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Primary Congenital Glaucoma

, PhD, FRCPath and , MD.

Author Information
, PhD, FRCPath
Department of Ophthalmology
College of Medicine
King Saud University
Riyadh, Saudi Arabia
Department of Ophthalmology
College of Medicine
University of Florida
Jacksonville, Florida
, MD
Wilmer Eye Institute
Johns Hopkins University School of Medicine
Baltimore, Maryland
King Khaled Eye Specialist Hospital
Riyadh, Saudi Arabia

Initial Posting: ; Last Update: March 20, 2014.

Summary

Disease characteristics. Primary congenital glaucoma (PCG) is characterized by elevated intraocular pressure (IOP), enlargement of the globe (buphthalmos), edema, and opacification of the cornea with rupture of Descemet's membrane (Haabs striae), thinning of the anterior sclera and iris atrophy, anomalously deep anterior chamber, and structurally normal posterior segment except for progressive glaucomatous optic atrophy. Symptoms include photophobia, blepharospasm, and excessive tearing (hyperlacrimation). Typically, the diagnosis is made in the first year of life. Depending on when treatment is instituted, visual acuity may be reduced and/or visual fields may be restricted. In untreated cases, blindness invariably occurs.

Diagnosis/testing. The diagnosis of PCG is based on clinical findings. Identification of biallelic pathogenic variants in CYP1B1 (encoding cytochrome P450 1B1) or LTBP2 (encoding latent-transforming growth factor beta-binding protein 2) confirms the diagnosis. Two other loci, GLC3B on 1p36 and GLC3C on 14q24.3, have been linked to PCG; however, the genes at these loci are not known.

In general, the probability of identifying biallelic pathogenic variants in CYP1B1 increases with the presence of bilateral and severe disease, a positive family history for the disease, and parental consanguinity.

Management. Treatment of manifestations: Surgery (goniotomy, trabeculotomy, or trabeculectomy) as early as possible or use of drainage implants or cyclodestruction if surgery fails; medication preoperatively and postoperatively to help control IOP; routine treatment of refractive errors and amblyopia.

Prevention of secondary complications: Discontinuation of medications such as phospholine (ecothiopate) iodide before surgery to prevent prolonged apnea.

Surveillance: Lifelong monitoring to ensure control of IOP.

Agents/circumstances to avoid: Alpha-2 agonists because of risk for apnea and bradycardia.

Evaluation of relatives at risk: If both pathogenic variants have been identified in the family, molecular genetic testing of at-risk sibs as soon as possible after birth in order to avoid repeated examinations under anesthesia in young children who do not have the pathogenic variants.

Genetic counseling. PCG caused by CYP1B1 or LTBP2 pathogenic variants is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants of an affected family member have been identified.

Diagnosis

Clinical criteria to establish the diagnosis of primary congenital glaucoma (PCG) are the following:

  • Elevated intraocular pressure (IOP) in an infant or child typically under age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry or pneumatonometry on at least two occasions is considered abnormally elevated. In general, normal eye pressures in children are 12.02 +/- 3.74 mm Hg [Sihota et al 2006].
  • Enlargement of the (infantile) globe (buphthalmos)
  • Increased corneal diameter
  • Anomalously deep anterior chamber

The classic clinical characteristics of PCG include the following:

  • Photophobia, blepharospasm, and excessive tearing (hyperlacrimation) (in infants)
  • Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
  • Thinning of the anterior sclera and atrophy of the iris (in infants)
  • Structurally normal posterior segment except for progressive optic atrophy
  • Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis

The typical findings may not be equally present in both eyes of an affected individual. It is also possible that some affected individuals have mild presentation with subtle clinical findings.

Molecular genetic testing can be used to confirm the diagnosis of PCG (Table 1). The presence of biallelic pathogenic variants in CYP1B1 or LTBP2 is confirmatory*.

Molecular genetic testing strategies include:

*The absence of biallelic CYP1B1 or LTBP2 pathogenic variants suggests either that the disease results from other genetic causes (see Evidence for possible further locus heterogeneity) or undetermined causes or that the clinical diagnosis is inaccurate (see Differential Diagnosis).

Table 1. Summary of Molecular Genetic Testing Used in Primary Congenital Glaucoma

Gene 1 Proportion of PCG Attributed to Pathogenic Variants in This GeneTest Method
CYP1B120%-100% of familial cases 2
10%-15% of simplex cases 3, 4
Sequence analysis 5
Targeted mutation analysis 6
Deletion/duplication analysis 7, 8
LTBP2Unknown 9Sequence analysis 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. The proportion of PCG caused by mutation of CYP1B1 varies. In general, the probability of identifying pathogenic variants in CYP1B1 increases with the presence of: positive family history for the disease, parental consanguinity, and bilateral and severe disease. However, differences in the number of individuals studied, the methods of ascertainment (familial vs simplex cases [i.e., only one affected individual in a family], unilateral vs bilateral disease), and the molecular genetic testing methods used make accurate estimates and comparisons of mutation detection frequency among ethnic groups difficult.

3. Simplex case = only one affected individual in a family

4. It is estimated that the proportion of PCG caused by mutation of CYP1B1 decreases to 10%-15% in simplex cases [Mashima et al 2001, Stoilov et al 2002, Curry et al 2004].

5. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. The p.Glu387Lys pathogenic variant is responsible for all the mutations in Rom Slovakian individuals [Plásilová et al 1999].

7. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8. Stoilov et al [1997]

9. Only two reports to date [Ali et al 2009, Narooie-Nejad et al 2009]

Evidence for possible further locus heterogeneity

  • Possible role of MYOC variants in the molecular etiology of PCG is unclear; further studies are needed. Note: (1) Kaur et al [2005] presented evidence in a single individual that the combination of a heterozygous pathogenic variant in MYOC and a heterozygous pathogenic variant in CYP1B1 was associated with PCG, suggesting digenic inheritance. (2) A report of a Chinese family segregating both primary congenital open-angle glaucoma (POAG) and PCG suggested that homozygous MYOC variants may cause PCG [Zhuo et al 2006].
  • The following loci have been linked to PCG; the related genes and pathogenic variants are not known.

Clinical Description

Natural History

Primary congenital glaucoma (PCG) is characterized by developmental defect(s) of the trabecular meshwork and anterior chamber angle that prevent adequate drainage of aqueous humor, resulting in elevated intraocular pressure (IOP) and stretching of the sclera that produces an enlarged globe (buphthalmos).

The following information comes from the detailed clinical papers on PCG of deLuise & Anderson [1983] and Ho & Walton [2004] unless otherwise noted.

By definition, congenital glaucoma is present at birth; it is typically diagnosed in the first year of life. PCG is more common in males (65%) and is bilateral in 70% of individuals.

The clinical signs and symptoms depend primarily on the age of onset and the severity of the disease. The classic symptoms include tearing, photophobia, and irritability. Occasionally, parents may notice cloudy and/or unusually large corneas in their child caused by corneal edema; the corneal enlargement generally occurs before age three years.

The most severe clinical features are typically seen in the newborn, who may present with corneal opacity, increased corneal diameter, increased IOP, and an enlarged globe [Walton 1998]. In 35 newborns with PCG, corneal edema was present in 100% of the eyes, either as diffuse (90% of cases) or localized (10%) opacity [Walton 1998].

Early detection and appropriate treatment of congenital glaucoma can improve visual outcome. In contrast to the permanent optic nerve cupping and visual field loss seen in adults with adult-onset glaucoma, the pressure-induced optic nerve cupping in infants and young children with PCG is reversible, particularly in the early stages of the disease. This favorable outcome is believed to be a result of the highly elastic nature of the tissues of the optic nerves of infants and young children [Allingham et al 2005]. A delay in treatment can result in reduced visual acuity and/or restricted visual fields. In untreated cases, blindness invariably occurs.

The ultimate visual outcome depends on the severity of the disease at diagnosis, the presence of other associated ocular abnormalities, response to surgical treatment, and success of control of IOP upon follow up. The earlier the onset of clinical manifestations of glaucoma, the worse the prognosis.

Despite early treatment and multiple surgical interventions, some individuals with severe disease evident at birth develop significant visual impairment from corneal opacification, advanced glaucomatous damage, or amblyopia and may eventually become legally blind.

Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.

The IOP is a significant prognostic factor for postoperative visual function, with substantially better vision observed in individuals with IOPs lower than 19 mm Hg.

Genotype-Phenotype Correlations

Walton and colleagues have shown that the phenotype can vary significantly in the same individual (one eye being more severely affected than the other) [Walton 1998].

No consistent correlation has been observed between the severity of the glaucoma phenotype and the CYP1B1 mutation type among individuals in the same family who have identical pathogenic variants [Bejjani et al 1998], and among families with identical pathogenic variants [Bejjani et al 1998, Bejjani et al 2000].

No information is available on correlation between the success of surgical therapy and the type of CYP1B1 pathogenic variant detected; however, people with PCG caused by mutation of CYP1B1 needed significantly more surgical procedures to control intraocular pressure than individuals with congenital glaucoma of unknown cause, when both eyes of an individual were evaluated (P=0.003) or the worst eye was evaluated (P=0.011) [Della Paolera et al 2010].

Patients with PCG caused by mutation of CYP1B1 tend to have a higher operative success rate than individuals with no CYP1B1 mutation in terms of better intraocular pressure control effect. Together, the presence or absence of mutation of CYP1B1 and the preoperative corneal opacity score can partially predict the outcome of PCG surgery [Chen et al 2014].

Compared to individuals with PCG without mutation of CYP1B1, those with PCG caused by mutation of CYP1B1 had higher last postoperative visit indices in terms of postoperative haze and the need for anti-glaucoma medications [Abu-Amero et al 2011].

Prevalence

The prevalence of CYP1B1 pathogenic variants in individuals with PCG varies: 20% in Japanese [Plásilová et al 1999], 33.3% in Indonesians [Sitorus et al 2003], 44% among Indians [Chakrabarti et al 2010], 50% among Brazilians [Stoilov et al 2002], 70% in Iranians [Chitsazian et al 2007], and 80%-100% among Saudi Arabians [Bejjani et al 2000, Abu-Amero et al 2011] and Slovakian Gypsies [Plásilová et al 1999]. The relatively higher prevalence of these pathogenic variants in the latter two populations could be attributed to consanguinity.

Some pathogenic variants are more common in specific ethnic groups. For example:

  • p.Glu387Lys accounts for all the pathogenic variants in the Rom Slovakian population.
  • p.Gly61Glu accounts for 72% of the pathogenic variants in Saudi Arabians [Bejjani et al 1998].

Additional pathogenic variants have been associated (although with lesser frequencies) with other specific ethnic groups [Belmouden et al 2002, Panicker et al 2002, Chakrabarti et al 2006].

PCG occurs in all ethnic groups. The birth prevalence, however, varies worldwide:

  • 1:5,000-22,000 in western countries
  • 1:2,500 in the Middle East
  • 1:1,250 in the Rom (Gypsy) population of Slovakia [Plásilová et al 1998]
  • 1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [Dandona et al 2001]

In Saudi Arabia and in the Rom population of Slovakia, PCG is the most common cause of childhood blindness [Plásilová et al 1998, Bejjani et al 2000].

Differential Diagnosis

A number of congenital ocular conditions can mimic PCG and must be considered by the clinician [Khan 2011]. For example, the nonspecific findings of tearing and redness of the eyes may mimic more common conditions such as conjunctivitis or congenital nasolacrimal duct obstruction; ocular irritation with photophobia and redness may mimic the more frequent problem of corneal abrasion.

Congenital glaucoma can be subcategorized by age of onset into the following three types:

  • Primary "newborn"-type congenital glaucoma. The most severe type; clinically apparent between birth and age one month
  • Primary "infantile" glaucoma (or infantile PCG, as described by Walton & Katsavounidou [2005]. Clinically recognized between age one month and two years
  • "Juvenile" ("late-recognized") primary infantile glaucoma. Onset clinically apparent after age two years

The types do not correlate with a specific genetic cause, although primary "newborn"-type congenital glaucoma is more likely to be caused by mutation of CYP1B1 than the other types of congenital glaucoma.

In the older child with juvenile onset, or in less severe cases, the increase in intraocular pressure (IOP) is gradual; thus, corneal edema and opacity may be less obvious than in the newborn type. Progressive enlargement of the globe or "buphthalmos" usually does not occur after age three to four years [Ho & Walton 2004, Allingham et al 2005].

Conditions/syndromes associated with infantile glaucoma. A number of well-recognized conditions and syndromes may present with infantile glaucoma, along with other ocular and/or systemic findings. Some conditions may not be compatible with life (e.g. trisomy 13, trisomy 18, Walker-Warburg syndrome (see Congenital Muscular Dystrophy Overview), and Zellweger Syndrome); others may be less severe or confined only to the eye.

It is important to establish the diagnosis of an associated syndrome because of the implications for genetic counseling and treatment.

Associated syndromes:

  • Aniridia is characterized by complete or partial iris hypoplasia with associated foveal hypoplasia, resulting in reduced visual acuity and nystagmus, presenting in early infancy. It is frequently associated with other ocular abnormalities, often of later onset, including cataract, glaucoma, and corneal opacification and vascularization. Inheritance is autosomal dominant.
  • Anterior segment dysgenesis syndromes are a heterogeneous group of disorders that are usually inherited in an autosomal dominant manner with reduced penetrance. In general, they appear to be phenotypically and genotypically distinct from PCG, although some cases of severe or advanced PCG are difficult to distinguish clinically from some of the anterior segment dysgenesis syndromes such as Peters anomaly. (See also Peters Plus Syndrome.)
  • Axenfeld-Rieger (A-R) anomaly is an anterior segment disorder that presents with posterior embryotoxon and one or more of the following: iris strands adherent to Schwalbe's line, iris hypoplasia, focal iris atrophy, and ectropion uveae. Glaucoma develops in approximately half of individuals with A-R anomaly, but is more common in those with central iris changes and marked anterior iris insertion. A-R anomaly is always bilateral, but may be distinctly asymmetric. A-R anomaly may occur in the setting of Rieger syndrome, which can include developmental defects of the teeth and facial bones, pituitary anomalies, cardiac disease, oculocutaneous albinism, and redundant periumbilical skin. A-R anomaly and Rieger syndrome are inherited in an autosomal dominant manner.
  • Microcornea is defined by a corneal diameter less than 10 mm. It can be associated with glaucoma and other ocular anomalies including congenital cataracts, sclerocornea, and corneal plana, or may be a feature of systemic syndromes.
  • Congenital hereditary endothelial dystrophy (CHED) is characterized by bilateral corneal opacification and may be difficult to distinguish from microcornea. However, the corneal diameter and IOP are usually normal in CHED. Both autosomal dominant and autosomal recessive inheritance are observed. Autosomal recessive CHED (CHED2) is associated with mutation of SLC4A11 [Kumar et al 2007]. The primary defect in the corneal endothelium leads to corneal edema and opacification. CHED and congenital glaucoma are known to coexist; the exact incidence is unknown [Ramamurthy et al 2007].
  • Lowe syndrome (oculocerebral renal syndrome) is characterized by involvement of the eyes, central nervous system, and kidneys. Dense congenital cataracts are found in all affected boys and infantile glaucoma in approximately 50%. All boys have impaired vision; corrected acuity is rarely better than 20/100. Almost all affected males have some degree of intellectual disability. Glomerulosclerosis associated with chronic tubular injury usually results in slowly progressive chronic renal failure and end-stage renal disease after age ten to 20 years. Inheritance is X-linked.
  • Neurofibromatosis type 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy. Congenital glaucoma is rarely observed in individuals with NF1. Inheritance is autosomal dominant.
  • Nance-Horan syndrome is an X-linked disorder characterized by cataract, microcornea, and skeletal features.
  • Sturge-Weber syndrome (SWS) is characterized by nevus flammeus of the face and angioma of the meninges. Congenital glaucoma with associated angle anomalies may be seen in as many as 60% of affected individuals.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to CYP1B1-related primary congenital glaucoma, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary congenital glaucoma (PCG), examination under anesthesia or sedation is warranted to make a complete assessment of both eyes. The examination includes the following:

  • Measurement of intraocular pressure (IOP) within the first few minutes of anesthesia
  • Measurement of corneal diameter
  • Examination of the anterior segment
  • Direct gonioscopy to rule out secondary glaucoma
  • Dilated fundus examination to evaluate for optic nerve damage
  • If the cornea is opaque, ultrasound biomicroscopy to aid in evaluating the anterior segment structures
  • Medical genetics consultation

Note: If the child is examined under anesthesia, consent may be obtained to perform the appropriate surgical procedure after evaluation under anesthesia.

Treatment of Manifestations

The primary goal of treatment is to decrease IOP to prevent vision-threatening complications including corneal opacification and glaucomatous optic atrophy. Early treatment to control IOP will reverse some of these complications in children.

Surgical treatment. The following approach is based on the work of deLuise & Anderson [1983], Ho & Walton [2004], Bowman et al [2011], and Sharaawy & Bhartiya [2011].

PCG is almost always managed surgically. The primary goal of surgery is to eliminate the resistance to aqueous outflow caused by the structural abnormalities in the anterior chamber angle. This goal may be accomplished through an internal approach (goniotomy) or an external approach (trabeculotomy or trabeculectomy).

In goniotomy, the surgeon visualizes the anterior chamber structures through a special lens (goniolens) to create openings in the trabecular meshwork. The goal of the procedure is to eliminate any resistance imposed by the abnormal trabecular meshwork. A clear cornea is necessary for direct visualization of the anterior chamber structures during this procedure.

In trabeculotomy, the trabecular meshwork is incised by cannulating Schlemm's canal with a metal probe or suture via an external opening in the sclera.

In trabeculectomy, a section of trabecular meshwork and Schlemm's canal is removed under a partial thickness sclera flap to create a wound fistula.

Note: In contrast to goniotomy, trabeculotomy and trabeculectomy can be performed in individuals with advanced glaucoma and cloudy corneas.

Glaucoma drainage implants or cyclodestruction may be used to control IOP when initial surgical procedures have failed.

More than one surgical intervention may be necessary to control IOP; thus, significant morbidity is associated with both PCG and the currently available surgical treatment options. Patients with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.

Clarity of the cornea and other ocular media, control of the ocular dimensions (corneal diameters and axial lengths), and optic nerve damage are important indicators of the course of the disease following surgery. Reported success rates for each (initial) procedure are approximately 80%. Infants with elevated IOP and cloudy corneas at birth have the poorest prognosis. The most favorable outcome is seen in infants in whom surgery is performed between the second and eighth month of life. With increasing age, surgery is less effective in preserving vision.

Medications. Beta-blockers (timolol), parasympathomimetics (pilocarpine), sympathomimetics (adrenergic agonists and alpha-2 adrenergic receptor agonists), carbonic anhydrase inhibitors, and prostaglandin agonists have all been used. These medications, particularly the alpha-2 adrenergic receptor agonists, may have severe side effects and must be used with caution in infants and children [Maris et al 2005, Papadopoulos & Khaw 2007].

Surgery should not be delayed in an attempt to achieve medical control of IOP.

Medication may be used preoperatively to lower the IOP to prevent optic nerve damage, to reduce the risk of sudden decompression of the globe, and to clear the cornea for better visualization during examination and surgery.

Postoperatively, medication may help control IOP until the success of the surgical procedure is established.

Medical therapy is also used when surgery may be life threatening or has led to incomplete control of the glaucoma [deLuise & Anderson 1983].

Treatment of refractive errors. Amblyopia from uncorrected refractive errors often associated with PCG must be treated to obtain optimal visual function.

Prevention of Secondary Complications

Medications such as Phospoline (ecothiopate) Iodide® need to be discontinued before surgery, especially if succinylcholine is used because of the prolonged apnea.

Surveillance

Lifelong monitoring is necessary to ensure control of IOP to preserve remaining vision and to prevent further loss of vision; the intervals at which monitoring needs to be performed vary depending on the severity of disease and control of IOP.

Once IOP is controlled and the child is visually rehabilitated, follow up is typically every three months to keep IOP at the "target" level, which depends on the severity of the glaucomatous optic nerve damage and the age of the patient. Standard clinical follow-up tests include optic nerve photography and visual field testing. The complete ophthalmic evaluation often requires examination under anesthesia or sedation in infants and in young and uncooperative children. This process may be challenging to the patient, the family, and the treating physician [deLuise & Anderson 1983, Ho & Walton 2004].

Agents/Circumstances to Avoid

Alpha-2 agonists should be avoided in children in the treatment of elevated IOP because of the risk for apnea and bradycardia.

Evaluation of Relatives at Risk

Testing at-risk sibs in the neonatal period may be helpful in establishing the diagnosis of PCG early and in avoiding repeated examinations under anesthesia in at-risk young children. Molecular genetic testing alone is appropriate in sibs of affected individuals in whom both pathogenic variants have been identified. If no definitive exclusion of the disease is possible by molecular genetic testing, repeat IOP measurements under anesthesia may be necessary.

Note: The literature is unclear as to timing of the onset of glaucoma, especially in families in whom pathogenic variants have been identified. In this high-risk group, it may be appropriate to perform yearly glaucoma screening into young adulthood.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Primary congenital glaucoma (PCG) caused by mutation of CYP1B1 or LTBP2 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with PCG caused by mutation of CYP1B1 or LTBP2 are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the CYP1B1 or LTBP2 pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If both pathogenic variants have been identified in either CYP1B1 or LTBP2 in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of the gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like PCG) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's Glaucoma Foundation
    2 Longfellow Place
    Suite 201
    Boston MA 02114
    Phone: 617-227-3011
    Fax: 617-227-9538
    Email: info@childrensglaucoma.com
  • Glaucoma Research Foundation
    251 Post Street
    Suite 600
    San Francisco CA 94108
    Phone: 800-826-6693 (toll-free); 415-986-3162
    Fax: 415-986-3763
    Email: question@glaucoma.org
  • International Glaucoma Association (IGA)
    Woodcote House
    15A Highpoint Business Village
    Ashford Kent TN24 8DH
    United Kingdom
    Phone: +44 1233 64 81 70; +44 1233 64 81 64
    Fax: +44 1233 64 81 79
    Email: info@iga.org.uk
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Primary Congenital Glaucoma: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Primary Congenital Glaucoma (View All in OMIM)

231300GLAUCOMA 3, PRIMARY CONGENITAL, A; GLC3A
600975GLAUCOMA 3, PRIMARY INFANTILE, B; GLC3B
601771CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 1; CYP1B1
602091LATENT TRANSFORMING GROWTH FACTOR-BETA-BINDING PROTEIN 2; LTBP2
613085GLAUCOMA 3, PRIMARY CONGENITAL, C; GLC3C
613086GLAUCOMA 3, PRIMARY CONGENITAL, D; GLC3D

Molecular Genetic Pathogenesis

In addition CYP1B1 and LTBP2 (mutation of which is known to cause primary congenital glaucoma [PCG]), FOXC1 (forkhead box C1; OMIM 601090) has been reported to be associated with PCG. FOXC1 is thought to play a role in the development of ocular tissues including the drainage structures. The FOXC1 protein, expressed in various ocular and non-ocular tissues, is found in the periocular mesenchyme cells that give rise to ocular drainage structures such as the iris, cornea, and the trabecular meshwork (TM). Both FOXC1-null (Foxc1-/-) mice and heterozygous (Foxc1+/-) mice have anterior segment abnormalities similar to those in humans with anterior segment dysgenesis (ASD) and congenital glaucoma: small to absent Schlemm’s canal, aberrantly developed TM, iris hypoplasia, severely eccentric pupils, and displaced Schwalbe’s line. However, the absence of FOXC1 pathogenic variants in individuals with PCG indicated a limited role for this gene in PCG pathogenesis [Chakrabarti et al 2009].

CYP1B1

Gene structure. CYB1B1 spans 12 kb, comprises three exons (exons 2 and 3 only are coding exons), and produces a 1,631-base mRNA product. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Currently 118 pathogenic variants are listed in the Human Gene Mutation Database (HGMD) (see Table A), including 81 missense/nonsense, 21 small deletions, and nine small insertions; the remainder are other types of mutations. See Prevalence for information about some specific pathogenic variants.

Normal gene product. Cytochrome P450 1B1 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. Cytochrome P450 1B1 localizes to the endoplasmic reticulum and metabolizes procarcinogens including polycyclic aromatic hydrocarbons and 17-β-estradiol [Murray et al 2001].

Abnormal gene product. In silico and in vitro studies have been carried out to determine the effect of CYP1B1 pathogenic variants on the structure and function of the protein. The findings of these studies can help further the understanding of mutation of CYP1B1 with the disease pathogenesis.

  • In persons with congenital glaucoma Hollander et al [2006] tried to correlate CYP1B1 pathogenic variants with (a) the degree of angle dysgenesis observed histologically and (b) disease severity (age at diagnosis and difficulty in controlling IOP). Their findings suggested that CYP1B1 pathogenic variants could be classified based on histologic findings, which may be used to correlate these variants with disease severity.
  • Certain CYP1B1 pathogenic variants have been analyzed in silico for their possible impact on the protein structure and function. Comparative modeling of human CYP1B1 using the x-ray structure of CYP2c9 as template along with molecular dynamics simulations revealed several structural differences that would potentially affect the functional domains [Acharya et al 2006b].
  • In vitro studies to determine the effect of CYP1B1 pathogenic variants on the stability and function of the protein were carried out by Jansson et al [2001]. The authors studied the effect of two missense variants (p.Gly61Glu and p.Arg469Trp) on the stability and enzymatic activity of CYP1B1. It was observed that p.Gly61Glu mutant had lost 60% of its stability, while p.Arg469Trp retained about 80% of the stability compared to the wild type. The effects of the mutants on the function of protein were further determined by an enzymatic assay that further confirmed their decreased metabolic activity (50%-70%) for all the substrates when compared to the wild type protein.
  • Bagiyeva et al [2007] compared the enzymatic activity of the two other mutant (p.Arg117Trp and p.Gly329Val) proteins with wild type. While there was no apparent difference in the expression levels of wild type and mutant proteins, enzymatic activity in the mutant proteins was less than in the wild type. This finding was attributed to the slower traffic of CYP1B1 through the endoplasmic reticulum (ER), which further contributed to the lower enzyme activity and conceivably led to PCG pathogenesis.

LTBP2

Gene structure. LTBP2 comprises 36 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Ali et al [2009] first reported that the LTBP2 pathogenic variants c.412delG, c.895 C>T, c.1243-1256del, and c.331 C>T caused PCG in four consanguineous families from Pakistan and in persons of Rom ethnicity. Narooie-Nejad et al [2009] subsequently reported two LTBP2 loss-of-function pathogenic variants in Iranian families with PCG: homozygosity for the deletion c.5376delC in exon 36 and homozygosity for the deletion c.1415delC in exon 7.

Although double heterozygosity (i.e., heterozygosity for a pathogenic variant at each of two separate genetic loci) for a CYP1B1 pathogenic variant and an LTBP2 pathogenic variant was reported by Azmanov et al [2011], the observed combination is of no clinical significance and digenic inheritance is unlikely.

Normal gene product. The encoded protein, comprising 1821 amino acids, belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multi-domain structure. This protein is the largest member of the LTBP family; it possesses unique regions and is the most similar to the fibrillins. It has thus been suggested that the protein may have multiple functions: as a member of the TGF-beta latent complex, as a structural component of microfibrils, and as a mediator of cell adhesion.

Abnormal gene product. Pathogenic variants are expected to extensively affect protein structure and function and to interfere with both fibrillin 1 and fibulin 5 binding [Narooie-Nejad et al 2009].

References

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Suggested Reading

  1. Fan BJ, Wiggs JL. Glaucoma: genes, phenotypes, and new directions for therapy. J Clin Invest. 2010;120:3064–72. [PMC free article: PMC2929733] [PubMed: 20811162]
  2. Pan Y, Varma R. Natural history of glaucoma. Indian J Ophthalmol. 2011;59 Suppl:S19–23. [PMC free article: PMC3038509] [PubMed: 21150029]
  3. Rao KN, Nagireddy S, Chakrabarti S. Complex genetic mechanisms in glaucoma: an overview. Indian J Ophthalmol. 2011;59 Suppl:S31–42. [PMC free article: PMC3038510] [PubMed: 21150032]
  4. Razeghinejad MR, Spaeth GL. A history of the surgical management of glaucoma. Optom Vis Sci. 2011;88:E39–47. [PubMed: 21131879]
  5. Sheffield VC, Alward WLM, Stone EM. The glaucomas. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; Chap 242. Available online. Accessed 3-17-14.
  6. Vijaya L, Manish P, Ronnie G, Shantha B. Management of complications in glaucoma surgery. Indian J Ophthalmol. 2011;59 Suppl:S131–40. [PMC free article: PMC3038515] [PubMed: 21150025]

Chapter Notes

Author History

Khaled K Abu-Amero, PhD, FRCPath (2011-present)
Bassem A Bejjani, MD, FACMG; Washington State University (2004-2011)
Deepak P Edward, MD (2004-present)

Revision History

  • 20 March 2014 (me) Comprehensive update posted live
  • 25 August 2011 (cd) Revision: sequence analysis of LTBP2 and deletion/duplication analysis of CYP1B1 available clinically as listed in the GeneTests Laboratory Directory
  • 21 July 2011 (me) Comprehensive update posted live
  • 3 December 2007 (me) Comprehensive update posted to live Web site
  • 30 September 2004 (me) Review posted to live Web site
  • 3 June 2004 (bab) Original submission
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