SOX2 mutations cause bilateral anophthalmia in an autosomal dominant pattern in humans. Some extraocular features may be associated, including brain malformations, male genital tract malformations, postnatal growth retardation, and facial dysmorphic features. In addition seizures, motor abnormalities and learning disabilities can be present. We report here familial recurrence of a strikingly variable clinical presentation of the SOX2 phenotype in two girls. Both had a c.70_86del SOX2 mutation and their mother had germinal mosaicism. The phenotype of the first affected child has been previously reported [Menetrey et al., 2002]. Briefly, she presented at birth with short palpebral fissures and closed eyelids, with no palpable eyeball. CT scan and post-mortem necropsy confirmed bilateral anophthalmia. She had type III esophageal atresia, and diagnosis of AEG syndrome (Anophthalmia, Esophageal atresia, Genital abnormalities, MIM (206900) was made. During her mother's subsequent pregnancy, an ultrasound scan examination detected severe and progressive triventricular hydocephalus. The pregnancy was interrupted at the 20th week. Autopsy of the female fetus demonstrated stenosis of the aqueduct of Sylvius, associated with corpus callosum hypoplasia, and identified the presence of 11 rib pairs. No other malformations were identified. External ocular examination was normal, and ocular length (10 mm) corresponded to that of age-matched fetuses (Fig. 1a). Furthermore, extensive microscopic examination ruled out any subtle anomaly of the ocular structures (Fig. 1b). Blood karyotype was normal (RHG banding, 550 bands). a: Histological sections of one eye of the fetus with hydrocephaly. 1, Retina; 2, optic nerve; 3, anterior chamber; 4, lens; 5, ciliary process. No pathological abnormality was identified. The variable width of the peripheral retina is artefactual and due to a tangential cut of a twisted fragment of detached retina. The lens, which appears small, is only rotated and displaced and not well preserved. Lens epithelium is well identified and fibers are normal, although not well preserved. b: Microscopic view of the retina (×40). The retina displays typical fetal organization, with a sharply defined outer nuclear layer of photoreceptor cells (6), inner nuclear layer (7), inner plexiform layer (8), and ganglionic cell layer (9). We hypothesized that SOX2 would be a good candidate for AEG syndrome based on the observation of genital anomalies in male patients with anophthalmia identified with SOX2 mutations [Fantes et al., 2003]. SOX2 sequencing identified a c.70_86del mutation (p.Asn24_Ala29>GlyfsX66) present in both children but not in their parents. Microsatellite marker segregation study ruled out a sampling error. These results suggested germinal mosaicism which was evidenced in the mother's blood and buccal cell samples using semiquantitative capillary electrophoresis of fluorescent SOX2 PCR fragments encompassing the deleted region (Fig. 2). Mosaicism in the mother could be estimated at approximately 3%. Evidence of c.70_86del mutation using capillary electrophoresis of SOX2 PCR products labeled with one fluorescent primer. Two fragments of 380 bp (wild-type) and of 363 bp (deleted) are seen in the patient with AEG syndrome (a), only a wild-type fragment is seen in healthy control (b). A small amount of the 363 bp deleted allele is detected the unaffected mother (c), whereas none was identified in the healthy father (d). Wild-type allele shaded area indicates an off-scale peak (c and d). The AEG syndrome has been associated with SOX2 mutations in three unrelated individuals [Williamson et al., 2006]. We report another example of the association of a SOX2 mutation (c.70_86del) with AEG syndrome. Two closely related mutations, c.70_89del and c.67_89del, leading to a similar protein defect, have been associated with bilateral anophthalmia and brain anomalies, thus providing further evidence that AEG and SOX2 anophthalmia syndromes are different phenotypic expressions of the same molecular defect. The common SOX2-associated ocular phenotype is bilateral clinical anophthalmia [Fantes et al., 2003; Ragge et al., 2005]. We report here a patient carrying a SOX2 mutation lacking any macroscopic or microscopic detectable eye malformation, which to our knowledge has not previously been reported. SOX2 expression appears essential for lens induction and eye differentiation processes in experimental models [Kamachi et al., 1995, 1998]. Presence of normal eyes in the second patient of the family supports the hypothesis of normal early eye development despite SOX2 mutation. SOX2 is involved in multiple developmental pathways and its differential roles depend upon the tissues and time where the gene is expressed, and the combined role of other transcription factors [Yuan et al., 1995; Kamachi et al., 1998]. In addition, SOX2 paralogues of the B1 SOX group such as SOX1 or SOX3 have been demonstrated to rescue SOX2 deficiency in animal models [Koster et al., 2000; Overton et al., 2002; Blanco et al., 2005]. The multiple stages of expression of SOX2 and its possible redundancy with one or several SOX B1 proteins could explain the variable severity of the ocular involvement encountered in SOX2 mutant patients. Whatever the underlying mechanisms, this observation demonstrates that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia. Brain malformations are frequent in SOX2 anophthalmia syndrome, but are mainly represented by mesial temporal malformations and hydrocephalus is not a common feature. In the child reported here, hydrocephalus could be coincidental, but we suspect the SOX2 mutation is causative. In fact, the role of SOX2 has been investigated in mouse central nervous system development [Ferri et al., 2004]. In this model, compound heterozygous embryos with markedly reduced SOX2 expression consistently display brain malformations including lateral and third ventricle enlargement. In addition, heterozygous mice occasionally display slight ventricular enlargement. Corpus callosum partial agenesis or hypoplasia, which is described in the mouse model, has been previously reported in patients with anophthalmia [Petrackova et al., 2004; Zenteno et al., 2005] and may be part of the syndrome. Vertebral and rib malformations (including rib fusion, 11 rib pairs, hemivertebra, and butterfly vertebra) have previously been described in three patients with AEG syndrome [Imaizumi et al., 1999; Bonneau et al., 2004; Hill et al., 2005] and we conclude that this is also part of the SOX2 mutation phenotype. The siblings reported here manifested highly variable expressivity and extend the SOX2 malformation spectrum from normal ocular development to AEG syndrome. The absence of ocular malformations in one patient suggests an alternative pathway of eye development. The SOX2 mutation clinical spectrum should be further explored as most of the studies focused on syndromic and non-syndromic anophthalmia or microphthalmia. Extraocular findings argue for a “midline development defect”, including brain malformations, esophageal atresia and genital abnormalities. This is the second report of a familial recurrence of a SOX2 mutation caused by gonadal mosaicism [Faivre et al., 2006], and the possibility of germinal mosaicism should be kept in mind for genetic counseling. We suggest that prenatal diagnosis should be offered to families where a SOX2 mutation has been identified in a child. Authors are indebted to Sandra Ibos for technical assistance and to Jennifer Jampoc for help in preparing the manuscript. We thank Dr Marie Gonzalès for helpful advice in pathological examination.
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