Within the physiological range, early pubertal timing is associated with an increased risk of mental health issues. Previous studies examining the associations of central precocious puberty (CPP) with mental health have yielded inconclusive results. To describe the risk for development of psychiatric disorders in patients with CPP and to identify periods during which patients with CPP are at heightened risk of developing psychopathological conditions. In this population-based, retrospective cohort study, patients with CPP and matched controls were identified from German health insurance data (approximately 6.5 million individuals) and followed from January 2010 to June 2023. Individuals were included if they had continuous insurance coverage for at least 2 years during the study period. Data were analyzed from July 2024 to March 2025. Diagnosis of CPP. Diagnosis of depression, anxiety disorders, oppositional defiant and conduct disorders (ODD/CD), and attention deficit/hyperactivity disorder (ADHD). Incidence rates for psychiatric disorders before and after the diagnosis of CPP were compared between patients and controls exactly matched for sex, birth year interval, insurance period, and obesity. After the application of validation criteria, 1094 patients with idiopathic CPP (438 born from 2010-2014 [40.0%]; 999 female [91.3%]; 249 [22.8%] with obesity) were identified and compared with 5448 controls (2184 born between 2010-2014 [40.1%]; 4975 female [91.3%]; 1242 with obesity [22.8%]). Compared with controls, patients with CPP were more likely to receive a diagnosis of any mental disorder (270 patients [24.7%] vs 920 controls [16.9%]; adjusted risk ratio [aRR], 1.48; 95% CI, 1.31-1.67), depression (82 patients [7.5%] vs 252 controls [4.6%]; aRR, 1.73; 95% CI, 1.37-2.20), anxiety disorders (88 patients [8.0%] vs 312 controls [5.7%]; aRR, 1.45; 95% CI, 1.16-1.82), ODD/CD (87 patients [8.0%] vs 243 controls [4.5%]; aRR, 1.76; 95% CI, 1.39-2.23), and ADHD (123 patients [11.2%] vs 397 controls [7.3%]; aRR, 1.53; 95% CI, 1.27-1.86). Temporal trends showed increased incidence rates for ODD/CD even before the diagnosis of CPP. For depression and ADHD, incidence rates remained increased for at least 8 years after the initial CPP diagnosis. In this retrospective cohort study of patients with CPP, CPP was associated with an increased risk of psychiatric disorders, with evidence supporting long-term mental health outcomes, suggesting that caretakers of children with CPP should be vigilant for the emergence of psychiatric symptoms to initiate psychiatric care at an early stage.

Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

Idiopathic central precocious puberty (ICPP) results from the premature reactivation of the hypothalamic-pituitary-gonadal axis leading to development of secondary sexual characteristics prior to 8 y in girls or 9 y in boys. Since the initial discovery of mutations in the maternally imprinted MKRN3 gene in 2013, several case reports have described mutations in this gene in ICPP patients from different populations, highlighting the importance of MKRN3 as a regulator of pubertal onset. We screened 29 Danish girls with ICPP for mutations in MKRN3. Expression of MKRN3 in human hypothalamic complementary DNA (cDNA) was investigated by PCR. One paternally inherited rare variant, c.1034G>A (p.Arg345His), was identified in one girl with ICPP and in her brother with early puberty. The variant is predicted to be deleterious by three different in silico prediction programs. Expression of MKRN3 was confirmed in adult human hypothalamus. Our results are in line with previous studies in which paternally inherited MKRN3 mutations have been found both in males and in females with ICPP or early puberty. Our report further expands the set of MKRN3 mutations identified in ICPP patients across diverse populations, thus supporting the major regulatory function of MKRN3 in pubertal onset.