Glaucoma 3, Primary Congenital, A
A number sign (#) is used with this entry because of evidence that this form of autosomal recessive primary congenital glaucoma (PCG, or buphthalmos) is caused by homozygous mutation in the cytochrome P4501B1 gene (CYP1B1; 601771) on chromosome 2p22.
Compound heterozygous or heterozygous mutations in the CYP1B1 gene can also cause juvenile- and adult-onset primary open angle glaucoma (POAG). For a general phenotypic description and a discussion of genetic heterogeneity of POAG, see 137760.
Mutations in the myocilin gene (MYOC; 601652) may also contribute to the phenotype via digenic inheritance.
DescriptionPrimary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years of age), increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal edema, and optic nerve head cupping. Congenital glaucoma is a chronic disease and a serious cause of blindness worldwide (summary by Azmanov et al., 2011).
Genetic Heterogeneity of Primary Congenital Glaucoma
Primary congenital glaucoma-3B (GLC3B; 600975) maps to chromosome 1p36.2-p36.1. GLC3C (613085) maps to chromosome 14q24.3. GLC3D (613086) is caused by mutation in the LTBP2 gene (602091) located on chromosome 14q24 but outside the locus for GLC3C. GLC3E (617272) is caused by mutation in the TEK gene (600221) on chromosome 9p21.
Clinical FeaturesThe ocular globe is usually large as a result of the increased intraocular pressure dating from intrauterine life, hence the term buphthalmos, meaning 'ox eye.' In only about half of cases are both eyes involved, and males are affected somewhat more often than females. The canal of Schlemm is present and communicates normally with the veins, as is proved by demonstrable filling of the canal with blood when the jugular veins are compressed. The defect is thought to involve the permeability of the trabeculum to aqueous humor.
DiagnosisDistinguishing megalocornea (see MGC1, 309300) from primary congenital glaucoma in infants is clinically challenging due to overlapping phenotypic features. Davidson et al. (2014) examined 18 unrelated patients with megalocornea and mutations in the CHRDL1 gene (300350) and observed that patients with MGC1 have a large corneal diameter and thin cornea, but no corneal edema or breaks in the Descemet layer. The authors also stated that the depth of the anterior chamber in MGC1 is typically significantly greater than in patients with primary congenital glaucoma, and that ultrasonography could reliably distinguish between the 2 conditions: if the ratio of the anterior chamber depth to the total axial length is greater than 0.19 mm by ultrasound, then a diagnosis of MGC1 is extremely likely, unless there is coexisting gross axial myopia (greater than 36 mm).
Clinical ManagementBecause the trabeculum is abnormal in eyes with congenital glaucoma, intraocular pressure-lowering medications are ineffective in lowering intraocular pressure and preserving sight. Thus, the primary mode of therapy is surgical. Law et al. (2001) followed 12 eyes of 6 consecutive patients with congenital glaucoma using axial length ultrasonography. Eight of 12 initially had increased axial length (buphthalmos). After surgery, good intraocular pressure control was achieved in 10 eyes; 3 eyes showed decreased axial length and 7 eyes showed unchanged axial length. However, these eyes all returned to axial growth patterns that paralleled the normal ocular growth curve for age. In the 2 eyes with poorly controlled pressure postoperatively, axial growth pattern remained greater than normal. The authors concluded that axial length measurements were useful in monitoring the control of congenital glaucoma.
InheritanceAutosomal recessive inheritance is quite certain in a significant proportion of glaucoma cases. Waardenburg (1950) suggested that recessive inheritance of some cases of glaucoma is proved by (1) a high frequency of parental consanguinity; (2) the presence of the disease in about 25% of sibs of probands; (3) the presence of the disease in all children of a marriage between 2 affected persons; and (4) the occurrence of glaucoma in collaterals of both parents in some families. Beiguelman and Prado (1963) reported a Brazilian pedigree as convincing evidence for recessive inheritance of juvenile glaucoma.
Bonaiti et al. (1978) concluded that about 30% of congenital glaucoma cases in the series they analyzed were of an autosomal recessive type. In Bratislava, Czechoslovakia, Gencik et al. (1980) studied 45 gypsy families with 118 persons with congenital glaucoma. Inheritance was autosomal recessive with complete penetrance. In addition, they studied 81 non-gypsy families with 87 affected persons. Among these, 26.6% were only unilaterally affected and onset was usually later and course milder. The population frequency was much lower and an excess of males (1.55:1) was noted. The authors concluded that multifactorial inheritance is likely in the latter group. The consanguinity rate was not increased. Demenais et al. (1981) confirmed genetic heterogeneity of congenital glaucoma. An analysis by Morton (1982) suggested that much etiologic heterogeneity exists in the category of congenital glaucoma.
A large gypsy pedigree with 31 affected persons in 18 sibships was reported from Slovakia by Gencikova and Gencik (1982). Ferak et al. (1982) published observations on the high frequency of congenital glaucoma in a relatively small gypsy subpopulation of Slovakia.
The syndrome of congenital glaucoma with mental retardation and decreased renal ammonium production (Lowe syndrome, 309000) is an X-linked recessive disorder.
MappingUsing a group of 17 families with primary congenital glaucoma and a combination of both candidate regional and general positional mapping strategies, Sarfarazi et al. (1995) mapped the locus, designated GLC3, to 2p. Eleven families showed no recombination with 3 tightly-linked markers, D2S177, D2S1346, and D2S1348, with a combined haplotype lod score of 11.50. Haplotype and multipoint linkage analysis of 14 DNA markers from 2p indicated to the authors that the disease gene is located in the 2p21 region and is flanked by DNA markers D2S1788/D2S1325 and D2S1356. Inspection of haplotype and heterogeneity analysis confirmed that 6 families are not linked to the 2p21 region, thus providing the first proof of genetic heterogeneity for this phenotype. The authors therefore designated the locus on 2p21 GLC3A. Of 7 genes mapping to the 2p21 region, they excluded, on the basis of linkage position, CAD (114010), CALM2 (114182), and LHCGR (152790) as candidates for GLC3A.
Plasilova et al. (1998) performed linkage analysis on 7 Slovak gypsy (Rom) families with 18 members with congenital glaucoma and found linkage to the GLC3A locus at 2p21, without heterogeneity.
In 3 large consanguineous Saudi families with primary congenital glaucoma, Bejjani et al. (1998) found tight linkage to 2p21. Formal linkage analysis in 25 Saudi PCG families confirmed both significant linkage to polymorphic markers in this region and incomplete penetrance, but it showed no evidence of genetic heterogeneity. For these 25 families, the maximum combined 2-point lod score was 15.76 at a recombination fraction of 0.021, with a polymorphic marker D2S177.
Molecular GeneticsPrimary Congenital Glaucoma 3A
Stoilov et al. (1997) used a combination of GLC3A-linked polymorphic markers (STRPs), YAC screening, and radiation hybrid mapping of published and newly generated data on STSs and ESTs to establish a critical region that harbors the defective gene in GLC3A. Of 5 potential candidate genes, 1 was placed outside the critical region and another 3 were screened for the presence of coding sequence changes. As a direct result of this screening, they identified 3 different truncating mutations in the human cytochrome P4501B1 gene (601771). A 13-bp deletion (601771.0001) was detected in 1 consanguineous and 1 nonconsanguineous family; a single cytosine insertion (601771.0002) was observed in another 2 consanguineous families; and a large deletion was found in an additional consanguineous family.
In 25 Saudi families with primary congenital glaucoma mapping to chromosome 2p21, Bejjani et al. (1998) sequenced the coding exons of CYP1B1 and identified homozygosity or compound heterozygosity for 3 missense mutations (G61E, 601771.0003; R469W, 601771.0006; and D374N, 601771.0007) that segregated with the phenotype in 24 families. Additional clinical and molecular data on some mildly affected relatives showed variable expressivity of PCG in this population, suggesting that genetic and environmental events must modify the effects of CYP1B1 mutations in ocular development. A small number of PCG mutations identified in this Saudi population made both neonatal and population screening attractive public health measures.
Following up on their report of 3 distinct CYP1B1 mutations in 24 Saudi families segregating PCG, Bejjani et al. (2000) analyzed 37 additional families and confirmed the initial finding of incomplete penetrance. Eight distinct mutations were identified; the most common Saudi mutations, G61E, R469W, and D374N, accounted for 72%, 12%, and 7%, respectively, of all the PCG chromosomes. Five additional homozygous mutations (2 deletions and 3 missense mutations) were detected, each in a single family. In 22 families, 40 apparently unaffected individuals had mutations and haplotypes identical to their affected sibs. Of these, 2 were subsequently diagnosed with glaucoma and 2 others had abnormal ocular findings consistent with milder forms of glaucoma. Analysis of these 22 kindreds suggested the presence of a dominant modifier locus that is not linked genetically to CYP1B1.
In Morocco, Belmouden et al. (2002) studied 32 unrelated patients with primary congenital glaucoma and identified 2 mutations in the CYP1B1 gene in 11 (34%) patients: G61E (601771.0003), previously found in Turkish and Algerian patients, and a 1-bp deletion (4339delG; 601771.0011). Seven patients were homozygous for 4339delG and 2 others for G61E, whereas the remaining 2 were compound heterozygotes. Close association of 4339delG with a rare allele of D2S177, a microsatellite marker located 270 kb upstream of CYP1B1, strongly suggested a founder effect for 4339delG, with the occurrence of the mutation tentatively estimated at between 900 and 1,700 years earlier.
In a Spanish patient with primary congenital glaucoma, Lopez-Garrido et al. (2009) identified homozygosity for a mutation (F261L; 601771.0018) in the CYP1B1 gene, which was carried in heterozygous state in her unaffected father but not her mother. Segregation analysis of markers on chromosome 2 was consistent with paternal uniparental isodisomy.
In 37 Roma/Gypsy probands with PCG, Azmanov et al. (2011) performed direct sequencing of the entire coding sequence of CYP1B1 as well as exon 4 of the LTBP2 gene (602091), harboring the R299X founder mutation (602091.0001). In 25 (approximately 70%) of the 37 patients, they identified homozygosity or compound heterozygosity for 5 different mutations in CYP1B1, including 4 that had previously been reported as disease-causing in other populations (see, e.g., R368H, 601771.0012 and E387K, 601771.0014) or for the R299X mutation in LTBP2. In 14 patients, no mutation was identified. Homozygosity for the R299X LTBP2 mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. Azmanov et al. (2011) stated that preliminary observations on patients with mutations in both CYP1B1 and LTBP2 suggested that the observed combinations were of no clinical significance and that digenic inheritance was unlikely. Genetic drift was suggested as the 'most plausible scenario' for the allelic heterogeneity seen in this Gypsy population.
Juvenile- and Adult-onset Primary Open Angle Glaucoma
In 4 sisters from a Caucasian French family, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene: (G232R, 601771.0013 and E387K, 601771.0014). Two of the sisters had primary congenital glaucoma, whereas the other 2 sisters had adult-onset (ages 35 and 40 years, respectively) primary open angle glaucoma (see 137760).
In a French Caucasian family ascertained through a proband who developed juvenile-onset primary open angle glaucoma at the age of 13 years, Melki et al. (2004) identified compound heterozygosity for mutations in the CYP1B1 gene in the proband and in his brother: a 1-bp deletion (3979delA; 601771.0015) and an asn423-to-tyr substitution (N423Y; 601771.0016). The proband's brother had primary congenital glaucoma. The mother carried the N423Y mutation but showed no glaucoma symptoms at the age of 49 years. The father could not be examined.
In 2 unrelated French Caucasian patients with adult-onset primary open angle glaucoma, Melki et al. (2004) identified a tyr81-to-asn substitution in the CYP1B1 gene (Y81N; 601771.0017). One of the 2 patients, diagnosed with glaucoma at the age of 52 years, had 2 sons heterozygous for the Y81N mutation who had onset of primary open angle glaucoma at 39 and 44 years of age, respectively.
Although PCG-associated CYP1B1 mutations in the heterozygous state had been evaluated for association with POAG in several small studies, their contribution to the occurrence of POAG was uncertain. Pasutto et al. (2010) conducted a study to determine whether heterozygous functionally characterized CYP1B1 mutations were associated with the disease in a large cohort of German patients with POAG (Pasutto et al., 2008). The entire coding region of CYP1B1 was directly sequenced in 399 glaucoma patients (270 with POAG, 47 with JOAG, and 82 with normal-tension glaucoma) and in 376 control subjects. All patients were screened for mutations in the myocilin (MYOC; 601652), optineurin (OPTN; 602432), and WD repeat domain 36 (WDR36; 609669) genes. In vitro functional assays were performed and relative enzymatic activity of the CYP1B1 variants were determined to assess their possible causative role. Apart from known polymorphic variants, Pasutto et al. (2010) identified 11 previously reported amino acid substitutions in CYP1B1 in both PCG and POAG cases. In vitro functional assays demonstrated marked reduction of enzymatic activity for variants P52L (601771.0019) and R368H (601771.0012), confirming their role as loss-of-function mutations. In contrast, 3 other variants showed no relevant effects and were thus classified as polymorphisms. Overall, 7 functionally impaired variants were present in 13 (3.6%) patients and in 1 (0.2%) control subject (P = 0.002). Reanalysis of previous studies reporting CYP1B1 mutations in patients with POAG based on updated functional validation showed a significant excess of carriers among patients compared to controls (P = 2.3 x 10(-7)). Pasutto et al. (2010) concluded that heterozygous CYP1B1 mutations with absent or reduced relative enzymatic activity could be considered a risk factor for POAG.
By Sanger sequencing, Gong et al. (2015) screened for mutations in the CYP1B1 gene in 416 Han Chinese patients with POAG and 657 unrelated ethnically matched controls, and identified 13 heterozygous missense mutations in 25 patients. Nine of the mutations had previously been identified in patients with PCG and/or POAG; 3 of 9 were also found in controls. The 4 novel mutations occurred at highly conserved residues and were not found in controls.
Digenic Inheritance
In a patient with primary congenital glaucoma with onset before 4 months of age, Kaur et al. (2005) identified 2 mutations: 1 in the CYP1B1 gene (601771.0012) and 1 in the MYOC gene (601652.0014). Each of the parents was heterozygous for 1 of the mutations. Kaur et al. (2005) suggested a role for the MYOC gene in primary congenital glaucoma via digenic interactions with other genes.
Associations Pending Confirmation
For discussion of a possible association between variation in the GPATCH3 gene and primary congenital glaucoma, see 617486.0001.
Population GeneticsChakrabarti et al. (2006) found that common mutations in CYP1B1 that cause primary congenital glaucoma occur on a uniform haplotype background among Indian patients, which is distinct from the modal haplotype background found among unaffected control subjects. They cited reports of similar findings in other populations, demonstrating strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds.
Dimasi et al. (2007) identified 10 different CYP1B1 mutations in 8 (21.6%) of 37 predominantly Caucasian Australian probands with primary congenital glaucoma.
The Slovak Rom population is known to have an unusually high frequency of primary congenital glaucoma. Plasilova et al. (1999) reported mutation screening of 43 patients from 26 Slovak Rom (Gypsy) families and identified the same mutation in the CYP1B1 gene in all families (E387K; 601771.0008). The E387K mutation appeared on a common haplotype in all patients, suggesting that it originated from a single ancestral mutational event.
Sivadorai et al. (2008) analyzed the CYP1B1 gene in 21 patients from 16 unrelated Bulgarian Gypsy families and detected 5 different mutations. The E387K mutation was detected in only 3 (8%) of 38 mutant alleles, and only 4 (0.56%) of 715 healthy Gypsy controls were heterozygous for the E387K mutation. Sivadorai et al. (2008) concluded that the molecular basis of primary congenital glaucoma in the Gypsy population is unresolved and that diagnostic analysis must extend beyond the E387K mutation.
Animal ModelAutosomal recessive glaucoma occurs in the rabbit (Hanna et al., 1962).