 89]. Under general anaesthesia for examination, measured IOP is artificially low, and obstructive sleep apnoea associated with hypomaxilla should be considered [12, 24]. The sources consulted do not describe disease-specific recommendations for pregnancy or lactation in women with ARS. The European SmPCs of IOP-lowering drugs state that latanoprost should not be used during pregnancy or breastfeeding, that dorzolamide should not be used during pregnancy (teratogenic in rabbits at maternally toxic doses) and that the decision during breastfeeding weighs the benefit to the woman and to the child, that brimonidine should be used during pregnancy only if the benefit justifies the risk and should not be used during breastfeeding, and that timolol should be used during pregnancy only if clearly necessary, with monitoring of the newborn in the first days if continued until delivery, being detectable in breast milk [83–85, 92]. The Portuguese SmPCs repeat these statements and add that oral acetazolamide (Carbinib®) should not be used during pregnancy, especially in the first trimester, because it is teratogenic and embryotoxic in animals [91, 93–96]. Transition to adult services should be planned at the end of adolescence in ARS and from about age 10 years in PTRPLS, to avoid interruption of follow-up, which is lifelong because IOP control is never definitively achieved [6, 12].

7.11. Developments in the Last 12 Months

Between October 2025 and October 2026, no interventional trial, regulatory application or authorisation specific to these diseases was identified in ClinicalTrials.gov or Europe PMC; this negative search does not prove their absence. The developments by level of evidence were as follows.

8. Reproductive Options and Family Counselling

8.1. PITX2- and FOXC1-Related ARS

ARS has autosomal dominant inheritance: each child of an affected individual has a 50% risk of inheriting the variant, with highly variable expressivity within and between families [12, 27]. The genetics clinic appointment should take place as early as possible after diagnosis, and the parents should be examined, because one of them may be affected with minimal signs, such as subtle posterior embryotoxon [9, 12]. In Japanese series, PITX2 variants were mostly de novo and FOXC1 variants mostly inherited, and in Australian sporadic cases two thirds of heterozygous variants were de novo [17, 49]. When the variant is not present in either parent, the risk to siblings is low, but not zero, because of the possibility of germline mosaicism, which the sources consulted do not quantify. Rare autosomal recessive forms, such as those associated with CPAMD8, carry a 25% risk to siblings [12].

Cascade testing of at-risk relatives, with ophthalmological examination and molecular testing for the familial variant, identifies carriers who need glaucoma surveillance, including carriers with an apparently normal anterior segment [3, 9]. The WGA consensus recommends examining relatives, including gonioscopy, to determine whether the patient belongs to an affected family or is a new case, and the Souzeau 2017 cohort showed that relatives diagnosed with primary congenital or open-angle glaucoma had mild signs of ARS and systemic manifestations that were recognised only after molecular testing [21, 76]. In the case of glaucoma, predictive testing serves to direct surveillance [60]. In children, testing is justified because ophthalmological surveillance begins in childhood and FOXC1-associated glaucoma often appears before age 2 years [3].

8.2. Isolated Peters Anomaly

Isolated Peters anomaly is mostly sporadic, but there are autosomal dominant and recessive forms, the latter in consanguineous families; the recurrence risk depends on the gene identified [5, 13]. Without a molecular diagnosis, counselling is based on examination of the parents, who may show minor signs of ASD, such as posterior embryotoxon or Axenfeld anomaly [15]. CYP1B1-associated Peters anomaly follows the recessive inheritance of primary congenital glaucoma, whose recurrence risk without consanguinity is estimated at about 5% [60].

8.3. Peters-plus Syndrome

PTRPLS is autosomal recessive. The parents of an affected individual are, in principle, heterozygous and should both be tested; if only one is a carrier, the hypotheses of a de novo variant in the proband or parental mosaicism arise, and apparent homozygosity requires exclusion of a deletion on the other allele or of uniparental isodisomy [6]. At conception, each sibling has a 25% chance of being affected, 50% of being an asymptomatic carrier and 25% of not being a carrier; at birth, the proportion of affected individuals is lower than 25% because of losses in the second and third trimesters [6]. There is intrafamilial variability, so the severity in one affected sibling does not predict that in another [6]. The children of an affected individual are obligate carriers, the parents' siblings have a 50% risk of being carriers, and carrier testing requires knowledge of the familial variants [6]. Thirty-seven per cent of couples with an affected child have recurrent miscarriages or stillbirths, and very low PAPP-A was observed in the losses; exome sequencing after recurrent low PAPP-A and multiple fetal anomalies in two consecutive pregnancies allowed diagnosis in one couple [31]. Preconception counselling is the ideal time to discuss these options [6]. When PTRPLS results from a 13q12.3 deletion encompassing BRCA2, as in the family of the founding study, heterozygous carriers of that deletion also have a BRCA2-associated cancer risk, which justifies targeted oncological counselling [30].

8.4. Prenatal and Preimplantation Diagnosis

Prenatal or preimplantation diagnosis is performed only when the variant or variants of the index case have been validated and segregation has been confirmed in the parents [12]. The French PNDS describes chorionic villus sampling at 11–14 weeks of gestation and amniocentesis from 16 weeks, with a fetal loss risk of about 1% and 0.5%, respectively; preimplantation genetic diagnosis requires in vitro fertilisation, and non-invasive prenatal diagnosis using circulating fetal DNA applies only to paternally derived variants [12]. In France these procedures are carried out in multidisciplinary prenatal diagnosis centres [12]. In ARS, variable expressivity makes it difficult to predict severity in a carrier fetus, which should be discussed before testing [3, 12]. Second-trimester ultrasound has low sensitivity for detecting recurrence of ASD [15].

In the case of Fortún Agud 2026, after the diagnosis of PTRPLS in twins, preimplantation genetic diagnosis was recommended, and in the next, spontaneous pregnancy, chorionic villus sampling again confirmed homozygosity [73].

8.5. Practical Points in Counselling

Counselling should address variability of expression, the high but incomplete penetrance of the cardinal features, the lifelong risk of glaucoma, which requires lifelong surveillance, and the differences between genes in extraocular manifestations [3, 12]. The molecular diagnosis guides extraocular surveillance (teeth, umbilicus and Meckel diverticulum with PITX2; hearing, heart and hip with FOXC1) and avoids unnecessary investigations [3]. In PTRPLS, counselling includes the developmental prognosis, which ranges from severe intellectual disability to normal cognition, and the risk of pregnancy loss [6, 31].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and What Each Figure Measures

Orphanet classifies Peters anomaly as below 1/1 000 000, with about 60 cases or families, but this number reflects cases published as a genetic entity and not the frequency of the morphological anomaly, which the New York data place at 1.5/100 000 infants [5, 20]. In New York State, between 1988 and 1997, 12 children (1.1/100 000) received 23 transplants in 19 eyes for Peters anomaly, and a 1995 survey by the Pediatric Keratoplasty Association attributed 65% of grafts in infants to Peters anomaly; the authors estimate about one infant transplant per 24 000 live births and 44 to 60 children per year with Peters anomaly in the USA [20]. ARS shows no sex predominance, and the associated glaucoma is bilateral and affects both sexes equally [3, 48].

9.2. Distribution by Gene and Ancestry

Zhou 2023's review brought together 593 published families: 316 with heterozygous FOXC1 variants and 251 with heterozygous PITX2 variants, and the proportion of patients of European ancestry was higher with FOXC1 (p=0.02) [42]. In the FOXC1 duplication cohort, 70% of individuals were European, 25% Asian and 5% Latin American [22]. In the Thai and American cohort of Seresirikachorn, Asian ancestry was associated with a higher risk of blindness (adjusted OR 6.06) [106]. Most PITX2 and FOXC1 variants are private, and there are no known founder alleles in ARS [3]. Among the affected relatives compiled by Zhou 2023, the proportion of Asian patients was lower with FOXC1 than with PITX2 (74/406 versus 81/328; p=0.02) [42].

In Peters-plus syndrome, the c.660+1G>A variant is present in almost all populations; in gnomAD v4, the allele frequency in exomes is about 0.106% overall, with 1364 alleles in 1 089 560 in non-Finnish Europeans, 32 in 44 636 in Latin Americans, 38 in 52 972 in Finns, 19 in 25 940 in Ashkenazi Jews, 12 in 85 606 in South Asians, 7 in 32 974 in Africans and 1 in 5 704 in Middle Eastern individuals [6, 56]. The exon 15 deletion is a founder variant in a village in Turkey, where 11 homozygotes from six families were identified, and a different splicing variant has been described in Tunisia [6].

9.3. Portugal and Brazil

The sources consulted do not include prevalence data for ARS, Peters anomaly or PTRPLS in Portugal or Brazil. For the differential diagnosis with congenital glaucoma, data from the European network for the surveillance of congenital anomalies (EUROCAT, 2000–2016) record a birth prevalence of congenital glaucoma of all causes of 2.2/100 000 in Europe, ranging between countries from 0.8/100 000 in Norway and 0.9/100 000 in Portugal to 6.6/100 000 in France and 6.5/100 000 in Spain [46]. The CYP1B1 variant c.182G>A p.(Gly61Glu) recurs as a founder allele in Iran, Portugal, Saudi Arabia, Brazil and Vietnam, and CYP1B1 accounted for 50% of primary congenital glaucoma in a Brazilian series [46, 52].

9.4. Special Populations

In young children, reliable IOP measurement requires a calm child or anaesthesia, and the compensatory increase in axial length up to age 2 years may mask a “normal” IOP [24]. Adults with PTRPLS are probably underdiagnosed, because many adults with disabilities have not undergone advanced genetic testing [6]. In Japan, ASD is a designated intractable disease, with medical support from severity grade III or a score of 3 or more on the modified Rankin scale [24].

9.5. Reference Networks and Patient Associations

The relevant European network is ERN-EYE (European Reference Network for rare eye diseases, https://www.ern-eye.eu/), which includes a distance-learning programme on paediatric rare eye diseases [25]. In France, the OPHTARA reference centre (Necker Hospital), the SENSGENE network and the patient association Gêniris (https://www.geniris.fr/) support patients with ARS, and the PNDS also refers to EURORDIS and Aniridia Europe [12, 108]. GeneReviews lists, in the USA, the American Cleft Palate-Craniofacial Association, the MAGIC Foundation (growth deficiency), the National Eye Institute's low-vision resources and the Pediatric Glaucoma and Cataract Family Association [6]. The Oxford Desk Reference mentions Contact (formerly Contact a Family, United Kingdom), NORD (USA) and the International Glaucoma Association, now Glaucoma UK [15, 60]. The French national cohort NCT05954403 is recruiting patients with congenital ocular malformations, including Peters anomaly and ARS, to study natural history over 10 years [97].

10. Illustrative Clinical Case

10.1. Infant with ARS due to a 6p25.3 Deletion Including FOXC1

Mourad and colleagues described in 2025 a boy born at term [74]. Prenatally, fetal MRI showed prominent fluid in the posterior fossa communicating with the fourth ventricle and mild hypoplasia of the cerebellar vermis, suggestive of a Blake pouch cyst, and ultrasound showed hyperechogenic bowel and bilateral pyelectasis [74]. At birth, the newborn had a broad glabella, hypertelorism, bitemporal narrowing and a flat nasal root, with mild labial and lingual frenula and feeding difficulties; postnatal MRI excluded Dandy-Walker malformation and showed a choroid plexus cyst, and newborn hearing screening was normal [74]. Chromosomal microarray identified a pathogenic 1.4 Mb interstitial deletion at 6p25.3 including FOXC1, GMDS and at least six other coding genes, probably de novo, because the three-generation pedigree showed no affected relatives [74].

In the first months, ophthalmological examination showed coloboma on the left, cloudy irides, posterior embryotoxon, corectopia and intermittent exotropia, with normal IOP, healthy lenses and optic nerves at follow-up and better control of the exotropia over time [74]. Figure 3 of the article, consulted directly (https://pmc.ncbi.nlm.nih.gov/articles/PMC12758440/figure/FIG3/), shows the infant's left eye with a dull-looking blue-grey iris, a small, irregular pupil displaced upwards and slightly temporally, with an inferior notch compatible with the coloboma; the posterior embryotoxon described in the text cannot be distinguished in the photograph [74]. Systemic assessment revealed mild bilateral renal pelvic fullness, a small atrial septal communication (patent foramen ovale or ostium secundum-type defect) without haemodynamic repercussion, growth below average with normal insulin-like growth factor 1 (IGF-1), without treatment, and appropriate development [74]. Initial audiological assessment suggested absent bilateral peripheral function, but brainstem auditory evoked potentials under sedation showed mild high-frequency sensorineural hearing loss (4000 Hz), with normal speech responses [74].

The case brings together several elements of the FOXC1 profile described in the Reis 2023 cohort: an ocular phenotype including coloboma, hypertelorism, septal heart disease, sensorineural hearing loss and posterior fossa changes [3]. The authors acknowledge the limitations: it is a single patient, the deletion encompasses several genes, so the phenotype cannot be attributed to FOXC1 alone, and follow-up is short [74]. Normal IOP in the first months does not exclude future glaucoma, which appears before age 2 years in about two thirds of FOXC1 carriers with glaucoma, and FOXC1-associated hearing loss may progress, which justifies the regular ophthalmological and audiological surveillance described in section 11 [3, 24].

10.2. Prenatal Diagnosis of Peters-plus Syndrome

Fortún Agud and colleagues described in 2026, in Málaga, a 33-year-old primigravida with a spontaneous monochorionic diamniotic twin pregnancy and a normal first trimester [73]. At 19+4 weeks, biometry was delayed in both fetuses (fetus 1 at 18+1 weeks and 235 g; fetus 2 at 17+4 weeks and 209 g with a single umbilical artery), and fetus 2 had bilateral ventriculomegaly (posterior horns of 11–13 mm) and a third ventricle of 7.3 mm [73]. Amniocentesis at 20+2 weeks showed normal quantitative fluorescent PCR (QF-PCR), karyotype and microarray (both male, XY) and negative serology for cytomegalovirus and the TORCH group (toxoplasmosis, other infections, rubella, cytomegalovirus and herpes); clinical exome sequencing identified the B3GLCT variant NM_194318.4:c.660+1G>A in homozygosity in both fetuses, and the parents were heterozygous [10, 73]. At 27+2 weeks, both fetuses had stage I growth restriction and marked rhizomelia; fetus 1 weighed 833 g (3rd centile) and had mild midface hypoplasia, without visible ocular anomalies, and fetus 2 weighed 686 g (0.23rd centile), with mild to moderate ventriculomegaly, an interhemispheric cyst and a thin corpus callosum; fetal MRI showed delayed sulcation [73].

Figure 4 of the article, consulted directly (https://pmc.ncbi.nlm.nih.gov/articles/PMC12843356/figure/life-16-00092-f004/), is an ultrasound of the lower limb of the fetus located in the left hemiabdomen at 27+2 weeks: the femur measures 3.99–4.11 cm, a length corresponding to about 23 weeks and below the 1st centile, documenting the rhizomelia; the figure shows no ocular findings [73]. The couple opted for legal termination of pregnancy for severe and incurable fetal disease, and preimplantation genetic diagnosis was recommended; in a new spontaneous pregnancy, at 12+3 weeks, there was an occipital meningocele, unilateral cleft lip, increased nuchal translucency, tricuspid regurgitation and a single umbilical artery, and chorionic villus sampling confirmed homozygosity, followed by a further termination [73].

The case shows that prenatal suspicion of PTRPLS rests on early IUGR, rhizomelia, craniofacial dysmorphism and mild central nervous system anomalies, because Peters anomaly is rarely visible on ultrasound, and that exome sequencing can establish the diagnosis after a normal karyotype and microarray [73]. Termination of pregnancy is a decision for the couple within the legal framework of each country and not a routine course of action; the recommendation of preimplantation diagnosis is consistent with the 25% recurrence risk described in GeneReviews [6].

11. Prognosis and Long-Term Follow-Up

11.1. Visual Prognosis in ARS

Glaucoma is often progressive and difficult to control, and may lead to partial visual loss or blindness in the child; amblyopia and sensory strabismus are relatively common [12]. In the Seresirikachorn 2026b cohort (96 patients, 189 eyes; mean follow-up of 8.72 years), glaucoma affected 55.5% of eyes, and the proportion of glaucomatous eyes that were blind according to the World Health Organization definition was 17.4% at presentation, 19.2% at 3 years, 27.5% at 5 years and 36.3% at 10 years, with bilateral blindness in 23.5% of patients with glaucoma [106]. The risk factors for blindness were poor initial acuity (adjusted OR 9.72), higher IOP (1.153 per mmHg), the number of operations (1.92), cloudy cornea (4.42), female sex (6.36) and Asian ancestry (6.06) [106]. In Bohnsack 2026, patients with glaucoma had higher initial IOP and worse final acuity (p<0.01) [62]. Untreated glaucoma causes irreversible constriction of the visual fields [60]. These figures come from tertiary centres, which concentrate the most severe cases, and do not represent the risk for all carriers.

11.2. Prognosis in Peters Anomaly and Peters-plus Syndrome

In the Japanese series cited by the guideline, visual acuity was below 0.1 (decimal) in 60% and below 0.01 in at least 40% of patients with Peters anomaly, and almost all patients with sclerocornea or anterior staphyloma had acuity below 0.01 [24]. In PK series, about half of children achieve functional vision, with better results in type I, without glaucoma and in bilateral disease [24, 99, 102]. In PTRPLS, corneal opacities never clear enough for normal vision [31]. Life expectancy in PTRPLS is unknown; one patient was alive at 41 years, and adults are probably underdiagnosed [6].

11.3. Surveillance

ADHD: attention deficit hyperactivity disorder; GH: growth hormone.

Absence of glaucoma at a given time does not exclude future glaucoma, and periodic examinations should continue into adulthood and beyond [12, 24]. Baseline findings (IOP, refraction, corneal diameter and thickness, axial length, cup-to-disc ratio and angle by UBM) should be recorded and photographed, and OCT of the retinal nerve fibre layer and wide-field photography (RetCam) in the infant complete the assessment when the fundus is visible [24]. The WGA consensus stresses that glaucoma associated with non-acquired ocular anomalies may be present at birth or appear later, so monitoring should be regular and lifelong, and that IOP measurement and optic disc appearance are fundamental elements throughout the life of the child with glaucoma [76]. Transition to adult services should avoid interruption of follow-up [12].

12. Summary and Final Considerations

Anterior segment dysgeneses form a spectrum of malformations of the cornea, iris, lens and angle in which the classic Axenfeld, Rieger and Peters phenotypes do not correspond to single genes. Axenfeld-Rieger syndrome is autosomal dominant and is due mainly to PITX2 (41% of probands) and FOXC1 (30%), with high but incomplete penetrance and variable expressivity. The gene determines the extraocular profile: PITX2 is associated with almost constant dental and umbilical anomalies and with Meckel diverticulum, and FOXC1 with early-onset glaucoma, progressive hearing loss, heart disease, hip disease and cerebral white matter changes, as well as with more varied ocular phenotypes, including a normal anterior segment and isolated juvenile glaucoma due to duplication.

Glaucoma affects about two thirds to three quarters of carriers in molecular cohorts, above the classically cited 50%, and is the main cause of visual loss: in tertiary centres, more than one third of glaucomatous eyes were blind at 10 years. Medical treatment is rarely sufficient, and surgery (drainage devices, trabeculectomy with antifibrotics, goniotomy or trabeculotomy when the cornea is clear) is needed in most; alpha-2 agonists should be avoided in the child.

Peters anomaly is a congenital central corneal opacity with a defect of the posterior stroma, Descemet membrane and endothelium, mostly sporadic and with an identified genetic cause in about one third of patients (PAX6, B3GLCT, SOX2, CYP1B1, FOXC1, PITX2 and others). The decision on keratoplasty, optical iridectomy or selective endothelial removal depends on the type, laterality and glaucoma, and the sources diverge: American series show functional vision in type I, and the Japanese guideline suggests not operating. Peters-plus syndrome, autosomal recessive due to biallelic B3GLCT variants (with c.660+1G>A as the most frequent allele), combines Peters anomaly with rhizomelic short stature, brachydactyly, typical facies, clefts and developmental delay, and may be suspected prenatally from growth restriction and rhizomelia.

The molecular diagnosis, with a panel that includes copy-number analysis, the PITX2 regulatory region and FOXC1 duplications, followed by genome sequencing when negative, guides extraocular surveillance, counselling and cascade testing of relatives with minimal signs. Ophthalmological surveillance is lifelong, and care should be multidisciplinary and centralised in experienced centres, coordinated in Europe by ERN-EYE.

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