Anophthalmia

Overview

Anophthalmia refers to comlete absense of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Anophthalmia can be unilateral or bilateral and is a hetrognous condition with various etiologies. It can be isolated or can occur with other anomalies as part of a well defined syndrome. About one-third of individuals with anophthalmia have associated malformations. Heritable causes of anophthalmia include chromosome abnormalities and syndromic or non syndromic single gene disorders. 

Mutations in the following genes are associated with Anophthalmia: SIX3, HESX1, BCOR, SHH, PAX6, RAX, SOX2 (SOX2 related eye disorders), POMT1 (Walker-Warburg Syndrome) and SIX6. 

Syndromic Anophthalmia: 

  • SOX2-related eye disorders
  • PAX6-related eye disorders  
  • Waardenburg anophthalmia syndrome
  • Delleman syndrome
  • Anophthalmia-plus syndrome

Symptoms

Complete absense of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). 

Causes

Anophthalmia may be isolated (i.e. with no other systemic involvement) or may be part of a syndrome with other associated anomalies. 

Environmental causes:

Prenatal exposures associated with anophthalmi include rubella, alcohol, thalidomide, retonic acid, hydantoin, and LSD.  

Heritable Causes: 

Deletions and apparantly balanced de novo translocations aare significant because they may help identify regions in which to search for candidate genes for anophthalmia. 

  • Trisomy 13
  • Mosaic trisomy 9 
  • deletion 7p15.1-p21.1
  • deletion 14q22.1q23.2
  • Xp22.3 microdeletion
  • rearrangement 46,XY,t(8;12)(q22;q21)

SOX2 related eye disorders are characterized by bilateral anophthalmia and/or microphthalmia, learning disability, delayed motor development, postnatal growth failure, and cryptorchidism and/or micropenis in males. Esophageal atresia with or without tracheoesophageal fistula are now known to be part of the spectrum of anomalies as reported heterozygous loss-of-function mutations in SOX2 in three indiciduals with the anphthalms-esophageal atresia-genital abnormalities (AEG) syndrome. 

Individuals with SOX2-related eye disorders have been reported with deletion of SOX2 associated with a de novo translocation invovlcing 3q27. 8-15% of individuals with bilateral severe eye malformations and fewer than 3% of individuals with unilateral eye involvement have a heterozygous loss-of-function mutation in the coding region of SOX2. Inheritance is autosomal dominant. 

PAX6 Mutations- Heterozygous PAX6 mutations are associated with isolated aniridia. In the rare cases of homozygous PAX6 mutation, severe craniofacial abnormalities, anophthalmia, absent or maldormed nose, absent adrenal glands, central nervous system malformations, and fetal or neonatal death have occurred. 

Waardenburg anophthalmia syndrome is characterized by anophthalmia, limb abnormalities, growth delays, and intellectual disability. Limb anomalies include syndactyly, oligodactyly, elboy and hip dislocation, bowed tibia, and absense of hypoplasiy or fibulae. Inheritance is autosomal recessive. 

Oculocerebrocutaneous syndrome or Delleman syndrome Anophthalmia and, more commonly, congenital cystic eye are associated with cerebral malformations, accessory skin tags, and focal dermal hypoplasia or aplasia, Cerebral malformations mainly include multiple fluid-dilled cysts in the cortex and agenesis of the corpus callosum, but occipital meningoencephalocele and cerebellar hypoplasia can occur. Cleft lip/palate has been noted in 15% reported an extended form of Dellman syndrome that included panhypopitutarism and seizure disorder. Inheritance is autosomal recessive. 

"Anophthalmia-plus" syndrome- bilateral anophthalmia was reported in two siblings, one of whom had bilateral cleft palate and scral neural tube defect. The second sibling did not have extraocular anomalies. 

Anophthalmia has been reported in association with pulmonary hypoplasia. One of two affected siblings had cleft palate. 

Diagnosis

Establishing the specific cause of anophthalmia/microphthalmia in a given individual usually involves medical history, physical examination, family history, neuroimaging, renal ultrasound examination, hearing screen, and karyotype. More studies may be warranted based on findings from physical examination or family history.

Family history. It is appropriate to obtain a three-generation family history of eye anomalies, including anophthalmia, microphthalmia, and coloboma. Complete eye examinations of both parents are warranted.

Physical examination. It is appropriate to examine a proband for evidence of a syndrome associated with anophthalmia/microphthalmia. If no specific syndrome is identified in infancy, re-examination by a medical geneticist after four to five years is warranted because features of several syndromes are more obvious as the child grows and develops.

Testing

  • Chromosome study to look for evidence of aneuploidy or a chromosomeduplication, deletion, or rearrangement
  • TORCH titers to evaluate for congenital infection

Molecular genetic testing is possible for mutations in numerous genes associated with anophthalmia/microphthalmia.

Treatment

  • Evaluation by an oculoplastic surgeon may be helpful in determining the best course of action in each individual.
  • Prosthetic intervention is appropriate in severe microphthalmia and anophthalmia. In many cases, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit by fitting the infant with conformers of progressively increasing size. In some cases, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity.
  • Surgery is appropriate in severe microphthalmia and anophthalmia. Surgical options include placement of orbital implants of fixed dimensions at one or more surgeries; placement of expandable implants (silicone balloon, hydrophilic polymers); or use of a dermis-fat graft, which has the capability of post-surgical growth. Considerations for surgical intervention are best made after six months of age when postnatal growth of the orbit can be assessed. Older individuals in whom the orbital dimensions are fixed or individuals with previous orbital irradiation may require extensive orbital reconstruction.
  • Early intervention and therapy to optimize psychomotor development, educational endeavors, life skills and mobility are essential in children with unilateral or bilateral involvement.
  • Protection of the healthy eye in children with unilateral involvement. Children with reduced vision in the fellow eye as a result of coloboma or other malformation may benefit from visual aids and other visual resources.
  • Surveillance: Individuals not seen since infancy should be re-evaluated by a medical geneticist at age four to five years for features of a syndrome that may have become more apparent over time.