Review
Genetic Basis of Non-Syndromic Childhood Glaucoma Associated
with Anterior Segment Dysgenesis: A Narrative Review
Nicola Cronbach 1 , Cécile Méjécase 1,2 and Mariya Moosajee 1,2,3, *
1 UCL Institute of Ophthalmology, London EC1V 9EL, UK; (N.C.);
(C.M.)
2 Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1AT, UK
3 Moorfields Eye Hospital NHS Foundation Trust, London EC1V 9EL, UK
* Correspondence:
Abstract
Twenty causative genes have been reported that cause non-syndromic childhood glaucoma
associated with anterior segment dysgenesis. FOXC1, PAX6 and PITX2 are the most well-
known, but cases linked to SLC4A11, PITX3 and SOX11 have also been reported. As genetic
testing becomes increasingly widespread and rates of molecular diagnosis rise, the extent
of phenotypic overlap between the different genetic causes of non-syndromic glaucoma
associated with anterior segment dysgenesis is becoming more evident. Taking aniridia as
an example, whilst PAX6 mutations remain the predominant cause, variants in CYP1B1,
FOXC1, PXDN and SOX11 have also been reported in patients with childhood glaucoma
and aniridia. Developments in molecular-based therapies for retinal and corneal disease
are advancing rapidly, and pre-clinical studies of gene-based treatments for glaucoma and
aniridia are showing promising results. Use of adeno-associated viral vectors for gene
delivery is most common, with improvements in intraocular pressure and retinal ganglion
cell survival in Tg-MYOCY437H mouse models of glaucoma, and successful correction of a
germline PAX6G194X nonsense variant in mice using CRISPR-Cas9 gene editing. This review
will explore the actions and interactions of the genetic causes of non-syndromic glaucoma
associated with anterior segment dysgenesis and discuss the current developments in
Academic Editor: Réjean Couture molecular therapies for these patients.
Received: 23 May 2025
Keywords: childhood glaucoma; anterior segment dysgenesis; gene editing; nonsense
Revised: 30 August 2025
Accepted: 6 September 2025 suppression; aniridia
Published: 9 September 2025
Citation: Cronbach, N.; Méjécase, C.;
Moosajee, M. Genetic Basis of
Non-Syndromic Childhood Glaucoma 1. Introduction
Associated with Anterior Segment Ocular development commences at gestational day 21 with induction of the eye
Dysgenesis: A Narrative Review.
field in the anterior neural plate prior to lateral evagination of the optic vesicles through
Pharmaceuticals 2025, 18, 1352.
https://doi.org/10.3390/
the cephalic mesenchyme [1,2]. At gestational day 27, the optic vesicle contacts the
ph18091352 surface ectoderm, and signaling through bone morphogenetic protein (BMP) and retinoic
acid first from the optic vesicle and then the lens placode stimulates invagination of
Copyright: © 2025 by the authors.
Licensee MDPI, Basel, Switzerland.
both structures to form the optic cup and lens vesicle, which are present by day 37
This article is an open access article (Figure 1a) [1]. By day 47, differentiation of the optic cup into primitive neural retina
distributed under the terms and and retinal pigment epithelium (RPE) has commenced, and neural crest cells from the
conditions of the Creative Commons periocular mesenchyme begin to migrate into the developing anterior segment under
Attribution (CC BY) license the control of PAX6 (Figure 1b) [3]. PITX2 and FOXC1, expressed by the presumptive
(https://creativecommons.org/
cornea, and PITX3 and FOXE3, expressed by the developing lens, have roles in regulating
licenses/by/4.0/).
Pharmaceuticals 2025, 18, 1352 https://doi.org/10.3390/ph18091352
,Pharmaceuticals 2025, 18, 1352 2 of 25
differentiation of the periocular mesenchyme into corneal keratocytes and endothelium,
and detachment of the lens vesicle from the cornea, respectively (Figure 1c) [2]. From
gestational week 15, PAX6, BMP4 and OTX1 stimulate elongation of the peripheral tips
of the optic cup, which express CYP1B1 and MEIS2, along the anterior lens surface
to form the epithelium of the ciliary body and iris (Figure 1d) [2,4–6]. Concurrently,
a second wave of migration of the periocular mesenchyme into the anterior segment
occurs, expressing PITX2, FOXC1 and FOXC2, which will form the ciliary body and iris
stroma [2,3,5]. Trabecular meshwork development occurs from gestational week 20 with
elongation, flattening and separation of mesenchymal cells in the iridocorneal angle
to form lamellae, accompanied by vascular development in the adjacent sclera which
becomes Schlemm’s canal (Figure 1e) [2,7].
Figure 1. Anterior segment embryological development: (a) at day 37 of gestation, a double
layered optic cup and lens vesicle can be seen; (b) at 47 days, the optic cup has formed primitive
neural retina and retinal pigment epithelium with the optic stalk forming primitive optic nerve.
Optic cup patterning is dependent on the PAX6 expression gradient, from high expression
at the peripheral optic cup tips down to low expression centrally. Cells of the central lens
placode migrate to the posterior lens vesicle and elongate to form primary lens fiber cells,
and the first wave of neural crest cells from the periocular mesenchyme migrates between the
lens and surface ectoderm; (c) at 57 days, the primitive corneal epithelium is formed from the
surface ectoderm, the corneal stroma and endothelium are formed from neural crest cells of the
periocular mesenchyme, and there is separation of the lens stalk and formation of the anterior
chamber; (d) by 15 weeks, elongation of optic cup tips along the anterior lens surface to form the
iris and ciliary body epithelium occurs, and there is a second wave of periocular mesenchyme
migration into the anterior chamber to form the iris and ciliary body stroma; (e) at 20 weeks,
there is an accumulation of periocular mesenchyme in the iridocorneal angle which subsequently
elongates and forms lamellae to become the trabecular meshwork, and vessels form in the
adjacent sclera which will become Schlemm’s canal. Gene expression is marked in red. RPE,
retinal pigment epithelium.
Glaucoma is an overarching term for optic neuropathies resulting from retinal
ganglion cell loss, which are typified by optic disc cupping and associated visual field
defects. Childhood glaucoma, affecting individuals under 18 years of age, accounts
for 5% of pediatric blindness worldwide [8]. In addition to optic nerve changes and
visual field defects, features of childhood glaucoma include corneal enlargement and
Haab striae, increased axial length and intraocular pressure >21 mmHg; two or more
features are required for diagnosis [9]. Childhood glaucoma is classified according to
, Pharmaceuticals 2025, 18, 1352 3 of 25
the underlying cause and whether this is primary or secondary to another ocular or
systemic condition [9]. Primary congenital glaucoma develops before 4 years of age
and may be further divided into neonatal (0–1 month), infantile (>1–24 months) and
late (>24 months) onset disease. It is a primary goniodysgenesis and presents with an
immature appearance of the iridocorneal angle (Figure 2a) [9,10]. Juvenile open angle
glaucoma presents after 4 years of age and with normal angle appearances. Secondary
causes of childhood glaucoma include onset following cataract surgery, glaucoma asso-
ciated with non-acquired ocular or systemic anomalies, and glaucoma associated with
acquired conditions such as trauma and uveitis.
(a) (b) (c) (d)
(e) (f) (g)
Figure 2. Clinical features of childhood glaucoma and anterior segment dysgenesis: (a) immature
scalloped appearance of iridocorneal angle in primary congenital glaucoma; (b) central corneal opacity
in Peters anomaly; (c,d) Axenfeld–Rieger anomaly: (c) iris hypoplasia and posterior embryotoxon;
(d) corectopia; (e–g) congenital aniridia: (e) iris hypoplasia; (f) aniridia-associated keratopathy;
(g) foveal hypoplasia.
Anterior segment dysgenesis (ASD) is a broad term that incorporates developmental
anomalies involving structures in the anterior segment of the eye [11–13]. These may
affect a single structure, such as microcornea, or involve multiple structures, such as the
iridocorneal and keratolenticular adhesions seen in Peters anomaly (Figure 2b). Between
30 and 75% of patients with ASD develop glaucoma depending on the subtype of dys-
genesis [14,15], and young patients with either glaucoma or ASD should be thoroughly
examined for features of each condition [13,15–17]. Many of the anterior segment dysge-
neses have variable phenotypes with considerable overlap; for example, Axenfeld–Rieger
anomaly (Figure 2c,d) may include corectopia, polycoria and iris hypoplasia in associa-
tion with posterior embryotoxon, and like Peters anomaly, may also feature iridocorneal
adhesions [15]. Patients with congenital aniridia (Figure 2e–g) present with underdevelop-
ment of the iris of variable severity and foveal hypoplasia; some will also have lenticular
opacities and optic nerve hypoplasia from birth, and many will develop glaucoma and
aniridia-associated keratopathy by adulthood [14,18].
The molecular pathways involved in anterior segment development are highly
complex. There is an overlap between the known genes that cause childhood glaucoma
and those that cause anterior segment dysgenesis [11–13], and there is increasing evi-
dence of digenic and likely polygenic influences on the development process, resulting
in phenotypic variation. For example, mice with either FoxC1+/− or Cyp1b1−/− muta-
tions who also carry the tyrosinase-deficient Tyrc–2J allele develop more severe anterior
segment anomalies and angle defects, respectively [19]. In humans, CYP1B1 mutations
Genetic Basis of Non-Syndromic Childhood Glaucoma Associated
with Anterior Segment Dysgenesis: A Narrative Review
Nicola Cronbach 1 , Cécile Méjécase 1,2 and Mariya Moosajee 1,2,3, *
1 UCL Institute of Ophthalmology, London EC1V 9EL, UK; (N.C.);
(C.M.)
2 Ocular Genomics and Therapeutics, The Francis Crick Institute, London NW1 1AT, UK
3 Moorfields Eye Hospital NHS Foundation Trust, London EC1V 9EL, UK
* Correspondence:
Abstract
Twenty causative genes have been reported that cause non-syndromic childhood glaucoma
associated with anterior segment dysgenesis. FOXC1, PAX6 and PITX2 are the most well-
known, but cases linked to SLC4A11, PITX3 and SOX11 have also been reported. As genetic
testing becomes increasingly widespread and rates of molecular diagnosis rise, the extent
of phenotypic overlap between the different genetic causes of non-syndromic glaucoma
associated with anterior segment dysgenesis is becoming more evident. Taking aniridia as
an example, whilst PAX6 mutations remain the predominant cause, variants in CYP1B1,
FOXC1, PXDN and SOX11 have also been reported in patients with childhood glaucoma
and aniridia. Developments in molecular-based therapies for retinal and corneal disease
are advancing rapidly, and pre-clinical studies of gene-based treatments for glaucoma and
aniridia are showing promising results. Use of adeno-associated viral vectors for gene
delivery is most common, with improvements in intraocular pressure and retinal ganglion
cell survival in Tg-MYOCY437H mouse models of glaucoma, and successful correction of a
germline PAX6G194X nonsense variant in mice using CRISPR-Cas9 gene editing. This review
will explore the actions and interactions of the genetic causes of non-syndromic glaucoma
associated with anterior segment dysgenesis and discuss the current developments in
Academic Editor: Réjean Couture molecular therapies for these patients.
Received: 23 May 2025
Keywords: childhood glaucoma; anterior segment dysgenesis; gene editing; nonsense
Revised: 30 August 2025
Accepted: 6 September 2025 suppression; aniridia
Published: 9 September 2025
Citation: Cronbach, N.; Méjécase, C.;
Moosajee, M. Genetic Basis of
Non-Syndromic Childhood Glaucoma 1. Introduction
Associated with Anterior Segment Ocular development commences at gestational day 21 with induction of the eye
Dysgenesis: A Narrative Review.
field in the anterior neural plate prior to lateral evagination of the optic vesicles through
Pharmaceuticals 2025, 18, 1352.
https://doi.org/10.3390/
the cephalic mesenchyme [1,2]. At gestational day 27, the optic vesicle contacts the
ph18091352 surface ectoderm, and signaling through bone morphogenetic protein (BMP) and retinoic
acid first from the optic vesicle and then the lens placode stimulates invagination of
Copyright: © 2025 by the authors.
Licensee MDPI, Basel, Switzerland.
both structures to form the optic cup and lens vesicle, which are present by day 37
This article is an open access article (Figure 1a) [1]. By day 47, differentiation of the optic cup into primitive neural retina
distributed under the terms and and retinal pigment epithelium (RPE) has commenced, and neural crest cells from the
conditions of the Creative Commons periocular mesenchyme begin to migrate into the developing anterior segment under
Attribution (CC BY) license the control of PAX6 (Figure 1b) [3]. PITX2 and FOXC1, expressed by the presumptive
(https://creativecommons.org/
cornea, and PITX3 and FOXE3, expressed by the developing lens, have roles in regulating
licenses/by/4.0/).
Pharmaceuticals 2025, 18, 1352 https://doi.org/10.3390/ph18091352
,Pharmaceuticals 2025, 18, 1352 2 of 25
differentiation of the periocular mesenchyme into corneal keratocytes and endothelium,
and detachment of the lens vesicle from the cornea, respectively (Figure 1c) [2]. From
gestational week 15, PAX6, BMP4 and OTX1 stimulate elongation of the peripheral tips
of the optic cup, which express CYP1B1 and MEIS2, along the anterior lens surface
to form the epithelium of the ciliary body and iris (Figure 1d) [2,4–6]. Concurrently,
a second wave of migration of the periocular mesenchyme into the anterior segment
occurs, expressing PITX2, FOXC1 and FOXC2, which will form the ciliary body and iris
stroma [2,3,5]. Trabecular meshwork development occurs from gestational week 20 with
elongation, flattening and separation of mesenchymal cells in the iridocorneal angle
to form lamellae, accompanied by vascular development in the adjacent sclera which
becomes Schlemm’s canal (Figure 1e) [2,7].
Figure 1. Anterior segment embryological development: (a) at day 37 of gestation, a double
layered optic cup and lens vesicle can be seen; (b) at 47 days, the optic cup has formed primitive
neural retina and retinal pigment epithelium with the optic stalk forming primitive optic nerve.
Optic cup patterning is dependent on the PAX6 expression gradient, from high expression
at the peripheral optic cup tips down to low expression centrally. Cells of the central lens
placode migrate to the posterior lens vesicle and elongate to form primary lens fiber cells,
and the first wave of neural crest cells from the periocular mesenchyme migrates between the
lens and surface ectoderm; (c) at 57 days, the primitive corneal epithelium is formed from the
surface ectoderm, the corneal stroma and endothelium are formed from neural crest cells of the
periocular mesenchyme, and there is separation of the lens stalk and formation of the anterior
chamber; (d) by 15 weeks, elongation of optic cup tips along the anterior lens surface to form the
iris and ciliary body epithelium occurs, and there is a second wave of periocular mesenchyme
migration into the anterior chamber to form the iris and ciliary body stroma; (e) at 20 weeks,
there is an accumulation of periocular mesenchyme in the iridocorneal angle which subsequently
elongates and forms lamellae to become the trabecular meshwork, and vessels form in the
adjacent sclera which will become Schlemm’s canal. Gene expression is marked in red. RPE,
retinal pigment epithelium.
Glaucoma is an overarching term for optic neuropathies resulting from retinal
ganglion cell loss, which are typified by optic disc cupping and associated visual field
defects. Childhood glaucoma, affecting individuals under 18 years of age, accounts
for 5% of pediatric blindness worldwide [8]. In addition to optic nerve changes and
visual field defects, features of childhood glaucoma include corneal enlargement and
Haab striae, increased axial length and intraocular pressure >21 mmHg; two or more
features are required for diagnosis [9]. Childhood glaucoma is classified according to
, Pharmaceuticals 2025, 18, 1352 3 of 25
the underlying cause and whether this is primary or secondary to another ocular or
systemic condition [9]. Primary congenital glaucoma develops before 4 years of age
and may be further divided into neonatal (0–1 month), infantile (>1–24 months) and
late (>24 months) onset disease. It is a primary goniodysgenesis and presents with an
immature appearance of the iridocorneal angle (Figure 2a) [9,10]. Juvenile open angle
glaucoma presents after 4 years of age and with normal angle appearances. Secondary
causes of childhood glaucoma include onset following cataract surgery, glaucoma asso-
ciated with non-acquired ocular or systemic anomalies, and glaucoma associated with
acquired conditions such as trauma and uveitis.
(a) (b) (c) (d)
(e) (f) (g)
Figure 2. Clinical features of childhood glaucoma and anterior segment dysgenesis: (a) immature
scalloped appearance of iridocorneal angle in primary congenital glaucoma; (b) central corneal opacity
in Peters anomaly; (c,d) Axenfeld–Rieger anomaly: (c) iris hypoplasia and posterior embryotoxon;
(d) corectopia; (e–g) congenital aniridia: (e) iris hypoplasia; (f) aniridia-associated keratopathy;
(g) foveal hypoplasia.
Anterior segment dysgenesis (ASD) is a broad term that incorporates developmental
anomalies involving structures in the anterior segment of the eye [11–13]. These may
affect a single structure, such as microcornea, or involve multiple structures, such as the
iridocorneal and keratolenticular adhesions seen in Peters anomaly (Figure 2b). Between
30 and 75% of patients with ASD develop glaucoma depending on the subtype of dys-
genesis [14,15], and young patients with either glaucoma or ASD should be thoroughly
examined for features of each condition [13,15–17]. Many of the anterior segment dysge-
neses have variable phenotypes with considerable overlap; for example, Axenfeld–Rieger
anomaly (Figure 2c,d) may include corectopia, polycoria and iris hypoplasia in associa-
tion with posterior embryotoxon, and like Peters anomaly, may also feature iridocorneal
adhesions [15]. Patients with congenital aniridia (Figure 2e–g) present with underdevelop-
ment of the iris of variable severity and foveal hypoplasia; some will also have lenticular
opacities and optic nerve hypoplasia from birth, and many will develop glaucoma and
aniridia-associated keratopathy by adulthood [14,18].
The molecular pathways involved in anterior segment development are highly
complex. There is an overlap between the known genes that cause childhood glaucoma
and those that cause anterior segment dysgenesis [11–13], and there is increasing evi-
dence of digenic and likely polygenic influences on the development process, resulting
in phenotypic variation. For example, mice with either FoxC1+/− or Cyp1b1−/− muta-
tions who also carry the tyrosinase-deficient Tyrc–2J allele develop more severe anterior
segment anomalies and angle defects, respectively [19]. In humans, CYP1B1 mutations
