| Autor: |
Sugisawa C; Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Kanagawa 227-8501, Japan.; Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan., Taniyama M; Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Kanagawa 227-8501, Japan.; Division of Diabetes and Endocrinology, Department of Internal Medicine, Showa University School of Medicine, Tokyo 142-8555, Japan., Sato T; Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan., Takahashi Y; Division of Diabetes and Endocrinology, Department of Internal Medicine, Showa University School of Medicine, Tokyo 142-8555, Japan., Hasegawa T; Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan., Narumi S; Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan.; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. |
| Abstrakt: |
Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that causes gonadotropin-releasing hormone (GnRH) deficiency and sexual immaturity. CHH may accompany an abnormal sense of smell (Kallmann syndrome, KS) or no such manifestation (normosmic-CHH). This unusual combination of manifestations is explained by the fact that GnRH neurons originate in the olfactory placode and migrate to the forebrain during embryogenesis. We describe the case of a 31-year-old man with normosmic-CHH, who also had obesity, type 2 diabetes and intellectual disability. He was noticed to have sexual immaturity (small testes with no pubic hair) at age 20 years, when diabetic ketoacidosis developed. Basal and GnRH-stimulated levels of LH (1.0→12.0 IU/L) and FSH (1.9→6.1 IU/L) were detectable but low. The results of the T&T olfactometer and the Alinamin test were definitely normal, with an anatomically normal olfactory system on MRI. Sequencing of 22 CHH-related genes was performed, and compound heterozygous PROKR2 variants were identified: one was a previously known loss-of-function variant (p.Trp178Ser) and the other was a nonsense variant (p.Trp212*). Through a literature review, we found 22 patients (including our patient) with CHH due to biallelic PROKR2 variants, which led us to recognize that most of the patients (86%) were diagnosed with KS. Clinical observations in this study indicate that, even though they have CHH, biallelic PROKR2 variant carriers may have a normal olfactory system as well as presumably normal migration of GnRH neurons. This suggests that the PROK2-PROKR2 pathway affects the function of GnRH neurons after their migration. |
