Clinical Diagnosis

Clinical criteria for diagnosis of primary congenital glaucoma (PCG) include 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

Genes (See Table 1)

• CYP1B1 (locus name GLC3A) encodes the protein cytochrome P450 1B1.

• LTBP2 (locus GLC3D) encodes the protein latent-transforming growth factor beta-binding protein 2.

Evidence for possible further locus heterogeneity

• MYOC. The role of MYOC mutations in the molecular etiology of PCG is unclear; further studies are needed.

  • MYOC may be associated with the molecular pathogenesis of PCG. Kaur et al [2005] presented evidence in a single individual that a heterozygous mutation in MYOC, combined with a heterozygous mutation in CYP1B1, was associated with PCG, suggesting digenic inheritance.

  • A report of a Chinese family segregating both primary congenital open-angle glaucoma (POAG) and PCG suggested that homozygous MYOC mutations may cause PCG [Zhuo et al 2006].

• The following loci have been linked to PCG; the related genes and causal mutations are not known.

• GLC3B on 1p36.2-p36.1 [Akarsu et al 1996]

• GLC3C on 14q24.3 [Stoilov 2002]

• Additional locus that does not appear to overlap GLC3C at critical region 14q24.2-q24.3 [Firasat et al 2008]

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

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Gene Symbol	Proportion of PCG Attributed to Mutations in this Gene	Test Method	Mutations Detected	Test Availability
CYP1B1	20%-100% of familial cases 1 10%-15% of simplex cases 2, 3	Sequence analysis	Sequence variants 4	Clinical
		Targeted mutation analysis	p.Glu387Lys 5
		Deletion / duplication analysis	Exonic or whole-gene deletions 6
LTBP2	Unknown 7	Sequence analysis	Sequence variants 4	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The percentage of CYP1B1 mutations causing PCG varies. In general, the probability of identifying mutations 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.

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

3. It is estimated that the frequency of CYP1B1 mutations decreases to 10%-15% in simplex cases [Mashima et al 2001, Stoilov et al 2002, Curry et al 2004].

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

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

6. Stoilov et al [1997]

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

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Autosomal recessive transmission is established if homozygous or compound heterozygous mutations in CYP1B1 are identified in an affected individual.

• The absence of CYP1B1 mutations suggests either that the disease results from other genetic or undetermined causes or that the clinical diagnosis is incomplete or inaccurate (e.g., the affected individual has anterior segment dysgenesis with glaucoma). In such cases, the mode of inheritance remains unclear.

• The identification of a single mutant CYP1B1 allele in an individual with PCG makes genetic counseling difficult.

Testing Strategy

To confirm/establish the diagnosis in a proband

• The diagnosis is established in an infant who meets clinical diagnostic criteria.

• Molecular genetic testing of CYP1B1 (sequence analysis followed by deletion/duplication analysis if two mutations are not identified) can be used to confirm the diagnosis.

• For individuals in whom mutations in CYP1B1 are not identified, sequence analysis of LTBP2 may be considered.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk infants. Molecular genetic testing of CYP1B1 can be used, particularly in at-risk neonates, to establish a diagnosis early and avoid repeated examinations under anesthesia.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

CYP1B1

Peters anomaly. Mutations in CYP1B1 have been described in Peters anomaly (OMIM 604229), a uni- or bilateral developmental disorder of the anterior chamber that is distinct from PCG. Clinical findings in Peters anomaly include central corneal opacity associated with corneal stromal thinning, absence of varying lengths of central Descemet's membrane, and irido-corneal and/or kerato-lenticular adhesions.

Juvenile open-angle glaucoma (JOAG). CYP1B1 mutations have also been implicated in three individuals with JOAG (OMIM 137750) [Vincent et al 2002]. In that study, a family with autosomal dominant glaucoma showed cosegregation of mutations in MYOC (the gene encoding myocilin) and CYP1B1 in an individual with more severe disease. These results suggest that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway [Vincent et al 2002].

Mutations in MYOC, the gene encoding myocillin, may, in conjunction with mutations in CYP1B1, increase the clinical severity of glaucoma in individuals with JOAG. Indeed, individuals who are heterozygous for mutations in both MYOC and CYP1B1 seem to have a more severe open-angle glaucoma phenotype than those who are heterozygous for mutations in MYOC alone [Vincent et al 2002]. Vincent et al [2002] hypothesized that CYP1B1 and MYOC may act through a common biochemical pathway with CYP1B1 acting as a modifier for MYOC.

Acharya et al [2006a] suggested that on rare occasions homozygous CYP1B1 mutations alone (i.e., without MYOC mutations) may cause JOAG.

LTBP2. Kumar et al [2010] detected a homozygous LTBP2 mutation in one family with microspherophakia.

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 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 molecular CYP1B1 genotype among individuals with identical mutations within the same family [Bejjani et al 1998], and among families with identical mutations [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 mutation detected; however, people with CYP1B1 mutations needed significantly more surgical procedures to control intraocular pressure than individuals with congenital glaucoma without CYP1B1 mutations, 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].

Prevalence

The prevalence of CYP1B1 mutations in individuals with PCG ranges from 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], to almost 100% among Saudi Arabians [Bejjani et al 2000] and Slovakian Gypsies [Plásilová et al 1999]. The relatively higher prevalence of these mutations in the latter two populations could be attributed to consanguinity and inbreeding.

Some mutations are more common in specific ethnic groups. For example, p.Glu387Lys is responsible for all the mutations in affected Rom Slovakian individuals, and p.Gly61Glu accounts for 72% of the mutations in Saudi Arabians [Bejjani et al 1998]. Additional mutations 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 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

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 of apnea and bradycardia.

Testing 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 mutations have been identified. If no definitive exclusion of the disease is possible by molecular testing, then repeated 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 mutations 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Primary congenital glaucoma (PCG) caused by CYP1B1 or LTBP2 mutations 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 CYP1B1 or LTBP2 mutations are obligate heterozygotes (carriers) for a disease-causing mutation.

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 once the CYP1B1 mutations have been identified in the family.

Carrier testing of at-risk relatives for mutations in LTBP2 may be available from laboratories offering clinical confirmation of mutations identified in research laboratories if the disease-causing mutations in the family have been identified. See .

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for PCG caused by mutations in CYP1B1 is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as PCG 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

In addition to the two genes in which mutations are 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 mutations in individuals with PCG indicated a limited role for this gene in PCG pathogenesis [Chakrabarti et al 2009].

CYP1B1

Normal allelic variants. CYB1B1 spans 12 kb, comprises three exons (exons 2 and 3 only are coding exons), and produces a 1,631-base mRNA product.

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

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 such as 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 impact of mutations in CYP1B1 on the structure and function of the protein. The findings of these studies can help in a better understanding of the association of CYP1B1 with the disease pathogenesis.

• In persons with congenital glaucoma Hollander et al [2006] tried to correlate CYP1B1 mutations 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 mutations could be classified based on histologic findings, which may be used to correlate these mutations with disease severity.

• Certain CYP1B1 mutations 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 mutations on the stability and function of the protein were carried out by Jansson et al [2001]. The authors studied the effect of two missense mutations (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 ER, which further contributed to the lower enzyme activity and conceivably led to PCG pathogenesis.

LTBP2

Normal allelic variants. LTBP2 comprises 36 exons.

Pathologic allelic variants. Ali et al [2009] first reported that the LTBP2 mutations 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 Gypsy ethnicity. Narooie-Nejad et al [2009] subsequently reported two LTBP2 loss of function mutations 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 mutation at each of two separate genetic loci) for a CYP1B1 mutation and an LTBP2 mutation were 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. Mutations 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].

Literature Cited

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2. Acharya MS, Reddy AB, Chakrabarti S, Panicker SG, Mandal AK, Ahmed N, Balasubramanian D, Hasnain SE, Nagarajaram HA. Disease-causing mutations in proteins: structural analysis of the CYP1B1 mutations causing primary congenital glaucoma in humans. Biophys J. 2006b;91:4329–39. [PMC free article: PMC1779944] [PubMed: 16963504]
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9. Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, Astle WF, Lupski JR. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet. 2000;9:367–74. [PubMed: 10655546]
10. Belmouden A, Melki R, Hamdani M, Zaghloul K, Amraoui A, Nadifi S, Akhayat O, Garchon HJ. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin Genet. 2002;62:334–9. [PubMed: 12372064]
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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 Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill; Chap 242. Available at www.ommbid.com. Accessed 7-18-11.
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]

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

• 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