cloudy cornea

Glaucoma, Congenital Primary D

Clinical Characteristics
Ocular Features: 

Evidence of glaucoma can appear in early childhood but may appear much later.  However, typical signs such as enlarged corneas or frank buphthalmos, cloudiness of the corneas, tearing and photophobia are present only when the pressure is elevated due to pupillary block or when the lens migrates into the anterior chamber.  Most patients have additional signs such as ectopia lentis and spherophakia.

Systemic Features: 

Some patients have osteopenia, a high arched palate, and a marfanoid habitus.

Genetics

This form of congenital glaucoma has been described primarily in Middle Eastern and Asian as well as Roma/Gypsy families and is inherited in an autosomal recessive pattern.  The mutations occur in the LTBP2 gene (14q24) which is in close proximity to GLC3C, another putative gene with mutations causing congenital glaucoma. 

Mutations in other genes are also associated with primary congenital glaucoma such as in CYP1B1 causing type A (231300) and in GLC3B causing type B (600975).

THIS IS NOT A PRIMARY GLAUCOMA DISORDER.  Microspherophakia and ectopia lentis are not features of primary congenital glaucoma.  Elevated pressures in these patients are found only when there is a pupillary block or when the lens dislocates into the anterior chamber.  The enlarged cornea is clear and has no breaks in the Descemet membrane.  THIS CONDITION IS THEREFORE RECLASSIFIED AS "MEGALOCORNEA, ECTOPIA LENTIS, AND SPHEROPHAKIA".     

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The usual surgical and pharmacological treatments for glaucoma apply but vision preservation is a challenge.  The spherophakic or dislocated lenses may need to be removed.

References
Article Title: 

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Azmanov DN, Dimitrova S, Florez L, Cherninkova S, Draganov D, Morar B, Saat R, Juan M, Arostegui JI, Ganguly S, Soodyall H, Chakrabarti S, Padh H, L??pez-Nevot MA, Chernodrinska V, Anguelov B, Majumder P, Angelova L, Kaneva R, Mackey DA, Tournev I, Kalaydjieva L. LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population. Eur J Hum Genet. 2011 Mar;19(3):326-33.

PubMed ID: 
21081970

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Brittle Cornea Syndrome 1

Clinical Characteristics
Ocular Features: 

This seems to be a subtype of the Ehlers-Danlos syndrome in which the ocular features are prominent.  The cornea is thin and can perforate following relatively minor trauma.  It is often misshapen as well resulting in keratoglobus and keratoconus.  The external appearance can suggest buphthalmos but intraocular pressure is normal.  The sclerae are bluish suggesting that the connective tissue defect is more widespread among eye tissues. The lens is not hypermobile, however.  This disorder differs from Ehlers-Danlos type VIA (225400) (sometimes called the ocular-scoliotic form) in which there is a defect in lysyl hydroxylase although the ocular phenotype has some similarities.

Systemic Features: 

The skin is hyperelastic as in other forms of Ehlers-Danlos and the joints are hypermobile and are susceptible to dislocation.  Some but not all cases reported from the Middle East have red hair and it has been suggested this may be part of the syndrome, at least in that part of the world.

Genetics

A mutation in the ZNF469 gene (16q24), encoding a defective zinc finger protein, is responsible for at least some cases of autosomal recessive brittle cornea syndrome.  This confirms its identity as a unique type of connective tissue disease apart from other forms of Ehlers-Danlos in which ocular disease is present (such as type VIA in which the mutation is in the PLOD1 gene).

Homozygous mutations in PRDM5 (4q27) have been found in several families with brittle cornea syndrome 2 (614170).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment beyond corneal repair is limited.

References
Article Title: 

Corneal Dystrophy, Endothelial X-Linked

Clinical Characteristics
Ocular Features: 

Corneal opacification is severe in males and has been described as resembling ground glass, or having a milky white appearance throughout the entire cornea.  Corneal clouding may be seen in infants but progresses with age in most cases.  In a 7 generation Austrian family, nine males had severe corneal opacification, seven with band keratopathy and 2 with the typical ground glass appearance.  Vision may be 20/20 even in adults but the majority have acuities in the range of 20/30 to 20/60 even into the 7th decade.  A few have vision of 20/100 to 20/400 even as young adults and one 19 year old was reported with nystagmus.  The corneas of twenty-two females and four males were said to have only a 'moon crater-like' appearance resulting from focal discontinuities in the endothelial layer.  Tissue studies of a keratoplasty button from a 60 year old male revealed endothelial degeneration and thickening of the Descemet membrane.  There may also be irregular thinning of the epithelial and Bowman layers.

Systemic Features: 

No systemic disease associations have been reported.

Genetics

This is the only endothelial dystrophy that is X-linked (Xq25).  A single family has been reported and the molecular mutation is unknown. Females may be affected but less severely than males and are usually asymptomatic.  In a large pedigree in which 60 individuals were studied, no male-to-male transmission was found.

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

The few reported cases and limited treatments used make generalizations difficult.  But males have had penetrating keratoplasty with good results lasting for decades.

References
Article Title: 

A new, X-linked endothelial corneal dystrophy

Schmid E, Lisch W, Philipp W, Lechner S, Gottinger W, Schlotzer-Schrehardt U, Muller T, Utermann G, Janecke AR. A new, X-linked endothelial corneal dystrophy. Am J Ophthalmol. 2006 Mar;141(3):478-487.

PubMed ID: 
16490493
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