goniodysgenesis

Microcoria, Congenital

Clinical Characteristics
Ocular Features: 

This disorder is a type of anterior chamber dysgenesis since the pupil and iris anomalies are associated with goniodysgenesis (prominent iris processes and high iris root insertion) and glaucoma.  The dilator muscle of the iris is hypoplastic and even topical mydriatics have little impact on pupil size. The pupil has a mean diameter of 0.8 mm and only dilates to a mean size of 1.4 mm.  The iris stroma is also hypoplastic and often lacks crypts and collarettes.  Transillumination defects of the iris are consistently present.  Axial myopia is a feature in some families (83% of affected individuals have refractive errors in the range of -10D) and seems to be progressive .  Juvenile glaucoma is frequently present (at least 30% require treatment) and is usually detected in the second (20%) through fourth decades of life.  All patients with glaucoma have evidence of 'trabeculodysgenesis' but the same features may also be seen in some patients without glaucoma.  The intraocular pressure is difficult to control pharmacologically.  Visual acuity varies widely but no retinal changes have been described.

Ultrastructural studies show lack of myofilaments and desmin in the stromal cytoplasmic processes of the anterior pigmented cells of the iris suggesting failure of full development of the pupil dilator muscle cells.

Systemic Features: 

There are no systemic abnormalities in this condition.

Genetics

This is an autosomal dominant disorder secondary to a mutation located at 13q13-q32.  The specific mutation responsible has not been identified but a large deletion at 13q32.1 in one patient has been reported. 

Congenital microcoria is also a feature of autosomal recessive Pierson syndrome (609049) caused by homozygous mutations in the LAMB2 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Glaucoma often requires surgery for control of intraocular pressure.

References
Article Title: 

Submicroscopic deletions at 13q32.1 cause congenital microcoria

Fares-Taie L, Gerber S, Tawara A, Ramirez-Miranda A, Douet JY, Verdin H, Guilloux A, Zenteno JC, Kondo H, Moisset H, Passet B, Yamamoto K, Iwai M, Tanaka T, Nakamura Y, Kimura W, Bole-Feysot C, Vilotte M, Odent S, Vilotte JL, Munnich A, Regnier A, Chassaing N, De Baere E, Raymond-Letron I, Kaplan J, Calvas P, Roche O, Rozet JM. Submicroscopic deletions at 13q32.1 cause congenital microcoria. Am J Hum Genet. 2015 Apr 2;96(4):631-9.

PubMed ID: 
25772937

Glaucoma, Congenital Primary B

Clinical Characteristics
Ocular Features: 

Type B congenital glaucoma is considerably more rare than type A and may be more common in Middle Eastern families.  Few families have been reported but the clinical features are similar: elevated intraocular pressure in infancy or early childhood, photophobia, and cloudy corneas (see Glaucoma, Congenital Primary A [231300] for a more complete description of the phenotype).

Systemic Features: 

No systemic abnormalities are associated.

Genetics

This is an autosomal recessive disorder caused by a mutation in GLC3B mapped to a locus at 1p36.2-p36.1.  Type A congenital glaucoma (231300) is caused by a mutation in CYP1B1 and type D by mutations in LTBP2 (613086).  A locus at 14q24.3 has been asssociated with another form of congenital glaucoma (613085; type C) but the nature of the gene is unknown.  Mutations in TEK are responsible for congenital glaucoma type GLC3E.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

As in other types of congenital glaucoma, pressure control is difficult and the best approach entails some form of glaucoma surgical filtration.

References
Article Title: 

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
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