Genetic factors of idiopathic central precocious puberty and their polygenic risk in early puberty

2021 ◽  
Author(s):  
Wei-De Lin ◽  
Chi-Fung Cheng ◽  
Chung-Hsing Wang ◽  
Wen-Miin Liang ◽  
Chien-Hsiun Chen ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Pubertal Timing ◽  
Central Precocious Puberty ◽  
P Value ◽  
Validation Group ◽  
Early Puberty ◽  
Genetic Characteristics ◽  
Polygenic Risk ◽  
Idiopathic Central Precocious Puberty ◽  
Group A

Objective: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. Design and methods: A bootstrap subsampling and genome-wide association study was performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. Results: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner [validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio [OR] = 5.00, 95% confidence interval [CI]: 1.5516.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.4455.83)]. Conclusions: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identify of individuals with a potential genetic risk of early puberty.

Effect of GnRHa 3.75 mg subcutaneously every 6 weeks on adult height in girls with idiopathic central precocious puberty

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Yan Liang ◽  
Hong Wei ◽  
Jie Li ◽  
Ling Hou ◽  
Jianling Zhang ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Adult Height ◽  
Recombinant Human Growth Hormone ◽  
Central Precocious Puberty ◽  
Healthy Children ◽  
Idiopathic Central Precocious Puberty ◽  
Significant Difference ◽  
Group A ◽  
Group B ◽  
Age Of Menarche

AbstractTo evaluate the long-term efficacy of triptorelin 3.75 mg subcutaneously every 6 weeks on the final height in girls with idiopathic central precocious puberty (ICPP).Forty females with ICPP received triptorelin 3.75 mg every 6 weeks subcutaneously in our hospital from 2002 to December 2010 and reached their final heights were enrolled. These patients were treated with triptorelin alone (group A, n=17) or triptorelin+recombinant human growth hormone (rhGH) (group B, n=23). Height, weight, annual growth velocity (GV), sexual development, predicted adult height (PAH), and adverse effects were observed. Bone age (BA) and height standard deviation score (SDS) were monitored yearly.Final adult heights (FAHs) were 159.81±1.20 cm and 161.01±1.02 cm in group A vs. group B, which exceeded target height (THt) by 1.51±1.04 cm, 4.86±0.94 cm, respectively. The values of (FAH-THt), (FAH-PAH posttreatment) showed significant difference between the two groups (p<0.05). FAH was positively correlated with Ht SDS-BA at the end of treatment, THt, course of rhGH treatment, and age of menarche (r2=0.66). Body mass index (BMI) increased after treatment in group B. However, there was no significant tendency of increase compared with healthy children at the same age. Ages of menarche and time to menarche from discontinuation were 11.74±0.16 vs. 12.18±0.15 years and 17.41±1.69 vs. 14.71±1.04 months in two groups.The FAH was improved effectively by triptorelin 3.75 mg subcutaneously every 6 weeks, and more height gain could be achieved when rhGH was used concomitantly. BMI maintained steadily and ovarian function restored quickly after treatment discontinuation with the age of menarche similar to that of normal children. Neither significant side effect nor polycystic ovary syndrome was observed.

scholarly journals GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes

2020 ◽  
Vol 183 (4) ◽  
pp. R107-R117
Author(s):  
Stephanie A Roberts ◽  
Ursula B Kaiser
Keyword(s):  
Precocious Puberty ◽  
Pubertal Timing ◽  
Association Studies ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Imprinted Genes ◽  
Genome Wide Association Studies ◽  
Early Puberty ◽  
Imprinted Gene

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader–Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

scholarly journals Central Precocious Puberty in a Girl and Early Puberty in Her Brother Caused by a Novel Mutation in the MKRN3 Gene

2014 ◽  
Vol 99 (4) ◽  
pp. E647-E651 ◽  
Author(s):  
Nikolaos Settas ◽  
Catherine Dacou-Voutetakis ◽  
Maria Karantza ◽  
Christina Kanaka-Gantenbein ◽  
George P. Chrousos ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Novel Mutation ◽  
Structural Alignment ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Central Precocious Puberty ◽  
Dimensional Structure ◽  
Sex Characteristics ◽  
Coding Region ◽  
Early Puberty

Context: Central precocious puberty (CPP), defined as the development of secondary sex characteristics prior to age 8 years in girls and 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal axis. Mutations in the imprinted gene MKRN3 have been recently implicated in familial cases of CPP. Objective: The objective of the study was to uncover the genetic cause of CPP in a family with two affected siblings. Design and participants: The entire coding region of the paternally expressed MKRN3 gene was sequenced in two siblings, a girl with CPP and her brother with early puberty, their parents, and their grandparents. Results: A novel heterozygous missense variant in the MKRN3 gene (p.C340G) was detected in the two affected siblings, their unaffected father, and the paternal grandmother. As expected, the mutated allele followed an imprinted mode of inheritance within the affected family. In silico analysis predicts the mutation as possibly damaging in all five software packages used. Furthermore, structural alignment of the ab initio native and mutant MKRN3 models predicts that the p.C340G mutation leads to significant structural perturbations in the 3-dimensional structure of the C3HC4 really interesting new gene motif of the protein, further emphasizing the functional implications of the novel MKRN3 alteration. Conclusions: We report a novel MKRN3 mutation (p.C340G) in a girl with CPP and her brother with early puberty. MKRN3 alterations should be suspected in all cases with familial CPP or early puberty, especially if male patients are also involved or the precocious puberty trend does not follow the usually observed mother-to-daughter inheritance.

Increased frequency of idiopathic central precocious puberty in girls during the COVID-19 pandemic: preliminary results of a tertiary center study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Sezer Acar ◽  
Behzat Özkan
Keyword(s):  
Precocious Puberty ◽  
Clinical Characteristics ◽  
Laboratory Data ◽  
Central Precocious Puberty ◽  
Pediatric Endocrinology ◽  
Idiopathic Central Precocious Puberty ◽  
Tertiary Center ◽  
One Year ◽  
The One ◽  
Endocrinology Clinic

Abstract Objectives Recent studies have demonstrated an increase in the frequency of idiopathic central precocious puberty (CPP) during the severe acute respiratory syndrome coronavirus 2 (COVID-19) pandemic. We compared the demographic, anthropometric, and clinical characteristics of idiopathic CPP patients diagnosed during a one-year period of the COVID-19 pandemic with the characteristics of patients diagnosed during the same period in the previous three-years. Methods Demographic, clinical, anthropometric, and laboratory data of all patients diagnosed in our Pediatric Endocrinology clinic with idiopathic CPP during a one-year period of the COVID-19 pandemic (April 2020–March 2021) and a three-year period before the pandemic (April 2017–March 2020) were evaluated retrospectively. Results A total of 124 patients (124 girls, zero boys) diagnosed with idiopathic CPP were included in this study. Sixty-six patients in the three-year period before the COVID-19 pandemic (April 2017–March 2020) and 58 patients (46.8%) in the one-year period during the COVID-19 pandemic period (April 2020–March 2021) were diagnosed with idiopathic CPP. Conclusions This study’s findings suggest that the number of girls diagnosed with idiopathic CPP during the one-year study period during the pandemic was more than double that of any of the previous three-years.

scholarly journals A diagnostic model of idiopathic central precocious puberty based on transrectal pelvic ultrasound and basal gonadotropin levels

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052093527
Author(s):  
Bo Yuan ◽  
Ya-Lei Pi ◽  
Ya-Nan Zhang ◽  
Peng Xing ◽  
He-Meng Chong ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Precocious Puberty ◽  
Endometrial Thickness ◽  
Central Precocious Puberty ◽  
Diagnostic Model ◽  
Transverse Diameter ◽  
Pelvic Ultrasound ◽  
Ovarian Volume ◽  
Idiopathic Central Precocious Puberty ◽  
Anterior Posterior

Objective To establish a diagnostic model of idiopathic central precocious puberty on the basis of transrectal pelvic ultrasound and basal gonadotropin. Methods A total of 669 girls with Tanner breast development stage II were enrolled in this study from January 2015 to December 2018. The participants were divided into the ICPP group and the premature thelarche group. We analyzed various variables, including age at initial diagnosis, basal luteinizing hormone levels, the long diameter of the uterus, the transverse diameter of the uterus, the anterior–posterior diameter of the uterus, the volume of the uterus, maximum ovarian diameter, average ovarian volume, maximum ovarian volume, number of follicles (≥4 mm), maximum follicular diameter, endometrial thickness, and vaginal wall thickness. Results The following diagnostic model was established: Y=−14.123 + 0.630 × age at initial diagnosis + 1.119 × transverse diameter of the uterus + 1.278 ×  anterior–posterior diameter of the uterus + 0.637 × average ovarian volume + 1.316 × maximum ovarian diameter + 0.146 ×number of follicles ≥4 mm + 2.925 × endometrial thickness + 0.559 × basal luteinizing hormone value. The area under curve was 0.922, sensitivity was 84.9%, and specificity was 86.2%. Conclusion Basal LH levels and transrectal pelvic ultrasound should be applied together to improve the accuracy of diagnosis in ICPP.

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