MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis

Abstract

MKRN3 mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of MKRN3 mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evaluating MKRN3 mutations in patients with CPP were considered eligible. A total of 22 studies, studying 880 subjects with CPP, fulfilled the inclusion criteria. Eighty-nine subjects (76 girls) were identified as harboring MKRN3 mutations. Girls, compared with boys, exhibited earlier age at pubertal onset (median, 6.0 years; range, 3.0 to 7.0 vs 8.5 years; range, 5.9 to 9.0; P < 0.001), and higher basal FSH levels (median, 4.3 IU/L; range, 0.7 to 13.94 IU/L vs 2.45 IU/L; range, 0.8 to 13.70 IU/L; P = 0.003), and bone age advancement ( Δ BA; median, 2.3 years; range, −0.9 to 5.2 vs 1.2 years; range, 0.0 to 2.3; P = 0.01). Additional dysmorphisms were uncommon. A total of 14 studies evaluating 857 patients were included for quantitative analysis, with a pooled overall mutation prevalence of 9.0% (95% CI, 0.04 to 0.15). Subgroup analysis showed that prevalence estimates were higher in males, familial cases, and in non-Asian countries. In conclusion, MKRN3 mutations are associated with nonsyndromic CPP and manifest in a sex-dimorphic manner, with girls being affected earlier. They represent a common cause of CPP in western countries, especially in boys and familial cases.

Outcomes of Patients with Central Precocious Puberty Due to Loss-of-Function Mutations in the MKRN3 Gene after Treatment with Gonadotropin-Releasing Hormone Analog

“…In this study, the mean CA of pubertal onset was similar in patients with CPP due to MKRN3 mutations and in those with idiopathic CPP, confirming the data reported previously [31,32]. In contrast with our data, Simon et al [6] demonstrated that girls with CPP due to MKRN3 mutation were younger at puberty onset than those without MKRN3 mutation [6].…”

“…The longitudinal analysis of categorical BMI in both groups revealed similar evolution. This information was lacking in previous studies on MKRN3 mutations [32].…”

“…Whether or not the severity of MKRN3 mutation has any influence on the clinical and hormonal phenotype of CPP remains unknown. Valadares et al [32] showed that the age during diagnosis of CPP was significantly low in patients with severe MKRN3 mutations. The impact of the subtype of MKRN3 mutations on long-term followup of these patients was not evaluated in the present study because most of the patients (10/11) had severe mutations.…”

“…Long-acting GnRHas are the treatment of choice for CPP, and outcomes after treatment of idiopathic CPP have been described in several studies [3,10,30]. In contrast, long-term follow-up of patients with CPP due to loss-of-function mutations of MKRN3 after GnRHa withdrawal has not been reported so far [6,31,32]. In the present study, we have described the initial clinical and hormonal data of 29 female patients with CPP due to MKRN3 mutations and long-term follow-up of a subset group (11 patients), taking into consideration anthropometric, metabolic, and reproductive features.…”

“…A systematic review and meta-analysis on MKRN3 mutations concerning CPP, which was reported earlier, included 22 studies comprising 880 patients with CPP [32]; 89 (76 girls) of them had MKRN3 defects [32]; in the pooled comparative analysis of clinical and biochemical data between girls and boys, the authors reported significant differences in clinical (age at pubertal onset and at diagnosis) and hormonal (basal FSH) parameters, which is related to sex-dimorphic characteristics. Conversely, we compared data between female patients with and without MKRN3 mutations, and no clinical or laboratory parameter was indicative of harboring MKRN3 defects.…”