ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This cross-sectional study identifies two pathogenic variants in the Delta-like noncanonical notch ligand 1 ( DLK1 ) gene in a French cohort of 121 children with idiopathic central precocious puberty (CPP).

DLK1 is a noncanonical ligand of the Delta Notch pathway known to be involved in adipocyte differentiation. Its hypothalamic expression suggests a potential role in coordinating reproductive and metabolic functions. Pathogenic variants in the DLK1 gene have been found in children presenting CPP^1,2. In this article, the authors hypothesized that measurement of the soluble form of DLK1 could offer a potential screening tool for patients with CPP.

121 French individuals with CPP (98 girls and 23 boys) had DNA sequenced for DLK1. Additionally, mean DLK1 serum levels were measured in 209 individuals (115 girls and 94 boys) from Brazilian and Spanish cohorts (18 with CPP and 191 with normal pubertal development). Translational experiments evaluated DLK1 levels at different stages of pubertal maturation in 5 female mice.

Two novel loss of function mutations in DLK1 were identified in two girls with non-syndromic CPP, inherited from their unaffected carrier father. Mean DLK1 levels were not different between patients with CPP and normal puberty (7.9±3.6 and 8.2±3 ng/mL, P=0.79). In children with normal pubertal development, serum DLK1 levels decreased across pubertal development with a sex specific pattern: in girls (n=97), DLK1 levels decreased from Tanner III to Tanner V while in boys (n=94), DLK1 levels decreased from Tanner II to V. No association was found between DLK1 levels and BMI SDS after linear regression analysis. In mice, serum DLK1 levels decreased gradually during pubertal maturation.

In summary, 2 novel mutations were described in DLK1 gene in two girls with CPP. In addition, the changes in DLK1 serum levels during puberty suggests a role for this factor in regulating pubertal development but do not help to distinguish between CPP and normal puberty.

References: 1. Andrew Dauber, Marina Cunha-Silva, Delanie B. Macedo, Vinicius N. Brito, Ana Paula Abreu, Stephanie A. Roberts, Luciana R. Montenegro, Melissa Andrew, Andrew Kirby, Matthew T. Weirauch, Guillaume Labilloy, Danielle S. Bessa, Rona S. Carroll, Dakota C. Jacobs, Patrick E. Chappell, Berenice B. Mendonca, David Haig, Ursula B. Kaiser, and Ana Claudia Latronico. Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty. J Clin Endocrinol Metab. 2017; 102(5): 1557–1567. 2. Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study. Luciana Montenegro, José I Labarta, Maira Piovesan, Ana P M Canton, Raquel Corripio, Leandro Soriano-Guillén, Lourdes Travieso-Suárez, Álvaro Martín-Rivada, Vicente Barrios, Carlos E Seraphim, Vinicius N Brito, Ana Claudia Latronico, Jesús Argente Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study. J Clin Endocrinol Metab. 2020; 105(10):dgaa461.