Microphthalmia, Syndromic 3

A number sign (#) is used with this entry because of evidence that syndromic microphthalmia-3 (MCOPS3) is caused by heterozygous mutation in the SOX2 gene (184429) on chromosome 3q26.

Description

Syndromic microphthalmia-3 (MCOPS3) is characterized by clinical anophthalmia or microphthalmia with or without defects of the optic nerve, optic chiasm, and optic tract. Extraocular abnormalities include brain anomalies, seizures, motor disability, neurocognitive delays, sensorineural hearing loss, and esophageal atresia. Hypoplasia of the anterior pituitary is another major complication, which frequently results in growth hormone deficiency; however, gonadotropin deficiency is likely to be the most consistent endocrinopathy in patients with SOX2 mutation (summary by Numakura et al., 2010).

Nomenclature

The term 'anophthalmia' has been misused in the medical literature. True or primary anophthalmia is rarely compatible with life; in such cases, the primary optic vesicle has stopped developing and the abnormal development involves major defects in the brain as well (Francois, 1961). The diagnosis can only be made histologically (Reddy et al., 2003; Morini et al., 2005; Smartt et al., 2005), but this is rarely done. In most published cases, the term 'anophthalmia' is used as a synonym for the more appropriate terms 'extreme microphthalmia' or 'clinical anophthalmia.'

Clinical Features

Rogers (1988) reported an 11-month-old male infant with bilateral clinical anophthalmia, esophageal atresia with tracheoesophageal fistula, and glanular hypospadias. The patient was noted to have normal intellectual development but delayed motor development. Arroyo et al. (1992) reported a male infant with bilateral clinical anophthalmia and esophageal atresia who had no other pathologic findings except for right cryptorchidism with normal scrotum and penis. The authors believed that this represented a second case of the disorder described by Rogers (1988).

Sandler et al. (1995) reported a boy and a girl from unrelated families with bilateral anophthalmia and proximal esophageal atresia. In addition to vestigial optic nerves and chiasma, MRI studies showed other central nervous system abnormalities: one had ectopic tissue in the hypothalamic region and the other had generalized ventriculomegaly associated with atrophy. Sandler et al. (1995) concluded that these defects represent a nonrandom concurrence.

Ulman et al. (1996) reported a boy with esophageal atresia, tracheoesophageal fistula, unilateral microphthalmia, and glanular hypospadias.

Shah et al. (1997) reported a male infant with bilateral microphthalmia, esophageal atresia with distal tracheoesophageal fistula, micropenis, and cryptorchidism. Other features included low-set posteriorly angulated ears with simple flat pinnae, right facial palsy, and hockey-stick palmar creases. CT scan revealed cavum septi pellucidi and extensive low attenuation of white matter bilaterally, suggesting leukomalacia. The patient was treated palliatively and died at day 8; autopsy revealed an absent gallbladder, extensive bilateral periventricular leukomalacia, olfactory aplasia, and multiple cerebellar cortical heterotopia. Shah et al. (1997) suggested the name 'anophthalmia-esophageal-genital syndrome' (AEG syndrome) for this disorder.

Imaizumi et al. (1999) reported 2 male patients with unilateral microphthalmia and esophageal atresia. Mild psychomotor delay and severe bilateral hearing loss were present in 1 patient; the other had T4-S hemivertebrae and 11 ribs on the left side. The authors concluded that these cases provide further support for recognizing this association as a distinct syndrome.

Menetrey et al. (2002) reported a newborn female with bilateral anophthalmia and esophageal atresia, who died shortly after birth. They stated that this was the seventh reported case of this syndrome and noted that all cases had been sporadic.

Messina et al. (2003) reported a male infant with left microphthalmia, esophageal atresia, and marked hypoplasia of the entire left half of the body. A chorioretinal coloboma was noted in the right eye; on CT scan, there was diffuse hypodensity of the white matter of both hemispheres.

Petrackova et al. (2004) reported a male infant with bilateral clinical anophthalmia and esophageal atresia with distal tracheoesophageal fistula. He had normal genitals, duplication of the left kidney, and significant psychomotor delay.

Bonneau et al. (2004) reported the eleventh case of anophthalmia/microphthalmia and esophageal atresia (AMEA). In her neonatal period, the proband had been operated on for type III esophageal atresia. At the age of 6 years, she received an ocular prosthesis for colobomatous microphthalmia of the right eye. The left eye was normal. No deletion of the SOX2 locus (184429), which had been implicated in anophthalmia/microphthalmia, was found; a search for SOX2 mutations was not performed.

Bardakjian and Schneider (2005) reported 3 unrelated boys and an unrelated girl with clinical anophthalmia/microphthalmia and esophageal atresia. All 3 boys had genital anomalies involving hypospadias and cryptorchidism, and 2 also had cardiac anomalies: 1 had a large ventricular septal defect and the other, patent ductus arteriosus and a patent foramen ovale. One boy had holoprosencephaly with marked dilation of the ventricles seen on head CT. Three of the 4 patients also had vertebral anomalies: 1 boy had underdeveloped vertebrae; a second boy had 2 ossified ribs on the right and 11 on the left and multiple vertebral anomalies between T3 and T8, including 2 hemivertebrae; and the girl had cervical hemivertebrae and T1-T7 hemivertebrae as well as 13 ribs. Although 1 patient was developmentally delayed, another had been valedictorian in high school and was attending college. Bardakjian and Schneider (2005) suggested that because the association of anophthalmia/microphthalmia and esophageal atresia is so rare and most cases have associated anomalies of the CNS, genitalia, and vertebrae as well as other systems, the entity might be better described as anophthalmia/microphthalmia and esophageal atresia with other associated malformations.

Hill et al. (2005) reported a female infant with right-sided clinical anophthalmia, esophageal atresia and tracheoesophageal fistula, and vertebral anomalies, including a T6 hemivertebra, T5 butterfly vertebra, fusion of the posterolateral third and fourth ribs, and fusion of S3 to S5 on the left sacrum. She had low-set ears with a slightly simple ear on the right, her fourth and fifth fingers overlapped the third fingers, and she had a right single palmar crease.

Morini et al. (2005) reported a female infant with pure esophageal atresia without tracheoesophageal fistula, bilateral clinical anophthalmia, and a patent ductus arteriosus. Microcephaly and mild developmental retardation were also observed.

Ragge et al. (2005) described the clinical features of 5 patients reported by Fantes et al. (2003) and 4 additional patients with bilateral clinical anophthalmia/microphthalmia. Extraocular features included mild facial dysmorphism, seizure disorder, global developmental delay, mesial temporal brain malformations, disordered muscle tone with evidence of mild basal ganglia dysfunction, growth failure, and male genital tract abnormalities. The authors noted that the neurologic features were relatively consistent but highly variable in severity.

Pedace et al. (2009) reported a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis. Ophthalmic examination confirmed the clinical anophthalmia/microphthalmia as well as congenital cataract; in addition, the patient had a depressed and widened nasal bridge and frontal bossing. Penile length was 2 cm, with normally descended testes. Brain MRI revealed that the right globe was virtually absent, whereas the left one was reduced in size with coloboma of the optic nerve. The hypothalamic-pituitary axis appeared normal, but there was bilateral dilatation of the temporal horns and hypoplasia of the hippocampus. Repeated endocrinologic evaluation and brain MRI in this patient did not reveal any morphologic or functional anomaly of the hypothalamic-pituitary axis.

Numakura et al. (2010) studied a 21-year-old Japanese man who had bilateral clinical anophthalmia, midface hypoplasia with a patulous lower lip, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability. Brain MRI showed a defect of the septum pellucidum and absence of the optic nerve, chiasm, and optic tract. In addition, the patient had difficulty with mastication, and mobility of the mandibular incisors as well as bilateral maxillary and mandibular deciduous molars were observed. Panoramic radiography revealed 9 unerupted teeth, including 5 premolars showing delayed eruption and 4 supernumerary impacted teeth. Noting that multiple supernumerary teeth are rare and usually associated with congenital malformation syndromes, Numakura et al. (2010) concluded that the supernumerary teeth in this patient were likely to be a manifestation of the SOX2 anophthalmia syndrome.

Cytogenetics

In a female infant with had bilateral clinical anophthalmia, congenital heart disease, and abnormal genitalia who died 45 hours after delivery, Chitayat et al. (1996) identified a terminal deletion of the long arm of chromosome 3 involving 3q27-qter.

In a female infant with bilateral clinical anophthalmia and a patent foramen ovale or small atrial septal defect on echocardiogram, and a male infant who was large for gestational age and had mild hypertelorism, severe bilateral microphthalmia, bilateral large colobomatous cysts, severe optic nerve hypoplasia, and bilateral sensorineural hearing loss, Driggers et al. (1999) and Kurbasic et al. (2000), respectively, reported de novo apparently balanced reciprocal translocations involving 3q27.

In 2 unrelated infants with clinical anophthalmia and microphthalmia who had constitutional deletions involving 3q27, Male et al. (2002) identified a 6.7-Mb minimum deleted region common to both patients at 3q26.33-q28. The male infant, who died at 40 days of age from respiratory failure, had multiple abnormalities including bilateral clinical anophthalmia, abnormalities of the first and second cranial nerves, partial absence of the corpus callosum, cleft palate and laryngeal cleft, 13 pairs of ribs, cleft odontoid peg, small penis with hypoplastic scrotum, and bilateral cryptorchidism. The female infant had right clinical anophthalmia and left microphthalmia. Both patients had intrauterine growth retardation with microcephaly and had strikingly similar dysmorphic facies consisting of bossed forehead, downward-slanting palpebral fissures, grooved bridge of the nose, prominent low-set ears, small downturned mouth, and small mandible.

Molecular Genetics

In the female infant reported by Driggers et al. (1999) with bilateral clinical anophthalmia and a de novo t(3;11)(q27;p11.2), Fantes et al. (2003) identified a submicroscopic deletion at the 3q breakpoint, containing the SOX2 gene. By subsequent SOX2 mutation analysis in 102 individuals with microphthalmia, clinical anophthalmia, or coloboma, they identified 3 heterozygous de novo truncating mutations in the SOX2 gene (184429.0001-184429.0003) in 4 unrelated individuals, 2 with bilateral clinical anophthalmia and 2 with unilateral clinical anophthalmia and contralateral microphthalmia. All 4 patients had associated extraocular abnormalities, including male genital tract abnormalities, myopathy, and spastic diplegia.

In 4 patients with bilateral clinical anophthalmia/microphthalmia, Ragge et al. (2005) identified heterozygous de novo mutations in the SOX2 gene, including a missense mutation (184429.0004) and 3 frameshift mutations.

In a 12-year-old girl with bilateral clinical anophthalmia and aplasia of the optic nerve, chiasm, and optic tracts, Hagstrom et al. (2005) identified heterozygosity for a de novo nonsense mutation in the SOX2 gene (184429.0005). The patient also had mild bilateral sensorineural hearing loss and global developmental delay.

In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay, Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion in the SOX2 gene (70del20; 184429.0010). The patient had frontal bossing and a broad nasal root, as well as congenital left hip dislocation. Orbital and brain CT scan demonstrated absence of eye globes, rudimentary optic nerves, partial agenesis of the corpus callosum, and marked cystic dilation of the third ventricle due to a suprasellar cyst.

Williamson et al. (2006) identified heterozygous loss-of-function mutations in the SOX2 gene (184429.0006-184429.0008) in 3 unrelated patients with microphthalmia and esophageal atresia: 1 was the original patient reported by Rogers (1988); another was the male infant described by Petrackova et al. (2004); and the third was a new case, a female infant with extreme bilateral microphthalmia, severe blepharophimosis, and esophageal atresia with distal tracheoesophageal fistula.

In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation, Faivre et al. (2006) identified heterozygosity for a missense mutation in the SOX2 gene (184429.0009). Cerebral MRI revealed a normal corpus callosum, ventricular diameter, and gray and white matter; ocular MRI showed empty orbits except for the presence of intraorbital muscles, and the optic nerve and chiasm could not be visualized. At 1 year of age, the patient could not sit unaided and expressed no sounds. Her unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated at 17 weeks' gestation due to severe hydrocephaly; the fetus was found to have a significantly increased occipitofrontal circumference, left cryptophthalmos and bilateral clinical anophthalmos, major dilation of the lateral and third ventricles with hypoplastic white matter and optic nerve agenesis, absence of the corpus callosum, and minor hypoplasia of the inferior cerebellar vermis.

Zenteno et al. (2006) described male monozygotic twin infants with esophageal atresia and a discordant ocular phenotype in whom they identified heterozygosity for the 70del20 mutation in the SOX2 gene. One twin had an irregular skull, facial asymmetry, left clinical anophthalmia, flat nasal bridge, retrognathia, low-set ears, bilateral cryptorchidism, and tracheoesophageal fistula. The other twin had normal ocular globes, narrowing of the right palpebral fissure, flat nasal bridge, normal genitalia, and tracheoesophageal fistula. Zenteno et al. (2006) stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia.

Kelberman et al. (2006) screened 235 probands with congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene and identified 6 patients with clinical anophthalmia or microphthalmia who had heterozygous de novo mutations (see, e.g., 184429.0001 and 184429.0010) and 2 patients with bilateral optic nerve hypoplasia who had heterozygous inherited mutations (see 184429.0012 and 184429.0013), One of the patients was a 13-year-old girl with bilateral clinical anophthalmia and a history of esophageal atresia who had previously been reported by Morini et al. (2005); she was found to be heterozygous for a 1-bp insertion in the SOX2 gene (184429.0011). In addition to bilateral eye defects, all patients with SOX2 mutations had various associated anomalies, including anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural hearing loss, and esophageal atresia.

In 2 female sibs, 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion in the SOX2 gene (184429.0014). The first sib had bilateral anophthalmia and esophageal atresia and died shortly after birth. During the mother's subsequent pregnancy, the fetus showed severe and progressive triventricular hydrocephalus on ultrasound, and the pregnancy was interrupted. Autopsy showed stenosis of the Sylvian aqueduct, hypoplasia of the corpus callosum, and 11 rib pairs, but normal external ocular examination and gestational age-appropriate ocular length. Extensive microscopic examination revealed no subtle anomaly of the ocular structures. The mother was found to have germinal mosaicism for the mutation, estimated at approximately 3%. Chassaing et al. (2007) concluded that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia.

In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies, Schneider et al. (2008) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0015). The younger sister's development was more advanced than her older sib at the same age, showing that differences in development can occur in sibs with the same SOX2 mutation. The younger sister also had hypothyroidism, which had not previously been reported in MCOPS3. The unaffected mother, who had 2 healthy older children, was found to have a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. Schneider et al. (2008) noted that this was the third report of a family in which an unaffected mosaic mother transmitted bilateral clinical anophthalmia to 2 female offspring (see Faivre et al., 2006 and Chassaing et al., 2007).

In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis, Pedace et al. (2009) analyzed the SOX2 gene and identified heterozygosity for a 2-bp insertion (184429.0016). The mutation was not detected in the patient's unaffected second-cousin parents or in his unaffected dizygotic twin, and was not found in 200 control chromosomes.

In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability, who was negative for mutation in the HESX1 gene (601802), Numakura et al. (2010) identified heterozygosity for a nonsense mutation in SOX2 (184429.0017). The patient also had a dental anomaly, consisting of multiple supernumerary impacted teeth and persistence of deciduous teeth. Although the role of SOX2 in dental development was as yet unknown, the authors considered the supernumerary teeth to be an extraocular symptom of the SOX2 anophthalmia syndrome.

Alatzoglou et al. (2011) reported 2 unrelated patients with bilateral clinical anophthalmia and nonprogressive pituitary tumors of early onset associated with SOX2 haploinsufficiency, due to heterozygosity for a 731-kb deletion on chromosome 3q26 encompassing SOX2 in 1 patient and a SOX2 nonsense mutation (F48X; 184429.0018) in the other. Alatzoglou et al. (2011) stated that this was the first time that SOX2 haploinsufficiency had been implicated in the generation of pituitary tumors. The patient with the deletion was born with bilateral clinical anophthalmia and had severely impaired language development and delayed motor milestones. She presented at 18 years of age with pubertal delay and was Tanner stage I with short stature on examination; endocrine evaluation revealed undetectable estradiol with low basal gonadotropins and flat luteinizing hormone (LH; 152780) and follicle-stimulating hormone (FSH: 136530) responses to GnRH (152760) stimulation, consistent with a diagnosis of hypogonadotropic hypogonadism. MRI revealed a sellar tumor with a cystic component, extending into the suprasellar area, with no evidence of compression syndrome. Hormone replacement therapy was declined, and at 24 years of age the patient developed spontaneous but incomplete puberty (breast Tanner stage 2). Repeat MRI at that time as well as sequential MR imaging over a 10-year period showed no significant change in size or morphology of the tumor, and there was no evidence of development of additional pituitary hormone deficiencies.

In an 8-year-old boy with bilateral clinical anophthalmia and endocrinologic abnormalities and his 8-month-old sister who had unilateral microphthalmia and retinal coloboma, Stark et al. (2011) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0019). Their mother, who was diagnosed with isolated hypogonadotropic hypogonadism (see 147950) and had undergone assisted reproduction to achieve fertility, was also heterozygous for the deletion. She had no dysmorphic features and a normal sense of smell, and ophthalmologic examination was normal. Sequencing results in the mother suggested possible mosaicism.

Genotype/Phenotype Correlations

Schneider et al. (2009) screened the SOX2 gene in 51 unrelated patients with clinical anophthalmia and/or microphthalmia and identified heterozygous SOX2 mutations in 10 of them, including 3 patients with the recurrent 20-bp deletion (70del20; 184429.0010). Analysis of all reported patients with SOX2 mutations suggested a potential genotype/phenotype correlation, with missense changes generally resulting in less severe ocular defects.