nuclear cataracts

Cataracts, Congenital, X-Linked

Clinical Characteristics
Ocular Features: 

The unique status of this type of X-linked cataract is uncertain as the phenotype is highly variable.  It is listed separately in this database because some patients do not have the dysmorphic features of Nance-Horan syndrome (302350) which also is caused by mutations in the NHS gene.  Lens opacities in males usually occur in the nucleus which may cause severe visual impairment.  Heterozygous females have granular opacities along the Y sutures but these may also be seen in males.  Microcornea, variable microphthalmia, and congenital glaucoma (usually secondary) have been noted in a few patients.  

Systemic Features: 

Facial dysmorphology, intellectual impairment, and dental anomalies are often found in patients with X-linked cataracts as part of the Nance-Horan syndrome (302350).  However, these signs may not always be apparent and therefore were not reported in early publications which adds uncertainty to the classification.  That said it is also true that some families in which X-linked cataracts segregate do not have the systemic features in spite of detailed examinations even though they have mutations in NHS. 

Genetics

A mutation in the NHS gene (Xp22.13) can be responsible for X-linked cataracts.   Mutations in the same gene cause Nance-Horan syndrome (302350).  Individuals with typical X-linked cataracts, however, may or may not have systemic malformations. 

A variety of alterations in the NHS gene, including copy number variations, intragenic deletions, and duplication/triplication arrangements, have been found and are likely responsible for the clinical heterogeneity and current nosological confusion.  Until additional fine genotyping is available for more patients it is not possible to determine if a category of X-linked cataracts without NHS mutations exists. 

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Visually significant cataracts must be removed early to allow normal visual development.  Secondary glaucoma and retinal detachments are post-operative risks. 

References
Article Title: 

X-linked cataract and Nance-Horan syndrome are allelic disorders

Coccia M, Brooks SP, Webb TR, Christodoulou K, Wozniak IO, Murday V, Balicki M, Yee HA, Wangensteen T, Riise R, Saggar AK, Park SM, Kanuga N, Francis PJ, Maher ER, Moore AT, Russell-Eggitt IM, Hardcastle AJ. X-linked cataract and Nance-Horan syndrome are allelic disorders. Hum Mol Genet. 2009 Jul 15;18(14):2643-55.

PubMed ID: 
19414485

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: 
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