Hypothalamic dysfunction in a female with isolated hypogonadotropic hypogonadism and compound heterozygous TACR3 mutations and clinical manifestation in her heterozygous mother.
OBJECTIVE
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.


METHODS
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.
Fukami
Maki
M
Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan.
Maruyama
Tetsuo
T
Dateki
Sumito
S
Sato
Naoko
N
Yoshimura
Yasunori
Y
Ogata
Tsutomu
T
D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000235:genetics* / Q000503:physiopathology*; D007031:Hypothalamus / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D055815:Young Adult
D018042:Receptors, Neurokinin-3