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SOX2-Related Eye Disorders

Includes: SOX2 Anophthalmia Syndrome, Anophthalmia-Esophageal Atresia-Genital (AEG) Abnormalities Syndrome
, MD, FRCP(EDIN)
Consultant in Pediatric Genetics
MRC Human Genetics Units
Edinburgh, United Kingdom

Initial Posting: ; Last Update: August 25, 2009.

Summary

Disease characteristics. SOX2-related eye disorders are characterized by anophthalmia and/or microphthalmia, which are usually bilateral, severe, and apparent at birth or by prenatal ultrasound examination. Other common findings include brain malformations, esophageal atresia, and cryptorchidism and/or micropenis in males. Postnatal growth failure, delayed motor development, and learning disability are common.

Diagnosis/testing. The diagnosis of SOX2-related eye disorders is established by clinical findings, cytogenetic or molecular analysis to detect deletions of 3q27 (which includes SOX2), and molecular genetic testing. SOX2 is the only gene associated with SOX2-related eye disorders. Molecular genetic testing to detect sequence variants identifies mutations in about 10%-15% of individuals with bilateral anophthalmia/microphthalmia.

Management. Treatment of manifestations: Use of optically clear expanders to stimulate growth of the orbit and periorbital tissues; special educational services for visually impaired infants and children; physiotherapy for motor impairment; special education for neurodevelopmental problems; use of melatonin for abnormal sleep patterns; antiepileptic drugs for seizure management.

Surveillance: Annual hearing test and annual neurodevelopmental assessment until age five years; measurement of height, weight, and head circumference every three to six months during childhood.

Genetic counseling. SOX2-related eye disorders are inherited in an autosomal dominant manner, most often resulting from a de novo mutation. The risk to the sibs of a proband is usually small; however, if a parent of a proband has germline mosaicism, the risk to the sibs may be as high as 50%. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Fetal ultrasound examination reveals marked reduction in the size of the globes.

Diagnosis

Clinical Diagnosis

The clinical features of SOX2-related eye disorders include the following:

  • Bilateral anophthalmia and/or microphthalmia
  • Learning disability
  • Delayed motor development
  • Postnatal growth failure
  • Cryptorchidism and/or micropenis in males

Testing

Cytogenetic analysis. Deletions of 3q27 known to include deletion of SOX2 have been observed:

  • One of the individuals in the original report of SOX2 mutations associated with bilateral anophthalmia had a 600-kb microdeletion including the entire SOX2 gene associated with a de novo t(3;11)(q27;p11.2) translocation [Fantes et al 2003]. The clinical and cytogenetic features of this individual had been reported previously [Driggers et al 1999].
  • The two reports of bilateral anophthalmia associated with a del(3)(q26.3;q28) that includes SOX2 involve a male infant [Male et al 2002] and a female fetus [Guichet et al 2004].

Deletions or chromosomal rearrangements of 3q27 known to be associated with anophthalmia/microphthalmia have been observed:

Molecular Genetic Testing

Gene. SOX2 is the only gene associated with SOX2-related eye disorders.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in SOX2-Related Eye Disorders

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2
SOX2Sequence analysis Sequence variants 38%-15% 4
Deletion/ duplication analysis 5Exonic and whole-gene deletions10%
FISHLarge (partial- and whole-gene) deletions4% 4

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Individuals with bilateral anophthalmia/microphthalmia

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Screening of individuals with severe eye malformations using a combination of mutation scanning of the entire coding region, direct sequencing of entire coding region, and FISH analysis for large-scale deletions detects SOX2 mutations in 8% to 19% of individuals with bilateral anophthalmia/microphthalmia and <3% of individuals with unilateral eye involvement [Fantes et al 2003, Hagstrom et al 2005, Ragge et al 2005b, Bakrania et al 2007, Zhou et al 2008].

5. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used [Bakrania et al 2007].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Establishing the diagnosis in a proband

  • Three-generation pedigree to look for evidence of autosomal dominant or X-linked recessive inheritance of eye malformations
  • Examination of the parents of an affected individual by an experienced pediatric ophthalmologist to exclude inherited eye malformation syndrome, particularly autosomal dominant optic fissure closure defects. This condition shows reduced penetrance; thus, severely microphthalmic children may have a parent with an asymptomatic retinal coloboma [Morrison et al 2002].
  • If findings are consistent with SOX2-related eye disorders, chromosome analysis, followed by MPLA for SOX2 deletions and molecular analysis for intragenic mutations of SOX2

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

More than 40 individuals with SOX2-related eye defects have been studied in detail to date [Fantes et al 2003, Guichet et al 2004, Hagstrom et al 2005, Ragge et al 2005b, Zenteno et al 2005, Faivre et al 2006, Williamson et al 2006, Zenteno et al 2006, Bakrania et al 2007, Sato et al 2007, Kelberman et al 2008, Schneider et al 2008, Zhou et al 2008, Pedace et al 2009].

Bilateral anophthalmia and/or microphthalmia. SOX2-related eye defects are usually bilateral, severe, and apparent at birth or on routine prenatal ultrasound examination. In the individuals reported to date, approximately 50% had bilateral anophthalmia, 15% had anophthalmia with contralateral microphthalmia, and 15% had bilateral microphthalmia. The remaining individuals have a wide spectrum of eye malformations including the following:

One individual with a loss-of-function mutation had two structurally normal eyes [Zenteno et al 2006].

The degree of visual impairment is usually severe and consistent with the degree of structural abnormality in the eye. In general, retina tissue that is present has some functional activity. For example, even in extreme microphthalmia, functional retinal tissue can give some light/dark perception with or without color perception.

Brain malformation. Five children had mesial temporal (hippocampal and parahippocampal) malformations evident on MRI. Two also had evidence of heterotopic grey matter in the mesial temporal region [Sisodiya et al 2006]. Pituitary hypoplasia [Kelberman et al 2006, Kelberman et al 2008] and agenesis or dysgenesis of the corpus callosum [Ragge et al 2005a, Bakrania et al 2007, Kelberman et al 2008] have been reported in multiple individuals.

Male genital abnormalities. Micropenis and cryptorchidism were reported in the majority of male cases.

Anterior pituitary hypoplasia. The majority of cases have some evidence of hypothalamo-pituitary axis dysfunction when detailed measurement of growth hormone and gonadotrophins are undertaken [Tziaferi et al 2008].

Esophageal atresia with or without tracheoesophageal fistula. Heterozygous de novo loss-of-function mutations in SOX2 have been identified in three unrelated individuals and monozygous twins with anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [Williamson et al 2006, Zenteno et al 2006]; thus, AEG syndrome does not appear to be a distinct entity, but rather part of the spectrum of SOX2-related eye disorders.

Postnatal growth failure. Birth weight in most infants is normal for gestational age. However, most children have a reduced growth velocity in the first years of life resulting in a symmetrical growth failure.

Delayed motor development was reported in the majority of cases, the age of achieving independent walking ranged from 12 months to four years. One five-year-old child was walking with assistance.

Myopathy. One female with normal intelligence had extensive investigations for delayed motor development including a muscle biopsy that showed nonspecific myopathic features. The neuromuscular disorder in this girl did not appear to be progressive.

Learning disability is highly variable and ranged from normal intelligence to severe learning disability with the majority of scoring cases between these extremes. The degree of learning disability is not predictable by mutation type or severity of the eye involvement.

Seizures were observed in six individuals; onset is variable, but common in early childhood. Information on the exact seizure type is limited, but most appeared to be grand mal tonic-clonic seizures, which appeared in early childhood and responded well to standard anticonvulsant medication.

Other. Two children had apparently non-progressive moderate sensorineural hearing loss requiring aiding.

Genotype-Phenotype Correlations

Almost all SOX2 mutations reported to date appear to represent heterozygous loss of function; thus, it is difficult to draw genotype-phenotype correlations.

The presence of optic nerve hypoplasia with roving nystagmus may be restricted to missense mutations within the activation domain [Kelberman et al 2006].

Penetrance

Penetrance appears to be complete for non-mosaic loss-of-function mutations.

Anticipation

Anticipation is not observed.

Nomenclature

The condition has also been called SOX2 anophthalmia syndrome [Ragge et al 2005b].

Microphthalmia-anophthalmia-coloboma (MAC) was used as an umbrella term for the spectrum of severe eye malformations in some early publications describing SOX2-related eye disorders. This may be an inappropriate acronym as it implies that coloboma is an intrinsic part of all microphthalmia, which no longer appears to be the case.

Each of the hypothetical explanations for the embryonic origin of the small or missing eyes associated with SOX2 mutations predicts a different spectrum of clinical phenotypes.

  • If the primary defect were in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
  • If lens induction were impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
  • If the main effects of SOX2 were in retinal differentiation, the predicted clinical manifestations would be retinal dystrophy > microphthalmia.
  • It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.

Thus, the term MAC has inadequate descriptive power to be useful. The particular spectrum associated with SOX2-related eye disorders is not yet clear because most affected individuals have very small or absent eyes, which are thus morphologically unclassifiable. Coloboma has been reported but is not a common feature.

Anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome was previously reported to be a distinct disorder, but it is now known to be associated with heterozygous loss-of-function mutations in SOX2 in some individuals [Williamson et al 2006, Zenteno et al 2006]; thus, it appears that esophageal atresia with or without tracheo-esophageal fistula is a feature of SOX2-related eye disorders and not a separate condition. This is consistent with the known expression of Sox2 in the endoderm and genital ridge during development of chick and mouse embryos.

Prevalence

Prevalence is approximately 1:250,000.

Differential Diagnosis

SOX2 mutations account for 15%-20% of bilateral anophthalmia, making it the most frequent known genetic cause of severe bilateral eye malformations. However, these disorders show marked etiologic heterogeneity.

One condition that resembles SOX2-related eye disorders is Lenz microphthalmia syndrome (LMS), characterized by unilateral or bilateral microphthalmia and/or anophthalmia with malformations of the ears, teeth, fingers, skeleton, or genitourinary system. Microphthalmia is often accompanied by microcornea and glaucoma. Coloboma is present in approximately 60% of microphthalmic eyes. Ears may be low set, anteverted, posteriorly rotated, simple, cup-shaped, or abnormally modeled; hearing loss has been observed. Dental findings include irregularly shaped, missing, or widely spaced teeth. Long cylindrical thorax with sloping, narrow shoulders, kyphoscoliosis, and exaggerated lumbar lordosis are common. Genitourinary anomalies include hypospadias, cryptorchidism, renal hypoplasia/aplasia, and hydroureter. Approximately 60% of affected males have mild-to-severe intellectual disability or developmental delay. Two loci on the X chromosome, MCOPS1 and MCOPS2, are known to be associated with LMS. The LMS-associated gene on MCOPS2 is BCOR. Inheritance is X-linked.

See Anophthalmia/Microphthalmia Overview for a more complete differential diagnosis. Mutations in CHX10, RAX, PAX6 (see Aniridia), and OTX2 can have overlapping phenotypes.

See Esophageal Atresia/Tracheoesophageal Fistula Overview for a more complete differential diagnosis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a SOX2-related eye disorder, the following evaluations are recommended in neonates with severe bilateral eye malformations in order to help establish the underlying cause:

  • General physical examination and dysmorphic assessment
  • Examination of affected individual by an experienced pediatric ophthalmologist
  • Audiometry
  • Baseline neurodevelopmental assessment
  • High-resolution cranial MRI for brain/pituitary malformations, optic nerve/chiasm/tract assessment
  • Corticosteroid, gonadotrphin, growth hormone, and thyroid function tests to assess pituitary function

Treatment of Manifestations

Visual impairment. The general management of visual impairment is not specific to anophthalmia or microphthalmia (see Anophthalmia/Microphthalmia Overview). Care includes:

  • Early referral to an experienced multidisciplinary team
  • Consideration of use of expanders to stimulate growth of the orbit and periorbital tissues. Because accurate assessment of visual function is necessary, optically clear expanders should be used.
  • Referral to special educational services for visually impaired infants

Other

  • Referral to physiotherapist if any evidence of motor impairment exists
  • Referral to special educational services for neurodevelopmental problems if necessary
  • Consideration of use of melatonin for regulation of circadian rhythm if sleep pattern is abnormal
  • Parent/care-giver training in seizure management

Prevention of Secondary Complications

Assess morning cortisol levels prior to anesthetic if MRI reveals pituitary hypoplasia.

Surveillance

The following measures are suggested:

  • Annual hearing test
  • Measurement of height, weight, and head circumference every three to six months during childhood
  • Neurodevelopmental assessment annually for the first five years of life

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SOX2-related eye disorders are inherited in an autosomal dominant manner, most often resulting from a de novo mutation. Rarely, parental germline mosaicism can result in a "pseudo-autosomal recessive" pattern of inheritance [Faivre et al 2006, Schneider et al 2008].

Risk to Family Members

Parents of a proband

  • No individuals diagnosed with a SOX2-related eye disorder have had an affected parent. However, one of the phenotypically normal parents may have germline mosaicism for the mutation. Recurrence of bilateral anophthalmia has been seen in two families in which the phenotypically normal mother had germline mosaicism of a loss-of-function mutation [Faivre et al 2006, Schneider et al 2008].
  • A proband with a SOX2-related eye disorder most often has the disorder as the result of a de novo heterozygous loss-of-function intragenic coding region mutation. The proportion of cases caused by such mutations is 92%.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include detailed ophthalmologic examination of the parents and, if the mutation in the proband has been identified, molecular genetic testing of DNA ideally extracted from more than one tissue source (e.g., leukocytes and buccal cells).

Sibs of a proband

Offspring of a proband. Each child of an individual with SOX2-related eye disorder has a 50% chance of inheriting the mutation.

Other family members of a proband. Because SOX2-related eye disorders occur as the result of a fully penetrant de novo mutation, unaffected family members other than parents of a proband are not at increased risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutationhas been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination/fetal MRI is also possible as the eye malformations in fetuses with SOX2-related eye disorders are usually severe and result in a marked reduction in eye size.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Children's Anophthalmia and Microphthalmia Network (ICAN)
    c/o Center for Developmental Medicine and Genetics
    5501 Old York Road
    Genetics, Levy 2 West
    Philadelphia PA 19141
    Phone: 800-580-4226 (toll-free)
    Email: ican@anophthalmia.org
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. SOX2-Related Eye Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for SOX2-Related Eye Disorders (View All in OMIM)

184429SRY-BOX 2; SOX2
206900MICROPHTHALMIA, SYNDROMIC 3; MCOPS3

Normal allelic variants. The coding region comprises one exon. Only one coding region polymorphism has been identified in SOX2: p.Val303Val (c.909G>C). This synonymous, third-position change has a minor allele frequency of approximately 30%. The SOX genes are defined as having greater than 60% homology within the HMG domain to human SRY. Within the SOX family, SOX2 belongs to the SOXB subgroup with SOX1, SOX3, SOX14, and SOX21.

Pathologic allelic variants. All SOX2 pathogenic mutations identified to date result in apparent loss of function. The most common mutation types are nonsense and frameshift. The remaining known mutations are whole-gene deletions. Details of all the known pathogenic variants are available in an online SOX2 mutation database.

Normal gene product. Transcription factor SOX-2 is a 317-amino acid peptide. It has an HMG DNA binding domain (between 39 and 120 in amino acid sequence) and a C-terminal transactivation domain. The N-terminal region is of unknown function and contains short polyglycine and polyalanine repeats.

SOX2 is expressed in mouse embryonic stem cells and has been shown to act as part of a transcriptional activator complex for several important developmental genes [Ambrosetti et al 2000, Tomioka et al 2002] including other genes known to be critical to eye development (e.g., PAX6 and MAF1) [Kamachi et al 2001, Muta et al 2002]. It is an early marker of neurulation in chick embryos and shows site- and stage-specific expression in the developing nervous system, genital ridge, and foregut in all vertebrates studied.

Abnormal gene product. Since SOX2 is a single-exon gene, it is not subject to nonsense-mediated decay and it is possible that truncated peptide may be produced in affected individuals. If these abnormal peptides were stable, they could have a dominant-negative effect. As more affected individuals are described, differences between the clinical features of those with whole-gene deletions and nonsense mutations would be expected if a dominant-negative effect exists.

The two missense mutations that have been identified are within the highly conserved HMG DNA binding domain. Functional studies using a modified yeast one-hybrid system confirm that these mutations severely diminish the activation of DC5 delta crystalline enhancer through loss of cooperative SOX2/PAX6 binding [Williamson et al 2006].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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  25. Zenteno JC, Perez-Cano HJ, Aguinaga M. Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes. Am J Med Genet A. 2006;140:1899–903. [PubMed: 16892407]
  26. Zhou J, Kherani F, Bardakjian TM, Katowitz J, Hughes N, Schimmenti LA, Schneider A, Young TL. Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia. Mol Vis. 2008;14:583–92. [PMC free article: PMC2275209] [PubMed: 18385794]

Chapter Notes

Acknowledgments

Professor Veronica van Heyningen for continued helpful collaboration

MACS family support organization for their interest and support

Revision History

  • 25 August 2009 (me) Comprehensive update posted live
  • 7 March 2008 (cd) Revision: FISH analysis available clinically
  • 5 December 2007 (cd) Revision: deletion/duplication analysis available cl
  • 23 February 2006 (me) Review posted to live Web site
  • 14 April 2005 (drf) Original submission
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