352 PEDIATRICS AND STRABISMUS

Congenital and Genetic Disease

ALBINISM Reduction or absence of pigmentation from defective production of melanin. There are many variations, depending on the pathway defect, as melanin is produced from tyrosine. Incidence 1:17,000; all types of albinism are autosomal recessive, except X-linked ocular and autosomal dominant albinoidism. May be total versus partial absence of pigmentation, and ocular alone versus oculocutaneous. Patients have decreased VA from foveal hypoplasia, absent stereovision from abnormal chiasmal decussation (75% cross vs. 53% normally; CNS pigment guides neural development), ON hypoplasia, photophobia, sensory nystagmus, decreased uveal and RPE pigmentation, iris TID. Also have increased incidence of strabismus, high refractive error, and cataract. VEP shows asymmetry (larger response of contralateral eye), normal ERG.

Albinoidism: autosomal dominant; decreased pigment without ocular abnormalities.

Oculocutaneous albinism (OCA): reduced melanin but normal number of melanosomes.

Type I, tyrosinase negative: OCA1A most common; autosomal recessive. Seen with Caucasian patients (no pigment) with VA 20/200 or worse. Tyrosinase, a chromosome 11 gene product, converts tyrosine to dihydroxyphenylalanine (DOPA). OCA1B ‘‘yellow’’ variant has some retained tyrosinase function.

Type II, tyrosinase positive: P gene on chromosome 15 codes for normal tyrosinase enzyme but has transport abnormalities and is autosomal recessive; patient has some pigmentation with VA 20/200 or better. Two potentially lethal forms:

Che´diak-Higashi syndrome: autosomal recessive (chromosome 1q43) disorder of microtubule formation with abnormal leukocytes that cannot release enzymes from lysosomes, causing reticuloendothelial incompetence, with recurrent sinopulmonary pyogenic infections, and increased risk of lymphoreticular malignancies. Patients also have neutropenia, lymphocytosis, anemia, thrombocytopenia, and impaired chemotaxis of PMNs. Histologic examination shows giant perioxidase-positive granules in leukocytes.

Hermansky-Pudlak syndrome: autosomal recessive (chromosome 10q23) disorder of platelets that leads to easy bruising and potentially lethal bleeding diathesis; usually seen in patients of Puerto Rican descent.

Type III: OCA3, gene map locus 9p23, tyrosinase-positive; patients have some pigmentation.

Type IV: OCA4, ‘‘brown’’ OCA, chromosome 9p.

Ocular albinism (OA): skin is normal, but eye tissues are hypopigmented.

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OA1 (Nettleship-Falls albinism): X-linked defect at Xp22 with giant pigment granules (macromelanosomes in retina and skin). Only males have full syndrome; females may have mosaicism (look for subtle iris TID).

OA2: autosomal recessive.

ANIRIDIA Ocular developmental disorder, especially involving failure of the iris to develop (although usually stump of iris is present). Also has anterior polar cataract, ectopia lentis, corneal pannus (epitheliopathy) from hypoplasia of limbal stem cells, foveal (enlarged FAZ on FA) and ON hypoplasia, nystagmus, and often glaucoma (50–75% angle-closure glaucoma, as iris stump may obstruct TM).

Two thirds of cases are familial: autosomal dominant; no Wilms’ tumor risk.

One third of cases are sporadic: 98% bilateral; 7q mutation at PAX6 gene, which is adjacent to Wilms’ tumor suppressor gene (like RB, need homozygous deletion to form tumor). Thus, a large PAX6 deletion is seen in 20% of patients, who will also get Wilms’ tumor (nephroblastoma).

Nephroblastoma has 90% mortality if untreated or 10% mortality if treated with chemotherapy and radiation.

WAGR syndrome: Wilms’ tumor, aniridia, genitourinary abnormalities, and retardation. Also known as 11por Miller’s syndrome.

CHARGE ASSOCIATION Acronym for the major features of this association: coloboma of the eye, congenital heart disease, choanal atresia, mental retardation, genital and ear anomalies. Need three major signs to make diagnosis. Eye is involved in 80% of cases, with unior bilateral coloboma of the iris, retina, choroid, and ON. Rarely may also see microor anophthalmos or cataract. Also associated with unior bilateral facial palsy, renal anomalies, tracheoesophageal fistula, micrognathia, cleft lip, cleft palate, and omphalocele.

CHROMOSOMAL ABNORMALITIES May involve whole genome (triploidy, tetraploidy, polyploidy) and be numerical (monosomies, trisomies) or structural (translocations, insertions, deletions, or duplications). Unlike genetic mutations involving a single gene, chromosomal changes are larger and involve multiple genes.

Trisomy 13 (Patau’s syndrome): most common chromosomal abnormality associated with congenital ocular malformations. Incidence 1:20,000; associated with advanced maternal age; M ¼ F. Usually involves severe mental retardation, seizures, and holoprosencephaly, and is lethal. May have microphthalmia, anophthalmia, colobomas, cartilage in the CB, PHPV (may be bilateral), and retinal dysplasia.

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354 PEDIATRICS AND STRABISMUS

18q-deletion (de Grouchy syndrome): severe mental and motor retardation, short stature, abnormal external ears, microcephaly, nystagmus, and optic atrophy.

Trisomy 18 (Edwards’ syndrome): second most common autosomal trisomy overall (1:6000); F:M ¼ 3:1; associated with advanced maternal age. Every organ system is affected, and condition is lethal; patients tend to die from apnea. May have microphthalmia, anophthalmia, hypoplastic orbits, ptosis, lid phimosis, strabismus, coloboma, congenital glaucoma, and abnormally long eyelashes.

Trisomy 21 (Down syndrome): many abnormalities seen, including mental retardation, hypoplastic midface, short, protruding tongue, and congenital heart disease (50%). Increased incidence of Alzheimer’s disease seen in patients >35 years old, along with retinoblastoma and leukemia. A 1:800 incidence is found after the 75% that are spontaneously aborted. Associated with advanced maternal age; risk for affected subsequent child 1%. Thirty-year survival rate is 71%.

Ophthalmic findings: upward slanting palpebral fissures and epicanthal folds, NLDO (33%), syringomas, strabismus (33–50%), astigmatism (20%), keratoconus (15%), cataract incidence (300x), Brushfield’s spots in one third of cases, especially light irides (called Wolfring’s spots if in non-Down patients), and ‘‘spoke wheel’’ appearance to the vessels as they emerge from the optic disk. Patients have better vision than hearing.

Ninety-five percent of cases are from meiotic nondisjunction (trisomy) of chromosome 21, 4% are Robertsonian translocations (heritable), and 1% are mosaic.

XXY (Klinefelter’s syndrome): primary hypogonadism with delay of secondary sex characteristics in males; also developmental delay. Eye findings uncommon.

XO (Turner’s syndrome): females with sexual ambiguity; may have ptosis, cataract, blue sclera, and nystagmus.

CONGENITAL INFECTIONS Maternal infections that particularly cause fetal morbidity; maternal IgM does not cross the blood–placental barrier (mnemonic: TORCH)

Congenital toxoplasmosis

Other: HIV/AIDS and syphilis. Fetal syphilitic infection is from maternal Treponema pallidum spirochetemia. If mother has primaryor secondary-stage syphilis, then approximately one half of fetuses will be infected. If mother has untreated tertiary syphilis, then about 30% of infants will be infected. Patients may have saddle nose, peg teeth, hearing loss, IK, and salt and pepper fundus appearance.

Rubella: salt and pepper fundus, heart defects, growth retardation, mental retardation, cataract (if early in pregnancy), or glaucoma (if later in pregnancy).

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Cytomegalovirus (CMV) most common congenital infection; 95% are subclinical and have chorioretinitis, optic atrophy, and CNS calcifications. Pathology shows basophilic cytoplasmic inclusions.

Herpes simplex virus (HSV): 70% are type 2; 60% mortality.

FETAL ALCOHOL SYNDROME (FAS) Multiple systemic and ocular abnormalities, including epicanthal folds, strabismus, blepharophimosis, long eyelashes, microphthalmia, telecanthus, anterior segment dysgenesis, and persistent hyaloid vessel in up to 30% of infants born to mothers who abuse alcohol. May consider disulfiram (Antabuse) treatment.

GOLDENHAR’S SYNDROME, OCULO-AURICULAR-CERVICAL DYSPLASIA

Characterized by preauricular skin tags, cervical spine dysplasia, mandibular hypoplasia, hemifacial microsomia, and cardiac defects. May have multiple choristomas (especially limbal dermoids), dislocated lens, Duane’s syndrome, and upper lid colobomas.

MUCOPOLYSACCHARIDOSES See Table 9–5 for ophthalmic presentations of mucopolysaccharidoses.

PEROXISOMAL DISORDERS Intracellular organelles that are defected. all disorders are characterized by hypotonia, seizures, and mental retardation.

Adrenaleukodystrophy: X-linked, incidence 1:15,000. Patients have adrenal insufficiency, spastic paresis, fluctuant vision, and RP.

Refsum’s disease: autosomal recessive disorder of lipid metabolism from decreased phytanic acid alpha-hydroxylase (chromosome 10p) with accumulation of phytanic acid in RPE and serum, causing atypical RP (granular RPE appearance), cerebellar ataxia, peripheral neuropathy, nerve deafness, anosmia, and EKG conduction defects.

TABLE 9–5

Ophthalmic Presentations of the Mucopolysaccharidoses

Note: All are autosomal recessive, except Hunter’s syndrome, which is X-linked recessive.

Spectrum of involvement from ( ) not affected up to (þ þ þ) significant tissue pathology often seen.

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