Short arm 11 deletion (11p13) syndrome: aniridia

Classic aniridia results from a defect in a gene that encodes a transcription factor needed for development of the eye. This developmental gene, PAX6, is located at 11p13. The PAX6 gene product is a transcription factor required for normal development of the eye. Classic aniridia is a panophthalmic disorder characterized by the following features:

• iris absence or severe hypoplasia

• cataracts (usually anterior polar)

• keratitis due to limbal stem cell failure

• subnormal visual acuity

• congenital nystagmus

• foveal or macular hypoplasia

• optic nerve hypoplasia

• glaucoma

• strabismus

• ectopia lentis

When working with a new patient with aniridia, the ophthalmologist should, if possible, conduct a careful examination of the patient’s parents for the variable expression of autosomal dominant aniridia. Although almost all cases of aniridia result from PAX6 mutations, a rare autosomal recessive disorder called Gillespie syndrome (phenotype OMIM number 206700) also produces partial aniridia, as well as cerebellar ataxia, mental deficiency, and congenital cataracts.

Aniridia (often with cataract and glaucoma) can also occur sporadically in association with Wilms tumor, other genitourinary anomalies, and cognitive disability, the so-called WAGR syndrome. This complex of findings is called a contiguous gene-deletion syndrome because it results from a deletion involving nearby genes. Most affected patients have a karyotypically visible interstitial deletion of a segment of 11p13. Patients with aniridia that is not clearly part of an autosomal dominant trait, and those with coincident systemic malformations, should undergo chromosome analysis (karyotyping) and observation for possible Wilms tumor.

Mutations of PAX6 have also been reported in Peters anomaly, autosomal dominant keratitis, and dominant foveal hypoplasia. The mechanism for disruption of normal embryology and the degenerative disease in aniridia and other PAX6 disorders appears to be haploinsufficiency, which, in this case, is the inability of a single active allele to activate transduction of the developmental genes regulated by the PAX6 gene product. In this way, aniridia is different from retinoblastoma and Wilms tumor, which result from an absence of both functional alleles at each of the homologous gene loci.

• Landsend ES, Utheim ØA, Pedersen HR, Lagali N, Baraas RC, Utheim TP. The genetics of congenital aniridia—a guide for the ophthalmologist. Surv Ophthalmol. 2018;63(1): 105–113.

Long arm 13 deletion (13q14) syndrome: retinoblastoma

Retinoblastoma is one of several heritable childhood malignancies. Ocular tumors, which are usually noted before the age of 4 years, affect between 1 in 15,000 and 1 in 34,000 live births in the United States. The disease exhibits both hereditary occurrence (approximately 30%–40%), in which tumors tend to be bilateral and multicentric, and sporadic occurrence, in which unilateral and solitary tumors are the rule. Only about 10% of patients with hereditary retinoblastoma have a family history of the disease; the remaining 90% have a new mutation in their germ cells.

Retinoblastoma does not develop in approximately 10% of all obligate carriers of a germline mutation (ie, incomplete penetrance). In addition, a karyotypically visible deletion of part of the long arm of chromosome 13 occurs in 3%–7% of all cases of retinoblastoma. The larger this deletion is, the more severe is the phenotypic syndrome, which includes cognitive disabilities and developmental delays, microcephaly, hand and foot anomalies, and ambiguous genitalia.

Although the hereditary pattern in familial retinoblastoma is that of an autosomal dominant mutation, the defect is recessive at the cellular level. The predisposition to retinoblastoma is caused by hemizygosity of the retinoblastoma gene (RB1) within band 13q14. RB1 is a member of a class of genes called recessive tumor suppressor genes. The RB protein regulates the cell cycle at the G1 checkpoint. The alleles normally present at these loci help prevent tumor formation. At least 1 active normal allele is needed to prevent the cell from losing control of proliferation. Patients who inherit a defective allele from 1 parent are at greater risk for losing the other allele through a number of mechanisms. Thus, tumor formation in retinoblastoma is due to the loss of function of both normal alleles. Homozygous deletions within the 13q14 band have been noted in retinoblastomas derived from enucleated eyes.

The first step in tumorigenesis in retinoblastoma is a recessive mutation of 1 of the homologous alleles at the retinoblastoma locus by inheritance, germinal mutation, or somatic mutation. Hereditary retinoblastomas arise from a single additional somatic event in a cell that carries an inherited mutation, whereas sporadic cases require 2 somatic events. In approximately 50% of tumors, homozygosity for such a recessive mutation results from the mitotic loss of a portion of chromosome 13, including the 13q14 band. The 2 resulting mutant alleles at this locus allow the genesis of the tumor. Retinoblastoma, therefore, seemingly represents a malignancy caused by defective gene regulation rather than by the presence of a dominant mutant oncogene. Those who inherit a mutant allele at this locus have a high incidence of nonocular second tumors thought to be caused by the same mutation. Almost half of these tumors are osteosarcomas.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.