The Role of DLK1 Deficiency in Central Precocious Puberty and Association with Metabolic Dysregulation.

Introduction: Precocious puberty is defined as the appearance of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys. Central precocious puberty (CPP) is a rare condition that is diagnosed when premature activation of the hypothalamic-pituitary-gonadal axis is detected, in association with precocious breast development or testicular growth. Idiopathic CPP is historically considered to be the most common form, but in recent years defects in a small but growing number of genes regulating the timing of puberty have been identified in an increasing proportion of cases of CPP. Delta-like non-canonical Notch ligand 1 (DLK1) is understood to be one of the key genes involved in the etiology of CPP, although its mechanistic role is not yet fully understood.

Case Presentation: We identified a novel de novo variant of DLK1 (c.835C>T; p.Gln279*) in an 8-year-old girl of Bangladeshi origin. She presented with an advanced Tanner staging of B4P4A2, significantly advanced bone age (BA, 13 years), a near-adult proportioned uterus, with a history of menarche at the age of 7.4 years. Diagnosis was confirmed by raised basal luteinizing hormone concentration. She was found to have truncal obesity associated with abnormal fasting insulin levels and mildly elevated cholesterol levels. These findings are consistent with previous literature describing an association between patients with DLK1 deficiency and an impaired metabolic profile. The patient was treated for 2 years with GnRH agonists with ongoing biochemical follow-up into adolescence.

Conclusion: This case illustrates the susceptibility to metabolic derangement for patients with mutations in DLK1 and the need for ongoing monitoring after puberty. Our summary of previously identified DLK1 variants and their metabolic consequences demonstrates the frequency of obesity, lipid abnormalities, and insulin dysregulation in this patient cohort in childhood and beyond. This knowledge can guide future clinical practice for patients with CPP patients due to DLK1 deficiency.