Abstract:

BACKGROUND/AIMS: TAC3 and TACR3 have recently been shown to be causative genes for an autosomal recessive form of isolated hypogonadotropic hypogonadism (IHH). Here, we report a Japanese female with IHH and compound heterozygous TACR3 mutations and her heterozygous parents, and discuss the primary lesion for IHH and clinical findings.
CASE REPORT: This female was identified through mutation analysis of TAC3 and TACR3 in 57 patients with IHH. At 24 years of age, an initial standard GnRH test showed poor gonadotropin response (LH <0.2-0.6 IU/l), whereas the second GnRH test performed after GnRH priming (100 microg i.m. for 5 consecutive days) revealed ameliorated gonadotropin responses (LH 0.3-6.4 IU/l; FSH 2.2-9.6 IU/l). The mother exhibited several features suggestive of mild IHH, whereas the father showed an apparently normal phenotype.
RESULTS: She had a paternally derived nonsense mutation at exon 1 (Y145X) and a maternally inherited single nucleotide (G) deletion from the conserved 'GT' splice donor site of intron 1 (IVS1+1delG).
CONCLUSIONS: The results suggest hypothalamic dysfunction as the primary cause for IHH in patients with biallelic TACR3 mutations and clinical manifestation in heterozygous females, together with the rarity of TAC3 and TACR3 mutations in patients with IHH.

日本語要旨:

全国から集積した特発性ゴナドトロピン欠損症患者５７例のゲノムDNAを対象として変異スクリーニングを行い、１例のTACR3複合ヘテロ変異陽性患者を同定した。本患者は、両アリルに完全機能喪失変異を有する世界ではじめての症例であった。さらに患者の臨床像から、TACR3異常症の主体が視床下部機能障害であることが明確となった。