Syndromic microphthalmia, type 3

Other Names: MCOPS3; Microphthalmia and esophageal atresia syndrome; Anophthalmia clinical with associated anomalies; Anophthalmia esophageal genital syndrome; AEG syndrome; Anophthalmia microphthalmia esophageal atresia; SOX2 anophthalmia syndrome; SOX2-related eye disorders

Syndromic microphthalmia, type 3 is a rare condition that affects the eyes and other parts of the body. Babies with this condition are generally born without eyeballs (anophthalmia) or with eyes that are unusually small (microphthalmia). Both of these abnormalities can be associated with severe vision loss. The term anophthalmia is often used interchangeably with severe microphthalmia because individuals with no visible eyeballs typically have some remaining eye tissue. These eye problems can cause significant vision loss. While both eyes are usually affected in SOX2 anophthalmia syndrome, one eye may be more affected than the other.

Epidemiology

SOX2 anophthalmia syndrome is estimated to affect 1 in 250,000 individuals. About 10 percent to 15 percent of people with anophthalmia in both eyes have SOX2 anophthalmia syndrome.

Cause

Mutations in the SOX2 gene cause SOX2 anophthalmia syndrome. This gene provides instructions for making a protein that plays a critical role in the formation of many different tissues and organs during embryonic development. The SOX2 protein regulates the activity of other genes, especially those that are important for normal development of the eyes.

Mutations in the SOX2 gene prevent the production of functional SOX2 protein. The absence of this protein disrupts the activity of genes that are essential for the development of the eyes and other parts of the body. Abnormal development of these structures causes the signs and symptoms of SOX2 anophthalmia syndrome.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

SOX2 anophthalmia syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases result from new mutations in the SOX2 gene and occur in people with no history of the disorder in their family. In a small number of cases, people with SOX2 anophthalmia syndrome have inherited the altered gene from an unaffected parent who has a SOX2 mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism.

Signs and symptoms

Other signs and symptoms of syndromic microphthalmia, type 3 may include seizures, brain malformations, esophageal atresia, delayed motor development, learning disabilities, and sensorineural hearing loss.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Anophthalmia(Absence of eyeballs)
• Esophageal atresia(Birth defect in which part of esophagus did not develop)
• Microphthalmia(Abnormally small eyeball)
• Tracheoesophageal fistula

30%-79% of people have these symptoms

• Agenesis of corpus callosum
• Cryptorchidism(Undescended testes)
• Hearing impairment(Deafness)
• Visual loss(Loss of vision)

5%-29% of people have these symptoms

• 11 pairs of ribs
• Global developmental delay
• Growth delay(Delayed growth)
• Hemivertebrae(Missing part of vertebrae)
• Holoprosencephaly
• Hydrocephalus(Too much cerebrospinal fluid in the brain)
• Hypoplasia of penis(Underdeveloped penis)
• Hypospadias
• Intellectual disability(Mental deficiency)
• Iris coloboma
• Cat eye
• Patent ductus arteriosus
• Sclerocornea(Hardening of skin and connective tissue)
• Ventricular septal defect(Hole in heart wall separating two lower heart chambers)

Diagnosis

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.

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 .

Treatment

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.

NIH genetic and rare disease info

• NIH info on Syndromic microphthalmia, type 3

Syndromic microphthalmia, type 3 is a rare disease.

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