retinal pigmentation

Pseudoxanthoma Elasticum

Clinical Characteristics
Ocular Features: 

Breaks in Bruch membrane lead to the classic non-diagnostic ocular sign in this disease known as angioid streaks.  These are typically bilateral, reddish-brown curvilinear bands that vaguely resemble a vascular pattern seen most commonly in the posterior pole radiating from the peripapillary area.  They typically have their onset after the skin lesions appear.  The fundus may also have areas of yellow mottling temporal to the fovea suggestive of an orange peel surface.  These are sometimes labeled 'peau d'orange' and their appearance frequently precedes the appearance of angioid streaks.  Optic disc drusen are said to occur 20-50 times more frequently than in the general population and may be apparent before the appearance of angioid streaks.  A significant proportion of patients have atrophy of the RPE and outer retina, especially those with early onset and rapid progression of the disease.

The major threat to vision comes from the formation of subretinal neovascular nets which often bleed resulting in secondary scarring and fibrosis.  These frequently involve the central macula which is why central vision is primarily impacted and peripheral vision usually remains normal.  Macular involvement is evident at a mean age of 44 years and the majority of patients are visually handicapped by the age of 52 years.

Systemic Features: 

The skin has characteristic changes of several types due to defective elastin.  It is often lax and redundant with localized plaques of hyperkeratotic papules giving the typical 'plucked chicken' appearance.  The latter are typically seen in the skin of the neck, in inguinal folds and in the popliteal and antecubital spaces.  These may have their onset in childhood but sometimes later.  They are generally asymptomatic and primarily of cosmetic importance.  The oral, rectal, and vaginal mucosa may also be involved.  Focal deposits of calcium are often seen.

Vascular disease secondary to calcification of elastic media and intima are responsible for the major health problems in this disease but they usually are not evident until later in life.  Hemorrhage or occlusion often results.  At least 10% of individuals with this disease experience a gastrointestinal hemorrhage at some point in their lives and this can be life-threatening.  Intermittent claudication can be incapacitating.  Coronary artery disease is frequently a symptom.  Occlusive disease of the renal arteries can result in hypertension.  Malfunction of heart valves, especially the mitral valve, is common.

Genetics

This is an autosomal recessive disorder caused by mutations in the ABCC6 gene (16p13.1).  Females are affected nearly twice as often as males.  Some heterozygotes have minor manifestations of the disease but the full clinical picture is only seen in homozygotes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Choroidal neovascularization should be treated.  Intravitreal injections of ranibizumab may be beneficial as a prophylactic measure for the preservation of central vision.  GI bleeds require prompt and vigorous treatment and cardiac valves sometimes require repair.  Redundant skin can be surgically removed.  Patients should avoid contact sports and activities requiring heavy lifting or straining.  Antibiotic prophylaxis should be considered for patients with heart valve disease before undergoing procedures.

References
Article Title: 

Stickler Syndrome, Type I

Clinical Characteristics
Ocular Features: 

High myopia and vitreous degeneration dominate the ocular manifestations of Stickler syndrome, type I.  The vitreous often appears optically empty as it liquefies and the fibrils degenerate.  The vitreous is sometimes seen to form ‘veils’, especially in the retrolenticular region but they may also float throughout the posterior chamber.  They are often attached to areas of lattice degeneration in the retina as well as other areas.  Posterior vitreous detachments are common.  Vitreoretinal degeneration is progressive and by the second decade rhegmatogenous detachments occur in half of affected patients.  As many as three quarters of adult patients have retinal breaks.  The retina has pigmentary changes with deposition circumferentially near the equator and more peripherally.  Hypopigmentation is more common early creating a tessellated appearance.  Lenticular opacities occur also early with cortical flecks and wedge-shaped changes.

The ERG may be normal early but evidence of rod and cone dysfunction soon appears and is progressive.  Dark adaptation is defective later in the course of the disease.  The EOG is virtually always depressed.  The visual field is constricted and may show a ring scotoma coincident with the equatorial chorioretinal atrophy.

Systemic Features: 

It has been suggested that there is a nonsyndromic or ocular type of Stickler syndrome lacking many of the extraocular features characteristic of the complete syndrome.  However, the evidence for the ocular type described here as a distinct entity remains slim and the clinical picture may simply reflect variable expressivity of mutations in the same gene.  Type I Stickler syndrome has multiple systemic features such as cleft palate, hearing impairment, premature arthritis, micrognathia, kyphoscoliosis, and some signs such as arachnodactyly that are found in the Marfan syndrome.

Genetics

This is an autosomal dominant disease of collagen formation as a result of mutations in the COL2A1 gene (12q13.11-q13.2). The mutations causing both syndromal and the suggested nonsyndromal ocular type of Stickler disease are in the same gene.  Mutations in the same gene are known to cause autosomal dominant rhegmatogenous retinal detachments in patients who have none of the systemic clinical signs (609508).  These patients may lack the signs of vitreous degeneration seen in Kniest dysplasia (156550)  and in the disorder described here.

There is better evidence for a second type of Stickler syndrome, STL2 or type II (604841) based on phenotypic differences and the fact that a second locus (1p21) containing mutations in COL11A1 has been linked to it. 

Type III is caused by mutations in COL11A2 and has systemic features similar to types I and II but lacks the eye findings since this gene is not expressed in the eye.

Type IV also has important ocular features but is an autosomal recessive disorder caused by mutations in COL9A2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The combination of progressive vitreoretinal degeneration, frequency of posterior vitreous detachments, and axial myopia creates a lifelong threat of retinal tears and detachments.   Half to three quarters of all patients develop retinal tears and detachments.  Certainly all patients with Stickler syndrome deserve repeated and thorough retinal exams throughout their lives.  In addition to prompt treatment of tears and detachments, some have advocated prophylactic scleral banding to reduce vitreous traction, or applying 360 degree cryotherapy.

References
Article Title: 

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. Erratum in: Hum Mutat. 2006 Nov;27(11):1156.

PubMed ID: 
16752401

Abetalipoproteinemia

Clinical Characteristics
Ocular Features: 

The major ocular manifestations of abetalipoproteinemia are in the retina which develops diffuse and sometimes patchy pigmentary changes often called atypical retinitis pigmentosa.  In other cases the picture resembles retinitis punctata albescens with perivascular white spots in the peripheral retina.  Night blindness is an early and prominent symptom with abnormal dark adaptation thresholds evident before fundus pigment changes are seen.  The ERG shows loss of rod function before that of cone function.  The macula may or may not be affected while peripheral fields are often severely constricted.  Loss of photoreceptors occurs throughout life and visual fields show progressive constriction, sometimes with central sparing.  A single case of bilateral disc swelling in a 9 year-old girl has been reported.

Systemic Features: 

Celiac disease and steatorrhea due to a deficiency of circulating chylomicra underlie the malabsorption of vitamins A and E which is probably responsible for the majority of systemic manifestations.  Red blood cells have a peculiar burr-like morphology that has led to the designation 'acanthocytes'.  Liver failure and cirrhosis sometimes occur.  Plasma lipids are generally low including cholesterol, triglycerides, and beta lipoproteins.  Central and peripheral nerve demyelination occurs leading to a progressive ataxia and other neurological symptoms.

Genetics

This autosomal recessive disease seems to result from an inability to synthesize the apoB peptide that is a part of the LDL and VLDL.   A mutation in the MTP gene (4q22-q24) is responsible.  The gene is sometimes called MTTP as it codes for micosomal triglyceride transfer protein.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with vitamins A and E may be beneficial.  Cone function improves before rod function with massive doses of vitamin A but usually only after months of treatment.  It has been reported that Vitamin A alone without vitamin E is insufficient to arrest the retinal disease.

References
Article Title: 

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
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