Yi Wang1,2,3, Chunxiu Gong1,2,3, Miao Qin1,2,3, Ying Liu1,4, Yuanyuan Tian1,2,3. 1. National Center for Children's Health, Capital Medical University, Beijing, China. 2. Department of Endocrinology, Genetics, Metabolism and Adolescent Medicine, Beijing Children's Hospital, Capital Medical University, Beijing, China. 3. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Children's Hospital, Capital Medical University, Beijing, China. 4. Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Abstract
CONTEXT: The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH. DESIGN: The clinical and genetic features of patients with CHH were analysed, and the relationships between hypospadias, dual defects and genetics were investigated. PATIENTS: Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH. MEASUREMENTS: The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotrophin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism. RESULTS: Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS. Micropenis combined with cryptorchidism was the most common phenotype (39%). Approximately two-third of patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases (51%) of 51 patients were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, P = .021). CONCLUSIONS: Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics, and the coexistence of hypospadias does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nHH). Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects.
CONTEXT: The diagnosis of congenital hypogonadotropic hypogonadism (CHH) in prepuberty has always been challenging. Here, we aimed at studying the clinical and genetic features of paediatric CHH, especially the phenotype of hypospadias and dual defects (patients showing hypothalamic and/or pituitary defects and testicular hypoplasia), so as to have a better understanding of CHH. DESIGN: The clinical and genetic features of patients with CHH were analysed, and the relationships between hypospadias, dual defects and genetics were investigated. PATIENTS: Patients who visited Beijing Children's Hospital and were positively diagnosed with CHH. MEASUREMENTS: The collected data included sex hormones, MRI of the olfactory bulb, human chorionic gonadotrophin (hCG) test and genetic testing. We analysed clinical features and genetic results, especially hypospadias and dual defects, and compared the stimulated testosterone (T) levels in patients with and without cryptorchidism. RESULTS: Sixty-four patients were positively diagnosed, and forty-seven (73.4%) had Kallmann syndrome (KS). Four patients (6.3%) had hypospadias, including 2 KS. Micropenis combined with cryptorchidism was the most common phenotype (39%). Approximately two-third of patients showed a poor response to hCG; 15 cases were diagnosed with dual defects, and there were no significant differences between those with and without cryptorchidism. Twenty-six cases (51%) of 51 patients were identified as having classical HH mutations, affecting 10 different genes, with oligogenic mutations in 5 cases (9.8%). The most common mutations were in PROKR2 (17.6%), FGFR1 (13.7%) and CHD7 (7.8%). The frequency of PROKR2 mutations was higher in dual HH when compared to other HH cases (6/15 vs 3/36, P = .021). CONCLUSIONS:Micropenis and/or cryptorchidism can serve as important signs for the diagnosis of HH in paediatrics, and the coexistence of hypospadias does not exclude the diagnosis of CHH, including KS or normosmic isolated HH (nHH). Testicular function may be impaired earlier than expected, and PROKR2 mutations need to be evaluated to identify presumed dual defects.
Authors: Catarina Inês Gonçalves; Filipa Marina Patriarca; José Maria Aragüés; Davide Carvalho; Fernando Fonseca; Sofia Martins; Olinda Marques; Bernardo Dias Pereira; José Martinez-de-Oliveira; Manuel Carlos Lemos Journal: Sci Rep Date: 2019-02-07 Impact factor: 4.379
Authors: Tanja Kuiri-Hänninen; Jaakko Koskenniemi; Leo Dunkel; Jorma Toppari; Ulla Sankilampi Journal: Front Endocrinol (Lausanne) Date: 2019-07-23 Impact factor: 5.555