Comprehensive Study on Central Precocious Puberty: Molecular and Clinical Analyses in 90 Patients

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.

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

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 magnetic resonance imaging) and collected their clinical and laboratory data. We measured serum DLK1 levels in 3 patients with TS14 and serum MKRN3 levels in 2 patients with MKRN3 genetic defects, together with some etiology-unknown patients with CPP and controls.

We detected 8 patients with TS14 (6, epimutation; 1, mosaic maternal uniparental disomy chromosome 14; 1, microdeletion) and 3 patients with MKRN3 genetic defects (1, PV; 1, 13-bp deletion in the 5'-untranslated region [5'-UTR]; 1, 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).

(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.