Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys

Abstract

Background: Congenital hypogonadotrophic hypogonadism (CHH) and Kallmann syndrome (KS) are caused by disruption to the hypothalamic-pituitary-gonadal (H-P-G) axis. In particular, reduced production, secretion or action of gonadotrophin-releasing hormone (GnRH) is often responsible. Various genes, many of which play a role in the development and function of the GnRH neurons, have been implicated in these disorders. Clinically, CHH and KS are heterogeneous; however, in 46,XY patients, they can be characterised by under-virilisation phenotypes such as cryptorchidism and micropenis or delayed puberty. In rare cases, hypospadias may also be present.

Results: Here, we describe genetic mutational analysis of CHH genes in Indonesian 46,XY disorder of sex development patients with under-virilisation. We present 11 male patients with varying degrees of under-virilisation who have rare variants in known CHH genes. Interestingly, many of these patients had hypospadias.

Conclusions: We postulate that variants in CHH genes, in particular PROKR2, PROK2, WDR11 and FGFR1 with CHD7, may contribute to under-virilisation phenotypes including hypospadias in Indonesia.

Keywords: Congenital hypogonadotrophic hypogonadism; Disorder of sex development; Hypospadias; Targeted gene sequencing; Under-virilisation.

Fig. 1

Under-virilisation in patients with CHH gene variants. a–d Representative images of external genitalia for four patients presenting with 46,XY DSD (see Table 1 for details)

Fig. 2

Novel variants in CHH genes. Just one novel variant in PROKR2 was found (p.W352G). This change found in patient 171, c.T1054G:p.W352G, is heterozygous and has good quality and depth (a). This change falls on a highly conserved residue (b) and lies within the cytoplasmic tail of this transmembrane receptor (c). Three novel variants in WDR11 were found in our cohort—all of which affect a highly conserved residue (d)