Genotype–Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations

Abstract

Context Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Methods Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusion Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty

“…The two boys presented with testicular enlargement (testicular size of more than 5 ml) and Tanner stage 2 of puberty before the age of 9 years. Results from the present, in conjunction with previous studies from our group (14,34), indicated that pathogenic (Table 2) or variants of uncertain significance (VUS) (Table 3) in the MKRN3 gene are the most prevalent cause of CPP in our cohort of Cypriot patients, in line with the current published literature (12). The MKRN3 p.Gly312Asp pathogenic variant, first reported in 2016 by Neocleous et al (14), was the most predominant genetic defect (seven cases) of the present study, followed by the previously reported p.Met268ValfsTer23 pathogenic variant identified in four cases (25) (Table 2).…”

“…At this time, genetic aberrations associated with the Makorin Ring Finger Protein 3 (MKRN3) gene are the leading genetic etiology of CPP (9). Since the groundbreaking discovery of loss-of-function mutations in the MKRN3 gene (11), numerous other studies followed and reported more than 40 novel variants, including missense, nonsense, and frameshift mutations in MKRN3 across families with CPP in a broad spectrum of geographical regions (9,12). MKRN3 gene is located in the Prader-Willi syndrome (PWS)-related region (15q11-q13) on chromosome 15.…”

An Approach to the Evaluation and Management of the Obese Child With Early Puberty

“…Researchers have investigated the inter-relationship among obesity, CPP, and some of these genetic causes. Obesity has not been shown to be associated (positively or negatively) with MKRN3 mutations, the most common monogenic cause of CPP [ 113 , 114 ]. However, obesity is a common finding among children with DLK1 mutations [ 115-118 ].…”

Response to Letter to the Editor from De Zegher and Ibanes: On the rising incidence of early breast development

“…Patients with such 'organic' forms of CPP have a moderately high BMI SDS at CPP diagnosis, similar to that of patients with isolated forms of CPP (6,7,8). In addition, studies of patients with monogenic CPP due to makorin RING finger protein 3 (MKRN3) loss of function, affecting the regulation of the hypothalamopituitary-gonadal axis, have also been reported to have a BMI SDS at the presentation that is moderately high and similar to that of patients with isolated and idiopathic CPP (9,10).…”