optic nerve drusen

Retinitis Pigmentosa 71

Clinical Characteristics
Ocular Features: 

Night blindness is noted in the first or second decades of life.  The fundus picture in this condition resembles classic retinitis pigmentosa with attenuated vessels, RPE anomalies with bone spicule clumping and areas of atrophy, and optic disc pallor.  Several patients had optic nerve drusen.  The retina appears to have microcysts, especially in the macula, and the outer retina is thinned.  

Systemic Features: 

Only a few patients have been reported with this form of RP and the full phenotype is unknown.  Some individuals are obese and one patient in addition had postaxial polydactyly and hypercholesterolemia suggestive of a Bardet-Biedl-like phenotype.  No reported patients have had rib dysplasia.

Genetics

Homozygous or compound heterozygous mutations in the IFT172 gene (2p23.3) have been identified in this condition.

The same gene is mutated in the recessive short-rib thoracic dysplasia 10 syndrome with or without polydactyly (615630).  Individuals with the short-rib syndrome may have night blindness and fundus changes resembling retinitis pigmentosa.

Because of the phenotypic overlap with other conditions such as Bardet-Biedl syndrome, the short-rib thoracic 10 syndrome (615630), Majewski syndrome (263520), Jeune syndrome (208520), short-rib thoracic dysplasia 9 (266920), and certain types of polycystic diseases of the kidney with abnormalities of the cilia, it has been suggested that RP71 should be classified as a syndromic ciliopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Said S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet. 2015 Jan 1;24(1):230-42.

PubMed ID: 
25168386

Nanophthalmos AD

Clinical Characteristics
Ocular Features: 

In the family reported, vision ranged from NLP to 20/20.  Refractive errors ranged from +8.25 to +15.50 D (mean +11.8 D).  Axial length ranged from 16.90 to 18.46 mm with a mean of 17.6 mm.  Angle closure glaucoma was diagnosed in 6 of 16 (37%) patients. Thickened sclera with prominent scleral vessels was described in affected family members.  Optic nerve drusen are often present and increased tortuosity of the retinal vessels has been described.

Systemic Features: 

No systemic abnormalities have been reported in spite of the fact that the TMEM98 gene is widely expressed in body tissues. 

Genetics

This is an autosomal dominant disorder resulting from a missense mutation in exon 8 of the TMEM98 (17p12-q12) gene.  The mutation has been reported in a single Australian family.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens removal may be considered in individuals with shallow anterior chambers and narrow angles but frequent postoperative macular edema and choroidal effusions have been seen and the visual prognosis is guarded.

References
Article Title: 

Nanophthalmos with Retinitis Pigmentosa

Clinical Characteristics
Ocular Features: 

Poor vision is present beginning in childhood and may progress to hand motion or even loss of light perception when retinal detachments occur.  Nystagmus has been seen in one patient.  Corneal diameters were 11 mm, the angles were open, and axial lengths were shortened to about 17 mm.  Alternating areas of hypo- and hyperfluorescence are seen with fluorescein angiography corresponding to areas with pigment clumping seen throughout the fundi.  The fundus pigmentation is atypical for retinitis pigmentosa, however, in spite of the title given by the authors.  No scotopic or photopic responses are seen on the ERG.  Drusen were present in the optic nerves. 

Systemic Features: 

No systemic disease is associated. 

Genetics

A single family with affected male and female sibs has been reported and a homozygous nonsense mutation in exon 5 of the CRB1 gene (1q31-32.1) was present in both. 

Another recessive form of microphthalmia with retinitis pigmentosa plus has been reported (611040) without nanophthalmos features and having a mutation in the MFRP gene. True nanophthalmos with retinopathy (267760) has some features similar to the disorder described here but with macular cysts.  No responsible mutation has been identified in this disorder however. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids might be helpful in early stages of the disease. 

References
Article Title: 

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: 

Alagille Syndrome

Clinical Characteristics
Ocular Features: 

The ocular findings in Alagille syndrome are often of little functional significance but can be sufficient to suggest the diagnosis without further study of the systemic features.  Posterior embryotoxon is found in 95% of individuals while iris abnormalities such as ectopic pupils are seen in 45%, abnormal fundus pigmentation is common (hypopigmentation in 57%, diffuse pigment speckling in 33%), and optic disc anomalies have been reported in 76%.  One study found that 90% of individuals have optic disk drusen by ultrasonography.  The anterior chamber anomalies are considered by some to be characteristic of Axenfeld anomaly.  The presence of these ocular findings in children with cholestasis should suggest Alagille syndrome.  Ocular examination of the parents can also be helpful in this autosomal dominant disorder as some of the same changes are present in one parent in more than a third of cases.

Systemic Features: 

A variety of  systemic features, some of them serious malformations, occur in Alagille syndrome.  Among the most common is a partial intrahepatic biliary atresia leading to cholestasis and jaundice.  Skeletal malformations include 'butterfly' vertebrae, shortened digits, short stature, a broad forehead, and a pointed chin.  The tip of the nose may appear bulbous.  These features have suggested to some that there is a characteristic facial dysmorphology.  Vascular malformations are common including aneurysms affecting major vessels, valvular insufficiency, coarctation of the aorta, and stenosis and these are often responsible for the most serious health problems.  In fact, vascular events have been reported to be responsible for mortality in 34% of one cohort.  Chronic renal insufficiency develops in a minority of patients.  This disorder should always be considered in children with cholestasis, especially when accompanied by cystic kidney disease.  Brain MRIs may show diffuse or focal hyperintensity of white matter even in the absence of hepatic encephalopathy.

Genetics

This is an autosomal dominant condition secondary to various mutations in the JAG1 gene located on chromosome 20 (20p12).  Penetrance is nearly 100% but there is considerable variation in expression.  A far less common variant of this disorder, ALGS2 (610205), is caused by a mutation in the NOTCH2 gene (1p13-p11).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No cure is available but individual organ disease may be treatable.  The ocular abnormalities generally do not cause vision difficulties.

Reversible of white matter changes has been noted in a single child following liver transplantation.

 

References
Article Title: 

CT-defined phenotype of pulmonary artery

Rodriguez RM, Feinstein JA, Chan FP. CT-defined phenotype of pulmonary artery
stenoses in Alagille syndrome
. Pediatr Radiol. 2016 Apr 4. [Epub ahead of print].

PubMed ID: 
27041277

Alagille syndrome: clinical and ocular pathognomonic features

El-Koofy NM, El-Mahdy R, Fahmy ME, El-Hennawy A, Farag MY, El-Karaksy HM. Alagille syndrome: clinical and ocular pathognomonic features. Eur J Ophthalmol. 2010 Jul 28. pii: 192165A5-8631-4C06-9C47-9AD63688B02A. [Epub ahead of print]

PubMed ID: 
20677167

Ocular abnormalities in Alagille syndrome

Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ, Mieli-Vergani G, Bird AC, Aclimandos WA. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999 Feb;106(2):330-7.

PubMed ID: 
9951486
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