Developmental glaucoma is a general term for glaucoma caused by developmental abnormalities of the aqueous humor outflow pathway, and is classified into early-onset and late-onset types based on the timing of onset. Early-onset developmental glaucoma corresponds to what was previously called “primary congenital glaucoma,” and the cause of elevated intraocular pressure is limited to developmental abnormalities of the trabecular meshwork. Late-onset developmental glaucoma has a milder degree of angle developmental abnormality, leading to later onset; it is difficult to detect abnormalities by gonioscopy, and corneal enlargement or Haab striae are often absent.
Primary congenital glaucoma (PCG) is a rare disease in which intraocular pressure rises due to genetically determined abnormalities of the trabecular meshwork and anterior chamber angle, without other ocular or systemic developmental abnormalities. Previously, terms such as trabeculodysgenesis, goniodysgenesis, and primary infantile glaucoma were used, but the 2013 international classification by the Childhood Glaucoma Research Network (CGRN) unified the term to primary congenital glaucoma 1).
Primary congenital glaucoma is the most common form of primary childhood glaucoma and is classified into the following four types based on the timing of onset 1).
The incidence in white Europeans is 1 in 12,000 to 18,000 births 1). In some regions of Eastern Europe, it is as high as 1 in 1,250. With consanguineous marriage, the incidence increases 5 to 10 times 1). 65–80% of cases are bilateral, and the male-to-female ratio is about 3:2, with a male predominance 1).
Primary congenital glaucoma accounts for less than 0.01% of all eye disease patients, but is estimated to account for 5% of childhood blindness worldwide. 75% are bilateral, 65% occur in boys, and 80% develop within the first year of life.
In a large ANZRAG cohort (290 cases of childhood glaucoma), PCG was the most common at 57.6% (167/290 cases), and infantile-onset PCG was the most common at 53.3% (89/167 cases). The male-to-female ratio for PCG was 1.46:1, and the median age at diagnosis was 0.25 years (IQR 0–0.6 years) 7).
Congenital glaucoma includes not only primary congenital glaucoma but also secondary types. The four categories of secondary childhood glaucoma according to the World Glaucoma Association (WGA) are shown below.
| Category | Main Diseases |
|---|---|
| Glaucoma associated with congenital ocular anomalies | Axenfeld-Rieger anomaly, Peters anomaly, congenital aniridia, etc. |
| Glaucoma associated with congenital systemic anomalies | Down syndrome, Sturge-Weber syndrome, neurofibromatosis, etc. |
| Glaucoma secondary to acquired conditions or drugs | Post-uveitis, steroid-induced, etc. |
| Glaucoma after congenital cataract surgery | Young age at surgery and microphthalmia are risk factors |
In Caucasians, it is reported in 1 in 12,000 to 18,000 births, but in regions with high consanguinity, it rises to 1 in 1,250. 65–80% of cases are bilateral1).
Patients with primary congenital glaucoma present with one or more of the following “clinical triad” as irritative symptoms due to corneal edema from elevated intraocular pressure1).
Visual loss due to corneal edema/opacity, progressive myopia, and astigmatism may also occur. In infants, caregivers often notice “white eye,” “large eye,” or “bluish eye” and seek medical attention.
Corneal Findings
Haab striae: Horizontal to oblique breaks in Descemet’s membrane, a strong indicator of congenital glaucoma 1).
Increased corneal diameter: Normal at birth is 9.5–10.5 mm. Over 12 mm before age 1, or over 13 mm at any age, strongly suggests glaucoma.
Corneal edema and opacity: Epithelial (sometimes stromal) edema. If untreated, it can lead to permanent scarring.
Ocular and Optic Nerve Findings
Buphthalmos: Enlargement of the entire eyeball due to elevated intraocular pressure. Corneal enlargement may progress until about age 3, and scleral stretching until about age 10.
Optic disc cupping: In infants, a cup-to-disc ratio of 0.3 or more suggests glaucoma. Cupping may improve (reverse) after normalization of intraocular pressure.
Increased axial length: Over 20 mm at birth, or over 22 mm after age 1, is abnormal 1).
About Haab striae: When the corneal diameter increases rapidly, Descemet’s membrane cannot stretch enough and tears. These tears are called Haab striae, which cause corneal astigmatism and can hinder visual development.
As a reference for normal corneal diameter, it is approximately 9.5–10.5 mm in newborns and increases to 10.0–11.5 mm by about 1 year of age. If it exceeds 12.0 mm shortly after birth, this condition is strongly suspected.
Diagnostic criteria (based on the Glaucoma Practice Guidelines)
According to the Glaucoma Practice Guidelines, the diagnosis is based on the presence of at least one of the following four findings:
According to the EGS 6th edition, a diagnosis of primary congenital glaucoma is made when at least 2 of the following 5 items are met1).
A corneal diameter exceeding 13 mm at any age is highly suspicious for glaucoma. In spontaneously arrested primary congenital glaucoma, buphthalmos and Haab striae may be present despite normal intraocular pressure, requiring follow-up as suspected glaucoma.
Most cases of primary congenital glaucoma are sporadic (no family history), but about 10–40% are familial with autosomal recessive inheritance and penetrance of 40–100%1). Linkage analysis has identified five genetic loci.
The main causative genes are as follows:
| Gene | Locus | Chromosome | Function |
|---|---|---|---|
| CYP1B1 | GLC3A | 2p22-p21 | Fatty acid/vitamin metabolism enzyme |
| LTBP2 | GLC3D | 14q24.2-q24.3 | Latent TGF-beta binding protein |
| TEK/TIE2 | GLC3E | 9p21 | Schlemm’s canal development signal |
According to the ANZRAG cohort report on genetic diagnostic yield, molecular diagnosis was achieved in 24.7% (125/506) of all cases. In PCG, molecular diagnosis was possible in 30.4% (41/135), including CYP1B1 biallelic mutations in 15.6% (21 cases), TEK heterozygous mutations in 5.9% (8 cases), CPAMD8 in 3.7% (5 cases), and FOXC1 heterozygous mutations in 3.7% (5 cases). Reclassification of PCG subtype based on genetic diagnosis occurred in 10.4% (FOXC1 mutations reclassified as ARS, CPAMD8 mutations as ASD) 7). CYP1B1 biallelic mutations tended to be more common in females with PCG (66.7% vs 33.3%, P=0.02) 7).
The probability of identifying a cause through genetic testing is approximately 24–40%. Genetic testing is recommended for exclusion of other congenital anomalies and for family planning 1).
Consanguineous marriage is considered a factor for disease severity and poor prognosis 1). The probability that a second child of a patient with primary congenital glaucoma will be affected is usually less than 3%, but if two children are already affected, it rises to 25% assuming autosomal recessive inheritance.
The EGS guidelines recommend genetic testing for exclusion of other congenital anomalies and for family planning 1). The ANZRAG cohort showed a genetic diagnostic rate of 30.4% for PCG, and genetic diagnosis led to reclassification of the disease subtype in 10.4% of cases 7). A negative test does not rule out primary congenital glaucoma, but it may contribute to diagnostic accuracy and appropriate management.
The diagnosis of primary congenital glaucoma can often be made clinically even if intraocular pressure measurements are not accurate. The presence of Haab striae is a strong indicator of congenital glaucoma 1).
Diseases that may be confused with primary congenital glaucoma are listed below1).
| Differential Diagnosis | Key Points for Differentiation |
|---|---|
| Conjunctivitis | Ocular discharge and injection present; corneal diameter normal |
| Nasolacrimal duct obstruction | Ocular discharge present; corneal diameter normal |
| PPMD | Vesicular changes on the posterior corneal surface |
| CHED | Bilateral corneal edema, normal intraocular pressure |
| X-linked megalocornea | Increased corneal diameter, normal intraocular pressure |
| Birth trauma | History of trauma, Haab’s striae usually vertical |
Surgery is the first-line treatment 2). This is because primary congenital glaucoma is caused by developmental abnormalities of the angle that can be surgically corrected, it is difficult to confirm the effectiveness of drug therapy in infants, and there are issues with caregiver-dependent adherence 2). Drug therapy is used as a perioperative or postoperative adjunct 2).
Surgery should be performed at a facility with sufficient experience in pediatric ophthalmology and glaucoma treatment, and comprehensive management including reoperation, long-term follow-up, and amblyopia treatment is necessary 2).
Medication therapy is an adjunctive treatment aimed at short-term intraocular pressure reduction before surgery and postoperative intraocular pressure control 2). Medications are used in combination according to primary open-angle glaucoma, but the following precautions are necessary.
Lifelong intraocular pressure monitoring is essential, and optimal visual development support through refractive correction and amblyopia treatment is also indispensable 1).
Primary congenital glaucoma is caused by abnormal development of the angle, which can be surgically corrected. In infants, it is difficult to confirm the effectiveness of medications, and there are also adherence issues. Furthermore, the drugs available for children are limited, such as contraindications to α₂ receptor agonists and reduced efficacy of prostanoids 2).
Elevated intraocular pressure in primary congenital glaucoma results from impaired aqueous humor outflow due to abnormal development of the anterior chamber angle 1).
In the 1950s and 1960s, the cause was explained by a non-perforating membrane (Barkan membrane) covering the angle, but subsequent histological studies have denied the existence of such a membrane. Currently, outflow obstruction is thought to originate from the trabecular meshwork itself.
Normally, during the third trimester of pregnancy, the ciliary body and peripheral iris move posteriorly away from the cornea and sclera. In primary congenital glaucoma, it is proposed that excessive or premature accumulation of collagen beams within the trabecular meshwork prevents this posterior migration, leaving the iris root and ciliary muscle attached anteriorly, obstructing the trabecular meshwork or compressing Schlemm’s canal.
Rao (2025) performed histological analysis of trabecular meshwork specimens from four patients with primary congenital glaucoma and reported enlargement of the juxtacanalicular meshwork (JCM) and corneoscleral meshwork, thickening of TM beams, an increase in spindle-shaped nuclei (suggesting epithelial-mesenchymal transition), and the presence of two morphologically distinct zones within the JCM 3). These findings suggest abnormal differentiation and heterogeneity of differentiation in various TM regions in primary congenital glaucoma.
GATT (gonioscopy-assisted transluminal trabeculotomy) is a relatively new procedure in which a microcatheter or suture is inserted into Schlemm’s canal under gonioscopy through a corneal incision to incise the entire circumference of the trabecular meshwork. Its efficacy is being established in adult glaucoma, and its application in children is advancing.
Song et al. (2022) reported a case of GATT performed on a 3-year-old boy with primary congenital glaucoma. The iris covered the entire angle up to Schwalbe’s line, making normal angle structures invisible, but the iris was detached using a hook to identify Schlemm’s canal, and GATT was successfully performed. Intraocular pressure was stable at 6 months postoperatively 4).
Elhusseiny et al. (2023) reported one-year outcomes of GATT in 7 eyes of 6 patients with primary congenital glaucoma who had previous glaucoma surgery. Mean intraocular pressure significantly decreased from 25.7±5.9 mmHg preoperatively to 12.0±1.5 mmHg at 12 months. The complete success rate was 85.7% (6/7 eyes), and including qualified success it was 100%; no eyes required additional glaucoma surgery. No serious complications were observed5).
Dada et al. (2022) reported a new technique for primary congenital glaucoma with corneal opacity, performing goniotomy while visualizing the angle structure using a 23G laser endoscope probe6). Traditionally, goniotomy required a clear cornea, but with endoscopic assistance, it may become feasible even in eyes with corneal opacity.
For high-risk groups such as those with a family history or in regions with high consanguinity, prenatal genetic screening may emerge as a preventive measure in the future. In the ANZRAG cohort, genetic diagnosis reclassified the PCG subtype in 10.4% of cases, suggesting that genetic diagnosis contributes to more accurate diagnosis and appropriate management7). Accumulation of evidence from future large international cohorts is expected.
A systematic review of QOL in pediatric glaucoma patients found that 10 types of patient-reported outcome measures (PROMs) have been used, but no questionnaire specific to pediatric glaucoma currently exists9). IVI_C, CVAQC, and LVP-FVQ-II received relatively high ratings (5/7 points) as vision-specific pediatric instruments. Pediatric glaucoma patients have concerns about the future (employment, family planning, fear of surgery) that are not adequately covered by existing PROMs9). Development of pediatric glaucoma-specific PROMs is a future challenge.
In successful surgical cases, long-term visual prognosis is relatively good. With either goniotomy or trabeculotomy, approximately 60% of successful cases maintain corrected visual acuity of 0.5 or better.
Health-Related QoL (HRQoL) in pediatric glaucoma patients is comparable to that of children with congenital heart disease or acute lymphoblastic leukemia (PedsQL 4.0 score approximately 76–79/100). Better QoL is associated with good visual acuity, primary type, and unilateral involvement; number of surgeries, number of eye drops, and bilateral involvement are associated with lower QoL9).
In successful surgical cases, approximately 60% maintain a corrected visual acuity of 0.5 or better. However, lifelong intraocular pressure management, refractive correction, and amblyopia treatment are essential. Addressing corneal astigmatism due to Haab’s striae and progressive myopia is key to maintaining visual function. In cases requiring GDD surgery, the success rate decreases over time: 87% at 12 months and 77% at 24 months, making long-term follow-up mandatory 8).
