SOX2 Disorder

Clinical characteristics.

The phenotypic spectrum of SOX2 disorder includes anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, esophageal atresia, hypogonadotropic hypogonadism (manifest as cryptorchidism and micropenis in males, gonadal dysgenesis infrequently in females, and delayed puberty in both sexes), pituitary hypoplasia, postnatal growth delay, hypotonia, seizures, and spastic or dystonic movements.

Diagnosis/testing.

The diagnosis of SOX2 disorder is established in a proband in whom molecular genetic testing identifies either a heterozygous intragenic SOX2 pathogenic (or likely pathogenic) variant or a deletion of 3q26.33 involving SOX2.

Management.

Treatment of manifestations: Treatment usually involves a multidisciplinary team including – as needed – an experienced pediatric ophthalmologist, ophthalmo-plastic surgeon (for children with anophthalmia and/or extreme microphthalmia), and early educational intervention through community vision services and/or school district; educational support for school-age children; pediatric endocrinologist; pediatric neurologist; and physical therapist and occupational therapist.

Surveillance: Routine follow up with specialists managing the vision, educational, endocrine, and neurologic manifestations.

Genetic counseling.

SOX2 disorder, caused by an intragenic SOX2 pathogenic variant or a deletion of 3q26.33 involving SOX2, is an autosomal dominant disorder. Approximately 60% of affected individuals have a de novo genetic alteration. Some affected individuals have inherited the genetic alteration from either an affected mother (transmission from an affected father to child has not been reported to date) or an unaffected parent with germline mosaicism. Once the causative genetic alteration has been identified in an affected family member (or in a parent who has a structural chromosome rearrangement involving the 3q26.33 region), prenatal testing for a pregnancy at increased risk is possible, and preimplantation genetic testing for SOX2 disorder may be possible, depending on the specific familial genetic alteration.

Suggestive Findings

SOX2 disorder should be considered in individuals with the following clinical and brain MRI findings and family history.

Clinical findings

• Bilateral anophthalmia and/or microphthalmia
• Unilateral anophthalmia or microphthalmia
• Genital abnormalities. Frequently cryptorchidism and/or micropenis in males (commonly a manifestation of hypogonadotropic hypogonadism); infrequently uterus hypoplasia and ovary or vaginal agenesis in females
• Tracheoesophageal fistula and/or esophageal atresia
• Delayed motor development / learning disability
• Postnatal growth failure
• Seizures with gray matter heterotopia
• Spasticity, dystonia, or status dystonicus

Brain MRI. Malformation and/or gray matter heterotopia of the mesial temporal structures (hippocampal and parahippocampal), pituitary hypoplasia, and agenesis or dysgenesis of the corpus callosum are core features of SOX2 disorder. Septum pellucidum defects, cerebellar hypoplasia, hypothalamic hamartoma, arachnoid cyst, and sellar or suprasellar tumors are also reported in multiple individuals [Ragge et al 2005, Sisodiya et al 2006, Gerth-Kahlert et al 2013, Blackburn et al 2018].

Family history is consistent with autosomal dominant inheritance, including simplex cases (i.e., a single occurrence in a family). Absence of a known family history does not preclude the diagnosis. See Genetic Counseling.

Establishing the Diagnosis

The diagnosis of SOX2 disorder is established in a proband in whom molecular genetic testing identifies either a heterozygous intragenic SOX2 pathogenic (or likely pathogenic) variant or a deletion that is intragenic or a deletion of 3q26.33 involving SOX2 (see Table 1).

For details about heterozygous deletions of 3q26.33 involving SOX2, see Molecular Genetics.

Note: Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel, and chromosomal microarray analysis [CMA]) and comprehensive genomic testing (CMA, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing that could include CMA (see Option 1), whereas those in whom the diagnosis of SOX2 disorder has not been considered or previously made by CMA may be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

SOX2 disorder comprises a phenotypic spectrum that can include anophthalmia and/or microphthalmia, brain malformations, developmental delay / intellectual disability, esophageal atresia, hypogonadotropic hypogonadism (manifest as cryptorchidism and micropenis in males, gonadal dysgenesis infrequently in females, and delayed puberty in both sexes), pituitary hypoplasia, postnatal growth delay, hypotonia, seizures, and spastic or dystonic movements.

To date, 174 individuals from 157 families have been identified with SOX2 disorder [Williamson & FitzPatrick 2014, Gorman et al 2016, Dennert et al 2017, Blackburn et al 2018]. The following descriptions are based on these key reports, together with all other published cases and the authors' unpublished data.

Bilateral anophthalmia and/or microphthalmia. SOX2 eye defects are usually bilateral, severe, and apparent at birth or on routine prenatal ultrasound examination. 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.

In the 174 individuals reported (114 individuals reviewed by Williamson & FitzPatrick [2014] plus 60 individuals reported subsequently), 76 (44%) had bilateral anophthalmia, 23 (13%) had anophthalmia with contralateral microphthalmia, and 20 (12%) had bilateral microphthalmia. The remaining individuals have a wide spectrum of eye malformations including the following:

• Unilateral anophthalmia or microphthalmia and a normal eye
• Unilateral anophthalmia with cataract in the contralateral eye
• Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
• Bilateral or unilateral coloboma
• Optic nerve hypoplasia or aplasia
• Bilateral or unilateral congenital aphakia
• Cataract
• Retinal dysplasia
• Anterior segment dysgenesis (including sclerocornea or microcornea)
• Refractive error

Thirteen individuals with loss-of-function SOX2 variants had bilateral structurally normal eyes. Seven had no ocular defects noted and six had mild ocular defects, including the following:

• A monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure whose twin had unilateral anophthalmia as part of anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [Zenteno et al 2006];
• A sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [Chassaing et al 2007];
• A woman with intellectual disability, corpus callosum agenesis, hypogonadotropic hypogonadism, vaginal agenesis, and spastic paraparesis [Errichiello et al 2018];
• A mother (with either heterozygosity or a high level of mosaicism of the SOX2 pathogenic variant) with isolated hypogonadotropic hypogonadism who, following assisted conception, had two children with anophthalmia or microphthalmia and coloboma [Stark et al 2011];
• Two individuals identified in an intellectual disability cohort with mild microcornea, delayed speech and walking, esophageal stenosis, hearing deficits and mild facial hypoplasia in one; and strabismus, delayed speech, dystonic movements and spastic diplegia, hypogonadotropic hypogonadism, and corpus callosum and hippocampus malformation in the other individual [Dennert et al 2017];
• Three individuals with mild ocular defects (esotropia, macro excavated optic disc, or thin retinal layer) and a combination of developmental delay, seizures, hypotonia or dystonia, tracheoesophageal fistula, suprasellar teratoma, and gonadal dysgenesis [Shima et al 2017, Blackburn et al 2018, Pilz et al 2019];
• Four individuals, one of whom had a de novo SOX2 frameshift variant and a phenotype of severe developmental delay, hypotonia, and facial dysmorphism with no ocular defects (see DECIPHER).

Anterior pituitary hypoplasia. The majority of affected individuals have some evidence of hypothalamic-pituitary axis dysfunction when detailed measurement of growth hormone and gonadotropins is undertaken [Tziaferi et al 2008]. Identification of significant dysregulation of the hypothalamic-pituitary-adrenal axis is particularly important to ensure that appropriate glucocorticoid supplementation is provided during periods of physiologic stress.

• 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 symmetric growth failure.
• Hypogonadotropic hypogonadism was reported in 20 individuals, including two females with normal eyes [Stark et al 2011, Errichiello et al 2018] and two individuals with either unilateral retinal detachment or unilateral strabismus [Takagi et al 2014, Dennert et al 2017].

Genital abnormalities. In males, micropenis and cryptorchidism (often a manifestation of congenital hypogonadotropic hypogonadism) are common. Occasionally hypospadias is observed.

In females, malformations are less frequent and can include hypoplastic or hemi-uterus, ovary or vaginal agenesis, and vaginal adhesions [Errichiello et al 2018].

Dystonia and spasticity. Status dystonicus (a movement disorder emergency in which there is prolonged, generalized, intense, and painful muscle contraction) was originally reported in individuals with bilateral anophthalmia and a specific variant (see Genotype-Phenotype Correlations and Table 7) [Gorman et al 2016]; however, other variants, including the most common SOX2 variant, were subsequently associated with this feature in two individuals with bilateral anophthalmia or bilateral optic disc abnormality [Martinez & Madsen 2019, Pilz et al 2019].

A minority of affected individuals develop early continual dystonic posturing that is similar to that seen in dystonic cerebral palsy but without evidence of basal ganglia injury on neuroimaging. These children should be considered at risk for status dystonicus, which can be triggered by any major physiologic stress and can lead to protracted periods of hospitalization and critical care.

Spasticity, including diplegia, paraparesis, or quadriparesis was reported in 13 individuals. One of these individuals, who also had a dystonic movement disorder and unilateral strabismus as the only eye defect, had a 1.6- to 2-megabase (Mb) deletion encompassing SOX2 [Dennert et al 2017].

Delayed motor development was reported in the majority of affected children; the age of achieving independent walking ranged from 12 months to four years, although some individuals never achieve independent ambulation.

Intellectual ability is highly variable, ranging from normal to profound learning disability, with the majority having moderate learning disability. The degree of learning disability is not predictable by pathogenic variant type or presence or absence of eye involvement [Dennert et al 2017, Blackburn et al 2018, Errichiello et al 2018].

Seizures were observed in 22 individuals. Information on exact seizure type is limited, but most appeared to be grand mal tonic-clonic seizures that appeared in early childhood and responded well to standard anticonvulsant medication.

Sensorineural hearing loss. Seven children had apparently nonprogressive moderate sensorineural hearing loss requiring hearing aids.

Esophageal atresia with or without tracheoesophageal fistula. Esophageal atresia or stenosis was reported in nine and three individuals, respectively. Tracheoesophageal fistula was seen in the presence or absence of esophageal atresia. As these features can be present in children without severe structural eye defects [Zenteno et al 2006, Dennert et al 2017], they are not restricted to individuals with the full AEG syndrome [Williamson et al 2006].

Additionally, feeding difficulty or gastroesophageal reflux was observed in multiple individuals.

Genotype-Phenotype Correlations

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

Variable expressivity is observed with some recurrent pathogenic variants (Table 7).

• The most common variant, p.Asn24ArgfsTer65, which alters the SOX2 N-terminal region polyglycine repeat, is associated primarily with bilateral anophthalmia/microphthalmia; however, two individuals had reduced palpebral fissure or optic disc abnormality [Zenteno et al 2005, Pilz et al 2019] and three individuals had normal eyes [Chassaing et al 2007, Blackburn et al 2018, Errichiello et al 2018].
• The p.Asp123Gly variant, which alters the SOX2 partner-binding region, displays phenotypes ranging from bilateral anophthalmia/microphthalmia (Families 1 and 2) to mild microcornea, retinal detachment, or refractive error with iris hypoplasia or retinal tuft (Family 1) [Mihelec et al 2009] or bilateral coloboma (Family 2) [Gerth-Kahlert et al 2013].
• The extraocular features of SOX2 disorder, including AEG syndrome and dystonia, presented with the common p.Asn24ArgfsTer65 variant, but were absent from the two families with the p.Asp123Gly variant. Status dystonicus or severe dystonic cerebral palsy were predominantly observed in individuals with loss-of-function variants at Tyr160 or the surrounding amino acid residues [Gorman et al 2016].
• Large deletions encompassing SOX2 and adjacent genes, ranging from 1.5 to ~9 Mb, do not cause any striking phenotypic differences when compared to smaller deletions (and intragenic variants) involving only SOX2. For details about heterozygous deletions of 3q26.33 involving SOX2, see Molecular Genetics.

Duplications encompassing SOX2, ranging from 40 kb to 104 Mb, do not appear to cause structural eye defects, but are associated with other features of SOX2 disorder: developmental delay, intellectual disability, motor delay, hypotonia, and gastroesophageal reflux. Inheritance was observed as de novo constitutive or de novo mosaic events, or, less frequently, from parents with constitutional duplications (see DECIPHER).

Penetrance

Penetrance appears to be complete for nonmosaic loss-of-function pathogenic variants. Although normal eye development is possible in SOX2 disorder, all such individuals had extraocular defects.

Nomenclature

Microphthalmia-anophthalmia-coloboma (MAC) was used as an umbrella term for the spectrum of severe eye malformations in early publications describing SOX2 eye disorders. This may be an inappropriate acronym, as it implies that coloboma is an intrinsic part of all microphthalmia, which is not the case: coloboma has been reported but is not a common feature.

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

• If the primary defect is 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 is impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
• If the main effects of SOX2 are 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.

It is not yet clear which of these spectra are associated with SOX2 eye disorders, as most affected individuals have very small or absent eyes, which are thus morphologically unclassifiable. Optic fissure closure defects have been reported but are not a common feature.

Anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome was previously reported to be a distinct disorder, but is now known to be associated in some individuals with heterozygous pathogenic loss-of-function variants in SOX2 [Williamson et al 2006, Zenteno et al 2006]; thus, it appears that esophageal atresia with or without tracheoesophageal fistula is a feature of SOX2 disorder 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 (UK estimate) [Author, personal data], extrapolated from Shah et al [2011], with no population differences noted.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SOX2 disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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 in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

SOX2 disorder, caused by an intragenic SOX2 pathogenic variant or a deletion of 3q26.33 involving SOX2, is an autosomal dominant disorder.

Risk to Family Members

Parents of a proband

• Approximately 60% of individuals diagnosed with SOX2 disorder have an identified de novo genetic alteration (i.e., a genetic alteration that is not detectable in the biological parents of the proband) [Williamson & FitzPatrick 2014, Harding et al 2020].
• Some individuals diagnosed with SOX2 disorder have an affected mother (transmission from an affected father to a proband has not been reported to date).
  • One individual with unilateral anophthalmia had a similarly affected mother [Gerth-Kahlert et al 2013].
  • Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [Mihelec et al 2009]; and a mother with bilateral coloboma and her child with bilateral anophthalmia/microphthalmia and coloboma [Gerth-Kahlert et al 2013].
  • A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [Stark et al 2011].
• Some individuals diagnosed with SOX2 disorder have a pathogenic variant inherited from an unaffected parent.
  • Maternal somatic/germline mosaicism was reported in four families with sib recurrence of SOX2 disorder [Faivre et al 2006, Chassaing et al 2007, Schneider et al 2008, Zhou et al 2008].
  • Paternal transmission of a SOX2 pathogenic variant is rare and has been reported in only two families to date. In both families, the fathers had somatic and germline mosaicism [Suzuki et al 2014] (see DECIPHER).
• Recommendations for the evaluation of the parents of a proband with an apparent de novo genetic alteration include detailed ophthalmologic examination and:
  • Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic SOX2 pathogenic variant;
  • Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• If the genetic alteration identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo genetic alteration. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
    The incidence of parental germline mosaicism in SOX2 disorder is approximately 4.5%. Recurrence of anophthalmia and/or microphthalmia has been reported in six families in which the phenotypically normal mother (4 families) or father (2 families) had confirmed somatic and germline mosaicism (see "Some individuals diagnosed with SOX2 disorder…" above). An additional instance of probable but unconfirmed maternal germline mosaicism has been reported [Schneider et al 2009].
• The family history of some individuals diagnosed with SOX2 disorder may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed without genetic testing of the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent is affected and/or has the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial clinical variability is observed in SOX2 disorder; a heterozygous sib may be more or less severely affected than the proband [Mihelec et al 2009].
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. The incidence of parental germline mosaicism in SOX2 disorder is approximately 4.5% (see Parents of a proband). If a parent of the proband has germline mosaicism, the risk to the sibs of inheriting the SOX2 pathogenic variant may be up to 50%.
• If a parent has a balanced structural chromosome rearrangement involving the 3q26.33 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.

Offspring of a proband

• Each child of a female proband with a constitutional SOX2 pathogenic variant has a 50% chance of inheriting the causative genetic alteration.
• Transmission of a constitutional loss-of-function pathogenic variant from a male proband to offspring has not been reported.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the causative genetic alteration or a balanced structural chromosome rearrangement, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the causative genetic alteration has been identified in an affected family member (or a parent is known to have a structural chromosome rearrangement involving the 3q26.33 region), prenatal testing for a pregnancy at increased risk is possible and preimplantation genetic testing for SOX2 disorder may be possible, depending on the specific familial variant.

Note: The severity of disease and specific clinical findings vary and cannot be accurately predicted by the family history or results of molecular genetic testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SOX2 encodes the transcription factor SOX2 (317 amino acids) which has an HMG DNA-binding domain (amino acids 40-111), a partner-binding region, and a C-terminal transactivation region. 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 including other genes known to be critical to eye development (e.g., PAX6 and MAF1). 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. For a review article see Julian et al [2017].

Mechanism of disease causation. Heterozygous loss of function

SOX2-specific laboratory technical considerations. As SOX2 is a single-exon gene, there are no alternative splice transcripts and it is not subject to nonsense-mediated decay; however, loss-of-function variants have been observed throughout the exon.

Reported heterozygous deletions of 3q26.33 involving SOX2 (~2%-3% of affected individuals, increasing to ~20% of affected individuals with bilateral anophthalmia/severe microphthalmia) [Williamson & FitzPatrick 2014; Author, unpublished data] include:

• A de novo deletion encompassing SOX2 as the only gene [Suzuki et al 2014, Dennert et al 2017] or as part of a multigene deletion [Gerth-Kahlert et al 2013, Suzuki et al 2014, Dennert et al 2017];
• A cytogenetically visible deletion of 3q26.33 that either encompasses SOX2 [Male et al 2002, Guichet et al 2004, Kelberman et al 2008] or involves an unbalanced translocation such as t(3;7)(q28;q21.1)-associated 6.7-Mb deletion [Male et al 2002];
• A de novo apparently balanced translocation involving 3q26.33, encompassing SOX2, such as t(3;11)(q26.3;p11.2)-associated 600-kb deletion and t(3;7)(q28;p21.3)-associated 2.7-Mb deletion [Fantes et al 2003, Williamson et al 2006].

Acknowledgments

• Professor Veronica van Heyningen for continued helpful collaboration
• MACS family support organization for their interest and support

Revision History

• 30 July 2020 (bp) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 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 clinically
• 23 February 2006 (me) Review posted live
• 14 April 2005 (drf) Original submission

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