SOX2 Heterozygous Mutations Cause Multiple Extraocular Phenotypes in Boys
The SRY-related high-mobility-group-box protein-2 (SOX2) is a critical transcription factor involved in early embryonic development. It is prominently expressed in the eye, placodes, forebrain, and hypothalamus-pituitary axis. Loss-of-function mutations or deletions in the SOX2 gene are well-known to cause uni- or bilateral anophthalmia/microphthalmia (A/M) and related disorders, such as anophthalmia/esophageal-genital syndrome. However, emerging evidence suggests that SOX2 mutations can also lead to a wide range of extraocular symptoms, including growth retardation, sensorineural hearing loss, intellectual disability, delayed puberty, and male genitourinary tract malformations such as micropenis, cryptorchidism, and hypospadias. While cases with SOX2 mutations and no or minor ocular symptoms are less frequently reported, this study highlights three Chinese boys with SOX2 mutations presenting primarily with genital abnormalities and craniofacial deformities, but without significant ocular malformations.
SOX2 and Its Role in Development
SOX2 is a key regulator of embryonic development, particularly in the formation of the eye, brain, and pituitary gland. Mutations in this gene have been associated with a spectrum of developmental disorders, ranging from severe ocular defects to isolated hypogonadotropic hypogonadism (HH). The phenotypic variability of SOX2 mutations underscores its pleiotropic effects on multiple organ systems. While the majority of reported cases exhibit major ocular deformities, a subset of patients presents with extraocular symptoms, including genital abnormalities, intellectual disability, and craniofacial dysmorphisms.
Case Presentations
This study reports three male patients referred to the endocrinology clinic due to micropenis and/or cryptorchidism, combined with craniofacial deformities or intellectual disability. All three patients underwent detailed clinical, hormonal, and genetic evaluations.
Patient 1
Patient 1 was first seen at 6 months of age with micropenis (2.3 cm in length and 1.2 cm in diameter) but no other physical or developmental abnormalities. Hormonal evaluations at 3.4 years of age revealed elevated anti-Mullerian hormone (AMH > 23.00 ng/mL), inhibin B (INHB 126.20 pg/mL), and testosterone (T 434 ng/dL) after a human chorionic gonadotropin (hCG) stimulation test. A luteinizing hormone-releasing hormone (LHRH) stimulation test at 3.5 years of age showed a normal pituitary response (peak LH/FSH ratio = 0.63). Genetic testing identified a heterozygous SOX2 mutation (p.T232N). The patient was treated with testosterone undecanoate for one month, resulting in significant penile growth (4 cm in length and 1.5 cm in diameter). Follow-up over 3.5 years revealed normal hearing, smell, and vision.
Patient 2
Patient 2, aged 2.6 years at the first visit, carried the same SOX2 mutation (p.T232N) as Patient 1. He presented with bilateral cryptorchidism and craniofacial deformities, including fanning ears, a low nasal bridge, a high palatal arch, a crooked mouth when crying, and a curved fifth finger. Hormonal evaluations indicated testicular dysplasia, with low baseline levels of LH (0.12 IU/L), FSH (0.34 IU/L), and testosterone (<20 ng/dL). At 3.2 years of age, the patient exhibited normal intelligence, hearing, smell, and vision, with no ocular abnormalities.
Patient 3
Patient 3 was first seen at 5 months of age with micropenis (1.0 cm in length and 0.6 cm in diameter), bilateral cryptorchidism, intellectual disability, and craniofacial deformities, including a sluggish face, flat nose, left ptosis, and high palatal arch. Hormonal evaluations revealed a normal pituitary response (peak LH/FSH ratio = 0.33) after an LHRH stimulation test. Genetic testing identified a de novo heterozygous nonsense mutation in SOX2 (p.Y110X). The patient exhibited normal hearing, smell, and vision, with no ocular abnormalities.
Genetic Findings and Pathogenicity
All three patients underwent next-generation sequencing (NGS) to identify genetic mutations. Patient 1 underwent panel sequencing of 167 genes involved in gonadal development, while Patients 2 and 3 underwent whole-exome sequencing. Sanger sequencing confirmed the mutations in family members. The mutations were classified as pathogenic based on the American Society of Medical Genetics and Genomics guidelines.
Patients 1 and 2 carried the same heterozygous mutation in SOX2 (p.T232N), located in the carboxy-terminal transcription activation region. This mutation was inherited from their mothers, who exhibited only delayed menarche. Patient 3 carried a de novo nonsense mutation (p.Y110X) in SOX2, which has not been previously reported, although a missense mutation at the same site (p.Y110C) has been associated with non-syndromic HH in a male patient.
Interestingly, all three patients also carried variants in other HH-related genes. Patient 1 inherited an FGFR1 variant (c.238C>T/p.R80C) from his father, Patient 2 had a de novo CHD7 mutation (c.2656C>T/p.R886W), and Patient 3 inherited a SEMA3A variant (c.1432G>A/p.E478K) from his mother. These additional genetic variants may contribute to the phenotypic variability observed in these patients.
Phenotypic Spectrum of SOX2 Mutations
Since the first report of SOX2 mutations in 2003, 123 cases have been documented, with a nearly equal distribution between males (52.3%) and females (47.7%). The age at presentation ranges from 20 weeks of gestation to 65 years. Among male patients, 43.9% exhibited genital abnormalities, including micropenis, cryptorchidism, and hypospadias.
The majority of patients with SOX2 mutations (91.1%) present with major ocular deformities. Extraocular symptoms include developmental delay/intellectual disability (40.7%), brain anomalies (28.5%), motor development delay (22.0%), male genital abnormalities (20.3%), short stature (17.1%), facial dysmorphism (12.2%), and non-syndromic HH (4.9%). The three patients in this study primarily exhibited genital abnormalities, craniofacial deformities, and intellectual disability, but no major ocular malformations.
Mutational Types and Inheritance Patterns
SOX2 mutations include frameshift (39.8%), deletion (22.0%), nonsense (19.5%), and missense (18.7%) mutations. The majority of mutations (72.6%) are de novo, while 15.1% are inherited from a parent with normal phenotypes. In rare cases, mutations are inherited from a parent with germinal mosaicism or abnormal syndromes.
In this study, the mutations in Patients 1 and 2 were inherited from their mothers, who exhibited only delayed puberty. Patient 3 had a de novo mutation, consistent with the broader pattern of SOX2 mutational inheritance.
SOX2 and Hypogonadotropic Hypogonadism
SOX2 mutations are known to cause pituitary hypoplasia, leading to low levels of LH and FSH, characteristic of HH. However, HH can also occur in patients without pituitary hypoplasia, suggesting that SOX2 mutations may disrupt gonadotropin-releasing hormone (GnRH) neuron migration or function. The three patients in this study exhibited normal pituitary imaging but had hormonal profiles suggestive of HH. Further follow-up is needed to confirm the diagnosis of isolated HH in these prepubertal patients.
Conclusion
SOX2 mutations are associated with a broad phenotypic spectrum, ranging from severe ocular malformations to isolated HH. This study highlights three male patients with SOX2 mutations presenting primarily with genital abnormalities and craniofacial deformities, but without significant ocular malformations. The presence of additional HH-related gene variants in these patients suggests a potential synergistic effect on the phenotype. These findings underscore the importance of considering SOX2 mutations in the differential diagnosis of patients with genital abnormalities and developmental disorders, even in the absence of ocular symptoms.
doi.org/10.1097/CM9.0000000000001805
Was this helpful?
0 / 0