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SOX2 Disorder

, PhD, , MBChB, MRCP (Edin), and , MD, FMedSci.

Author Information

Initial Posting: ; Last Update: July 30, 2020.

Estimated reading time: 27 minutes

Summary

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 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.

GeneReview Scope

With the current widespread use of advanced molecular genetic testing, it is apparent that the clinical spectrum associated with SOX2 pathogenic variants includes anophthalmia and/or microphthalmia as well as phenotypes with minimal or absent ocular findings. The term "SOX2 disorder" is used in this GeneReview to refer to the complete phenotypic spectrum associated with heterozygous SOX2 pathogenic variants. It encompasses all individuals with a SOX2 pathogenic variant who should be evaluated for medically actionable manifestations across the entire phenotypic spectrum (regardless of clinical findings that prompted molecular genetic testing).

Diagnosis

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 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.

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).

Option 1

When the phenotypic findings suggest the diagnosis of SOX2 disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of SOX2 is performed first. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis (which can include CMA).
    Note: Most deletions involving SOX2 are large enough to be detected by CMA; those below the limit of detection by CMA can be detected by a gene-targeted deletion assay.
  • A developmental eye defects/oculome or intellectual disability multigene panel that includes SOX2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of SOX2 disorder, some panels for intellectual disability may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing, which does not require the clinician to determine which gene is likely involved, is an option when SOX2 disorder is not an easily achievable diagnosis. CMA is often used as a first step. If CMA does not detect a copy number variant, genome sequencing and/or exome sequencing may be used.

If exome sequencing is not diagnostic, exome array (when clinically available) can detect copy number variants, such as (multi)exon deletions or duplications that may not be identified by exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SOX2 Disorder

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
S0X2Sequence analysis 3~76% 4
Gene-targeted deletion/duplication analysis 5~24% (~21% that could also be resolved by CMA & ~3% that are below the limit of detection by CMA) 4, 5
CMA 6~21% 4, 5
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, whole-exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Suzuki et al [2014]) may not be detected by these methods [Chassaing et al 2014].

6.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including SOX2) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 3q26.33 region. CMA designs in current clinical use target the 3q26.33 region.

Clinical Characteristics

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.

Table 2.

Select Features of SOX2 Disorder: Frequency of Human Phenotype Ontology (HPO) Terms

Frequency of Phenotypic
Feature in Case Reports (n=38)
HPO TermHPO Term Frequency 1
in Case Reports (n=38)
Highly frequentAnophthalmia92
Microphthalmia37
Micropenis22
Seizures21
Cryptorchidism16
Developmental delay15
Dystonia12
Moderately frequentGeneralized hypotonia8
Hypoplasia of corpus callosum8
Motor delay7
Fever7
Coloboma7
Optic nerve hypoplasia7
Frontal bossing7
Spastic diplegia7
Feeding difficulties6
Wide nasal bridge6
Short stature6
Arachnoid cyst6
Growth delay6
Cataract6
Less frequentHydrocephalus5
Delayed puberty5
Esophageal atresia5
Hypertelorism5
Short palpebral fissure5
Delayed speech & language development5

Data were extracted from full text case reports exclusively describing SOX2 disorder (n=38) using exact string matching. The Human Phenotype Ontology (HPO) enables use of precise, standardized, computationally accessible terms to describe phenotypic abnormalities. The ontology structure describes the relationship of terms to each other [Köhler et al 2019]. HPO terms that appear fewer than four times were excluded.

1.

Frequency refers to the number of times the term was used in all included case reports.

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.

Differential Diagnosis

Genes associated with ocular manifestations frequently observed in SOX2 disorder (with or without nonocular comorbidities) are summarized in Table 3.

Table 3.

Genes of Interest in the Differential Diagnosis of SOX2 Disorder

GeneDisorderMOIOcular PhenotypeOther Clinical FeaturesComment
ALDH1A3Isolated microphthalmia 8 (OMIM 615113)ARBilateral microphthalmia &/or anophthalmiaDD or autism in ~20% of affected persons
BMP4Syndromic microphthalmia 6 (OMIM 607932)ADBilateral anophthalmia, optic disc aplasia/hypoplasiaSmall kidneys/renal cyst, small earsComorbidities present in 2 families 1
GJA8Cataract 1 (OMIM 116200)ADBilateral microphthalmia, coloboma, cataract 2None
NAA10Lenz microphthalmia syndrome (OMIM 309800)XLUnilateral or bilateral microphthalmia &/or anophthalmia
  • Malformations of the ears, teeth, fingers, skeleton, or genitourinary system
  • Mild-to-severe ID or DD in ~60% of affected males
Polyadenylation signal variants are assoc w/familial anophthalmia. 3
OTX2OTX2 anophthalmia syndrome (MCOPS5) (OMIM 610125)ADOcular features almost identical to those frequently observed in SOX2 disorder 4Brain features almost identical to those of SOX2 disorder 4Esophageal atresia/tracheo-esophageal fistula & dystonia are not assoc w/OTX2 pathogenic variants.
PAX6PAX6 isolated aniridia (See PAX6-Related Aniridia.)ADBilateral microphthalmia &/or coloboma, iris hypoplasia, cataract, lens subluxation 5None
RAXRAX microphthalmia (OMIM 611038)ARBilateral microphthalmia &/or anophthalmia~50% of affected individuals had DD or autism.
VSX2
(CHX10)
VSX2 microphthalmia (OMIM 142993)ARBilateral microphthalmia &/or anophthalmiaNoneAffected families are of Middle Eastern ethnicity.

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MCOPS5 = microphthalmia, syndromic 5; MOI = mode of inheritance; XL = X-linked

1.

Reis et al [2011]; Author, unpublished data

2.
3.
4.
5.

Management

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.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with SOX2 Disorder

System/ConcernEvaluationComment
ConstitutionalMeasurement of weight, length/height, & head circumferenceAssess for growth failure.
EyesComplete ophthalmologic exam by experienced pediatric ophthalmologist
  • Incl best corrected visual acuity, assessment of refractive error, fundus exam
  • Consider referral to ophthalmo-plastic surgeon for children w/anophthalmia & extreme microphthalmia.
Brain malformationHigh-resolution cranial MRI
  • W/attention to brain/pituitary malformations, optic nerve/chiasm/tract
  • Mesial temporal heterotopia is highly assoc w/future epilepsy.
Anterior pituitary
hypoplasia
Endocrine evalAssess:
  • Growth hormone & thyroid function;
  • Gonadotropins (when age appropriate).
GenitourinaryMales: Assessment for micropenis &/or cryptorchidism
  • Consider referral to urologist for cryptorchidism or other genital malformations.
  • For those w/micropenis, refer to endocrinologist for consideration of eval for hypogonadotropic hypogonadism.
Females: Consider pelvic ultrasound exam &/or MRI, particularly in pubertal or postpubertal females.Assess for uterine & ovarian anomalies.
DD/IDDevelopmental assessment
  • Incl motor, adaptive, cognitive, & speech/language eval
  • Eval for early intervention / special education
SeizuresNeurologic examIncl EEG
SpasticityNeurologic examReferral to OT/PT to assess:
  • Gross motor & fine motor skills
  • Mobility, ADL, & need for adaptive devices
  • Need for ongoing PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
DystoniaNeurologic history & examAssess axial & peripheral tone to advise on likely efficacy of antispasmodic medications & procedures.
Hearing lossAudiologic evalAssess for sensorineural & conductive hearing loss.
Esophageal atresia ±
tracheoesophageal
fistula
Focused neonatal assessmentThese major malformations constitute a surgical emergency.
Genetic counselingBy genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of SOX2 disorder to facilitate medical & personal decision making
Family support/
resources
Assess:

ADL = activities of daily living; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy/therapist; PT = physical therapy/therapist

1.

Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with SOX2 Disorder

Manifestation/
Concern
TreatmentConsiderations/Other
DD/IDSee Developmental Delay / Intellectual Disability Management Issues.Referral to physiotherapist if evidence of motor impairment
Anophthalmia/
Microphthalmia
Early referral to an experienced multidisciplinary team
  • Prostheses: Consider optically clear expanders to stimulate growth of the orbit & periorbital tissues.
  • Community vision services through early intervention or school district
Anterior pituitary
hypoplasia
Hormone replacement by pediatric endocrinologist
Hypogonadotropic
hypogonadism
Hormone replacement prior to expected onset of puberty by pediatric endocrinologist
SeizuresStandardized treatment w/AEDs by experienced neurologistEducation of parents/caregivers 1
SpasticityOrthopedist / physical medicine & rehab / PT/OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices & disability parking placard.
Dystonia / Status
dystonicus
PT, hydration, intensive careDystonia may worsen & can show acute change to status dystonicus, which should be considered a medical emergency.
Hearing lossHearing aids may be helpful per audiologist/otolaryngologist.Community hearing services through early intervention or school district
Esophageal atresia ± tracheoesophageal
fistula
Perinatal surgeryThis constitutes a surgical emergency.

AED = antiepileptic drug; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Communication Issues

Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Table 6.

Recommended Surveillance for Individuals with SOX2 Disorder

System/ConcernEvaluationFrequency
ConstitutionalHeight, weight, & head circumferenceEvery 3-6 mos during childhood
Anophthalmia/
Microphthalmia
MRI, assessment of vision, ophthalmologic evalEvery 3-6 mos during childhood w/MRI only if change in clinical status, e.g., sudden change in light-dark or color perception
Follow-up eval w/ophthalmo-plastic surgeon
Brain malformationNeurologic evalRepeat MRI if change in neurologic status.
Anterior pituitary
hypoplasia
Pituitary axis endocrine evalEvery 3-6 mos
Hypogonadotropic
hypogonadism
Gonadotropin endocrine evalInfancy, mid-childhood, then every 3-6 mos from age 8 yrs
Developmental delay /
Intellectual disability
Neurodevelopmental assessmentAnnually for 1st 5 yrs
Monitor school progress.Annually
SeizuresEEG, brain MRIIf change in seizure frequency or type
SpasticityBy OT/PTEvery 3-6 mos during childhood or w/any progression of symptoms or signs, or deteriorating function
Dystonia / Status
dystonicus
Neurologic eval
Sensorineural hearing lossAudiogramAnnually
Esophageal atresia ± tracheoesophageal fistulaPer treating pediatric surgeonPer treating pediatric surgeon

OT = occupational therapist; PT = physical therapist

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.

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 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).
  • Some individuals diagnosed with SOX2 disorder have a pathogenic variant inherited from an unaffected parent.
  • 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

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, his or her 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.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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.

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
  • Microphthalmia, Anophthalmia and Coloboma Support
    United Kingdom
    Phone: 0800 169 8088
    Email: enquiries@macs.org.uk
  • 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 Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org

Molecular Genetics

Note on Table A, Locus-Specific Databases: See also the DECIPHER database.

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 Disorder: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SOX23q26​.33Transcription factor SOX-2SOX2 @ The Human Genetics Unit Edinburgh U.K.SOX2SOX2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SOX2 Disorder (View All in OMIM)

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

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:

Table 7.

Notable SOX2 Pathogenic Variants

Reference SequencesDNA
Nucleotide
Change
Predicted
Protein Change
Comment [Reference]
NM_003106​.4
NP_003097​.1
c.70_89del20p.Asn24ArgfsTer65Most common pathogenic variant; accounts for ~20% of all pathogenic variants [Williamson & FitzPatrick 2014].
c.368A>Gp.Asp123GlyRecurrent familial variant assoc w/broad range of ocular phenotypes [Mihelec et al 2009, Gerth-Kahlert et al 2013].
c.479dupA,
c.480C>G,
c.480C>A
p.Tyr160Ter

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

References

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Chapter Notes

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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