#ShareForRare: Congenital Glaucoma
This #GlaucomaAwarenessMonth, we’re shedding light on Congenital Glaucoma, a rare eye condition affecting infants and young children. Join us in raising awareness by exploring the intricacies of this condition, from its causes and early symptoms to treatment options.
What is Congenital Glaucoma?
Congenital glaucoma (CG) is a rare eye condition affecting infants and young children, setting it apart from adult-onset glaucoma commonly tied to aging. This condition is marked by elevated intraocular pressure (IOP), which, if untreated, can lead to irreversible vision loss and typically presents at birth or early childhood. In about 65–80% of cases, congenital glaucoma affects both eyes.
Accounting for around 60% of all childhood glaucoma, CG’s incidence varies from 1 in 10,000 to 30,000 live births. However, this rate increases significantly, up to 5–10 times higher in children born to consanguineous families. Notably, regions such as Saudi Arabia report higher incidences, reaching 1 in 2500, while, in Slovakia, the Roma population reports an even higher rate of 1 in 1250.
The diagnosis is usually made in the first year of life in about 4 out of 5 cases. A male preponderance was reported in CG, with a male-to-female ratio of approximately 3 to 2 in the United States and Europe, and a similar pattern is observed in Japan with a male majority of 6 to 5.
While most cases are sporadic, around 10–40% are familial, with an autosomal recessive inheritance pattern and penetrance varying from 40–100%. Five gene loci have been linked to this disease, including GLC3A, GLC3B, GLC3C, GLC3D, and GLC3E. Among them, the most commonly causal gene for autosomal recessive cases is the CYP1B1 gene, followed by the MYOC and LTBP2 genes.
Molecular aspects of Congenital Glaucoma
Being a rare disease, the etiology of CG is still quite poorly understood. However, experts agree that the disorder’s main cause is the excessive collagen meshwork within the trabeculum that prevents normal insertion of the ciliary body and iris. This results in an anteriorly inserted iris root and obstructs the trabecular meshwork. This specialized eye tissue is essential in regulating intraocular pressure, and thus its blockage causes ocular hypertension.
The main genes that have been found to have a connection to CG are CYP1B1 and MYOC. Both genes are part of the curation of ClinGen’s Glaucoma Variant Curation Expert Panel. In particular, MYOC has gene-specific guidelines for the application of the ACMG rules, which are embedded into Franklin’s classification.
Mutations in LTBP2 (14q24.3) and some additional loci have also been linked to congenital glaucoma.
CYP1B1
CYP1B1 (OMIM 601771) is the most common gene associated with primary congenital glaucoma (OMIM 231300). The CYP1B1 gene, located in the GLC3A locus in chromosome 2, encodes for an enzyme called Cytochrome P450 1B1, which is thought to metabolize a steroid that acts as a signaling molecule involved in eye development. Homozygous or compound heterozygous variants in this gene seem to cause the defect in the trabecular meshwork development and the anterior chamber angle that results in elevated IOP.
As of January, according to Franklin, at least 93 pathogenic SNPs have been identified in the CYP1B1 gene. While most of the LOF variants are classified as pathogenic (33 out of 35), the majority of missense variants are currently classified as VUS (Variant of Uncertain Significance).
MYOC
While MYOC (OMIM 601652) is the most common gene associated with adult- and juvenile-onset primary open-angle glaucoma (OMIM 137750) in an autosomal dominant manner with incomplete penetrance, it also has some connection to Congenital Glaucoma.
The MYOC gene is located in 1q24.3 and it is responsible for encoding the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many ocular tissues, including the trabecular meshwork.
According to Franklin, there are at least 81 pathogenic variants reported in this gene as of January 2024. In this case, the vast majority of deleterious mutations are missense or in-frame indels, with only a few pathogenic variants with a loss of function effect (75 versus 5). Similar to what we see for CYP1B1, there is a high burden of VUSs reported for this gene as well.
Clinical features and diagnosis of CG
Diagnosis is made in the first year of life in about 80% of cases. The classic triad includes epiphora, blepharospasm, and photophobia. This triad of symptoms is classically presented due to the corneal edema that results from the elevated IOP and causes irritation. Hence, affected children are noted as having red watery eyes, cloudy corneas, and ocular enlargement, caused by stretching of the immature eye due to elevated intraocular pressure.
In more advanced cases, reduced vision can also occur from corneal edema/opacification or progressive myopia and/or astigmatism. Amblyopia can further worsen vision. Typically, children older than 3 years develop progressive myopia and insidious field loss.
Early diagnosis is key to improving prognosis. Diagnosis is made by a complete ophthalmologic examination, which reveals a hazy cornea of increased size and presence of Haab’s striae, increased intraocular pressure, deep anterior chamber, abnormally high insertion of iris, poorly developed scleral spur, increased cup-to-disc ratio of the optic nerve head and refraction testing showing myopia and astigmatism. Occasionally, an examination under anesthesia is performed if necessary.
When CG is suspected, the family history of glaucoma and consanguineous marriage between parents should be taken into consideration. Genetic screening, analysis, and pedigree chart evaluation can be performed in cases with incomplete penetrance to reach a final diagnosis.
Treatments and clinical trials
Congenital glaucoma is primarily treated with angle surgery, where procedures like goniotomy or trabeculotomy are chosen based on the severity of the condition. In refractory cases, glaucoma drainage devices and diode laser cyclophotocoagulation are utilized. Late complications include amblyopia, corneal scarring, and cataracts, highlighting the importance of early visual rehabilitation.
Usually in conjunction with the surgical approach or as an initial treatment while the surgery is scheduled, medical therapies are used. Topical or oral antiglaucoma drugs, which act by either decreasing the aqueous production or increasing the aqueous outflow, are prescribed to manage corneal edema, control IOP, and improve visibility for procedures.
Lifelong follow-ups are often required to monitor intraocular pressure. Prognosis is better with early diagnosis and prompt surgical intervention, maintaining stable optic nerves and fully functional visual fields into adulthood. Corneal edema and optic nerve head changes are reversible if timely intervention is done; however, late presentation and diagnosis can lead to sight-threatening complications.
In January 2024, there are currently 4 clinical trials recruiting and 3 additional trials announced but not yet recruiting in ClinicalTrials.gov related to this disease, with at least 2 of them focusing on different disease management strategies for congenital glaucoma.
Resources and initiatives
Interesting resources exist for patients and caregivers, such as the NIH’s Genomic and Rare Disease (GARD) and MedlinePlus. Furthermore, the Glaucoma Research Foundation offers a free reference guide on Childhood Glaucoma with educational materials for families and individuals.
For doctors and other help professionals, the website Orphanet, the American Academy of Ophthalmology, and the NIH’s Genetic Testing Registry offer information to help with diagnosis and testing.
Regarding advocacy, several NGOs are especially dedicated to connecting families affected by the disease, such as the Children’s Glaucoma Foundation and the Pediatric Glaucoma Foundation Family Associates. In addition, the NORD (National Organization for Rare Disorders) offers education programs, advocacy, research, and patient services for many rare diseases, and has resources for patients, caregivers, clinicians, and researchers.
What’s #ShareForRare?
In line with Franklin’s commitment to advancing the field of rare disease diagnosis and treatment, this initiative aims to raise awareness of uncommon disorders in the Franklin Community and encourage collaboration among community members.
Our team of clinical curators has prepared a monthly spotlight on different genetic diseases to help educate and connect professionals from around the world who are working on similar conditions.
If you’d like us to focus on a particular disease you’ve been working on, make your suggestion here!
