Institute of Biomedicine/Physiology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
PLoS One. 2012;7(6):e39450. doi: 10.1371/journal.pone.0039450. Epub 2012 Jun 19.
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.
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).
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.
先天性低促性腺激素性性腺功能减退症（HH）是导致青春期延迟或缺失的罕见原因。这些患者在成年后可能会自发恢复 HH。迄今为止，无法预测谁会在以后的生活中发生 HH 逆转。在此，我们研究了具有先天性低促性腺激素性性腺功能减退症（HH）逆转的芬兰患者是否具有共同的表型或基因型特征。
纳入了 32 名嗅觉缺失/减退的男性 HH 患者（卡尔曼综合征，KS；n=26）或嗅觉正常的 HH 患者（nHH；n=6）（年龄范围 18-61 岁）。对患者进行临床检查，并在停止治疗后评估 HH 逆转情况。筛查了 KAL1、FGFR1、FGF8、PROK2、PROKR2、CHD7、WDR11、GNRHR、GNRH1、KISS1R、KISS1、TAC3、TACR3 和 LHβ 是否存在突变。6 名 HH 患者（2 名 KS，4 名 nHH）被证实 HH 逆转。在大多数情况下，逆转发生在成年早期（中位数年龄 23 岁；范围 21-39 岁）。所有患者在接受睾酮替代治疗（TRT）时均出现自发性睾丸生长。由于血清 T 下降，1 名 nHH 患者重新开始 TRT。2 名逆转变异患者具有相同的 GNRHR 突变（R262Q），同时伴有另一个 GNRHR 突变（R139H 或 del309F）。此外，2 名 KS 患者均存在 CHD7（p.Q51X）或 FGFR1（c.91+2T>A）突变。
相当比例的 HH 患者（KS 先证者的 8%）可能在成年早期恢复。TRT 期间自发性睾丸增大高度提示 HH 逆转。那些具有 GNRHR 突变 R262Q 并伴有另一个 GNRHR 突变的患者可能容易逆转，尽管即使是具有 CHD7 截断突变或 FGFR1 剪接位点突变的患者也可以恢复。我们建议所有先天性 HH 的青少年和年轻人都应被告知逆转的可能性。
