Abstract
Background The SOX2 gene is widely expressed in the eyes and the central nervous system. Heterozygous mutations could cause eye malformations and hypopituitarism, and serve as the causative gene for syndromic and non-syndromic hypogonadotropic hypogonadism (HH). Our study reports three children with chromosome 46, XY, SRY (+), but SOX2 mutations.Methods Three children visited our endocrine clinic because of micropenis and/or cryptorchidism. Clinical data were collected, and one took PANEL sequencing and the others for whole exome sequencing. Then we summarized characteristics of the patients and compared with those mentioned in literature.Results Patient 1 manifested with micropenis, patient 2 with bilateral cryptorchidism and craniofacial deformities, both carrying the same reported SOX2 gene mutation (T232N), and both mutations from mothers with delayed puberty only. Patient 3 showed micropenis, mental retardation and craniofacial deformities, and the child carried a spontaneous truncation mutation (Y110X) of the SOX2 gene. This site has reported that a missense mutation caused adolescent adolescence without major eye signs. All three patients carried another gene mutations that affected hypothalamic-pituitary function: Patient 1, FGFR1: c.238C>T/p.R80C (uncertain) from father; Patient 2, CHD7: c.2656C>T/p.R886W (pathogenic) de novo; Patient 3, SEMA3A: c.1432G> A/p.E478K (uncertain) from mother. None had major ocular malformations, and all showed genitourinary tract malformations. Two patients had craniofacial deformities, and one patient had muscle anomality and intellectual disability. We summarized previous studies with SOX2 gene mutations and it showed: 71.2% of mutations are de novo, all patients reported whose variants inherit from parents, 15.1% parents (including mother 11.0% and father 4.1%) show completely normal phenotypes, 4.1% (3/73) variants inherit from mother with germinal mosaicism. Except for major ocular malformations (91.1%), the most common phenotype is developmental delay/mental retardation (DD/MR), accounting for 40.7%, followed by brain anomely (BA), accounting for 28.5%, male genital abnormalities (GA) for 20.3%, non-syndromic HH accounted for 4.9%, the younger the patients visit the doctor, the more common the retardation are. Conclusion SOX2 mutations could cause a broad phenotype spectrum from completely normal to severe ocular malformations, retardation and most mutations are de novo. Except for major ocular malformations and retardation, GA/HH is another common symptom. GA/HH may be the only symptom, and SOX2 may cooperate with another HH pathogenic genes to cause non-syndromic HH.
A clinical case of SYNGAP1, с2214_2217delTGAG de novo gene mutations in a girl with epilepsy, mental retardation, autism, and movement disorders