TY - JOUR
T1 - Digenic Congenital Hypogonadotropic Hypogonadism Due to Heterozygous GNRH1 p.R31C and AMHR2 p.G445_L453del Variants
AU - Stuckey, Bronwyn G.A.
AU - Jones, Timothy W.
AU - Ward, Bryan K.
AU - Wilson, Scott G.
PY - 2023/6
Y1 - 2023/6
N2 - A 28-year-old man with congenital hypogonadotropic hypogonadism (CHH) was found to be heterozygous for the GNRH1 p.R31C mutation, reported in the literature as pathogenic and dominant. The same mutation was found in his son at birth, but the testing of the infant at 64 days confirmed the hormonal changes associated with minipuberty. This led to further genetic sequencing of the patient and his son, which found a second variant, AMHR2 p.G445_L453del, in the heterozygous form, reported as pathogenic in the patient but not in his son. This suggests a digenic cause of the patient’s CHH. Together, these mutations are postulated to contribute to CHH by the lack of anti-Müllerian hormone (AMH) signalling, leading to the impaired migration of gonadotrophin releasing hormone (GnRH) neurons, the lack of the AMH effect on GnRH secretion, and altered GnRH decapeptide with reduced binding to GnRH receptors. This led us to the conclusion that the observed GNRH1 mutation in the heterozygous state is not certain to be dominant or, at least, exhibits incomplete penetrance and variable expressivity. This report also emphasises the opportunity afforded by the time window of minipuberty in assessing the inherited genetic disorders of hypothalamic function.
AB - A 28-year-old man with congenital hypogonadotropic hypogonadism (CHH) was found to be heterozygous for the GNRH1 p.R31C mutation, reported in the literature as pathogenic and dominant. The same mutation was found in his son at birth, but the testing of the infant at 64 days confirmed the hormonal changes associated with minipuberty. This led to further genetic sequencing of the patient and his son, which found a second variant, AMHR2 p.G445_L453del, in the heterozygous form, reported as pathogenic in the patient but not in his son. This suggests a digenic cause of the patient’s CHH. Together, these mutations are postulated to contribute to CHH by the lack of anti-Müllerian hormone (AMH) signalling, leading to the impaired migration of gonadotrophin releasing hormone (GnRH) neurons, the lack of the AMH effect on GnRH secretion, and altered GnRH decapeptide with reduced binding to GnRH receptors. This led us to the conclusion that the observed GNRH1 mutation in the heterozygous state is not certain to be dominant or, at least, exhibits incomplete penetrance and variable expressivity. This report also emphasises the opportunity afforded by the time window of minipuberty in assessing the inherited genetic disorders of hypothalamic function.
KW - AMHR2
KW - congenital hypogonadotropic hypogonadism
KW - GNRH1
KW - Kallmann syndrome
KW - minipuberty
UR - http://www.scopus.com/inward/record.url?scp=85164011186&partnerID=8YFLogxK
U2 - 10.3390/genes14061204
DO - 10.3390/genes14061204
M3 - Article
C2 - 37372384
AN - SCOPUS:85164011186
SN - 2073-4425
VL - 14
JO - Genes
JF - Genes
IS - 6
M1 - 1204
ER -