cataract

Stickler Syndrome, Type II

Clinical Characteristics
Ocular Features: 

Virtually all (85%) patients have a nonprogresssive axial myopia.  The vitreous degeneration has a beaded pattern without the veils of type I, claimed by some to be important in the distinction of the two types.  Paravascular lattice retinopathy is seen in 38% of patients and 64% have cataracts, sometimes with wedge opacities similar to those in type I Stickler syndrome.  Nearly half (42%) of patients are reported to have retinal detachments.

Systemic Features: 

Hearing loss occurs early and many individuals (80%) eventually require hearing aids.    Midline clefting is present frequently with bifid uvula, a highly arched palate, or an actual cleft palate.  Joint laxity is common.

Genetics

There are reasons to classify type II Stickler syndrome as a unique disorder apart from type I (108300).  In addition to phenotypic evidence (vitreoretinal disease, amount of hearing loss, and degree of epiphyseal disease), mutation in two different genes are involved.  Type II results from a mutation in the COL11A1 (1p21) and type I (108300) in COL2A1.  Both types are inherited in autosomal dominant patterns.

Type IV (614234) with vitreoretinal changes, myopia, and a high risk of retinal detachment is inherited in an autsomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Patients with type II Stickler disease need lifelong ophthalmologic monitoring because of the risk of retinal detachments and cataracts with treatment as indicated.
 

References
Article Title: 

Clinical features of type 2 Stickler syndrome

Poulson AV, Hooymans JM, Richards AJ, Bearcroft P, Murthy R, Baguley DM, Scott JD, Snead MP. Clinical features of type 2 Stickler syndrome. J Med Genet. 2004 Aug;41(8):e107.

PubMed ID: 
15286167

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

Retinoschisis, Juvenile

Clinical Characteristics
Ocular Features: 

Retinoschisis is a retinal disorder characterized by a cystic degeneration of the retina, leading to a split of retinal layers mainly at the level of the nerve fiber layer. Almost all patients have macular involvement, most commonly with foveal spoke-like streaks consisting of microcystic cavities that may coalesce over time. Retinal pigment epithelium atrophy and pigment clumping may occur.  Peripheral schisis is evident in about 50% of patients with large bullous cavities that may resolve spontaneously leaving a pigmented demarcation line. Other retinal findings are white retinal flecks, exudative retinopathy with retinal detachment, perivascular sheathing and dendritiform vessels in the periphery. Vitreous veils are commonly seen that are caused by separation of the thin inner wall of a peripheral schisis cavity and inner wall holes. Bridging vessels may rupture into the cystic cavity or the vitreous. The onset of the disorder has been detected as early as three months, but the majority of cases are five years old or older. Many present with mildly decreased vision that cannot be corrected with glasses and the diagnosis is often delayed. Visual acuity is highly variable ranging from 20/20 to 20/200, but may decline with age and with complications such as vitreous hemorrhage and macular detachment.  The disorder is also associated with axial hyperopia, posterior subcapsular cataract and strabismus. Fluorescein angiography shows minimal or no leakage as opposed to cystoid macular edema. Focal areas of vascular leakage into schisis cavity may be present as well as peripheral capillary nonperfusion. Electroretinograms exhibit a reduced b-wave and a preserved a-wave.

Systemic Features: 

No general systemic manifestations are associated with juvenile retinoschisis.

Genetics

Juvenile retinoschisis is an X-linked recessive disorder that affects mainly males. The causative mutations involve the gene RS1 located on the X chromosome at Xp22. Female carriers may have peripheral schisis amd many allelic variants have been reported.  The encoded protein retinoschisin is a secreted protein produced by photoreceptors and bipolar cells and may be involved in cell-cell adhesion or ion channel regulation.

Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but decreased vision later in life can be aided with low vision aids. Cases with posterior subcapsular cataract can be treated with cataract extraction.  Improvement in the cystic macular lesions, central foveal zone thickness, and visual acuity have been reported to benefit from topical dorzolamide treatment.

References
Article Title: 

Peripheral fundus findings in X-linked retinoschisis

Fahim AT, Ali N, Blachley T, Michaelides M. Peripheral fundus findings in X-linked retinoschisis. Br J Ophthalmol. 2017 Mar 27. pii: bjophthalmol-2016-310110. doi: 10.1136/bjophthalmol-2016-310110. [Epub ahead of print].

PubMed ID: 
28348004

X-linked retinoschisis: an update

Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D. X-linked retinoschisis: an update. J Med Genet. 2007 Apr;44(4):225-32. 2006 Dec 15.

PubMed ID: 
17172462

Peters Anomaly

Clinical Characteristics
Ocular Features: 

Peters anomaly occurs as an isolated malformation but also as a feature of other syndromes.  It is often unilateral.  A wide variety of other ocular findings may occur with Peters anomaly as well. Here we limit our description to 'simple' Peters anomaly in which the findings are limited to the eye having the classic findings of adhesions of the iris to the posterior cornea and a central or paracentral corneal leukoma.  The lens may also be adherent to the cornea and is often opacified to some degree.  Descemet's membrane and portions of the posterior stroma are usually missing as well.  Glaucoma is frequently present.  Importantly, there is a wide range in the presentation of clinical features.

Systemic Features: 

Peters anomaly is a frequent feature of numerous syndromes, both ocular and systemic, among them the Peters-plus (261540) syndrome (sometimes called the Kivlin-Krause (261540) syndrome) and has been reported in a case with aniridia (106210).

Genetics

Isolated Peters anomaly usually occurs in an autosomal recessive pattern but autosomal dominant patterns have been reported as well.  The recessive disorder may be caused by a mutation in several genes, notably PAX6, PITX2CYP1B1, FOXC1, and FOXE3.  The latter gene is also mutated in anterior segment mesenchymal dysgenesis (107250) and congenital primary aphakia (610256).  The variety of clinical features are likely the result of a disruption in some common pathway or pathways.  Mutations in B3GALTL associated with the Peters-Plus syndrome have not been identified in isolated Peters anomaly.

This is a genetically and clinically heterogeneity condition as whole genome sequencing reveals numerous additional gene mutations in patients with both syndromic and isolated Peters anomaly.

PITX2 is also mutated in ring dermoid of the cornea (180550) and in Axenfeld-Rieger syndrome type 1 (180500).  PAX6 mutations also cause diseases of the cornea, fovea, optic nerve and iris.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma is the most serious threat to vision on Peters anomaly but also the most difficult to treat.  Less than a third of patients achieve control of intraocular pressure even with the most vigorous combinations of therapy.  Corneal opacities can be treated with transplantation but the prognosis is often guarded when glaucoma is present.

From eye bank and other data, it has been estimated that 65% of penetrating keratoplasties in infants for visually significant congenital corneal opacities are performed in patients with Peters anomaly. 

References
Article Title: 

Whole exome sequence analysis of Peters anomaly

Weh E, Reis LM, Happ HC, Levin AV, Wheeler PG, David KL, Carney E, Angle B, Hauser N, Semina EV. Whole exome sequence analysis of Peters anomaly. Hum Genet. 2014 Sep 3. [Epub ahead of print].

PubMed ID: 
25182519

Ectopia Lentis et Pupillae

Clinical Characteristics
Ocular Features: 

This disorder is generally considered to consist of simple displacement of the pupil and dislocation of the lens (usually in opposite directions).  However, other abnormalities are often present such as persistent pupillary membrane (87%), iridohyaloid adhesions, increased corneal thickness, enlarged corneal diameters, and axial myopia.  The iris may transilluminate (67%) and the pupils dilate poorly.  Iridodenesis is common (85%).  The lens is often malformed and in some cases frankly microspherophakic.  The lens displacement can progress and cataracts seem to form at a relatively young age.  Visual acuity is highly variable, ranging from 20/20 to light perception depending upon the density of cataracts which often develop at a relatively young age. Prominent iris processes into the anterior chamber angle have been reported and glaucoma, both acute and chronic, is sometimes seen.  Retinal detachment is a risk.

Studies in families with ectopia lentis et papillae have revealed that as many as 50% of individuals with dislocated lenses do not have ectopic pupils.

Systemic Features: 

None reported

Genetics

This disorder is usually inherited in an autosomal recessive pattern.  Multiple affected sibs have been born to consanquineous matings.  However, other families in which detailed ophthalmological examinations were done have suggested dominant inheritance based upon the presence of more subtle ocular signs in relatives.  This is likely a more clinically heterogeneous disorder than has been appreciated.

In five Norwegian families a homozygous 20 bp deletion has been found in the gene ADAMTSL4 on chromosome 1 (c.767_786del20) (1q21.3) producing a frameshift and the introduction of a stop codon leading to truncation of the protein product.  Mutations in the same gene have also been found in the autosomal recessive form of isolated ectopia lentis (225100).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma, retinal detachments, and cataracts may require surgery.

References
Article Title: 

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