Endocrine Abstracts (2012) 29 P1110

Expanding the clinical and genetic spectrum of the reversal of congenital hypogonadotropic hypogonadism

E. Laitinen1,2, J. Tommiska1,2, T. Sane3, K. Vaaralahti1,2, J. Toppari4 & T. Raivio1,2

1University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; 2University of Helsinki, Helsinki, Finland; 3Helsinki University Central Hospital, Helsinki, Finland; 4University of Turku, Turku, Finland.

Introduction: Up to 10% of patients with congenital hypogonadotropic hypogonadism (HH) may undergo reversal of hypogonadotropism and some of them even attain normal sperm count in adulthood. However, clinical and molecular genetic features of these patients and the triggers leading to reversal of HH are not well understood. We studied whether Finnish reversal variants displayed a common phenotypic or genotypic feature that would predict the clinical course of HH.

Patients and methods: 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 years). 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.

Results: Six HH patients (2 KS, 4 nHH) were verified to have reversal of HH (median age, 23 years; range, 21–39 years). All of them 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 KS patients had a mutation in CHD7 (p.Q51X) or in FGFR1 (c.91+2T>A), two nHH patients were compound heterozygotes for mutations in GNRHR (R139H/R262Q and R262Q/del309F), while only two remained without a molecular genetic diagnosis.

Conclusions: Considerable proportion of patients with HH recovered in early adulthood. Spontaneous testicular enlargement during TRT was highly suggestive for reversal of HH, but we did not find phenotypic features that would have predicted reversal. However, those with the GNRHR mutation R262Q accompanied by another GNRHR mutation may be prone to reversal. Conversely, 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.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.

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