ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab. 2025 May 19;110(6):1570-1576. doi: 10.1210/clinem/dgae762. PMID: 39468766.

Brief summary: This longitudinal study evaluated changes in DLK1 serum levels in healthy girls during infancy and puberty. DLK1 was also measured in girls with central precocious puberty (CPP) before and after treatment with GnRH agonists (GnRHa)

DLK1 plays a critical inhibitory role in the Delta Notch pathway regulating reproductive and metabolic systems (1). Pathogenic variants in DLK1 have been found in children presenting CPP (2) but data regarding serum DLK1 levels changes during pubertal development in healthy girls or girls with CPP is scarce.

Median DLK1 levels were measured sequentially in healthy infant girls (n=85), in healthy peripubertal girls (n=15) and in girls with CPP before and after GnRHa treatment (n=15) from 3 Danish longitudinal cohorts. Median serum concentrations of DLK1 levels declined markedly through the first year of life (from 17.6 ng/ml to 9.9 ng/ml, P=0.02). Serum DLK1 levels were similar in girls in late infancy and before pubertal onset (10 ng/ml and 10.7 ng/ml, P=0.093). In girls with normal pubertal development, serum DLK1 levels decreased as puberty progressed. In girls with CPP, circulating DLK1 levels remained unchanged during treatment with GnRH. In the first available individual sample in infant girls (median age 44 days) and in healthy peripubertal girls (median age 9.4 years), DLK1 was inversely correlated with birthweight and body fat percentage.

This study demonstrates that DLK1 levels decline during infancy, remain stable in childhood, then decrease again with the onset of puberty, and continue to decrease throughout pubertal development. However, due to the high interindividual variability in DLK1 concentrations at the onset of puberty, it is not possible to establish a reliable cutoff level to distinguish between prepubertal and pubertal girls. Hence, DLK1 serum level is not a reliable diagnostic marker for puberty onset.

References: 1. Aguirre RS, Eugster EA. Central precocious puberty: From genetics to treatment. Best Pract Res Clin Endocrinol Metab. 2018 Aug;32(4):343-354.2. Montenegro L, Seraphim C, Tinano F, Piovesan M, Canton APM, McElreavey K, Brabant S, Boris NP, Magnuson M, Carroll RS, Kaiser UB, Argente J, Barrios V, Brito VN, Brauner R, Latronico AC. Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels. Eur J Endocrinol. 2023 Sep 1;189(3):422-428.