ESPEYB25 7. Puberty Clinical Guidance and Studies (8 abstracts)
7.4. Comprehensive study on central precocious puberty: molecular and clinical analyses in 90 patients
Hiromune N , Tomoe O , Hideaki Y , Keisuke N , Tatsuki U , Tomohiro S , Shun S , Saori K , Shinichiro S , Mitsukazu M , Shintaro T , Sumito D , Satoshi N , Yasuhiro N , Reiko H , Tsutomu O , Maki F & Masayo K
J Clin Endocrinol Metab. 2025 Mar 17;110(4):1023-1036. doi: 10.1210/clinem/dgae666. PMID: 39324648
Brief summary: This multicenter cohort study recruited 90 patients with idiopathic central precocious puberty (CPP) and normal brain MRI. Using molecular analyses (targeted sequencing, methylation analysis, and aCGH), the authors identified potential (epi)genetic causes in 12.2% of cases.
CPP can be associated with various pathogenic gene variants, as well as imprinting disorders such as Temple syndrome (TS14) or Silver-Russell syndrome (1). In this Japanese study, 90 patients with CPP (81 sporadic, 9 familial) underwent targeted sequencing of MKRN3, DLK1, MECP2, KISS1 and KISS1R, alongside methylation analysis to screen for associated imprinting disorders. 11 of 90 patients had identifiable (epi)genetic causes: 8 with TS14 (6 epimutations, 1 UPD(14)mat, 1 microdeletion) and 3 with MKRN3 defects (1 pathogenic variant, one deletion in the 5′-untranslated region, one microdeletion). Six of the 8 patients with TS14 were born small for gestational age (SGA) and presented with features such as short stature and hypotonia. All MKRN3-related cases had a paternal history of early puberty and low circulating MKRN3 levels. No pathogenic variants were identified in KISS1, KISS1R, or MECP2.
In conclusion, (epi)genetic testing for TS14 and MKRN3 defects should be considered in CPP patients born SGA or paternal familial CPP, respectively. TS14 can be underdiagnosed due to nonspecific clinical features (2), but genetic diagnosis is crucial for appropriate management and long-term follow-up. This study reinforces the importance of imprinted gene regulation in pubertal timing.
References: 1. Brito VN, Canton APM, Seraphim CE, et al. The congenital and acquired mechanisms implicated in the etiology of central precocious puberty. Endocr Rev. 2023;44(2):193-221.2. Ioannides Y, Lokulo-Sodipe K, Mackay DJ, Davie JH, Temple IK. Temple syndrome : improving the recognition of an underdiagnosed chromosome 14 imprinting disorder: an analysis of 51 published cases. J Med Genet. 2014;51(8):495-501.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
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