CYP1B1

Anterior Segment Dysgenesis 6

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions can be seen.  Increased intraocular pressure is a risk and ectopia lentis is often present.  Peters anomaly and defects in all layers of the cornea may be present.

No foveal hypoplasia is present.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

A single male patient of native American/French Canadian background has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2).

See Anterior Chamber Dysgenesis 8 for another autosomal recessive disorder with somewhat similar clinical features.  Three families with 4 affected individuals have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions.

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lifelong pressure monitoring is important.

References
Article Title: 

Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly

Vincent A, Billingsley G, Priston M, Williams-Lyn D, Sutherland J, Glaser T, Oliver E, Walter MA, Heathcote G, Levin A, Heon E. Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly. J Med Genet. 2001 May;38(5):324-6. PubMed PMID: 11403040; PubMed Central PMCID: PMC1734880.

PubMed ID: 
11403040

Glaucoma, Congenital Primary A

Clinical Characteristics
Ocular Features: 

This may be the most common type of early (infantile, congenital) glaucoma.  Elevated intraocular pressure may be present at birth but sometimes is not evident until the first year of life or in some cases even later.  Irritability, photophobia, and epiphora are early signs.  The globe is often buphthalmic, the cornea is variably cloudy, and breaks in the Descemet membrane (Haab striae) may be present.  Frequently the iris root is inserted anteriorly in the region of the trabecular meshwork.  The anterior chamber often appears abnormally deep.  Early reports of a membrane covering the angle structures have not been confirmed histologically.  The mechanism causing elevated IOP seems to be excessive collagen tissue in the anterior chamber angle that impedes normal aqueous outflow.   The pressure is usually in the range of 25-35 mmHg but this is variable as the course can be intermittent.  It should be considered a bilateral disease although about one-fourth of patients have only unilateral elevations of pressure even though trabecular abnormalities are present.

Optic cupping may begin temporally but the more typical glaucomatous cupping eventually occurs.

Systemic Features: 

No consistent systemic abnormalities are associated with primary congenital glaucoma.  However, it is important to note that glaucoma is a feature of many congenital malformation syndromes and chromosomal aberrations.

Genetics

Congenital glaucoma of this type can result from both homozygous (25%) and compound heterozygous mutations (56%) in the CYP1B1 gene on chromosome 2 (2p22-p21) which codes for cytochrome P4501B1.

Evidence from many sources suggests that congenital glaucoma of this type is an autosomal recessive disorder. Parental consanguinity is common, the segregation ratio is approximately 25%, and the occurrence of congenital glaucoma among all offspring of two affected parents can be cited as support for this mode of inheritance.  Many cases occur sporadically but this is consistent with expectations in small human sibships.  Curiously, though, males are affected more often than females.

Another autosomal recessive infantile (congenital) glaucoma (600975), GLC3 or type B, is caused by mutations in GLC3B located at 1p36.2-p36.1.  A third locus at 14q24.3 has also been proposed  for GLC3, type C.  Autosomal recessive primary congenital glaucoma (so-called) type D (613086) is caused by a mutation in LTBP2 located at 14q24 near the GLC3C locus and heterozygous mutations in TEK are responsible for type E (617272).

Other modes of inheritance have been described and, for now, this form of glaucoma, like others, has to be considered a genetically and clinically heterogeneous disorder pending additional genotyping.  Early onset glaucoma is also a feature of numerous malformation and chromosomal disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Some of the usual glaucoma drugs are ineffective as a result of obstruction to aqueous flow through the trabecular meshwork so that surgical treatment is the therapy of choice in most cases.   Monitoring of axial length has been proposed as helpful in gauging the effectiveness of pressure control.  In some patients the pressure normalizes spontaneously. 

It is important in the evaluation of patients with glaucoma that systemic evaluations be done because of the frequent syndromal associations.

References
Article Title: 

Congenital glaucoma and CYP1B1: an old story revisited

Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem M, Abdulwahab F, Ibrahim N, Aldahmesh MA, Alkuraya FS. Congenital glaucoma and CYP1B1: an old story revisited. Hum Genet. 2018 Mar 19. doi: 10.1007/s00439-018-1878-z.

PubMed ID: 
29556725

Peters Anomaly

Clinical Characteristics
Ocular Features: 

Peters anomaly occurs as an isolated malformation but also as a feature of other syndromes.  It is often unilateral.  A wide variety of other ocular findings may occur with Peters anomaly as well. Here we limit our description to 'simple' Peters anomaly in which the findings are limited to the eye having the classic findings of adhesions of the iris to the posterior cornea and a central or paracentral corneal leukoma.  The lens may also be adherent to the cornea and is often opacified to some degree.  Descemet's membrane and portions of the posterior stroma are usually missing as well.  Glaucoma is frequently present.  Importantly, there is a wide range in the presentation of clinical features.

Systemic Features: 

Peters anomaly is a frequent feature of numerous syndromes, both ocular and systemic, among them the Peters-plus (261540) syndrome (sometimes called the Kivlin-Krause (261540) syndrome) and has been reported in a case with aniridia (106210).

Genetics

Isolated Peters anomaly usually occurs in an autosomal recessive pattern but autosomal dominant patterns have been reported as well.  The recessive disorder may be caused by a mutation in several genes, notably PAX6, PITX2,  CYP1B1, FOXC1, and FOXE3.  The latter gene is also mutated in anterior segment mesenchymal dysgenesis (107250) and congenital primary aphakia (610256).  The variety of clinical features are likely the result of a disruption in some common pathway or pathways.  Mutations in B3GALTL associated with the Peters-Plus syndrome have not been identified in isolated Peters anomaly.

This is a genetically and clinically heterogeneity condition as whole genome sequencing reveals numerous additional gene mutations in patients with both syndromic and isolated Peters anomaly.

PITX2 is also mutated in ring dermoid of the cornea (180550) and in Axenfeld-Rieger syndrome type 1 (180500).  PAX6 mutations also cause diseases of the cornea, fovea, optic nerve and iris.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma is the most serious threat to vision on Peters anomaly but also the most difficult to treat.  Less than a third of patients achieve control of intraocular pressure even with the most vigorous combinations of therapy.  Corneal opacities can be treated with transplantation but the prognosis is often guarded when glaucoma is present.

From eye bank and other data, it has been estimated that 65% of penetrating keratoplasties in infants for visually significant congenital corneal opacities are performed in patients with Peters anomaly. 

References
Article Title: 

Whole exome sequence analysis of Peters anomaly

Weh E, Reis LM, Happ HC, Levin AV, Wheeler PG, David KL, Carney E, Angle B, Hauser N, Semina EV. Whole exome sequence analysis of Peters anomaly. Hum Genet. 2014 Sep 3. [Epub ahead of print].

PubMed ID: 
25182519
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