corneal opacity

Cataracts 34

Clinical Characteristics
Ocular Features: 

Two families with mutations in the FOXE3 associated with cataracts have been reported.  The lens opacities may be present at birth or found soon thereafter.  In 1 family with 5 affected sibs membranous cataracts were present along with corneal opacities, microcornea and nystagmus.  In another family, 7 sibs had posterior subcapsular cataracts but no other ocular findings.

Systemic Features: 

No systemic abnormalities were associated with the ocular findings.

Genetics

Homozygous mutations in the FOXE3 (1p33) gene segregated with the eye findings in the two families.  FOXE3 is a transcription gene and its mutations are responsible for a variety of ocular abnormalities.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical cataract removal may be indicated.  Amblyopia is a risk and requires rehabilitation.

References
Article Title: 

FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

Khan SY, Vasanth S, Kabir F, Gottsch JD, Khan AO, Chaerkady R, Lee MC, Leitch CC, Ma Z, Laux J, Villasmil R, Khan SN, Riazuddin S, Akram J, Cole RN, Talbot CC, Pourmand N, Zaghloul NA, Hejtmancik JF, Riazuddin SA. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nat Commun. 2016 Apr 6;7:10953. doi: 10.1038/ncomms10953. PubMed PMID: 27218149; PubMed Central PMCID: PMC4820811.

PubMed ID: 
27218149

GAPO Syndrome

Clinical Characteristics
Ocular Features: 

Progressive optic atrophy is considered part of this syndrome but it is not a consistent feature.  One patient with the suspected diagnosis had papilledema while other individuals may have congenital glaucoma, buphthalmos, band keratopathy, and keratoconus.  White eyelashes have been described.  Myelinated nerve retinal nerve fibers may be prominent.

Systemic Features: 

This is a rare congenital disorder with so far incomplete phenotypic delineation. The diagnosis can be made soon after birth from the general facial and body morphology.  The dysmorphism is secondary to marked bone growth retardation and metaphyseal dysplasia, resulting in a flat midface, frontal bossing, micrognathism, chest deformities, and vertebral anomalies. Psychomotor retardation is common but the extent of cognitive deficits is unknown.  The permanent teeth may begin to develop but fail to erupt (pseudoanodontia). Even primary dentition is often abnormal.  Alopecia is a feature although some individuals do have sparse body hair, at least for a period of time.  Anomalous blood vessels such as dilated scalp veins are sometimes evident.   Hypogonadism has been reported in both sexes.  Individuals are subject to recurrent ear and respiratory infections. 

Genetics

GAPO occurs in both sexes.  Homozygous mutations in the ANTXR1 gene (2p13.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at individual problems.  Prompt treatment of respiratory infections is important.

References
Article Title: 

Mutations in ANTXR1 cause GAPO syndrome

Stranecky V, Hoischen A, Hartmannova H, Zaki MS, Chaudhary A, Zudaire E, Noskova L, Baresova V, Pristoupilova A, Hodanova K, Sovova J, Hulkova H, Piherova L, Hehir-Kwa JY, de Silva D, Senanayake MP, Farrag S, Zeman J, Martasek P, Baxova A, Afifi HH, St Croix B, Brunner HG, Temtamy S, Kmoch S. Mutations in ANTXR1 cause GAPO syndrome. Am J Hum Genet. 2013 May 2;92(5):792-9.

PubMed ID: 
23602711

Ophthalmic findings in GAPO syndrome

Ilker SS, Ozturk F, Kurt E, Temel M, Gul D, Sayli BS. Ophthalmic findings in GAPO syndrome. Jpn J Ophthalmol. 1999 Jan-Feb;43(1):48-52.

PubMed ID: 
10197743

Cataracts, Congenital with Sclerocornea and Glaucoma

Clinical Characteristics
Ocular Features: 

The ocular features are evident at birth or within the first year of life and may be asymmetrical.  The phenotype is heterogeneous but does not appear to be progressive.  The anterior chambers are of normal depth and the fundi are normal when visualization is possible.  The corneal opacification is usually denser peripherally and resembles corneoscleralization but it can extend centrally to a variable degree.  In individuals with glaucoma and buphthalmos the cornea is more opaque and usually vascularized. In such eyes the cornea is thinned.  In most patients the corneal diameters were 5-8 mm in diameter but in those with elevated pressures the anterior segment was obviously buphthalmic. Iridocorneal adhesions may be present.  The lenses are cataractous but the capsules are normal.  Microphthalmia has been reported in some patients.  Vision is often in the range of hand motions.    

Systemic Features: 

None.

Genetics

Homozygous mutations in PXDN (2p25.3) encoding peroxidasin are believed responsible for this autosomal recessive condition.  Mammalian peroxidasin localizes to the endoplasmic reticulum but is also found in the extracellular matrix and is believed important to the maintainence of basement membrane integrity.  The protein is one of several that aids in the extracellular breakdown of hydrogen peroxide and free radicals.  In mouse eyes it localizes to the corneal and lens epithelium but its role in maintaining transparency of the lens and cornea is unknown.

See also Cataracts, Congenital Zonular Pulverulent 1 (116200) in this database for a condition with a similar phenotype but caused by heterozygous mutations in the GJA8 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No information regarding treatment is available but cataract and corneal surgery may be beneficial.   

References
Article Title: 

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

Choi A, Lao R, Ling-Fung Tang P, Wan E, Mayer W, Bardakjian T, Shaw GM, Kwok PY, Schneider A, Slavotinek A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2014 Jun 18. doi: 10.1038/ejhg.2014.119. [Epub ahead of print] PubMed PMID: 24939590.

PubMed ID: 
24939590

Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma

Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 2011 Sep 9;89(3):464-73.

PubMed ID: 
21907015

Cataracts, Congenital, Autosomal Recessive 3

Clinical Characteristics
Ocular Features: 

This type of congenital cataract has been reported in two unrelated Pakistani families.  The phenotype was dissimilar in the two families.  In one, only posterior subcapsular opacification was present.  In the other the cataract was membranous and accompanied by a corneal opacity, microcornea, and nystagmus.  Nothing is known about the course of the opacification.

Systemic Features: 

No systemic disease is apparently present.

Genetics

Consanguinity was reported for both families.  Fine mapping identified a locus at 1p34.3-p32.2 that cosegregates with the lens opacities but the mutation is unknown.  This region is distinct from the locus containing the mutation(s) causing Volkmann (115665) and posterior polar (116600) autosomal dominant cataracts.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Visually significant lens opacities could be removed.

References
Article Title: 

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

Corneal Dystrophy, Avellino Type

Clinical Characteristics
Ocular Features: 

There is little to support the designation of a corneal dystrophy as 'Avellino type' but it is included in this database because it is entrenched in the literature.  It has features of both lattice dystrophy, type I, and granular dystrophy type I, which might be expected since all of these result from mutations in the same gene, TGFBI on chromosome 5.  Not surprisingly, reported cases have clinical and histological features of both lattice and granular dystrophy and hence are labeled as having combined granular-lattice corneal dystrophy.  There is considerable variation of the nature and quantity of the stromal deposits both within and among families, a common characteristic of autosomal dominant disorders.  Even though clinical evidence may suggest primarily lattice or granular dystrophy, histological studies can reveal changes characteristic of both.

Early cases could be traced to the Avellino region of Italy from which the title was derived but more recent reports have described families from around the world.

Systemic Features: 

No systemic disease is associated with this disorder.

Genetics

Mutations in the TGFBI (5q31) have been found in this so-called combined dystrophy.   Autosomal dominant transmission is evident from familial cases.  Mutations in the same gene also cause Thiel-Behnke (602082), Reis-Bucklers (608470), granular (Groenouw) type I (121900), lattice type I (122200) and epithelial basement membrane dystrophy (121820).  The combined features of lattice and granular dystrophies in the same corneas resulting from mutations in the same gene calls into question the value of relying solely on clinical and histological evidence to classify disease.  Modern genotyping now enables greater accuracy in the nosology and already the Cornea Society has incorporated this information in its recent reclassification of these dystrophies (Cornea Society IC3D Corneal Dystrophies(c)). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Penetrating keratoplasty can improve vision at least temporarily but deposits tend to recur.  LASIK has been reported to exacerbate the number and density of the opacities.  Patients treated with PRK may do better and can retain corneal clarity for a decade or more.

References
Article Title: 

Avellino corneal dystrophy after LASIK

Jun RM, Tchah H, Kim TI, Stulting RD, Jung SE, Seo KY, Lee DH, Kim EK. Avellino corneal dystrophy after LASIK. Ophthalmology. 2004 Mar;111(3):463-8.

PubMed ID: 
15019320

Cornea Plana

Clinical Characteristics
Ocular Features: 

Enlargement of the cornea with flattening is characteristic of cornea plana although corneal diameters vary widely.  Corneal thinning may be present.  The mean corneal refraction value at the horizontal median has been measured at 37.8 D for the dominant form (CNA 1) of the disease, compared with 29.9 D for the recessive form (CNA 2) and 43.4 D for controls accounting for the hyperopia found among many patients.  The limbal margin may be widened with blurring of the corneolimbal junction.  Recessive cases can often be distinguished from the dominant ones by the presence of a central 5 mm area of thickening and clouding.  Recessively inherited cases are also more likely to have anterior synechiae and other iris anomalies.  Early onset arcus has been reported.

Vision in mild cases may be as good as 20/25 or 20/30 but considerably worse in recessive cases with central opacification.  Glaucoma may occur in older individuals.

Systemic Features: 

None reported.

Genetics

Multiple families in Finland have been reported with inheritance patterns suggesting autosomal recessive inheritance (CNA2).  The gene has been mapped to chromosome 12 (12q21) in a region containing the KERA gene.  A Cuban family with autosomal dominant cornea plana (CDA1) also yielded linkage to 12q where the recessive gene is located.  However, this locus could be excluded in two Finnish families suggesting that at least 3 autosomal mutations may be responsible.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Correction of the hyperopia may be helpful.  Patients need to be followed and treated for glaucoma if it develops.  Outcomes of penetrating keratoplasty are not available but the procedure carries increased risk since the stroma is often thinner than normal. 
 

References
Article Title: 

The genetics of cornea plana congenita

Tahvanainen, E.; Forsius, H.; Kolehmainen, J.; Damsten, M.; Fellman, J.; de la Chapelle, A. :  The genetics of cornea plana congenita. J. Med. Genet. 33: 116-119, 1996.

PubMed ID: 
8929947

Mutations in KERA, encoding keratocan, cause cornea plana

Pellegata, N. S.; Dieguez-Lucena, J. L.; Joensuu, T.; Lau, S.; Montgomery, K. T.; Krahe, R.; Kivela, T.; Kucherlapati, R.; Forsius, H.; de la Chapelle, A. :  Mutations in KERA, encoding keratocan, cause cornea plana. Nature Genet. 25: 91-95, 2000.

PubMed ID: 
10802664
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