DLK1 and Central Precocious Puberty

Central precocious puberty (CPP) is characterized by premature activation of the hypothalamic-pituitary-gonadal axis leading to early secondary sexual development. While mutations in the imprinted MKRN3 gene are the most common monogenic cause, loss-of-function defects in the paternally expressed Delta-like homolog 1 (DLK1) have emerged as a definitive etiology of familial and sporadic CPP. DLK1 regulates neurogenesis and adipogenesis, linking pubertal timing with metabolic homeostasis.

Genetic Evidence

Multiple unrelated families have been reported with paternally inherited DLK1 deletions or truncating variants leading to nonsyndromic CPP. A 14-kb paternal deletion encompassing the DLK1 5′ UTR and first exon co-segregated with CPP in five affected females across a multigenerational kindred (PMID:28324015). A recurrent frameshift, c.479delC (p.Pro160fsTer50), was identified in a father–son pedigree in China (PMID:36353763). Additional de novo nonsense variants such as c.835C>T (p.Gln279Ter) have been described in isolated cases (PMID:39419009) as well as stop-gain alleles c.2T>G (p.Met1Arg) and c.372C>A (p.Cys124Ter) in French cohorts (PMID:37703313). Segregation analyses consistently confirm paternal inheritance, in line with DLK1 imprinting.

Variant Spectrum and Segregation

DLK1 variants include large deletions, frameshift (c.479delC (p.Pro160fsTer50)), and nonsense mutations distributed across the gene. These defects result in undetectable serum DLK1 levels in affected individuals and absence of additional Temple syndrome features aside from increased adiposity (PMID:28324015; PMID:30462238). Affected_relatives demonstrate autosomal dominant transmission with paternal parent-of-origin expression, with at least five relatives showing cosegregation per kindred.

Functional Evidence

DLK1 mRNA and protein are expressed in mouse hypothalamus and kisspeptin-secreting neuronal cells, supporting a neuroendocrine role in pubertal initiation. In vitro assays show that DLK1 loss-of-function disrupts adipocyte differentiation and gonadotropin-releasing hormone regulation, mirroring the human CPP and metabolic phenotype (PMID:10234807; PMID:31972862).

Integration and Clinical Utility

Collectively, DLK1 loss-of-function variants form a definitive cause of CPP. The genetic and functional data establish haploinsufficiency of paternally expressed DLK1 as a key pathogenic mechanism. Detection of truncating or deletion variants facilitates genetic diagnosis, informs recurrence risk counseling, and guides early intervention with GnRH agonist therapy to optimize adult height. Measurement of serum DLK1 can serve as a biomarker for variant pathogenicity and metabolic monitoring.

Key Take-home: DLK1 mutations cause paternally inherited CPP with associated metabolic derangements; genetic testing and serum DLK1 assays enhance diagnostic precision and management planning.

References

• The Journal of clinical endocrinology and metabolism • 2017 • Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty PMID:28324015
• Molecular genetics & genomic medicine • 2022 • Chinese familial central precocious puberty with hyperuricemia due to recurrent DLK1 mutation: Case report and review of the literature PMID:36353763
• Hormone research in paediatrics • 2024 • The Role of DLK1 Deficiency in Central Precocious Puberty and Association with Metabolic Dysregulation PMID:39419009
• European journal of endocrinology • 2023 • Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels PMID:37703313
• The Journal of clinical endocrinology and metabolism • 2019 • DLK1 Is a Novel Link Between Reproduction and Metabolism PMID:30462238
• Seminars in reproductive medicine • 2019 • DLK1, Notch Signaling and the Timing of Puberty PMID:31972862

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