ESPE Abstracts

Background: Disorders of sex development (DSD) are often due to disruption of the genetic programs that regulate gonad development. Some genes have been identified in these developmental pathways such as DAX-1, SOX-9, GATA-4 and others. The GATA-4 gene, located on chromosome 8p23.1, encodes GATA-binding protein 4 (GATA-4), a transcription factor that is essential for cardiac and gonadal development and sexual differentiation. Congenital heart disease (CHD) and DSD can be isolated or combined. We report the case of an 8-year-old child with a DSD, central precocious puberty and GATA4 mutation without CHD.

Case Description: Second-born child of healthy non-consanguineous parents, born at term by CT after a normal pregnancy. Birth weight 3900 g, length 54 cm. In the second month of life testosterone therapy was administered for 3 months because of micropenis (1,5x1 cm). At 2 years old, orchidopexy was performed for bilateral cryptorchidism. After 6 years he came back under our observation for increase of sexual pubic hair (pubarche). Auxological parameters: height 147 cm (+2,95 SDS), weight 42 kg (+2,21 SDS), bone age 11.25 yrs vs 8 yrs of chronological age. Physical examination showed hyperthelorism and singular cafe-au-lait macule in abdominal seat. At the GnRH test, the LH peak was 74.7 mIU/ml and we found elevated IGF1, testosterone, LH and FSH basal levels. Testicular volumes were 1 ml at ultrasonography. Pituitary MRI was normal. No organ pathology was detected in echocardiography and thyroid ultrasonography. Precocious puberty was then detected and GnRHa treatments was started, even if the elevation of gonadotrophins to GnRH test could suggest a future diagnosis of hypergonadotropic hypogonadism. So, we decided to perform genetic tests for DSD. Chromosome analysis revealed a 46, XY karyotype. Array-CGH study identified a de novo 815 Kb micro-deletion in 2q34 region that interests a part of ERBB4 gene, not described as associated with DSD and precocious puberty. NGS genetic investigation showed heterozygous variant c.671CG (p.Ser224Cys) in GATA-4 gene. According to The American College of Medical Genetics and Genomics, the latter variant was probably pathogenetic.

Conclusions: The variant c.671CG in GATA-4 gene has not been previously associated with DSD. In addition, a peculiarity of this case is the finding of a clinical pattern compatible with central precocious puberty despite the lack of increased testicular volume. To the best of our knowledge, this is the first case of a DSD due to GATA-4 mutation that develops precocious puberty.