A homozygous R262Q mutation in the gonadotropin-releasing hormone receptor presenting as constitutional delay of growth and puberty with subsequent borderline oligospermia.
BACKGROUND
The GnRH receptor plays a central role in regulating gonadotropin synthesis and release, and several mutations in the GNRHR gene have been reported in patients with idiopathic or familial forms of isolated hypogonadotropic hypogonadism (IHH).


OBJECTIVE
The objective of the study was to investigate whether partial loss-of-function mutations in the GnRH receptor might be responsible for delayed puberty phenotypes.


METHODS
Patients included sibling pairs with delayed puberty (n = 8) or those in whom one brother had delayed puberty and another had hypogonadotropic hypogonadism (n = 3).


METHODS
Methods included mutational analysis of the GNRHR gene.


RESULTS
A homozygous R262Q mutation in the GnRH receptor was identified in two brothers from one family. In this kindred, the proband presented at 15 yr of age with delayed puberty. After a short course of testosterone, he seemed to be progressing through puberty appropriately and was discharged from follow-up. His younger brother was also referred with delayed puberty but showed little progress after treatment. Frequent sampling revealed detectable but apulsatile LH and FSH release. His clinical progress was consistent with IHH, and he requires ongoing testosterone replacement.


CONCLUSIONS
Homozygous partial loss-of-function mutations in the GnRH receptor, such as R262Q, can present with variable phenotypes including apparent delayed puberty. Ongoing clinical vigilance might be required when patients are discharged from follow-up, especially when there is a family history of delayed puberty or IHH because oligospermia and reduced bone mineralization can occur with time.
Lin
Lin
L
Institute of Child Health and Department of Medicine, University College London, UK.
Conway
Gerard S
GS
Hill
Nathan R
NR
Dattani
Mehul T
MT
Hindmarsh
Peter C
PC
Achermann
John C
JC
D000293:Adolescent; D004252:DNA Mutational Analysis; D005640:Follicle Stimulating Hormone / Q000097:blood; D006130:Growth Disorders / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008954:Models, Biological; D009154:Mutation; D009845:Oligospermia / Q000235:genetics*; D011628:Puberty, Delayed / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics*; D013739:Testosterone / Q000097:blood
D011966:Receptors, LHRH; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone