Juvenile open-angle glaucoma (JOAG) is a type of primary childhood glaucoma that develops after age 4 and is an open-angle glaucoma5). It does not involve globe enlargement and is not associated with congenital ocular anomalies or systemic diseases 5).
It corresponds to the condition previously called “late-onset developmental glaucoma” or “juvenile primary open-angle glaucoma.” Because the developmental abnormalities of the angle and trabecular meshwork are mild, the onset is delayed, and it follows a pattern and course similar to adult primary open-angle glaucoma.
The 5th edition of the Glaucoma Practice Guidelines classifies childhood glaucoma into primary and secondary types. Among primary childhood glaucomas, those with severe angle dysgenesis and globe enlargement (buphthalmos) are classified as primary congenital glaucoma (PCG), while those with mild angle dysgenesis without globe enlargement are classified as JOAG 5).
The estimated prevalence is rare, at 0.38 to 2 per 100,000 people aged 4 to 20 years 3). In a large registry from Australia and New Zealand (ANZRAG), JOAG accounted for 56 (19.3%) of 290 children with glaucoma, second only to PCG (57.6%) 1). Among early-onset glaucoma (age 18 to <40 years), JOAG was the most common, accounting for 271 (73.2%) of 370 patients 1).
Age of onset: The median age at diagnosis of childhood JOAG is 14 years (IQR 12–16 years) 1)
Bilaterality: 94.6% of JOAG cases are bilateral, which is higher than PCG (83.6%) 1)
Sex difference: In childhood JOAG, 50.0% are male, with no clear sex difference 1)
Family history: 64.4% of JOAG patients have a family history of glaucoma, significantly higher than 35.7% in PCG (P=0.007) 1)
Compared to adult primary open-angle glaucoma, it has the following characteristics:
Intraocular pressure often exceeds 40 mmHg and may reach 50 mmHg or higher 3)4)
Rapid progression
Resistance to medication, with frequent need for surgery (40–70%) 3)4)
Autosomal dominant inheritance with high penetrance 1)2)
QCan juvenile open-angle glaucoma (JOAG) occur in children?
A
JOAG can develop from age 4 onward. However, it is often diagnosed in the late teens to 30s. Since it is often asymptomatic in the early stages, regular eye examinations from childhood are important if there is a family history of glaucoma. Because 64.4% of JOAG cases have a family history, early screening of relatives is useful for preserving vision.
Similar to primary open-angle glaucoma, it is often asymptomatic until visual field defects progress. However, some patients may experience the following symptoms from a relatively young age:
Blurred vision: Easily noticed during periods of very high intraocular pressure
Decreased vision: Appears with progression of optic nerve damage due to chronic high intraocular pressure
Eye strain / heavy sensation in the eye: Occurs when intraocular pressure is 40 mmHg or higher
Headache: May be reported as a symptom associated with markedly high intraocular pressure
The triad of tearing, photophobia, and corneal opacity seen in primary congenital glaucoma (PCG) is not observed in JOAG3)4).
Clinical Findings (Findings Confirmed by Physician Examination)
Intraocular pressure: Markedly high values are characteristic. In the ANZRAG study (660 cases), the median intraocular pressure in the JOAG group was 29 mmHg (IQR 23–38), and it was even higher in MYOC mutation carriers at 40 mmHg (IQR 29–45)1). Temporal fluctuations in intraocular pressure are also large, and seasonal variations are prominent. Even if the intraocular pressure at diagnosis is not very high, optic nerve damage from past periods of high pressure may be severe.
Corneal findings: No increase in corneal diameter. This is an important distinguishing feature from PCG. Haab striae (Descemet’s membrane rupture) are also absent.
Angle findings: Gonioscopy shows an open angle3). The degree of angle dysgenesis is mild, but high iris insertion and prominent iris processes may be seen3)4). Basic angle findings in developmental glaucoma include high iris insertion, hypoplasia of the angle recess, increased width of the trabecular meshwork, and anterior displacement or thickening of Schwalbe’s line, but in JOAG these abnormalities may be subtle and sometimes appear normal.
Optic disc: Shows glaucomatous optic disc cupping. The cupping is enlarged overall, and the optic nerve color may be relatively good, so optic nerve damage may progress even at a stage without visual field defects. The degree of damage often differs between eyes. Bilateral cupping is often found on dilated examination.
Visual field findings: When intraocular pressure fluctuations are large, progression of visual field defects is faster than in typical open-angle glaucoma. The interval between visual field tests needs to be shortened. The Humphrey automated perimeter is the standard test; Goldmann perimetry is also used in young children.
Myopia progression: Because the sclera at the posterior pole retains elasticity, elevated intraocular pressure causes myopia to progress. Unlike PCG, where the entire eyeball enlarges, this appears as localized deformation of the posterior pole.
JOAG is mainly inherited in an autosomal dominant pattern with high penetrance, and genetic factors are strong1)2). The following related genes have been identified.
MYOC (Myocilin) Gene
Located at the GLC1A locus (chromosome 1q24.3-q25.2)2)
Mutations found in 9.5% of JOAG cases (24 out of 252 in the ANZRAG study)1)
Clinical features of MYOC mutation carriers: Median IOP 40 mmHg (IQR 29–45), median age of onset 29 years (IQR 15–35), 100% positive family history1)
Phenotype-genotype correlation: The Gln368Stop mutation shows a relatively mild phenotype, while Tyr437His and Ile477Asn mutations are associated with more severe and early-onset phenotypes
Functional significance: Myocilin is expressed in the trabecular meshwork, and mutations increase resistance to aqueous humor outflow2). The overall frequency of MYOC mutations in POAG is 2–4%, but when selecting patients with young onset, high IOP, and positive family history, it rises to 16–40%2)4)
Other related genes
CYP1B1: Biallelic mutations have been reported in 3.2% of JOAG cases1). It is also a major causative gene for PCG, indicating a genetic overlap between JOAG and PCG1)
CPAMD8: Encodes a protein involved in anterior chamber pressure dynamics. Mutations have been reported in some JOAG cases1)
TBK1 and OPTN: Associated with normal-tension JOAG. The median IOP in TBK1 mutation cases is 13 mmHg, and in OPTN mutation cases it is 18 mmHg, both low1)
FOXC1: Causative gene for Axenfeld-Rieger syndrome, but mutations have also been reported in JOAG cases1)
In the ANZRAG study (252 JOAG patients), molecular diagnosis was obtained in only about 15.5% of cases, and the causative gene remains unidentified in the majority1). International collaborative research is needed to identify new genetic loci.
Myopia: 87% of JOAG patients have myopia. Residual elasticity of the posterior sclera may allow high IOP to promote myopia progression
Male sex: Some studies report a male predominance (64%), but the ANZRAG study did not find a clear sex difference1)
QShould individuals in JOAG families undergo genetic testing?
A
JOAG often follows an autosomal dominant inheritance pattern with a strong family history. The lifetime risk of developing glaucoma in MYOC mutation carriers is reported to be 60–100% 4). Genetic testing can help identify risk early and initiate regular check-ups, which can preserve vision. However, currently about 85% of JOAG cases have unidentified causative genes 1), so a negative test does not rule out risk. Consultation with a glaucoma specialist is recommended.
By around age 10, basic ophthalmic examinations including static perimetry become possible. In JOAG, intraocular pressure (IOP) shows large temporal fluctuations and significant seasonal variation, so a single measurement may not reflect true IOP.
Goldmann applanation tonometer: The gold standard for IOP measurement. Multiple measurements are recommended considering diurnal and seasonal variation.
Slit-lamp examination: Evaluation of the anterior segment and angle.
Gonioscopy: To rule out angle closure and evaluate angle dysgenesis (high iris insertion, increased trabecular meshwork width, anterior displacement of Schwalbe’s line)3)4)
Fundus examination: Evaluation of the optic disc cup-to-disc ratio, cupping morphology, and color.
Static perimetry: Humphrey Field Analyzer is standard. If IOP fluctuation is large, shorten the test interval. For young children who have difficulty cooperating, use the Goldmann perimeter.
Optical coherence tomography (OCT): Useful for analyzing retinal nerve fiber layer (RNFL) thickness and ganglion cell complex (GCC). Normal axial length elongation with growth must be considered.
Corneal thickness measurement: Its formal role in JOAG is not established, but it is recommended as part of a comprehensive examination.
The degree of angle developmental abnormality varies, and differentiation from primary open-angle glaucoma (POAG) can be difficult except by the degree of angle development and age of onset. Late-onset JOAG has more diseases to differentiate compared to early-onset. History and detailed examination can help differentiate.
Primary open-angle glaucoma (POAG): Differentiation from adult-onset POAG depends on age and degree of angle dysgenesis.
Normal-tension glaucoma (NTG): Differentiation from JOAG with borderline IOP. In cases with TBK1 or OPTN mutations, IOP may be within normal range1)
Late-onset primary congenital glaucoma (PCG): Differentiated by presence of globe enlargement and Haab striae5).
Secondary glaucoma in children: Also rule out neovascular glaucoma associated with retinoblastoma, phakomatoses, juvenile xanthogranuloma, etc.
QHow is JOAG differentiated from congenital glaucoma?
A
Primary congenital glaucoma (PCG) is a disease that causes globe enlargement (buphthalmos) due to severe angle dysgenesis, and most cases develop before 2 years of age5). The classic triad of epiphora, photophobia, and corneal opacity is characteristic, and corneal enlargement and Haab striae (Descemet’s membrane rupture) are also observed. JOAG lacks these findings, develops after age 4, and presents with an open angle (normal angle appearance), which differentiates it.
Treatment of JOAG generally follows that of primary open-angle glaucoma, but because it shares features with PCG such as angle dysgenesis and marked ocular hypertension, these aspects must be considered5). If the patient and family understand, treatment can start with eye drops, and surgery is chosen if the effect is insufficient. However, reports comparing medical and surgical treatment show that surgical treatment has a higher probability of controlling intraocular pressure to 18 mmHg or lower and of slowing visual field progression5).
The target intraocular pressure and treatment plan are determined based on age and the degree of intraocular pressure, optic nerve damage, and visual field damage.
Drug Class
Representative Drugs
Indications/Selection Criteria
Precautions
PG-related drugs
Latanoprost, etc.
First choice when IOP > 25 mmHg
Periorbital pigmentation
Beta-blockers
Timolol, etc.
First choice when IOP 20–25 mmHg
Contraindicated in bronchial asthma and bradycardia
Oral use: caution for metabolic acidosis and growth suppression
PG-related drugs (prostanoid FP receptor agonists): Latanoprost, etc. In children, they have been confirmed to have a greater IOP-lowering effect than beta-blockers. Even if optic nerve and visual field damage is mild, they are used from the start when IOP exceeds 25 mmHg. Periorbital pigmentation is a common side effect in young patients. Efficacy may be poor in cases with underdeveloped uveoscleral outflow pathways. Some reports indicate no difference in efficacy between PG-related drugs and beta-blockers5)
Beta-blockers: Used for moderate IOP elevation of 20–25 mmHg when considering side effects such as periorbital pigmentation. Confirm no history of asthma, etc. Special caution is needed in infants due to reports of apnea.
Carbonic anhydrase inhibitors (CAI): Used as adjunctive therapy. Oral administration (acetazolamide 5–10 mg/kg every 6–8 hours) requires caution for metabolic acidosis and growth suppression.
Pilocarpine hydrochloride (miotic): Can lower intraocular pressure in some cases, but issues include reduced tolerability due to miosis and induced myopia, as well as frequency of instillation.
Alpha-2 adrenergic receptor agonists (e.g., brimonidine): Contraindicated in children under 2 years of age due to risk of neuropsychiatric symptoms5).
In response to intraocular pressure fluctuations, it may be necessary to change or add eye drops, and in young patients, to reduce the number of eye drops once the pressure has decreased.
Trabeculotomy (first choice): In young patients with mild visual field damage, considering the risk of intraocular pressure re-elevation and bleb infection, trabeculotomy from the inferior approach is selected. Goniotomy may also be effective. In a study of 10 eyes, 360-degree trabeculotomy (using an illuminated microcatheter) reduced mean intraocular pressure by 50%. GATT (gonioscopy-assisted transluminal trabeculotomy) showed better outcomes compared to KDB (Kahook Dual Blade) goniotomy, with mean IOP reduction of 44% vs. 14%, and reoperation rates of 5/36 eyes for GATT vs. 8/13 eyes for KDB.
Trabeculectomy (with MMC): Selected for cases with advanced visual field damage or after multiple trabeculotomies. Reports indicate a medication-free IOP control rate of 50–87% at 3 years postoperatively. In families with MYOC mutations, 83% required filtration surgery.
Tube shunt surgery (glaucoma drainage device): Selected when filtration surgery is difficult due to conjunctival scarring or in refractory cases. A meta-analysis of GDD in pediatric glaucoma (32 studies, 1,221 eyes) showed preoperative IOP of 31.8±3.4 mmHg decreased to 16.5 mmHg (95% CI 15.5–17.6) at 12 months and 17.6 mmHg (95% CI 16.4–18.7) at 24 months6). Success rates were 0.87 (95% CI 0.83–0.91) at 12 months and 0.77 (95% CI 0.71–0.83) at 24 months6).
In a prospective study of 30 eyes with JOAG, 43% maintained ≥20% IOP reduction without additional treatment at 12 months. In eyes where Schlemm’s canal was visible on anterior segment OCT, the success rate of SLT was 8.3–21.4 times higher. Eyes with a hyperreflective membrane on the trabecular meshwork did not respond. However, the response rate to laser trabeculoplasty is generally considered low in young patients.
There are reports of small numbers of cases using Xen gel stent and Hydrus stent. In general, MIGS has been reported to achieve IOP reduction of 15–50%, reduction in medication use of 0.4–1.8 agents, and low complication rates (hyphema <20%, hypotony <15.4%) 7). Although large-scale evidence specific to JOAG is lacking, it can be a valid option.
QIs treatment with eye drops alone sufficient for JOAG?
A
Treatment begins with eye drops, but in JOAG, adequate IOP control is often not achieved with medication alone. It is reported that 40–70% of patients eventually require surgical treatment 3)4). Studies comparing medical and surgical treatment show that surgery is superior in terms of probability of achieving IOP ≤18 mmHg and suppressing progression of visual field damage 5). Trabeculotomy is the first choice, and in young patients, an inferior approach is recommended.
The basic pathology of JOAG is increased aqueous outflow resistance and elevated IOP due to angle dysgenesis. Late-onset type has milder angle abnormalities compared to early-onset type (PCG), leading to later onset, but the basic mechanism of IOP elevation due to angle dysgenesis is common to both, making clear distinction difficult.
In the trabecular meshwork, compact tissue resembling juxtacanalicular connective tissue is thickly present beneath Schlemm’s canal. This tissue consists of trabecular cells with short cell processes, fibrous components of collagen and elastin-like fibers, and abundant amorphous material showing basement membrane-like morphology, without lamellar structure. The presence of this thick tissue occupying the intercellular spaces of the trabecular meshwork is thought to contribute to increased aqueous outflow resistance and IOP elevation.
In a study of 11 trabeculectomy specimens, abnormal basement membrane-like material (fingerprint pattern) was present in the outer corneoscleral and cribriform layers of the trabecular meshwork, causing more severe thickening of the cribriform layer compared to adult POAG.
Function of MYOC: Myocilin is a protein expressed in the trabecular meshwork (trabecular beams and adjacent tissues of Schlemm’s canal), and mutations are thought to increase resistance to aqueous humor outflow 2). Animal experiments have confirmed that MYOC expression levels correlate with intraocular pressure2). GLC1A to GLC1P have been reported as causative loci for open-angle glaucoma, among which five causative genes—MYOC, OPTN, WDR36, NTF4, and TBK1—have been identified. MYOC and NTF4 genes, which cause elevated intraocular pressure, are considered to be associated with JOAG, but the phenotype varies even within families carrying the same genetic abnormality.
Involvement of CYP1B1: CYP1B1 is a major causative gene for PCG, but biallelic mutations have also been identified in 3.2% of JOAG cases 1). The presence of CYP1B1 mutations in both PCG and JOAG indicates genetic overlap between the two diseases and supports the understanding of them as a continuum of angle dysgenesis.
Trabecular meshwork cells are derived from the neural crest, while the juxtacanalicular connective tissue is derived from vascular endothelial cells. The greatest resistance to aqueous humor outflow exists at the junction of these two tissues of different origins.
Posterior Scleral Elasticity and Myopia Progression
In JOAG, because the sclera in the posterior pole retains elasticity, elevated intraocular pressure leads to progression of myopia. Unlike PCG, where the entire eyeball enlarges (buphthalmos), JOAG is characterized by localized deformation of the posterior pole.
Studies using OCT-A (optical coherence tomography angiography) have shown that peripapillary vessel density is significantly lower in JOAG compared to adult POAG. Vessel density shows a strong positive correlation with RNFL thickness and best-corrected visual acuity, suggesting that reduced vascular perfusion of the optic nerve may be involved in the pathogenesis of JOAG.
The ANZRAG study (Australia and New Zealand, 660 cases) is the largest genetic analysis study of JOAG to date 1). Molecular diagnosis was obtained in 15.5% of 252 JOAG cases, identifying mutations in MYOC (9.5%), CYP1B1 (3.2%), FOXC1 (0.8%), CPAMD8 (0.4%), and OPTN (0.4%) 1). Genetic diagnosis led to reclassification of clinical diagnosis in 10.4% of patients 1).
In the majority of cases, the causative gene remains unidentified, and international collaborative research is needed to identify new genes 1).
It is becoming clear that the severity of JOAG varies depending on the type of MYOC mutation 1)2). The Gln368Stop mutation shows a relatively mild, late-onset phenotype, whereas Tyr437His and Ile477Asn mutations are associated with more severe and early-onset phenotypes. CYP1B1 mutations are more common in females (66.7% vs 33.3%, P=0.03) and are also found in non-European populations 1). In the future, personalized treatment plans based on genetic testing panels may become possible.
Evaluation of Schlemm’s canal visualization and the presence of hyperreflective membrane on the trabecular meshwork using anterior segment OCT may allow prediction of the treatment effect of SLT in advance. In cases without angle abnormalities, the success rate of SLT is four times higher.
A systematic review of QOL assessment in childhood glaucoma found that 10 types of PROMs (patient-reported outcome measures) were used, but no PROM specifically developed for childhood glaucoma existed 8). Issues unique to JOAG, such as the need for continued eye drop treatment, repeated surgeries, and the hereditary nature of the disease, may be overlooked in QOL assessment 8).
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Xu Z, Hysi PG, Khawaja AP. Genetic Determinants of Intraocular Pressure. Annu Rev Vis Sci. 2021;7:727-746. doi:10.1146/annurev-vision-031021-095225.
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