glaucoma

Glaucoma, Pigment Dispersion Syndrome

Clinical Characteristics
Ocular Features: 

This is a form of open angle glaucoma with early onset (usually before the age of 40 years).  Marked pigment deposition in the trabecular meshwork, on the lens, zonules, and the corneal endothelium can often be seen prior to elevation of the intraocular pressure. It can be present asymmetrically, even unilaterally, but primarily in early stages.  The pigment source in humans seems to be the iris in which hypopigmentation leads to radial transillumination defects and mouse models corroborate this.  The iris configuration is sometimes described as flat or even concave.  The pattern of pigment deposition on the posterior surface of the cornea is known as a Krukenberg spindle and considered diagnostic.  Untreated, the characteristic optic nerve damage and visual field changes of glaucoma eventually occur.  Early-onset and rapidly progressive nuclear cataracts have been reported in some patients.

In one longitudinal study of 113 patients diagnosed with pigment dispersion and followed for 24 years, 23 had glaucoma initially and 9 more eventually required treatment for elevated pressure. The mean age at diagnosis was 42 years and myopic males were the most commonly affected.

The syndromic nature of PDS is suggested by the association of lattice degeneration, retinal tears, and detachments in a significant number of individuals.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal dominant form of glaucoma-related optic neuropathy that shares some features with open angle juvenile glaucoma (137750), such as myopia and early onset.  The pigment dispersion syndrome described here, however, maps to a different locus (7q35-q36).  Another candidate locus is located at 18q11-q21 but the causative mutations remain elusive.

A four generation family with an apparent autosomal recessive pattern has been reported.

The autosomal dominant pattern is not always apparent from history alone and examination of relatives is necessary to document the familial nature of this disease. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual glaucoma therapies are indicated.  Some have advised limiting vigorous impact sports to reduce the amount of pigment released.  All individuals with pigment dispersion must be followed vigilantly for development of glaucoma as the risk is high.  It has been estimated to be 10% within 5 years and 15% in 15 years, regardless of age and family history.  Further, the pigment dispersion is progressive along with the risk of elevated pressure as eventually 30 -50% of patients develop glaucoma.  However, regression of pigment deposition, decrease of iris transillumination and even stabilization of pressure has also been noted in some, mostly younger, patients.

Laser iridotomy has been suggested as therapeutically useful in the reduction of the IOP but there is no statistical confirmation of this.

References
Article Title: 

Nanophthalmos with Retinopathy

Clinical Characteristics
Ocular Features: 

This is a rare syndrome consisting of a pigmentary degeneration of the retina in association with nanophthalmos.  The globe is small with a thickened choroid and sclera and the macula becomes atrophic later in life. Some patients have cystic macular changes early without fluorescein leakage.  The anterior chamber is shallow, the angle is narrow, and the cornea may be small leading to angle closure glaucoma in most patients.  Extensive anterior and posterior synechiae can be seen.  The retina has a postequatorial bone spicule pattern of pigmentation with narrowing of arterial vessels.  Hyperopia is usually present and nightblindness may be noted in the first decade of life.  The ERG early shows loss of rod function and progression of the retinal disease subsequently leads to extinction of all rod and cone responses by midlife.  The EOG may be subnormal and visual fields are severely constricted.  Pallor and crowding of the optic nerve are common.  The vitreous may contain prominent fibrils and fine white granules.  Visual acuity is often 20/200 or worse.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is likely an autosomal recessive disorder based on frequent parental consanguinity and sibships with multiple affected individuals of both sexes.  However, the first reported family in 1958 with 13 affected individuals in 4 generations suggested autosomal dominant inheritance. No molecular defect has been identified.

This may be the same disorder as microphthalmia with retinitis pigmentosa (611040) in which so far no molecular mutation has been identified. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Narrow angles with shallow anterior chamber depth should be treated with prophylactic iridotomies.

References
Article Title: 

Glaucoma, Open Angle, Juvenile

Clinical Characteristics
Ocular Features: 

Primary open angle glaucoma is a genetically and clinically heterogeneous condition.  The type described here often has its onset in juveniles, much earlier than the usual type, and is much more rare.  Onset is often in the second or third decade with an average age of onset of 18 years.  It is rare for this form of POAG to be diagnosed after 40 years of age.  IOP is commonly as high as 50 mmHg and the pressure is difficult to control.  Glaucomatous changes in the optic nerve progress rapidly. The usual pharmacologic agents can be helpful early but surgical control is often required.  Myopia is common (87%) but no anterior chamber anomalies are present.  Juvenile POAG is more common in African Americans.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Juvenile onset open angle glaucoma, GLAC1A, is inherited in an autosomal dominant pattern with high penetrance.  It is caused by a mutation in MYOC located at 1q21-q31.  The usual adult onset glaucoma is caused by different mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The usual pharmacologic treatment may be effective in some, especially early, but some form of glaucoma filtration surgery is eventually required in over 80% of patients.

References
Article Title: 

Axenfeld-Rieger Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

As in RIEG1 and RIEG3, glaucoma is the most serious ocular problem.  In a large family with 11 affected members, 9 had glaucoma.  All had the classic ocular signs of anterior segment dysgenesis, primarily posterior embryotoxon and iris adhesions (for a full description of the ocular features see Axenfeld-Rieger syndrome, RIEG1 [180500]).

Systemic Features: 

Oligodontia, microdontia, and premature loss of teeth are common in type 2.  Maxillary hypoplasia is less common as is hearing loss.  Umbilical anomalies were not present in any affected individuals.  Cardiac defects are rare.

Genetics

This is an autosomal dominant disorder as in the other types.  The locus is at 13q14 but no molecular defect has been defined.  At least two individuals purported to have type 2 were found to have deletions of this segment of chromosome 13.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The high risk of glaucoma demands lifelong monitoring of intraocular pressure.

References
Article Title: 

Axenfeld-Rieger Syndrome, Type 3

Clinical Characteristics
Ocular Features: 

The most important ocular feature is glaucoma, found in greater than 50% of patients.  It is frequently difficult to control and blindness is far too common.  The ocular phenotype has many similar features found in type 1 (RIEG1) but is discussed separately in this database since it is caused by a different mutation (see Axenfeld-Rieger syndrome, type 1 for a full description of the phenotype).  It has the typical findings of anterior segment dysgenesis including anterior displacement of Schwalbe's line, iris stromal hypoplasia, correctopia, and, of course, glaucoma.

Systemic Features: 

Patients with this type of Axenfeld-Rieger disorder are less likely to have the systemic anomalies such as craniofacial and dental defects often seen in RIEG1.  However, they often have a sensorineural hearing impairment and many have cardiac valvular and septal defects not usually seen in RIEG1.

Genetics

This is an autosomal dominant disorder resulting from a mutation in the FOXC1, a transcription factor gene located at 6p25.  Mutations in the same gene also cause iris hypoplasia/iridogoniodysgenesis (IGDA) (IRID1) 601631) which is sometimes reported as a unique disorder but is either allelic or the same disorder as the type of Axenfeld-Rieger syndrome discussed here.

Type 1 Axenfeld-Rieger syndrome (180500) results from mutations in the PITX1 transcription factor gene and type 4 from mutations in PRDM5, also a transcription factor gene.  However, digenic cases have also been reported with mutations in both PITX1 and FOXC1 genes.

The mutation responsible for type 2 Axenfeld-Rieger syndrome (601499) has as yet not been identified.  Diagnosis is best made by ruling out mutations in PITX1 and FOXC1 although it is claimed that maxillary hypoplasia and umbilical defects are less common in type 2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

All patients with Axenfeld-Rieger syndromes must be monitored and treated for glaucoma throughout their lives.

References
Article Title: 

Axenfeld-Rieger syndrome

Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2017 Oct 3. doi: 10.1111/cge.13148. [Epub ahead of print] Review.

PubMed ID: 
28972279

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: 

Corneal Dystrophy, Posterior Polymorphous 3

Clinical Characteristics
Ocular Features: 

This is a genetically and clinically heterogeneous type of corneal dystrophy.  Endothelial metaplasia seems to play a role as these cells acquire some characteristics of epithelial cells.  The posterior cornea has guttae and lesions of various sizes surrounded by a grayish halo.  These may become confluent and lead to stromal edema extending into the epithelium.  The thickness of the Descemet membrane is highly variable and a retrocorneal membrane may be present.  Onset is variable as some infants will have corneal edema whereas many, if not most, adults are asymptomatic.  The condition in severely affected children may resemble congenital hereditary corneal dystrophy.

Systemic Features: 

No consistent systemic abnormalities have been reported.  However, some patients have been reported with inguinal hernias, hydroceles, and possible bone abnormalities suggesting that the ZEB1 mutation may have extraocular effects as well.

Genetics

This is an autosomal dominant disorder caused by a mutation in the ZEB1 gene (10p11.2).  Mutations in the same gene have recently been found in some cases with late-onset Fuchs endothelial dystrophy.

For other forms of posterior polymorphous dystrophy see PPCD1 (122000) and PPCD2 (609140).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Most patients do well and require no treatment.  Corneal transplantation may be required for the more severe cases but, as in many dystrophies, the lesions tend to recur in the graft.

References
Article Title: 

Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells

Krafchak CM, Pawar H, Moroi SE, Sugar A, Lichter PR, Mackey DA, Mian S, Nairus T, Elner V, Schteingart MT, Downs CA, Kijek TG, Johnson JM, Trager EH, Rozsa FW, Mandal MN, Epstein MP, Vollrath D, Ayyagari R, Boehnke M, Richards JE. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet. 2005 Nov;77(5):694-708.

PubMed ID: 
165384081

Corneal Dystrophy, Posterior Polymorphous 1

Clinical Characteristics
Ocular Features: 

This form of corneal dystrophy is often asymptomatic but some patients experience endothelial decompensation and corneal edema, which may even be seen soon after birth. The edema may extend into the epithelium.  The basic mechanism entails metaplasia of endothelial cells which seem to acquire some characteristics of epithelial cells.  Posterior corneal lesions of variable morphology appear in various patterns and are often surrounded by grayish halos.  When these become confluent the corneal edema is more severe and may resemble a congenital endothelial dystrophy.  The endothelial cell count is often low.  The Descemet layer also becomes abnormal.  The posterior border of the cornea appears nodular and grayish in color, often in a geographic pattern.  Surprisingly, endothelial function often is maintained and patients may remain asymptomatic for many years.

Some patients have features of anterior chamber dysgenesis with iris anomalies, anterior synechiae, and glaucoma.  It is also sometimes confused with EDICT syndrome (614303).

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

This is a genetically heterogeneous autosomal dominant disorder caused by several mutations including the promotor of OVOL2 at 20p11.23 responsible for PPCD1 described here.  Another locus for this disease has been mapped to 20q11, the same locus responsible for congenital hereditary corneal edema 1 (CHED1) and it is possible that these are allelic or clinical variants of the same mutation.  The latter is made more likely by the fact that both disorders have been found in relatives.  OMIM has combined the entities CHED1 and PPCD1 as a single disorder (122000).

For other forms of posterior polymorphous corneal dystrophy see, PPCD2 (609140) and PPCD3 (609141).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Few patients require treatment since the endothelial changes are frequently stable. Among those that do undergo corneal transplantation, the changes often recur in the donor button.

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

Ehlers-Danlos Syndrome, Type VIA

Clinical Characteristics
Ocular Features: 

The globe is thin and fragile and ruptures easily.  This results from scleral fragility which is in contrast to type VIB EDS  (229200) in which the cornea seems to be more fragile.  Retinal detachment is always a risk but no quantitative assessment can be made since early case reports did not always provide good classification of EDS types.  Other ocular abnormalities such as keratoconus and structural changes in the cornea are less common but frequent changes in classification and lack of genotyping in early cases make definitive clinical correlations difficult.

Systemic Features: 

The primary clinical manifestations of this form (VIA) of Ehlers-Danlos syndrome are extraocular.   The skin is soft, thin, easily extensible, and bruises easily.  The joints are highly flexible with a tendency to dislocate.  Arterial ruptures are not uncommon, often with severe consequences.  Scoliosis begins almost at birth and often progresses to severe kyphoscoliosis.  Patients are floppy (hypotonic).  Intellect is normal and there are generally no developmental delays.  Thirty per cent of infants have a club foot at birth.

Genetics

This an autosomal recessive disorder caused by molecular defects in the PLOD1 gene (1p36.3-p36.2).  The gene product is an enzyme, lysyl hydroxylase 1, important for the normal crosslinking of collagen. Mutations in PLOD1 may result in hydroxylase dysfunction with abnormal hydroxylation of lysine, weakened crosslinks, and fragile tissue.  

The classification of Ehlers-Danlos disease is under constant revision as new mutations and clinical subtypes are found (see 130000).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Joint dislocations, ocular trauma and vascular ruptures require prompt attention.  Longevity is not impacted by this syndrome.

References
Article Title: 

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