Faculty Opinions recommendation of Central precocious puberty caused by mutations in the imprinted gene MKRN3.

2013 ◽  
Author(s):  
Antonio Bellastella
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Imprinted Gene

scholarly journals Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3

2014 ◽  
Vol 99 (6) ◽  
pp. E1097-E1103 ◽  
Author(s):  
Delanie B. Macedo ◽  
Ana Paula Abreu ◽  
Ana Claudia S. Reis ◽  
Luciana R. Montenegro ◽  
Andrew Dauber ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Copy Number ◽  
Age Of Onset ◽  
Ring Finger ◽  
In Silico Analysis ◽  
Central Precocious Puberty ◽  
Paternal Allele ◽  
Chromosome 15 ◽  
Loss Of Function ◽  
Imprinted Gene

Context: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3 mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.

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 Caused by Mutations in the Imprinted Gene MKRN3

2013 ◽  
Vol 368 (26) ◽  
pp. 2467-2475 ◽  
Author(s):  
Ana Paula Abreu ◽  
Andrew Dauber ◽  
Delanie B. Macedo ◽  
Sekoni D. Noel ◽  
Vinicius N. Brito ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Imprinted Gene

Utility of basal LH in comparison to the GnRH test for identifying central precocious puberty in girls

2014 ◽  
Author(s):  
Elizabeth Shepherd ◽  
Leena Patel ◽  
Indi Banerjee ◽  
Peter Clayton ◽  
Sarah Ehtisham ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

2019 ◽  
Author(s):  
Wannes S ◽  
Elmaleh-Berges M ◽  
Simon D ◽  
Zenaty D ◽  
Martinerie L ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
High Prevalence

Development of Prediction Models Using Machine Learning Algorithms for Girls with Suspected Central Precocious Puberty: Retrospective Study (Preprint)

2018 ◽  
Author(s):  
Liyan Pan ◽  
Guangjian Liu ◽  
Xiaojian Mao ◽  
Huixian Li ◽  
Jiexin Zhang ◽  
...  
Keyword(s):  
Machine Learning ◽  
Retrospective Study ◽  
Random Forest ◽  
Precocious Puberty ◽  
Prediction Models ◽  
Central Precocious Puberty ◽  
Machine Learning Algorithms ◽  
Stimulation Test ◽  
Gnrh Analogue ◽  
Prediction Probability

BACKGROUND Central precocious puberty (CPP) in girls seriously affects their physical and mental development in childhood. The method of diagnosis—gonadotropin-releasing hormone (GnRH)–stimulation test or GnRH analogue (GnRHa)–stimulation test—is expensive and makes patients uncomfortable due to the need for repeated blood sampling. OBJECTIVE We aimed to combine multiple CPP–related features and construct machine learning models to predict response to the GnRHa-stimulation test. METHODS In this retrospective study, we analyzed clinical and laboratory data of 1757 girls who underwent a GnRHa test in order to develop XGBoost and random forest classifiers for prediction of response to the GnRHa test. The local interpretable model-agnostic explanations (LIME) algorithm was used with the black-box classifiers to increase their interpretability. We measured sensitivity, specificity, and area under receiver operating characteristic (AUC) of the models. RESULTS Both the XGBoost and random forest models achieved good performance in distinguishing between positive and negative responses, with the AUC ranging from 0.88 to 0.90, sensitivity ranging from 77.91% to 77.94%, and specificity ranging from 84.32% to 87.66%. Basal serum luteinizing hormone, follicle-stimulating hormone, and insulin-like growth factor-I levels were found to be the three most important factors. In the interpretable models of LIME, the abovementioned variables made high contributions to the prediction probability. CONCLUSIONS The prediction models we developed can help diagnose CPP and may be used as a prescreening tool before the GnRHa-stimulation test.

scholarly journals Clinical characteristics and treatment patterns with histrelin acetate subcutaneous implants vs. leuprolide injections in children with precocious puberty: a real-world study using a US claims database

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Lawrence A. Silverman ◽  
Xu Han ◽  
Huan Huang ◽  
Aimee M. Near ◽  
Yiqun Hu
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Treatment Costs ◽  
Interquartile Range ◽  
Duration Of Treatment ◽  
Claims Database ◽  
Total Treatment ◽  
Patient Groups ◽  
Hormone Analogs ◽  
Index Treatment

Abstract Objectives Gonadotropin-releasing hormone analogs are the treatment of choice for central precocious puberty (CPP). This study characterizes patients treated with histrelin implant or leuprolide injection. Methods A US claims database was used to identify patients aged ≤20 years with ≥1 histrelin or leuprolide claim (index treatment) between April 2010 and November 2017 and continuous enrollment ≥3 months before and ≥12 months after the index treatment date. Results Overall, 4,217 patients (histrelin, n=1,001; leuprolide, n=3,216) were identified. The percentage of patients with CPP diagnosis was greater in the histrelin (96.5%) vs. leuprolide (68.8%; p<0.0001) cohort. In patients with CPP (histrelin, n=966; leuprolide, n=2,214), mean age at treatment initiation was similar for histrelin (9.0 ± 2.0 years) and leuprolide (9.1 ± 2.3 years), with >50% of patients aged 6–9 years. Mean treatment duration was significantly longer for histrelin (26.7 ± 14.8 months) vs. leuprolide (14.1 ± 12.1 months; p<0.0001), and was longer in younger patient groups. More patients switched from leuprolide to histrelin (12.3%) than vice versa (3.6%; p<0.0001). Median annual total treatment costs were slightly lower for the histrelin cohort ($23,071 [interquartile range, $16,833–$31,050]) than the leuprolide cohort ($27,021 [interquartile range, $18,314–$34,995]; p<0.0001). Conclusions Patients with CPP treated with histrelin had a longer duration of treatment, lower rates of index treatment discontinuation, and lower annual treatment costs vs. those treated with leuprolide.

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