When EYE Grow Up Syndromes and phakomatoses: pediatric presentation with long- term results Kimberley 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 genes during embryonic development), also responsible for aniridia, Peters anomaly

Aniridia

• Bilateral, genetic defect (PAX6 on 11p13):

sporadic in 1/3 or familial in 2/3 (AD with complete penetrance and variable expressivity) • Rudimentary iris present • Panocular • Foveal hypoplasia, Nystagmus with Va <20/100, Glaucoma, Optic nerve hypoplasia, 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 mitral valve • 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 brain damage, 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 of tissues 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% for NF1), but also have large percentage of cases as sporadic

NF, type 1

• Genetic locus: long arm of chromosome 17 (17q11.2) • Codes for protein neurofibromin, involved in

regulation of cellular proliferation and tumor suppression • 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 in prepubescents or >15mm in postpubescents

• 2 or more neurofibromas of any type or 1 plexiform neurofibroma • Freckling of axillary, inguinal or other intertriginous areas • 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 or without 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 soft tissue 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, hypothalamic dysfunction), 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 or tinnitus • Ocular findings predate auricular: PSC or wedge cortical cataracts, less commonly: retinal hamartoma & 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, tumor growth suppressors • Vogt triad: mental retardation, seizures & facial angiofibromas (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 cases in 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) and tuberous 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, usually cerebellum, limited proliferative capacity but exudation across this vessel walls causing fluid accumulation • Cysts and tumors elsewhere: kidneys(renal cell carcinoma), 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 grayish disc then pink globular mass 1-3 DD in size • Hallmark of mature tumor is a pair of markedly dilated vessels running between the lesion and the optic disc • FA shows that the vessels are leaky causing lipid accumulation, 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 malformation

resulting 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 to retinal 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 thickening of the involved skin. • Treatment: pulsed-dye laser can reduce the vascularity • 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 suppressor

genes • primarily involves CNS (cerebellum), ocular surface, skin and immune system • Possibly the most common cause of progressive ataxia in early childhood • Onset in 2nd year of life with truncal ataxia, followed by dyarthria, dystonia, & choreoathetosis with serious disability by 10 years

AT

• Recognition of ocular features is often the key to diagnosis: ocular motor abnormalities (inability to intiate 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 chemotherapeutic agents

• Defective T-cell function, hypoplasia of thymus, decreased immunoglobulin levels => recurrent respiratory infections & death in adolescence or young 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 affected

persons are female, mother to daughter transmission • Involves skin, brain, & eyes • Skin is normal at birth but erythema & bullae develop during 1st few days of life, usually on extremities and persist for weeks to months • 2 months of age – 2nd phase of verrucous changes that 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 of mental deficiency

• 2/3 have dental abnormalities (missing or malformed teeth • 1/4 have ocular abnormalities: proliferative retinal vasculopathy (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 shunt blood flow directly from arteries to veins and do not 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. American Academy of Ophthalmology.