corneal opacification

Kenny-Caffey Syndrome, Type 2

Clinical Characteristics
Ocular Features: 

Congenital cataracts have been reported in one patient.  There is a report of pseudopapilledema in a 6 year old and another patient has been described with tortuous and dilated retinal vessels.  The hyperopia is likely the result of the small globes.  In an autopsied patient microscopic calcification was noted in the cornea and the retina.

Systemic Features: 

Hypocalcemia and hyperphosphatemia similar to hypoparathyroidism is seen in individuals with KCS2 but it may be transient and self-limited.  Macrocephaly with short stature is characteristic.  Alopecia, delayed closure of the anterior fontanel, and apparent thickening of the cortex in long bones may be seen.  Males have small testicles but there is no evidence regarding fertility.  In an autopsied case no parathyroid tissue could be identified.  Brain imaging may show calcification in the basal ganglia, dentate nuclei, and parts of the cerebrum and cerebellum.  Intelligence is normal.

Genetics

Several heterozygous mutations in the FAM111A gene (11q12.1) have been found.  Many of these seem to be new mutations but there are a number of published families in which there was transmission from mother to child (of both sexes).

Heterozygous mutations in the same gene are responsible for the autosomal dominant  allelic disorder known as Gracile Bone Dysplasia (602361). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normalization of serum calcium and phosphorous levels would likely be beneficial but complete correction of all the findings is unlikely.  Removal of congenital cataracts should be considered.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Ocular findings in Kenny's syndrome

Boynton JR, Pheasant TR, Johnson BL, Levin DB, Streeten BW. Ocular findings in Kenny's syndrome. Arch Ophthalmol. 1979 May;97(5):896-900.

PubMed ID: 
444124

Anterior Segment Mesenchymal Dysgenesis

Clinical Characteristics
Ocular Features: 

The unique status of this entity remains to be established as there are overlapping features with aniridia (106210), and Peters anomaly (604229), posterior embryotoxon, and iridogoniodysgenesis type 1 (601631) and type 2 (137600).  Anterior segment mesenchymal dysgenesis itself is clinically heterogeneous even within families.  Schwalbe line is often anteriorly placed and there may be iris adhesions to the cornea, with or without corneal opacities.  Some patients have microcornea.  All layers of the cornea are dysplastic from the epithelium to the endothelium suggesting abnormal migration or function of neural crest cells.  Lens opacities are highly variable but they can be progressive. Curiously, elevated intraocular pressure is usually not present.  Visual acuity is highly variable with some patients having 20/20 vision and others bare hand motions depending on the degree of opacification of the lens and cornea.

Systemic Features: 

No systemic abnormalities are present.

Genetics

This is an autosomal dominant disorder secondary to mutations in either PITX3 (10q24.32) or FOXE3 (1p32)  which are both transcription factors.  The latter gene is also mutant in congenital primary aphakia (610256) and some cases of Peters anomaly (604229).

See also Anterior Segment Dysgenesis 6 (617315) and Anterior Segment Dysgenesis 8 (617319) for autosomal recessive conditions in which mutations result in malformations of the anterior chamber.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated in some cases and corneal transplantation has been attempted in a few individuals.

References
Article Title: 

Sclerocornea

Clinical Characteristics
Ocular Features: 

This is a disorder of the cornea and anterior chamber that is sometimes considered to be a form of anterior segment or mesenchymal dysgenesis.  The primary feature is corneal clouding, most prominent peripherally and extending to the central cornea to a variable extent.  Vascular arcades are usually present over the area of clouding and there is no clear limbal demarcation.  Corneal fibers are often disorganized and larger than normal.  The anterior chamber may appear shallow and the iris usually has a flat appearance, often with a posterior embryotoxon.  Iris processes to the cornea and anterior synechiae are frequently present.  Some degree of microcornea has also been noted in many cases.  Rotary and horizontal nystagmus are uncommon. Sclerocornea may be a feature of cornea plana as well and the distinction between these disorders is unclear, especially in reported dominant pedigrees in which hyperopia is a feature.

Most cases are bilateral but there is often considerable asymmetry between the two eyes.  Visual acuity is dependent on the extent of corneal opacification but may be normal.  It is not a progressive disease.

Systemic Features: 

No systemic abnormalities have been reported.  However, sclerocornea can be a feature of numerous somatic and chromosomal disorders (e.g., oculocerbral syndrome with hypopigmentation (257800 ).

Genetics

No DNA mutations have as yet been found.  Most cases occur sporadically, and others are part of anterior chamber dysgenesis disorders.  However, rare autosomal dominant pedigrees have been reported in which the degree of opacification and anterior chamber anomalies are not as severe as those in which the pattern is most consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Severe cases in which the central media is compromised may require corneal transplantation.  Glaucoma requires treatment as well.

References
Article Title: 

A review of anterior

Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior
segment dysgeneses. Surv Ophthalmol. 2006 May-Jun;51(3):213-31. Review.

PubMed ID: 
16644364

Hereditary sclerocornea

Elliott JH, Feman SS, O'Day DM, Garber M. Hereditary sclerocornea. Arch
Ophthalmol. 1985 May;103(5):676-9.

PubMed ID: 
3994576

Megalocornea

Clinical Characteristics
Ocular Features: 

The corneal diameter is enlarged at birth to between 13.0 and 16.5 mm and the anterior chamber is deep.  Male patients may develop early arcus, and eventually a crocodile shagreen pattern in the cornea.  Presenile cataracts, iris thinning, and iridodenesis have also been reported.  Glaucoma does not seem to be a part of this syndrome.  The ERG has revealed mild cone system dysfunction in some patients.. 

Systemic Features: 

Isolated megalocornea is not associated with systemic disease by definition but systemic evaluation must be performed to rule out other syndromes.

Some patients have been reported to have a focal loss of white matter myelination with superior cognitive abilities.

Genetics

Only a few pedigrees have been reported.  X-linked (male only) inheritance is most common.  Carrier females do not have ocular disease.  Multiple mutations in CHRDL1 (Xq23) have been found in at least 7 families. The gene encodes ventroptin, a morphogenic protein antagonist with multiple functions including specification of topographic retinotectal projections..  The gene is expressed in corneal development, anterior segment, and retina as well as brain.

Notably, megalocornea not only occurs as an isolated trait but also may be a part of systemic syndromes such as the Marfan syndrome (154700), Down syndrome andRieger syndrome (180500 ).  It is also a part of an autosomal recessive mental retardation syndrome, sometimes called Neuhauser syndrome (249310).

Autosomal inheritance (usually recessive) has also been suggested but no locus has been found on autosomes.

Homozygous mutations in LTBP2 have been reported in consanguineous families in which sibs have congenital Megalocornea, Ectopia Lentis, and Spherophakia.

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

There is no treatment for the overall condition but correction of refractive errors, cataract surgery, and low vision aids could be helpful.
 

References
Article Title: 

Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhäuser Syndrome and Central Corneal Thickness

Davidson AE, Cheong SS, Hysi PG, Venturini C, Plagnol V, Ruddle JB, Ali H, Carnt N, Gardner JC, Hassan H, Gade E, Kearns L, Jelsig AM, Restori M, Webb TR, Laws D, Cosgrove M, Hertz JM, Russell-Eggitt I, Pilz DT, Hammond CJ, Tuft SJ, Hardcastle AJ. Association of CHRDL1 Mutations and Variants with X-linked Megalocornea, Neuhauser Syndrome and Central Corneal Thickness. PLoS One. 2014 Aug 5.

PubMed ID: 
25093588

X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development

Webb TR, Matarin M, Gardner JC, Kelberman D, Hassan H, Ang W, Michaelides M, Ruddle JB, Pennell CE, Yazar S, Khor CC, Aung T, Yogarajah M, Robson AG, Holder GE, Cheetham ME, Traboulsi EI, Moore AT, Sowden JC, Sisodiya SM, Mackey DA, Tuft SJ, Hardcastle AJ. X-Linked Megalocornea Caused by Mutations in CHRDL1 Identifies an Essential Role for Ventroptin in Anterior Segment Development. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print].

PubMed ID: 
22284829
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