Comprehensive study on central precocious puberty: molecular and clinical analyses in 90 patients

Hiromune Narusawa; Tomoe Ogawa; Hideaki Yagasaki; Keisuke Nagasaki; Tatsuki Urakawa; Tomohiro Saito; Shun Soneda; Saori Kinjo; Shinichiro Sano; Mitsukazu Mamada; Shintaro Terashita; Sumito Dateki; Satoshi Narumi; Yasuhiro Naiki; Reiko Horikawa; Tsutomu Ogata; Maki Fukami; Masayo Kagami

doi:10.1210/clinem/dgae666

Comprehensive study on central precocious puberty: molecular and clinical analyses in 90 patients

J Clin Endocrinol Metab. 2024 Sep 26:dgae666. doi: 10.1210/clinem/dgae666. Online ahead of print.

Authors

Hiromune Narusawa^{1

2}, Tomoe Ogawa¹, Hideaki Yagasaki², Keisuke Nagasaki³, Tatsuki Urakawa¹, Tomohiro Saito⁴, Shun Soneda^{5

6}, Saori Kinjo⁷, Shinichiro Sano⁸, Mitsukazu Mamada⁹, Shintaro Terashita¹⁰, Sumito Dateki¹¹, Satoshi Narumi¹, Yasuhiro Naiki¹², Reiko Horikawa¹², Tsutomu Ogata^{13

14}, Maki Fukami¹, Masayo Kagami¹

Affiliations

¹ Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
² Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan.
³ Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan.
⁴ Department of Pediatrics, Yamanashi Prefectural Central Hospital, Kofu, Japan.
⁵ Tanaka Growth Clinic, Tokyo, Japan.
⁶ Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.
⁷ Department of Pediatrics, Okinawa Chubu Hospital, Uruma, Japan.
⁸ Department of Pediatric Endocrinology and Metabolism, Shizuoka Children's Hospital, Shizuoka, Japan.
⁹ Department of Pediatrics, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
¹⁰ Department of Pediatrics, Faculty of Medicine, University of Toyama, Toyama, Japan.
¹¹ Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹² Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
¹³ Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
¹⁴ Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan.

PMID: 39324648
DOI: 10.1210/clinem/dgae666

Abstract

Context: Defects in MKRN3, DLK1, KISS1, and KISS1R and some disorders, such as Temple syndrome (TS14), cause central precocious puberty (CPP). Recently, pathogenic variants (PVs) in MECP2 have been reported to be associated with CPP.

Objective: We aimed to clarify the contribution of (epi)genetic abnormalities to CPP and clinical and hormonal features in each etiology.

Subjects and methods: We conducted targeted sequencing for MKRN3, DLK1, MECP2, KISS1, and KISS1R and methylation analysis for screening of imprinting disorders such as TS14 associated with CPP in 90 patients with CPP (no history of brain injuries and negative brain MRI) and collected their clinical and laboratory data. We measured serum DLK1 levels in three patients with TS14 and serum MKRN3 levels in two patients with MKRN3 genetic defects, together with some etiology-unknown patients with CPP and controls.

Results: We detected eight patients with TS14 (six, epimutation; one, mosaic maternal uniparental disomy chromosome 14; one, microdeletion) and three patients with MKRN3 genetic defects (one, PV; one, 13-bp deletion in the 5'-untranslated region (5'-UTR); one, microdeletion) with family histories of paternal early puberty. There were no patients with PVs identified in MECP2, KISS1, or KISS1R. We confirmed low serum MKRN3 level in the patient with a deletion in 5'-UTR. The median height at initial evaluation of TS14 patients was lower than that of all patients. Six patients with TS14 were born small for gestational age (SGA).

Conclusion: (Epi)genetic causes were identified in 12.2% of patients with CPP at our center. For patients with CPP born SGA or together with family histories of paternal early puberty, (epi)genetic testing for TS14 and MKRN3 genetic defects should be considered. (271/250).

Keywords: MECP2; MKRN3; Central precocious puberty; Imprinted genes; Imprinting disorders; Temple syndrome.

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