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. 2019 Mar 25;3(5):979-995.
doi: 10.1210/js.2019-00041. eCollection 2019 May 1.

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

Luciana Pinto Valadares  1 , Cinthia Gabriel Meireles  1 , Isabela Porto De Toledo  2 , Renata Santarem de Oliveira  3   4   5 , Luiz Cláudio Gonçalves de Castro  4 , Ana Paula Abreu  6 , Rona S Carroll  6 , Ana Claudia Latronico  7 , Ursula B Kaiser  6 , Eliete Neves Silva Guerra  2 , Adriana Lofrano-Porto  1   3
Affiliations

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

Luciana Pinto Valadares et al. J Endocr Soc. .

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 (ΔBA; 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.

Keywords: MKRN3; central precocious puberty; meta-analysis; systematic review.

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Figures

Figure 1.
Figure 1.
Flow chart for identifying eligible studies.
Figure 2.
Figure 2.
Structure of the MKRN3 human protein showing the location of the mutations in coding sequence identified to date. Notably, 36% (14 of 39) of mutations are located in the loop structure between 2 C3H1 zinc finger motifs in the aminoterminal region of the protein and these are almost all frameshift mutations, thereby affecting protein structure. The C3HC4 is the second domain where mutations tend to cluster; this area has mostly missense mutations.
Figure 3.
Figure 3.
Pooled overall prevalence of MKRN3 mutations in patients with central precocious puberty (9.0%; 95% CI, 0.04 to 0.15; I2, 80.91%; P = 0.00). ES, prevalence estimate.
Figure 4.
Figure 4.
Pooled prevalence of MKRN3 mutations among central precocious puberty patients from Asian (2.0%; 95% CI, 0.01 to 0.04; I2, 0.0%) and non-Asian countries (11.0%; 95% CI, 0.04 to 0.21; I2, 81.31%).
Figure 5.
Figure 5.
Pooled prevalence of MKRN3 mutations according to family history. The pooled prevalence of MKRN3 mutations in patients with familial CPP was 19.0% (95% CI, 0.05 to 0.36; I2, 69.16%). Considering the sporadic cases, the pooled estimates for prevalence was 2.0% (95% CI, 0.01 to 0.04; I2, 0%).
Figure 6.
Figure 6.
Pooled prevalence of MKRN3 mutations according sex. The prevalence of MKRN3 mutations in males was 22.0% (95% CI, 0.0 to 0.62; I2, 70.19) and in females 7.0% (95% CI, 0.03 to 0.13; I2, 77.73%).
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