When EYE GrowUpSyndromes and phakomatoses:pediatric presentation with long-term resultsKimberley Lovelace, M.D.March 7, 2020

Overview• Anterior segment dysfunction• Lens disorders• Phakomatoses • No financial interests

Anterior Segment Dysgenesis• Posterior embryotoxon – prominent Schwalbe line

• Associated with other syndromes• Isolated finding in 15% of normal patients

• Axenfeld-Rieger syndrome• Posterior embryotoxon + attached iris strands, iris

hypoplasia, & anterior chamber dysgenesis• Progression to glaucoma as child or adult in 50% of cases• Nonocular abnormalities: small teeth, redundant

periumbilical skin, hypospadias, pituitary gland anomalies• Usually AD inheritance, PITX2 gene on 4q25 band (paired

homeobox gene that regulates expansion of other genesduring embryonic development), also responsible foraniridia, Peters anomaly

Aniridia

• Bilateral, genetic defect (PAX6 on 11p13):sporadic in 1/3 or familial in 2/3 (AD withcomplete penetrance and variableexpressivity)

• Rudimentary iris present• Panocular

• Foveal hypoplasia, Nystagmus with Va<20/100, Glaucoma, Optic nervehypoplasia, Cataracts (small anterior polar),Corneal stem cell deficiency

Lens Disorders• Cataract

• Syndromes associated with cataracts• Structural or positional lens abnormalities

Lowe Syndrome

• Oculocerebrorenal syndrome• X-linked recessive• Severely hypotonic at birth, renal tubulopathy in 1st

year of life, rickets, mental retardation common• Congenital bilateral cataracts, congenital glaucoma –

recalcitrant to treatment• Carrier mothers – snowflake, radial opacities in lens

cortex

Alport Syndrome• X-linked>AD or AR• Progressive renal failure (hematuria), deafness,

anterior lenticonus, cataract, fleck retinopathy

Structural Lens Abnormalities• Congenital aphakia – absence of lens, rare• Spherophakia – bilateral, dislocates anteriorly,

secondary glaucoma• Coloboma – flattening, absent zonules

Positional Lens Abnormalities

• Simple ectopia lentis – AD, bilateral, superotemporal• Ectopia lentis et pupillae – AR, rare

• bilateral displacement of pupil (usually inferotemporal)• lens dislocation in opposite direction• Microspherophakia• Miosis & poor pupil dilation with mydriatics

• Marfan syndrome• Homocystinuria• Weill-marchesani syndrome• Sulfite oxidase deficiency

Marfan Syndrome

• Systemic disease involving cardiovascular,musculoskeletal, and ocular

• AD trait but FH- in 15%• Mutation in the fibrillin gene (chromosome 15)

responsible for extracellular microfibrils• Tall, long limbs & fingers (arachnodactyly), loose &

flexible joints, scoliosis, chest deformities• Cardiac – enlargement of aortic root, dilation of the

descending aorta, dissecting aneurysm, floppy mitralvalve

• Life expectancy = half the normal population

Homocystinuria

• Rare, AR, 1 in 100,000• Classic form caused by abnormal enzyme cystathionine B-synthase:

homocystine accumulates in plasma & excreted in urine• Clinical manifestations vary but can involve:

• Eye: lens dislocation downward or into anterior chamber b/t 3-10 years(zonules typically break)

• Skeletal system: tall w/ osteoporosis, scoliosis, chest deformities• CNS: 50% mental retardation and seizures• Vascular system: thrombotic dz anywhere in body (high risk with

general anesthesia), HTN, cardiac murmurs, cardiomegaly • Medical management: normalize biochemical abnormality through

diet, low methionine, high cystine, coenzyme supplements(pyridoxine or vitamin B6)

Weill-Marchesani Syndrome• AD or AR• Clinical opposite of Marfan• Short stature, short fingers & limbs• Microspherophakia – consider prophylactic LPI

Sulfite Oxidase Deficiency• Very rare hereditary disorder of sulfur metabolism• Severe neurologic disorder & ectopia lentis• Neurologic abnormalities: infantile hemiplegia,

choreoathetosis, seizures, irreversible braindamage, death by age 5

Phakomatoses• Neurocutaneous syndromes• Multiple discrete lesions of 1 or a few histologic

types that are found in 2 or more organ systems,including skin and CNS

• Usually hamartomas (abnormal proliferations oftissues normally found in the involved organs)

Phakomatoses• Neurofibromatosis – type 1 & 2• Tuberous sclerosis• Von Hippel-Lindau Disease• Sturge-Weber Syndrome• Ataxis-Telangiectasia• Incontinentia Pigmenti• Wyburn-Mason Syndrome

Neurofibromatosis• Von Recklinghausen disease• Lesions composed of melanocytes or neuroglial

cells (derivatives of neural crest mesenchyme)• Most lesions do not become evident until years

after birth• Two forms: type 1 & 2

• Differences: genetics, diagnostic criteria, morbidity,and treatment

• Similarities: AD with high penetrance (100% forNF1), but also have large percentage of cases assporadic

NF, type 1• Genetic locus: long arm of chromosome 17

(17q11.2)• Codes for protein neurofibromin, involved in

regulation of cellular proliferation and tumorsuppression

• Prevalence of 1 in 3000-5000

NF, type 1• Melanocytic lesions of skin & eye

• Café-au-lait spots—flat, sharply demarcated,uniformly hyperpigmented macules of varying size& shape• Few present at birth, number & size increase during 1st

decade of life• Clusters in axillary or inguinl region• Many unaffected people have spots

• Lisch nodules• Small (< 1mm) sharply demarcated, dome-shaped• Usually tan in color, inferior distribution, infrequently

seen before 3 years of age• Hyperpigmented lesions in eyelid, conjunctiva and

choroid are also possible

NF, type 1• Diagnostic criteria: 2 or more of the following

• 6 or more café-au-lait spots >5mm in diameter inprepubescents or >15mm in postpubescents

• 2 or more neurofibromas of any type or 1 plexiformneurofibroma

• Freckling of axillary, inguinal or other intertriginousareas

• Optic nerve glioma• 2 or more iris Lisch nodules• A distinctive osseous lesion, such a sphenoid bone

dysplasia or thinning of the long-bone cortex with orwithout pseudarthrosis

• A 1st degree relative with NF1

NF, type 1• Glial cell lesions• Nodular neurofibromas—most common• Cutaneous or subcutaneous soft papulonodules,

coloring is normal to violescent, can be disfiguring• Plexiform neurofibromas—30% of patients &

develop earlier in life• Extensive subcutaneous swellings with indistinct

margins• Can have hyperpigmentation or hypertrichosis of

overlying skin plus hypertrophy of underlying softtissue and bone

• Feel like a “bag or worms” in minority of cases

NF, type 1• Optic glioma• Low-grade pilocystic astrocytoma involving optic

nerve, chiasm or both• Present in 15% but symptomatic in 1-5% causing

vision loss, proptosis or other complications• Fusiform or cylindrical enlargement• Symptomatic before 10 years of age• Treatment: chemo, if chemo fails => radiation,

surgery is controversial• Tumors involving chiasm may produce significant

morbidity (hydrocephalus, hypothalamicdysfunction), mortality rate of 50% or higher

NF, type 1• Eye exam• Assessment of vision (acuity & color)• Pupillary light reaction• Slit lamp exam (iris)• Ophthalmoscopy (optic disc pallor or edema,

choroidal lesions)• IOP• Any ocular finding needs MRI• Periodic ophthalmic assessment: 1-2 years• Adults must have blood pressure monitored for

risk of pheochromocytoma

NF, type 2• Genetic locus: long arm of chromosome 22

(22q12.2)• Diagnosis: Bilateral acoustic neuromas (CN 8

tumors) or 1st degree relative with NF2 &presence of unilateral acoustic neuroma,neurofibroma, meningioma, schwannoma, glioma,or early-onset posterior subcapsular cataract

• Present in teens to adult with decreased hearing ortinnitus

• Ocular findings predate auricular: PSC or wedgecortical cataracts, less commonly: retinalhamartoma & combined hamartomas of retina &RPE, lisch nodules can occur but not expected

Tuberous Sclerosis• Bourneville disease—familial, AD, (new

mutations account for as many as 80% of cases)• 1:6000 to 1:100,000• two distinct genes (TSC1 9q34 & TSC2 16p13.3:

that encode proteins hamartin & tuberin, tumorgrowth suppressors

• Vogt triad: mental retardation, seizures & facialangiofibromas (present in 30% of patients)

• Benign tumor growth in multiple organs (skin,brain, heart, kidney & eye)

TS• Primary features:

• Facial angiofibroma “andenoma sebaceum”• Ungual fibromas• Cortical tuber• Subependymal nodule (giant cell astrocytoma)• Multiple subependymal nodules protruding into

the ventricle• Multiple retinal astrocytomas

TS• Earliest cutaneous sign: white spot, or

hypopigmented macule, present in almost all casesin infancy

• Sharply demarcated “ash leaf spot”• Facial angiofibromas appear in childhood• Shagreen patch or collagenoma, present in 25%,

lumbosacral area• Plagues involving forehead sometimes extend onto

eyelid

TS• Seizures in 80%• Severe mental retardation in 50%• Intelligence can be normal• Neuroimaging: nodular periventricular or basal

ganglion calcifications (benign astrocytomas) andtuberous malformations of the cortex

• Malignant astrocytomas are infrequent• CNS tumors can obstruct causing hydrocephalus or

cardiac tumors can lead to early death

TS• Ocular findings:• Astrocytic hamartomas: phakomas involving

retina, optic disc or both, vision is rarely affected• Two distinct appearances:

• 1. Flat with smooth surface, indistinct margins, gray-white color, somewhat translucent

• 2. Sharply demarcated, elevated, irregular surface“mulberry” lesion

Von-Hippel Lindau Disease• Retinal angiomatosis• AD, incomplete penetrance with both benign and

malignant tumors of multiple organs• Mutation of tumor suppressor gene, 3p26-p25• 1 in 36,000 births• Hemangioblastomas—Most common finding,

vascular tumors or retina and CNS, usuallycerebellum, limited proliferative capacity butexudation across this vessel walls causing fluidaccumulation

• Cysts and tumors elsewhere: kidneys(renal cellcarcinoma), pancreas, liver, epidiymis, & adrenal

VHL• Retinal lesions present between ages 10-35• Bilateral in as many as 1/2, multiple in 1/3• Typically in peripheral fundus• Initially appears as small, reddish dot or non-

specific vascular anomaly that enlarges to grayishdisc then pink globular mass 1-3 DD in size

• Hallmark of mature tumor is a pair of markedlydilated vessels running between the lesion and theoptic disc

• FA shows that the vessels are leaky causing lipidaccumulation, RD and loss of vision

• Treatment: cryotherapy or laser photocoagulation

Sturge-Weber Syndrome• Encephalofacial angiomatosis• Facial cutaneous angioma (port wine stain) with

ipsilateral leptomeningeal vascular malformationresulting in:• Cerebral calcification• Seizures• Focal neurologic deficits• Variable degree of mental deficiency

• Sporadic, lesions always present at birth

SWS• Ocular involvement• Skin lesion involving eyelids• Any portion of ocular circulation may be

anomalous• Increased conjunctival vascularity causes pinkish

discoloration, also can involve episclera• Tortuous retinal vessels• Most significant site: choroid—uniform bright red

or red-orange color “tomato catsup”• Usually asymptomatic in childhood but choroid

become thickened in adolescence can lead toretinal detachment

SWS• Klippel-Trenaunay-Weber syndrome is applied to

cases with extensive lesions of the extremities• Hypertrophy of soft tissue and bone underlying the

angioma is common in childhood and thickeningof the involved skin.

• Treatment: pulsed-dye laser can reduce thevascularity

• Not all children with a port-wine stain have SWS

Ataxia Telangiectasia• Louis-Bar syndrome• AR, rare, 1:40,000, ATM 11q22.3, gene involved

in repair of DNA & regulation of tumor suppressorgenes

• primarily involves CNS (cerebellum), ocularsurface, skin and immune system

• Possibly the most common cause of progressiveataxia in early childhood

• Onset in 2nd year of life with truncal ataxia,followed by dyarthria, dystonia, & choreoathetosiswith serious disability by 10 years

AT• Recognition of ocular features is often the key to

diagnosis: ocular motor abnormalities (inability tointiate saccades with preservation of vestibulo-ocular movements)

• Head thrusts are used to compensate for saccades• Telangiectasia of conjunctival presents at 3-5 years

of age

AT• Increased sensitivity to tissue-damaging effects of

therapeutic radiation and many chemotherapeuticagents

• Defective T-cell function, hypoplasia of thymus,decreased immunoglobulin levels => recurrentrespiratory infections & death in adolescence oryoung adulthood

• Increased malignancies, lymphoma & leukemia• DX: blood test• Heterozygous carriers are generally normal but 7

times more likely to develop breast cancer

Incontinentia Pigmenti• Bloch-Sulzberger syndrome• X-linked dominance with presumed lethal effect

on hemizygous male fetus, nearly all affectedpersons are female, mother to daughtertransmission

• Involves skin, brain, & eyes• Skin is normal at birth but erythema & bullae

develop during 1st few days of life, usually onextremities and persist for weeks to months

• 2 months of age – 2nd phase of verrucous changesthat subside after a few more months

• Lastly, clusters of small hyperpigmented macules

IP• 1/3 of cases has CNS problems: microcepharly,

hydrocephalus, seizures and varying degrees ofmental deficiency

• 2/3 have dental abnormalities (missing ormalformed teeth

• 1/4 have ocular abnormalities: proliferative retinalvasculopathy (resembles ROP)

• Treatment: similar to ROP

Wyburn-Mason• Racemose angioma• Nonhereditary arteriovenous malformation of eye

and brain, typically optic disc or retina & midbrain• CNS lesions can hemorrhage & cause: seizures,

mental changes, hemiparesis, papilledema• Ocular manifestations: unilateral, congenital,

markedly dilated & tortuous vessels that shuntblood flow directly from arteries to veins and donot leak

• Vision ranges from normal to markedly reduced ,possible complication are 2ndary NV glaucoma &intraocular hemorrhage

References• T.W. Sadler. Langman’s Medical Embryology. 7th

Edition. 1995.• Pediatric Ophthalmology and Strabismus. Basic

and Clinical Science Course, Section 6. AmericanAcademy of Ophthalmology.