heterochromia

Retinal Nonattachment, Congenital

Clinical Characteristics
Ocular Features: 

The common denominator in this condition is, of course, congenital nonattachment of the retina.  Many eyes are small as well.  Some patients in addition have a vascularized hyperplastic vitreous and often present with blindness and a congenital leukocoria.  Many at some stage have lens opacification, as well as glaucoma and anterior chamber anomalies including anterior synechiae and some degree of corneal opacification.  These signs are often progressive beginning in childhood.  Pendular nystagmus and esotropia are common.  MRI studies reveal optic nerves and the chiasm that are either absent or abnormally small.

Systemic Features: 

This condition is nonsyndromic and has no systemic abnormalities.

Genetics

Congenital retinal nonattachment consists of a group of sometimes familial conditions for which no responsible gene has been identified.  In a genomic study of 21 consanguineous NCRNA Pakistani families 3 had mutations in ATOH7 and 10 had mutations in familial exudative vitreoretinopathy genes.  Genotyping did not reveal associated mutations in the remaining 38% of these families. It is likely that multiple entities are represented but until the molecular etiologies are identified, no more specific classification is possible.

Studies in mice document that the Atoh7 gene is important to retinal ganglion cell neurogenesis.  In humans, both autosomal recessive PHPV and congenital nonattachment of the retina are associated with microsatellite linkage and haplotype matching to a region at 10q21 adjacent to the ATOH7 gene but so far no causative mutation has been found in this region.  However, studies in large consanguineous kindreds in which a deleted DNA segment adjacent to ATOH7 segregated with the NCRNA phenotype suggest that a transcription regulator may be at fault in the timing and level of ATOH7 expression.

The disorder known as persistent hyperplastic primary vitreous is generally not considered hereditary since it usually occurs unilaterally and sporadically.  It is sometimes found in association with a number of syndromal conditions as well.  However, it has also been reported in familial patterns consistent with both autosomal recessive and autosomal dominant patterns.  DNA mapping of individuals with bilateral disease found in a consanguineous Pakistani kindred with presumed autosomal recessive disease suggests that a locus at 10q11-q21 may be responsible.

Evidence for autosomal dominant inheritance of persistent hyperplastic primary vitreous comes from rare families with an apparent vertical transmission of the condition.

Congenital nonattachment of the retina is also seen in the osteoporosis-pseudoglioma syndrome (250770).  However, this is a syndromal disorder with neurologic and joint disease in addition to porotic, thin, fragile bones (sometimes called the ocular form of osteogenesis imperfecta) resulting from mutations in LRP5 on chromosome 11.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

With rare exceptions, the retina cannot be reattached successfully and phthisis with blindness is the usual outcome.

References
Article Title: 

Coloboma, Isolated

Clinical Characteristics
Ocular Features: 

Colobomas of the uveal tract are often found in association with other ocular anomalies including those with systemic disease. They are usually located in the inferonasal quadrant as a result of defective closure of the embryonic fissure in the optic cup.  Most involve the nearly complete iris and resemble a keyhole but they may also be partial resulting in an oval pupil.  They are sometimes unilateral in which case the involved iris may be more heavily pigmented than the contralateral one.  They may involve only the iris (simple coloboma) but often are more extensive with involvement of the ciliary body, retina, lens, choroid, and even the optic nerve.  They are frequently associated with microphthalmia (or microphthalmia with cyst [5.6%]) and microcornea (79%). 

Systemic Features: 

None by definition.

Genetics

Isolated colobomas are clinically and genetically heterogeneous resulting from mutations in SHH (7q36.3), PAX6 (11p13), and ABCB6 (2q35) among others.  Large pedigrees with typical autosomal dominant transmission patterns have been reported.

Homozygous mutations in SALL2 (14q11.1-q12.1) have also been reported in patients with isolated colobomas.  Studies of sall2-deficient mice show defects in closure of the anterior optic fissure while posterior closure proceeds normally.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Simple iris colobomas usually do not require treatment.  The visual prognosis depends upon the structures involved.  Those with microcornea usually have a lower acuity and, of course, eyes with the most extensive involvement of the uveal tract and/or the optic nerve may have the least vision. Low vision aids can be helpful in selected individuals.

References
Article Title: 

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Kelberman D, Islam L, Lakowski J, Bacchelli C, Chanudet E, Lescai F, Patel A, Stupka E, Buck A, Wolf S, Beales PL, Jacques TS, Bitner-Glindzicz M, Liasis A, Lehmann OJ, Kohlhase J, Nischal KK, Sowden JC. Mutation of SALL2 causes recessive ocular coloboma in humans and mice. Hum Mol Genet. 2014 Jan 12. [Epub ahead of print].

PubMed ID: 
24412933

ABCB6 Mutations Cause Ocular Coloboma

Wang L, He F, Bu J, Liu X, Du W, Dong J, Cooney JD, Dubey SK, Shi Y, Gong B, Li J, McBride PF, Jia Y, Lu F, Soltis KA, Lin Y, Namburi P, Liang C, Sundaresan P, Paw BH, Li DY, Phillips JD, Yang Z. ABCB6 Mutations Cause Ocular Coloboma. Am J Hum Genet. 2012 Jan 13;90(1):40-8.

PubMed ID: 
22226084

Retinoblastoma

Clinical Characteristics
Ocular Features: 

Retinoblastoma is the most common intraocular malignancy of childhood occurring in 1 in 18,000 to 1 in 30,000 live births worldwide. The majority of cases are diagnosed before the age of 3 years. The most common clinical feature at time of diagnosis is leukocoria (white pupillary reflex) followed by strabismus. Other presenting features include intraocular inflammation, spontaneous hyphema, hypopyon, heterochromia, proptosis, spontaneous globe perforation, retinal detachment, cataract, neovascularization of iris, glaucoma, nystagmus, tearing and anisocoria.

Retinoblastoma can usually be observed during fundus exam as a white subretinal or vitreous mass, occasionally with multifocal nodules, typically with calcification of the surface. The growth of the tumor can be endophytic, exophytic or diffuse. Endophytic growth of retinoblastoma occurs when the tumor penetrates the inner limiting membrane of the retina and can result in vitreous seeding and growth and can simulate iridocyclitis or endophthalmitis.  Exophytic growth occurs when the tumor grows into the subretinal space, which results in accumulation of subretinal fluid and retinal detachments. If the tumor infiltrates Bruchs membrane, there is an increased risk of invasion of choroidal vessels or ciliary nerves and vessels. Diffuse growth is rare and characterized by slow infiltration of retina with diffuse thickening.

Imaging studies such as ultrasound, computerized tomography, and MRI can show the extent of tumor and the presence of calcification.

Systemic Features: 

In heritable cases there is an increased risk of developing other malignant neoplasms throughout life such as osteosarcomas, cutaneous melanomas, pinealomas, and thyroid carcinomas. The risk for secondary malignancies is higher in areas treated with radiation, where osteogenic sarcoma, fibrosarcoma and soft tissue sarcomas may occur. Patients should be closely monitored for secondary tumors throughout life.

Genetics

Retinoblastoma is a malignant tumor of the developing retinal cells caused in most cases by mutations in both copies of the RB1 gene.  The RB1 gene is a tumor suppressor gene, located on chromosome 13q14 and is the first human cancer gene to be cloned. The gene codes for the tumor suppressor protein pRB, which by binding to the transcription factor E2F, inhibits the cell from entering the S-phase during mitosis.  Recent evidence suggests that post-mitotic cone precursors are uniquely sensitive to pRB depletion and may be the cells in which retinoblastoma originates.

However, more recent information suggests that the occurrence and viability of retinoblastic cells may be more complex than suggested by simple loss of function of the RB1 alleles.  There is increasing evidence for the role of epigenetic factors such as DNA methylation impacting the differential expression of more than 100 additional genes which may be influencing the retinoblastoma phenotype.  Among these is an upregulation of spleen tyrosine kinase (SYK) required for tumor cell survival which, if inhibited, leads to retinoblastoma cell death in vivo and in vitro.

Pedigrees of familial cases have an autosomal dominant pattern but the disease requires homozygosity of the RB1 mutation.  This complicates genetic counseling for retinoblastoma. One third of cases have a germline mutation with a mutation in only one of the two gene copies in every cell.  A somatic mutation in the second allele then leads to  homozygosity causing tumor development.  Since one of the parents contributed the germinal mutation, and there is high penetrance (as much as 85%), this leads to the autosomal dominant pattern in these families. In 6% of retinoblastoma cases with germline mutations the family history is positive. The risk for developing bilateral and multifocal retinoblastoma is high and the age of onset is around 14 months.  This is the case for virtually all bilateral tumors.  The mean number of tumors is about 5 in the two eyes.  The offspring of a parent with bilateral retinoblastoma have a 45% chance of developing a tumor (they have a 50% chance of inheriting the germline mutant allele).  Reduced penetrance of 10 to 15% lowers the expected occurrence of disease from 50% to 45%.

However, two thirds of cases are of non-germinal origin with both somatic mutations occurring in a single retinal progenitor cell.  Because this is a highly unlikely event, these cases are generally unilateral and unifocal with an average age of onset of 24 months. Sporadic cases constitute about 94% of all retinoblastomas, of which about 60% have unilateral disease with no germline mutations.  Individuals who acquire mutations in both alleles somatically (with single, unilateral tumors) do not have a mutation in their germ cells and therefore usually transfer no tumor risk to their offspring.  Laterality and number of tumors alone, however, cannot be used for accurate predictions in this case since about 15% of patients with unilateral and monofocal tumors actually have germline mutations.  This leaves a residual risk of transferring heritability of about 1-5% in unilateral patients without a family history.

To further complicate the story, recent evidence suggests that retinoblastoma is genetically heterogeneous.  About 6% of patients have no RB1 mutation.  In one study, about half of such individuals have up-regulation of the MYCN oncogene (2p24.3) suggesting a second mechanism leading to clinical retinoblastoma.  For unknown reasons, such tumors tend to  be larger, more aggressive, and discovered at an earlier age than unilateral non-familial RB1 tumors.  The MYCN gene product is a transcription factor important for organ development during embryogenesis.  Its amplification has been implicated in about 25% of neuroblastomas.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Enucleation may be necessary to eliminate the primary tumor, especially large ones, but other treatments can be used successfully to treat smaller tumors and spare vision. Intravenous chemotherapy is the most common treatment, which can be combined with subtenon chemotherapy, cryotherapy, thermotherapy, and plaque brachytherapy. External beam radiation can be used for refractive cases and recurrences. Another treatment alternative is localized ophthalmic artery intra-arterial chemotherapy.

It is necessary to follow all offspring of parents with bilateral tumors throughout the first decade because of the risk for new tumor development, as late as 5 to 7 years of age.   There are even a few case reports of retinoblastoma diagnosed in adults. However, since the retinal cells are generally mature by the age of 2.5 years, such events are very rare.  All parents of children with retinoblastoma should have complete fundus evaluations since rare tumors spontaneously regress leaving retinal scars, which in such a family pattern suggests that a germline mutation was inherited.

Survivors of hereditary retinoblastomas must be followed the rest of their lives, and especially so if radiation treatment was applied, because of the high risk of developing secondary neoplasms.  The risk rises with age.

References
Article Title: 

Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies

Rushlow DE, Mol BM, Kennett JY, Yee S, Pajovic S, Th?(c)riault BL, Prigoda-Lee NL, Spencer C, Dimaras H, Corson TW, Pang R, Massey C, Godbout R, Jiang Z, Zacksenhaus E, Paton K, Moll AC, Houdayer C, Raizis A, Halliday W, Lam WL, Boutros PC, Lohmann D, Dorsman JC, Gallie BL. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol. 2013 Mar 12:327-34.

PubMed ID: 
23498719

A novel retinoblastoma therapy from genomic and epigenetic analyses

Zhang J, Benavente CA, McEvoy J, Flores-Otero J, Ding L, Chen X, Ulyanov A, Wu G, Wilson M, Wang J, Brennan R, Rusch M, Manning AL, Ma J, Easton J, Shurtleff S, Mullighan C, Pounds S, Mukatira S, Gupta P, Neale G, Zhao D, Lu C, Fulton RS, Fulton LL, Hong X, Dooling DJ, Ochoa K, Naeve C, Dyson NJ, Mardis ER, Bahrami A, Ellison D, Wilson RK, Downing JR, Dyer MA. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature. 2012 Jan 11;481(7381):329-34.

PubMed ID: 
22237022
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