Alex V. Levin

BASICS

DESCRIPTION

• Lesions characterized by reduced or absent pigment in or absence of the retinal pigmented epithelium or choroid present at birth.

• Includes, but is not limited to: Tumors (retinoblastoma, astrocytic hamartoma of tuberous sclerosis, congenital benign gliotic tumors), infections (cytomegalovirus, toxoplasmosis, varicella), retinal dystrophies (torpedo maculopathy, Leber congenital amaurosis), and congenital abnormalities (coloboma, Aicardi syndrome)

RISK FACTORS

• Family history of retinoblastoma or tuberous sclerosis

• Congenital infections: Cytomegalovirus (CMV), toxoplasmosis, varicella

• Chromosomal aberration

• Parental consanguinity leading to autosomal recessive disease

Genetics

• Retinoblastoma is an autosomal dominant disease associated with loss of heterozygosity of the RB1 gene (13q14).

• Tuberous sclerosis is autosomal dominant (associated with TSC1 or TSC2 gene mutations)

• Coloboma-CHARGE syndrome (CHD7, SEMA3E, CHX10, OTX2, SHH genes and others, del22q11.2 and other chromosomal aberrations. Multiple systemic syndromes associated with coloboma

• Isolated coloboma can be either autosomal dominant or autosomal recessive.

• Aicardi syndrome-X-linked dominant inheritance

• Leber congenital amaurosis- autosomal recessive (GUCY2D, RPE65, RDH12, AIPL1, LRAT, RPGRIP1, SPATA7, CRX, CRB1, RPGR1P1, CEP290, IMPDH1 and other genes)

GENERAL PREVENTION

• For conditions with genetic associations, genetic counseling, and/or prenatal testing (if mutated gene is known or congenital abnormalities are identified in family members)

• For infections:

– Toxoplasmosis-pregnant women should not eat undercooked meat and avoid exposure to cat litter. With confirmed maternal infection, systemic treatment may prevent infection of fetus.

– Varicella-women should be vaccinated no later than 1 month before pregnancy. If a nonimmunized previously noninfected mother is exposed to varicella virus, consider administration of prophylactic treatment with varicella zoster immune globulin (VZIG) or acyclovir or valacyclovir to prevent fetal infection.

– Cytomegalovirus-good hygiene is essential to prevent maternal infection. If mother becomes infected, consider treatment with CMV immune globulin to protect fetus.

PATHOPHYSIOLOGY

• Hypopigmented retinal epithelium due to a wide range of disease processes; cell may contain a low amount of melanin or there may be a complete absence of RPE.

• In coloboma, a failure of complete closure of the choroid fissure results in a gap in the choroid and overlying dysplastic retina (intercalary membrane).

• Infections result in RPE destruction.

• Retinoblastoma and astrocytic hamartoma are neoplastic processes.

ETIOLOGY

• Genetic mutation (two-hit mechanism in retinoblastoma and astrocytic hamartoma)

• Cytomegalovirus, Toxoplasma gondii spread through the placenta in utero.

COMMONLY ASSOCIATED CONDITIONS

• Retinoblastoma may also affect pineal gland or bone marrow, later secondary tumors especially if radiated.

• Astrocytic hamartoma of tuberous sclerosis

– may have seizures, skin lesions, subependymal periventricular tubers, developmental delay

• Prenatal varicella

– Microphthalmia, optic atrophy, cataracts, cicatricial skin lesions, atrophy/hypoplastic lesions of limbs

• Cytomegalovirus

– Jaundice, thrombocytopenia/purpura/

• Petechia, hepatosplenomegaly, porencephalic cyst

• Toxoplasmosis

– Intracranial calcifications, uveitis, hydrocephalus

• Coloboma

– Systemic abnormalities (e.g., Coloboma + Heart + Atresia choanae + Retardation + Genitourinary + Ear defines full expression of CHARGE syndrome)

• Aicardi syndrome

– Central nervous system malformation (absent corpus callosum), seizures, developmental delay, skeletal abnormalities

• Leber congenital amaurosis

– Renal disease, deafness, developmental delay

DIAGNOSIS

HISTORY

• Family history of retinoblastoma, tuberous sclerosis, coloboma, Aicardi syndrome, or Leber congenital amaurosis

• History of prior fetal loss with infection or Aicardi (male fetuses)

– Known exposure to infection in utero

– Other known associated anomalies

PHYSICAL EXAM

• Complete ophthalmologic and systemic exam

• In retinoblastoma, Tumors may be endophytic or exophytic, unilateral or bilateral, single or multiple, may have vitreous seeding, or rarely inflammatory involvement of anterior segment or orbit

• Coloboma may also affect iris and/or optic nerve, retinal detachment caused by breaks in dysplastic retina within coloboma.

• Astrocytic hamartoma in infancy presents with gray–white and translucent with a smooth surface, in retina or optic nerve.

• Toxoplasmosis chorioretinal scars are large and up to 5 optic disc diameters in size. Uni or multifocal, preferential involvement of macula, hyperpigmented margins

• Chorioretinal scars of congenital varicella are similar to those of toxoplasmosis.

• Leber congenital amaurosis examination in infancy can have yellow–white “macular coloboma”, may or may not have other signs of retinal dystrophy, poor vision.

• In Aicardi syndrome, hypopigmented lacunar lesions are multiple, bilateral, and characterized by pigmented borders with preferential involvement of posterior pole.

• Cytomegalovirus lesions are usually necrotic/inflammatory macular lesions (maculitis) in one or both eyes.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

• Karyotype for congenital abnormalities

• Gene analysis based on diagnosis

• Serology test for toxoplasmosis, varicella, cytomegalovirus

Follow-up & special considerations

• Consult genetics counselor if genetic disorder

• Low vision support, as needed

• Evaluation of family members if genetic disease

Imaging

Initial approach

• Ultrasound to confirm tumor in retinoblastoma (calcification)

• MRI or CT to confirm diagnosis of retinoblastoma, tuberous sclerosis, Aicardi, congenital infection

Follow-up & special considerations

For progressive conditions, continue to monitor patients.

Diagnostic Procedures/Other

• Bone marrow test or lumbar puncture if retinoblastoma

• Electroretinogram to assess for Leber’s amaurosis (ERG severely reduced or isoelectric)

Pathological Findings

• See Retinoblastoma chapter

• Cytomegalovirus infections: Retinal necrosis and edema with nuclear viral inclusions

• Astrocytic hamartomas of tuberous sclerosis: Elongated fibrous astrocytes with interlacing cytoplasmic processes in the nerve fiber layer of retina (1)

• Toxoplasmosis: Tachyzoites appear as crescent shapes and stain well with Giemsa or Wright stain.

• Leber congenital amaurosis: Underdeveloped and hypomelanized retinal pigmented epithelium and photoreceptors

• Aicardi syndrome: Thinned out RPE and decreased number and size of vessels

DIFFERENTIAL DIAGNOSIS

Astrocytic hamartoma of tuberous sclerosis.

• Retinoblastoma

• Coloboma

• Cytomegalovirus

• Toxoplasmosis

• Varicella

• Leber congenital amaurosis

• Aicardi syndrome

• Astrocytic hamartoma of tuberous sclerosis

• Torpedo maculopathy

TREATMENT

MEDICATION

• For active congenital toxoplasmosis lesions (overlying vitreitis, active retinitis): Systemic pyrimethamine, sulfadiazine, trisulfapyrimidine, folinic acid

• For cytomegalovirus retinitis usually no treatment is needed – self-limiting, if infant immune system normal

• For varicella lesions – no treatment needed (inactive scars)

• Chemotherapy for retinoblastoma (see chapter Retina Retinoblastoma)

ADDITIONAL TREATMENT

General Measures

Low vision early intervention.

Issues for Referral

• Genetic consultation

• Oncology for retinoblastoma

• Enucleation may be indicated in retinoblastoma patients followed by ocularist.

Additional Therapies

• See Retinoblastoma chapter

• Seizure management in Aicardi

COMPLEMENTARY & ALTERNATIVE THERAPIES

None known.

SURGERY/OTHER PROCEDURES

• Surgery for retinal detachment in coloboma patients.

• Enucleation for some retinoblastoma patients.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

See Retinoblastoma chapter.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Long-term follow-up is recommended for all retinoblastoma patients (see Retinoblastoma chapter).

• Low vision support and intervention

• Monitor coloboma every 6–12 months for detachment

• Monitor toxoplasmosis for activation of lesions

PATIENT EDUCATION

• http://www.tsalliance.org/

• http://www.aicardisyndrome.org/site/

• http://www.blindness.org/

• http://www.ffb.ca/

PROGNOSIS

• Retinoblastoma has variable prognosis depending on size and extent of tumor.

• Ocular lesions of tuberous sclerosis usually not visually significant

• Leber congenital amaurosis usually blindness but gene therapy now becoming available for certain gene mutations

• Aicardi syndrome usually complicated by cortical visual impairment

• Toxoplasmosis may or may not reactivate, poor vision if fovea involved

• CMV maculitis self-limited

• Varicella lesions rarely progress.

• Coloboma may be asymptomatic or visually devastating.

COMPLICATIONS

• Retinoblastoma; death, visual loss

• Coloboma: Retinal detachment

• Toxoplasmosis: Reactivation

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