ESPE2024 Poster Category 1 Pituitary, Neuroendocrinology and Puberty 1 (9 abstracts)
Comprehensive study on central precocious puberty: molecular and clinical analyses in 90 patients
Masayo Kagami 1 , Hiromune Narusawa 1,2 , Tomoe Ogawa 1 , Hideaki Yagasaki 2 , Keisuke Nagasaki 3 , Tatsuki Urakawa 1 , Tomohiro Saito 4 , Shun Soneda 5,6 , Shinichiro Sano 7 , Mitsukazu Mamada 8 , Shintaro Terashita 9 , Sumito Dateki 10 , Satoshi Narumi 1 , Yasuhiro Naiki 11 , Reiko Horikawa 11 & Tsutomu Ogata 12,13
1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan. 2Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan. 3Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan. 4Department of Pediatrics, Yamanashi Central Prefectural Hospital, Kofu, Japan. 5Tanaka Growth Clinic, Tokyo, Japan. 6Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan. 7Department of Pediatric Endocrinology and Metabolism, Shizuoka Children’s Hospital, Shizuoka, Japan. 8Department of Pediatrics, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan. 9Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan. 10Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 11Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan. 12Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. 13Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan
Background: Defects of MKRN3, DLK1, KISS1, and KISS1R and some disorders, such as Temple syndrome (TS14), cause central precocious puberty (CPP). Furthermore, MECP2 was reported as a causative gene for CPP in 2023. To our knowledge, comprehensive studies on (epi)genetic abnormalities, clinical features, and hormonal features in patients with CPP have not been reported.
Methods: In 90 CPP patients without histories of encephalitis or CNS lesions resulting in CPP, we conducted target sequencing for MKRN3, DLK1, MECP2, KISS1, and KISS1R, methylation analysis for screening of imprinting disorders such as Temple syndrome (TS14) and Silver-Russell syndrome leading to CPP, and collected their clinical and laboratory data. We measured serum DLK1 and MKRN3 levels in patients with TS14 and MKRN3 deficiency, respectively, and characterized the clinical features of TS14 and MKRN3 deficiency.
Results: We detected eight patients with TS14 and three female patients with MKRN3 deficiency and had no patients with SRS and gene mutations in KISS1, KISS1R, DLK1, and MECP2. Eight patients with TS14 consisted of six patients with epimutation, one with a mosaic maternal uniparental disomy chromosome 14, and one with a microdeletion including DLK1. Three patients with MKRN3 deficiency consisted of a rare pathogenic variant, a 13-bp deletion in the 5'-untranslated region (5'-UTR), and a deletion containing MKRN3 on a paternally inherited allele. The fathers had the same variants as their children on parental allele and showed early onset puberty. Serum MKRN3 level in a patient with a 13-bp deletion in 5'-UTR was lower than the minimal detectable concentrations. In a comparison of clinical features among CPP patients with TS14, MKRN3 deficiency, and unknown etiologies, patients with TS14 had rapid progression of secondary sexual characteristics. Patients with TS14 had lower median height-standard deviation scores than all CPP patients at initial evaluation, and six of them were born SGA.
Discussion: Among 90 patients with CPP, we identified eight patients with TS14 and three with MKRN3 deficiency. A certain percentage of the patients have (epi)genetic causes for CPP. We had no patients with MECP2 gene mutations. The differences in the detection rate of MECP2 gene mutation with a previous study may depend on the sample size, ethnicity, and other factors between our study and a previous study. For CPP patients born SGA or with a family history, including a father with early puberty, genetic testing for TS14, mutation screening, and/or copy number analysis encompassing MKRN3 should be considered.
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