Gene Mutations Detection、Clinical Analysis And Treatment With Idiopathic Hypogonadotropic Hypogonadism

BACKGROUND：Idiopathic hypogonadotropic hypogonadism （IHH） is a rarecongenital disease. Hypogonadism is due to gonadotropin releasing hormone （GnRH）deficiency resulting probably from neurons of GnRH migration failure duringembry-onic development, which could mainly results delayed puberty, adults areinfertile，the patients may also manifest a variety of other nonreproductive disorderssuch as osteoporosis, renal agenesis, cardiovascular disease, etc. The patients couldrecover normal physiological characteristics and return to gonadal function by meansof hormone replacement therapy. It has been known that more than10genescontribute to the mutations in the basic research of IHH. IHH may be inherited asX-linked recessive, autosomal dom-inant, or autosomal recessive modes. Throughsuch treatment patients may resume undeveloped physiologicalcharacteristics.Exploring the genetic characteristics of Idiopathic Hypogon-adotropicHypogonadism through the detection of KAL1and Fibroblast Growth FactorReceptor1Gene in Patients with IHH and analysing the family of the patients withmutation. Retrospectively analyzed the treatment results. which could provideimportant basis for prognosis and genetic counseling.METHODS：The objects were96cases of male patients with IHH in the ClinicalHospital of Jilin University from June2009to September2011.Besides that,80casesof normal male were collected as the control group, who are normal male volunteers.The history-taking of the object through questionnaire and physical examination.Detecting the karyotype and serum reproductive hormone levels of the objects.Testing serum reproductive hormone level and karyotype on the objects,Thepolymerase chain reaction-single strand conformation polymorphism （PCR-SSCP）technology combined with PCR product direct sequencing technique could be appliedin the peripheral blood taken in the research objects in order to analyze the KAL1andFGFR1gene exon mutation of IHH patients. The same detection applied in the familyof patients with mutation after taking their consent. Combinating therapy of human chorionic gonadotropin （HCG）, human menopausal gonadotropin （HMG） andtestosterone undecanoate is conducted in60patients in those objects. The treatmenteffect is determined by testicular volume, serum reproductive hormonelevels and semen.RESULTS：The KAL1gene of the96patients with IHH have been detected,then2cases of frameshift mutation and one case of nonsense mutations were found.Abnomal exon was not found in the80cases of controls. Three cases of mutations arec.1886₁887delTT, c.1270C>T and c.279₂80delAG. All of above are KS patients,the mutation rate is3.1﹪（3/96）, the mutation rate of KS is7.3﹪（3/41）.The FGFR1gene of the96patients with IHH have been detected, then threecases of missense mutations were found. Abnomal exon was not found in the80casesof controls. The three cases of mutations are c.569G>C, c.709G>A and c.346G>A.All of above are heterozygous mutation, the mutation rate is3.1﹪（3/96）, themutation rate of KS is4.8﹪（2/41）, the mutation rate of nIHH is1.8﹪（1/55）.The polymerase chain reaction-single strand conformation polymorphism（PCR-SSCP） technology combined with PCR product direct sequencing techniquecould be applied in the peripheral blood taken in the six family of patients withmutation in order to analyze the KAL1and FGFR1gene exon mutation of IHHpatients. In family1we found there is a heterozygous frameshift mutation1886₁887delTT （p.L629fs） in the13th exon of KAL1gene in the mother ofpropositus1, frameshift mutation1886₁887delTT （p.L629fs） in the13th exon ofKAL1gene in the brother of propositus1, also in the mother’s younger male cousin;there is a heterozygous point mutations c.C1270T （p.Arg424ter）in the9th exon ofKAL1gene in the mother of propositus2; there is a heterozygous frameshift mutationc.279₂80delAG （p.G94fs） in the3rd exon of KAL1gene in the mother of propositus3; Gene mutation were not found in family4to family6.CONCLUSIONS：1. The Y chromosome polymorphism may not be the cause of KS clinicalperformance.2. The mutation rates of this study in KAL1gene and FGFR1gene are lowerthan those reported abroad.3. Three families of patients with mutation in KAL1gene have been collected. The families have the same mutations in the same place, according to their geneticlineage, such suggestion can be made that patients and their family members with thesame gene mutation originate from a common maternal ancestor. If IHH or KS whoserelatives are affected with hypogonadism symptoms, it is suggested that genemutations detection should be conducted as early as possible in order to consider aclinical diagnosis.4. Three family of patients with mutation in FGFR1gene have been collected.There is no gene mutation in the three families, which suggests that the vastmajority of IHH patients with mutation in FGFR1gene showed clinically sporadic,only a small number of familial.5. IHH patients to treatment at24months, patients reproductive hormone levelsand secondary sexual characteristics will improve significantly. Suggesting thatpatients with IHH should attach great importance to early treatment. and the firstcourse of treatment should last for at least24months, which will help prognosis.