Clinical 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 (Haab's 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. 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 individuals, blindness invariably occurs.

Diagnosis/testing.

The diagnosis of PCG is based on clinical criteria including: elevated IOP in a child typically before age one year, enlargement of the globe, increased corneal diameter, cloudy corneas, breaks in Decsemet’s membrane (Haab’s striae) and anomalously deep anterior chamber. Identification of biallelic pathogenic variants in CYP1B1 or LTBP2 or identification of a heterozygous pathogenic variant in TEK confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Surgery (goniotomy, trabeculotomy, trabeculectomy, or deep sclerectomy) as early as possible; 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 Iodide^® (echothiophate) 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 the pathogenic variant(s) 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 variant(s).

Genetic counseling.

PCG caused by biallelic pathogenic variants in CYP1B1 or LTBP2 is inherited in an autosomal recessive manner. PCG caused by a heterozygous pathogenic variant in TEK is inherited in an autosomal dominant manner.

• Autosomal recessive inheritance. 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. Heterozygotes (carriers) are asymptomatic; carrier testing for at-risk family members is possible if the pathogenic variants in the family are known.
• Autosomal dominant inheritance. Each child of an individual with TEK-related PCG has a 50% chance of inheriting the pathogenic variant.

Prenatal testing for a pregnancy at increased risk is possible if the PCG-causing pathogenic variant(s) in the family are known.

Suggestive Findings

Primary congenital glaucoma (PCG) should be suspected in infants or children with the following clinical features:

• Photophobia, blepharospasm, and excessive tearing
• 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
• 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 or associated systemic disease.

Establishing the Diagnosis

The diagnosis of PCG is established in a proband by the following clinical criteria:

• Elevated intraocular pressure (IOP) in an infant or child typically (but not always) before age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry, I-care tonometry^™, or pneumotonometry on at least two occasions is considered abnormally elevated. In general, normal intraocular pressure in children is 12.02 ± 3.74 mm Hg [Sihota et al 2006].
• Enlargement of the (infantile) globe (buphthalmos)
• Increased corneal diameter and cloudy corneas
• Breaks in Decsemet’s membrane (Haab’s striae)
• Anomalously deep anterior chamber
• Bilateral or unilateral findings

Identification of biallelic pathogenic (or likely pathogenic) variants in CYP1B1 or LTBP2 or a heterozygous TEK pathogenic (or likely pathogenic) variant on molecular genetic testing (see Table 1) confirms the diagnosis if clinical features are inconclusive.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Serial single-gene testing. Perform sequence analysis of CYP1B1, followed by deletion/duplication analysis if only one or no pathogenic variant is found. If no CYP1B1 pathogenic variants are identified, consider sequence analysis of LTBP2. Sequence analysis and gene-targeted deletion/duplication analysis of TEK can be considered next if one or no pathogenic has been identified.
  Targeted analysis for CYP1B1 pathogenic variant p.Glu387Lys may be performed first in individuals of Rom Slovakian ancestry.
  CYP1B1 pathogenic variant p.Gly61Glu may be performed first in individuals of Saudi Arabian ancestry.
• A multigene panel that includes CYP1B1, LTBP2, TEK, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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%) 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 individuals, 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 in controlling IOP on 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 IOP <19 mm Hg.

Phenotype Correlations by Gene

CYP1B1. Individuals with CYP1B1 pathogenic variants 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]. The correlations with genotype have been inconsistent.

Individuals with CYP1B1 pathogenic variants tend to have a higher operative success rate than individuals without identified CYP1B1 pathogenic variants in terms of better intraocular pressure control effect. Together, the presence or absence of pathogenic variants in CYP1B1 and the preoperative corneal opacity score can partially predict the outcome of PCG surgery [Chen et al 2014b].

Individuals with CYP1B1 pathogenic variants had higher last postoperative visit indices in terms of postoperative haze and the need for anti-glaucoma medications than individuals without pathogenic variants in CYP1B1 [Abu-Amero et al 2011].

LTBP2. Individuals with LTBP2-related PCG had clinical features not seen in individuals with pathogenic variants in CYP1B1 or TEK; these features included ectopia lentis, high arched palate, and mild-to-moderate osteopenia [Ali et al 2009].

TEK. Individuals with TEK-related congenital glaucoma exhibit a clinical phenotype that is variable in severity and age of onset [Souma et al 2016].

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].

CYP1B1. No consistent genotype-phenotype correlation has been observed for CYP1B1 pathogenic variants. Intra- and interfamilial variability is reported among individuals with identical CYP1B1 pathogenic variants [Berraho et al 2015, de Melo et al 2015]. No information is available on correlation between the CYP1B1 pathogenic variants and the success of surgical therapy.

LTBP2. No genotype-phenotype correlation has been observed for LTBP2 pathogenic variants.

TEK. No genotype-phenotype correlation has been observed for TEK pathogenic variants.

Prevalence

CYP1B1. 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 the Rom Slovakian population [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 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].

CYP1B1

CYP1B1-related congenital glaucoma can be associated with an extreme form of anterior segment dysgenesis that includes recalcitrant glaucoma, corneal opacification, juvenile [Abu-Amero et al 2015] and adult open-angle glaucoma [Micheal et al 2015], and aniridia [Alzuhairy et al 2015].

Primary open-angle glaucoma (POAG). CYP1B1 pathogenic variants have been reported in individuals of French ancestry with POAG, suggesting that CYP1B1 pathogenic variants could pose a significant risk for early-onset POAG and could also modify the glaucoma phenotype in individuals who do not have an MYOC pathogenic variant [Melki et al 2004].

Congenital anterior staphylomas. CYP1B1 pathogenic variants may be associated with congenital anterior staphylomas [Al Judaibi et al 2014].

Peters anomaly. Pathogenic variants in CYP1B1 have been described in individuals with 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 iridocorneal and/or keratolenticular adhesions.

Juvenile open-angle glaucoma (JOAG). CYP1B1 pathogenic variants 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 a pathogenic variant in MYOC and a pathogenic variant in CYP1B1 in an individual with more severe disease. Pathogenic variants in MYOC may, in conjunction with pathogenic variants in CYP1B1, increase the clinical severity of glaucoma in individuals with JOAG. Indeed, individuals who are heterozygous for a pathogenic variant in both MYOC and CYP1B1 appear to have a more severe open-angle glaucoma phenotype than those who are heterozygous for a pathogenic variant in MYOC alone [Vincent et al 2002]. 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].

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

In the study of Abu-Amero et al [2015]:

• 12 of 14 unrelated Saudi Arabians with JOAG had at least one CYP1B1 variant.
• Eight were homozygous for the p.Gly61Glu pathogenic variant.
• Two were compound heterozygous for the p.Gly61Glu and p.Leu432Val variants.
• Two were heterozygous for the p.Gly61Glu variant with no other variant identified.

No genotype-phenotype correlation was demonstrated in those with biallelic CYP1B1 pathogenic variants. None of the 14 had mutation of MYOC or LTBP2.

LTBP2

Kumar et al [2010] detected a homozygous LTBP2 pathogenic variant in one family with microspherophakia. LTBP2 pathogenic variants have also been associated with Weill-Marchesani syndrome. Homozygous LTBP2 pathogenic variants were identified in eight individuals with congenital megalocornea from three families [Khan et al 2011].

TEK

Heterozygous TEK pathogenic variants have been identified in multiple individuals with hereditary and sporadic venous malformations.

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 or optical coherence tomography to aid in evaluating the anterior segment structures
• Measurement of axial length

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

Consultation with a clinical geneticist and/or genetic counselor is recommended.

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. A Cochcrane review analyzed the literature that addressed the surgical management of congenital glaucoma but could not draw any conclusions from the analysis [Ghate & Wang 2015].

Surgical treatment. The following approach is based on the work of deLuise & Anderson [1983], Ho & Walton [2004], Bowman et al [2011], Sharaawy & Bhartiya [2011], and Al-Obeidan et al [2014].

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 [Morales et al 2013, Chen et al 2014a].

In deep sclerectomy the dissection of a deep scleral flap, deroofing of Schlemm's canal, and preserving the structural integrity of the trabecular meshwork results in improved aqueous outflow outside the anterior chamber.

Note: In contrast to goniotomy, deep sclerectomy, 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. 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.

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 (e.g., timolol), parasympathomimetics (e.g., pilocarpine), sympathomimetics (e.g., 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 Phospholine Iodide^® (echothiophate) need to be discontinued before surgery, especially if succinylcholine is used because of the danger of 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 individual. 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 individual, 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 the pathogenic variant(s) have been identified.
• If the PCG-related pathogenic variant(s) have not been identified in an affected family member (i.e., no definitive exclusion of the disease is possible by molecular genetic testing), screening including IOP measurements under anesthesia/sedation 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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

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

PCG caused by a pathogenic variant in TEK is inherited in an apparent autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one CYP1B1 or LTBP2 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier for a CYP1B1 or LTBP2 pathogenic variant.

Carrier detection. Carrier testing for at-risk family members requires prior identification of the CYP1B1 or LTBP2 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• All probands with TEK-related PCG reported to date have the disorder as a result of a de novo pathogenic variant.
• Recommendations for the evaluation of parents of a proband with an apparent de novo TEK pathogenic variant include molecular genetic testing.

Sibs of a proband

• All affected individuals reported to date have had a de novo TEK pathogenic variant, suggesting a low risk to sibs.
• If the TEK pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated at 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with TEK-related PCG has a 50% chance of inheriting the pathogenic variant.

Other family members. Given that all individuals with TEK-related PCG reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CYP1B1, LTBP2, or TEK pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for PCG and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

CYP1B1

Gene structure. CYP1B1 spans 12 kb, comprises three exons (exons 2 and 3 are coding exons), and produces a 1,631-base mRNA product. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Nearly 200 pathogenic variants are listed in the Human Gene Mutation Database (HGMD) (see Table A), including missense and nonsense variants, small deletions/insertions/duplications, and exon and whole-gene deletions.

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. 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 mutated protein p.Gly61Glu had lost 60% of its stability, while p.Arg469Trp retained about 80% of the stability compared to the wild type. The effects of mutation on protein function 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.

LTBP2

Gene structure. LTBP2 transcript NM_000428.2 comprises 36 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Ali et al [2009] first reported four LTBP2 missense variants and small deletions that 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.

Normal gene product. The encoded protein NP_000419.1, comprising 1821 amino acids, belongs to the family of latent transforming growth factor (TGF)-beta binding proteins (LTBP), which are extracellular matrix proteins with multidomain 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].

TEK

Gene structure. TEK has multiple transcript variants, the longest of which is NM_000459.4 which is 4.7 kb in length and comprises 23 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Ten pathogenic variants are listed in HGMD, including missense, nonsense, and splicing variants, small deletions & insertions resulting in frameshifts, and one gross deletion of exons 2-4 [Souma et al 2016].

Normal gene product. TEK encodes a tyrosine-protein kinase that acts as cell-surface receptor, the angiopoietin-1 receptor. It is expressed almost exclusively in endothelial cells.

Abnormal gene product. Souma et al [2016] proposed that gain-of-function pathogenic variants in TEK result in venous malformations in nonocular tissues, whereas loss-of-function variants affect anterior chamber vascular development and result in primary congenital glaucoma.

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

• 17 August 2017 (sw) Comprehensive update posted live
• 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 live
• 30 September 2004 (me) Review posted live
• 3 June 2004 (bab) Original submission

Literature Cited

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