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Patients self-selected one of the 4 treatments: pulsatile Gonadorelin pump (PGP), cyclical gonadotropins therapy (CGT), human menopausal gonadotropin monotherapy, or testosterone replacement treatment. Clinical assessments were performed every 3 months for 3 years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Outcomes<\/jats:title><jats:p>The pathogenicity of variants was determined. Baseline clinical features, spermatogenesis outcomes were analysed.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>62 variants were identified in 51 patients (69.9%), 17 of which were novel. Among these mutations, variants on FGFR1, PROKR2, CHD7, ANOS1 and NSMF gene were 16.1%, 16.1%, 11.3%, 8.1% and 8.1% respectively. 11 patients followed the oligogenic pattern (21.6%). All CHD7 patients had hearing impairment or structural deformities of external\/inner ear, and were diagnosed as CHARGE syndrome. 24.7% of CHH patients manifested with ear\/hearing anomalies. KS patients had higher rates of cryptorchidism history and ear\/hearing anomalies than normosmic CHH subjects. Male patients with PROKR2 mutations showed relatively better testicular development, less dental deformity when compared with FGFR1 mutations. About 30% normosmic patients defined by simple olfactory assessment showed olfactory nerve center (ONC) dysplasia under nasal sinus MRI examination. Among the CHH males treated with CGT or PGP, 70.2% reached spermatogenesis within 3 years of treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Implications<\/jats:title><jats:p>No direct correlation was observed between certain responsible genes and spermatogenic outcomes. When CHH patients were identified with CHD7 variants, ear\/hearing evaluation should be carefully performed. The precise assessment of ONC development was advised for normosmic CHH subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Strengths &amp; Limitations<\/jats:title><jats:p>This study provided informative long-term treatment data of CHH male patients screened with whole exome sequencing. The limitations included small number of subgroups with multifaceted gene variants, clinical heterogeneity, and uncontrolled sperm-inducing treatment method. The seventeen novel mutations worth experimental validation in the future.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p>The clinical severity is partially related with specific gene variants, and detailed individualized data and outcomes were provided. Ear\/hearing anomalies were closely connected with CHD7 variants, and were common problems for CHH patients. Simple olfactory assessment underestimated the true olfactory deficit.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.jsxm.2021.07.001","type":"journal-article","created":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T10:59:41Z","timestamp":1627815581000},"page":"1500-1510","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic Profiles and Three-year Follow-up Study of Chinese Males with Congenital Hypogonadotropic Hypogonadism"],"prefix":"10.1093","volume":"18","author":[{"given":"Luyao","family":"Zhang","sequence":"first","affiliation":[{"name":"First Affiliated Hospital, Sun Yat-sen University , Guangzhou , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuting","family":"Gao","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital, Sun Yat-sen University , Guangzhou , 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