Reversible congenital hypogonadotropic hypogonadism in patients with CHD7, FGFR1 or GNRHR mutations.
BACKGROUND
Congenital hypogonadotropic hypogonadism (HH) is a rare cause for delayed or absent puberty. These patients may recover from HH spontaneously in adulthood. To date, it is not possible to predict who will undergo HH reversal later in life. Herein we investigated whether Finnish patients with reversal of congenital hypogonadotropic hypogonadism (HH) have common phenotypic or genotypic features.


RESULTS
Thirty-two male HH patients with anosmia/hyposmia (Kallmann Syndrome, KS; n = 26) or normal sense of smell (nHH; n = 6) were enrolled (age range, 18-61 yrs). The patients were clinically examined, and reversal of HH was assessed after treatment withdrawal. KAL1, FGFR1, FGF8, PROK2, PROKR2, CHD7, WDR11, GNRHR, GNRH1, KISS1R, KISS1, TAC3, TACR3, and LHβ were screened for mutations. Six HH patients (2 KS, 4 nHH) were verified to have reversal of HH. In the majority of cases, reversal occurred early in adulthood (median age, 23 yrs; range, 21-39 yrs). All had spontaneous testicular growth while on testosterone replacement therapy (TRT). One nHH subject was restarted on TRT due to a decline in serum T. Two reversal variants had a same GNRHR mutation (R262Q), which was accompanied by another GNRHR mutation (R139H or del309F). In addition, both of the KS patients had a mutation in CHD7 (p.Q51X) or FGFR1 (c.91+2T>A).


CONCLUSIONS
Considerable proportion of patients with HH (8% of KS probands) may recover in early adulthood. Spontaneous testicular enlargement during TRT was highly suggestive for reversal of HH. Those with the GNRHR mutation R262Q accompanied by another GNRHR mutation may be prone to reversal, although even patients with a truncating mutation in CHD7 or a splice-site mutation in FGFR1 can recover. We recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal.
Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Eeva-Maria
EM
Laitinen
Johanna
J
Tommiska
Timo
T
Sane
Kirsi
K
Vaaralahti
Jorma
J
Toppari
Taneli
T
Raivio
D000293:Adolescent; D000328:Adult; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005838:Genotype; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism / Q000151:congenital* / Q000235:genetics* / Q000628:therapy; D017436:Kallmann Syndrome / Q000235:genetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D011966:Receptors, LHRH / Q000235:genetics*; D055815:Young Adult
D004268:DNA-Binding Proteins; C484844:GNRHR protein, human; D011966:Receptors, LHRH; D051496:Receptor, Fibroblast Growth Factor, Type 1; D004265:DNA Helicases; C491434:CHD7 protein, human