scholarly journals SUN-725 Clinical and Genetic Features of Families with Maternally Inherited Central Precocious Puberty

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Flávia Rezende Tinano ◽  
Ana Pinheiro Machado Canton ◽  
Luciana Ribeiro Montenegro ◽  
Andrea de Castro Leal ◽  
Carolina Ramos ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Association Studies ◽  
Brain Mri ◽  
Family Members ◽  
Central Precocious Puberty ◽  
Breast Development ◽  
Female Group ◽  
Genome Wide Association Studies ◽  
Abnormal Gait ◽  
Genetic Features

Abstract Context: The clinical recognition of familial central precocious puberty (CPP) has significantly increased in the last years. This fact can be related to the recent descriptions of genetic causes associated with this pediatric condition, such as loss-of-function mutations of two imprinted genes (MKRN3 and DLK1). Inherited defects in both genes cause paternally inherited CPP. However, no genetic abnormality has been described in families with maternally inherited CPP so far. Objectives: To characterize the clinical and genetic features of several families with maternally inherited CPP. Setting and Participants: We analyzed clinical and genetic features of children with familial CPP. No brain MRI alterations were detected in the selected patients with CPP. MKRN3 and DLK1 pathogenic mutations were excluded. Whole-exome sequencing was performed in selected cases. Results: We studied 177 children from 141 families with familial CPP. Paternal inheritance was evidenced in 44 families (31%), whereas 58 (41%) had maternally inheritance. Indeterminate inheritance was detected in the remaining families. Maternally inherited CPP affected mainly female patients (69 girls and two boys). Thelarche occurred at mean age of 6.1 ± 1.9 years in this female group. Most of girls had Tanner 3 (41%) and Tanner 4 (35%) breast development at first evaluation. One boy had additional syndromic features (macrosomia, autism, bilateral eyelid ptosis, high arcade palate, irregular teeth and abnormal gait). The pedigree analysis of patients with maternally inherited CPP revealed the following affected family members: 42 mothers, 10 grandmothers, 11 sisters, 12 aunts, and 11 female cousins. Most of the families (41) had two affected consecutive generations, while eight families had three affected generations. No consanguinity was referred. Ongoing molecular analysis revealed two rare heterozygous variants in the boy with syndromic CPP and three affected family members with precocious menarche (mother, maternally half-sister, and maternally aunt): a frameshift deletion (p.F144fs) in MKKS; and a missense variant (p.P267L) in UGT2B4, which encodes a protein involved in estrogen hydroxylation and it was related to menarche timing in genome-wide association studies. Conclusions: Maternally inherited CPP was diagnosed mainly in girls, who had thelarche at mean age of 6 years old. Dominant pattern of inheritance was more prevalent, with direct maternal transmission in 72% of the studied families. New candidate genes might be implicated with maternally inherited CPP.

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.

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study

2018 ◽  
Vol 90 (3) ◽  
pp. 190-195 ◽  
Author(s):  
Anna Grandone ◽  
Grazia Cirillo ◽  
Marcella Sasso ◽  
Gianluca Tornese ◽  
Caterina Luongo ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Serum Levels ◽  
Breast Development ◽  
Control Group ◽  
Ring Finger Protein ◽  
Finger Protein ◽  
17Β Estradiol ◽  
Puberty Onset

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.

Using Zebrafish to Test the Genetic Basis of Human Craniofacial Diseases

2017 ◽  
Vol 96 (11) ◽  
pp. 1192-1199 ◽  
Author(s):  
R. Grecco Machado ◽  
B. Frank Eames
Keyword(s):  
Candidate Genes ◽  
Genetic Manipulation ◽  
Association Studies ◽  
Underlying Disease ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genetic Loci ◽  
Large Numbers ◽  
Genetic Features ◽  
New Treatments

Genome-wide association studies (GWASs) opened an innovative and productive avenue to investigate the molecular basis of human craniofacial disease. However, GWASs identify candidate genes only; they do not prove that any particular one is the functional villain underlying disease or just an unlucky genomic bystander. Genetic manipulation of animal models is the best approach to reveal which genetic loci identified from human GWASs are functionally related to specific diseases. The purpose of this review is to discuss the potential of zebrafish to resolve which candidate genetic loci are mechanistic drivers of craniofacial diseases. Many anatomic, embryonic, and genetic features of craniofacial development are conserved among zebrafish and mammals, making zebrafish a good model of craniofacial diseases. Also, the ability to manipulate gene function in zebrafish was greatly expanded over the past 20 y, enabling systems such as Gateway Tol2 and CRISPR-Cas9 to test gain- and loss-of-function alleles identified from human GWASs in coding and noncoding regions of DNA. With the optimization of genetic editing methods, large numbers of candidate genes can be efficiently interrogated. Finding the functional villains that underlie diseases will permit new treatments and prevention strategies and will increase understanding of how gene pathways operate during normal development.

AMH levels at central precocious puberty and premature thelarche: is it a parameter?

2015 ◽  
Vol 28 (11-12) ◽  
Author(s):  
Nursel Muratoglu Sahin ◽  
Sibel Tulgar Kinik ◽  
Mustafa Agah Tekindal ◽  
Nilufer Bayraktar
Keyword(s):  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Breast Development ◽  
Premature Thelarche ◽  
Pubertal Onset ◽  
Antimullerian Hormone ◽  
The Mean ◽  
Antimüllerian Hormone

AbstractThe possible difference of antimüllerian hormone (AMH) levels at central precocious puberty (CPP) and premature thelarche (PT) has not been properly evaluated.By evaluating AMH levels in girls with diagnosed CPP and PT, we aim to show the change of AMH levels at the pubertal onset.Sixty-five girls who have breast development before the age of 8 years and 25 healthy girls were enrolled in the study.The subjects were divided into two groups as CPP and PT, according to results of GnRH test. AMH levels were determined in the two groups.The mean AMH levels of the CPP group were significantly lower than those in the PT group (13.57±9.85 pmol/L and 58.42±12.78 pmol/L, respectively, p=0.022).These results suggest that the AMH levels decrease in the duration of the hypothalamus-pituitary-ovarian axis activation. We thought that AMH might/may be a marker for distinguishing between CPP and PT.

scholarly journals The utility of basal serum LH in prediction of central precocious puberty in girls

2012 ◽  
Vol 166 (2) ◽  
pp. 295-299 ◽  
Author(s):  
Yehonatan Pasternak ◽  
Michael Friger ◽  
Neta Loewenthal ◽  
Alon Haim ◽  
Eli Hershkovitz
Keyword(s):  
Precocious Puberty ◽  
Predictive Value ◽  
Central Precocious Puberty ◽  
Stimulation Test ◽  
Breast Development ◽  
Basal Serum ◽  
Serum Lh ◽  
Before And After ◽  
Design And Methods ◽  
Prepubertal Girls

ObjectiveThe mainstay of distinction between prepubertal girls and girls who are suspected of having central precocious puberty (CPP) is based on gonadotropin measurements after a GnRH stimulation test to evaluate hypothalamic–pituitary–gonadal axis maturity. The objective of this study was to determine whether a single basal gonadotropin measurement carries a useful predictive value in verifying or refuting the diagnosis of CPP.Design and methodsBasal serum LH and FSH were measured by a chemiluminescent immunometric assay in a cohort of girls who had been evaluated for CPP before and after GnRH stimulation test. Peak LH levels higher than 5 IU/l were considered a pubertal response.ResultsEighty girls with suspected breast development before 8 years of age were enrolled to the study, out of whom 42 had CPP.Low basal serum LH (≤0.1 IU/l) was sufficient to rule out the diagnosis of CPP in 94.7% of the 38 prepubertal girls; the sensitivity of basal LH levels for this purpose was only 64%. The basal FSH and the basal LH to FSH ratio achieved less efficient predictive value with 76 and 71% sensitivity and 73 and 86% specificity respectively.ConclusionA single basal LH measurement may be adequate to confirm but not to refute the presence of CPP in most of the girls who are evaluated for early pubertal signs.

scholarly journals RubricOE: a learning framework for genetic epidemiology

2021 ◽  
Author(s):  
Subrata Saha ◽  
Aldo Guzmán-Sáenz ◽  
Aritra Bose ◽  
Filippo Utro ◽  
Daniel E. Platt ◽  
...  
Keyword(s):  
Genetic Epidemiology ◽  
Association Studies ◽  
Disease Incidence ◽  
Data Sets ◽  
Genome Wide Association Studies ◽  
Single Marker Analysis ◽  
Area Of Interest ◽  
Error Bar ◽  
Genetic Features ◽  
Single Marker

AbstractGenetic epidemiology is a growing area of interest in the past years due to the availability of genetic data with the decreasing cost of sequencing. Machine learning (ML) algorithms can be a very useful tool to study the genetic factors on disease incidence or on different traits characterizing a population. There are many challenges that plagues the field of genetic epidemiology including the unbalanced case-control data sets, fallibility of standard genome wide association studies with single marker analysis, heavily underdetermined systems with millions of markers in contrast of a few thousands of samples, to name a few. Ensemble ML methods can be a very useful tool to tackle many of these challenges and thus we propose RubricOE, a pipeline of ML algorithms with error bar computations to obtain interpretable genetic and non-genetic features from genomic or transcriptomic data combined with clinical factors in the form of electronic health records. RubricOE is shown to be robust in simulation studies, detecting true associations with traits of interest in arbitrarily structured multi-ethnic populations.

scholarly journals Dual effects of a gonadotropin-releasing hormone agonist on an adolescent girl with pelvic congestion syndrome and precocious puberty: a case report

2020 ◽  
Vol 48 (9) ◽  
pp. 030006052095469
Author(s):  
Jwo-Huey Yu ◽  
Hung-Hsiang Fang ◽  
Shih-Yao Liu ◽  
Wei-Chou Chang ◽  
Chiung-Chen Liu ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Precocious Puberty ◽  
Young Patients ◽  
Central Precocious Puberty ◽  
Gonadotropin Releasing Hormone ◽  
Breast Development ◽  
Releasing Hormone ◽  
Pelvic Congestion Syndrome ◽  
Non Invasive ◽  
Pelvic Congestion

Pelvic congestion syndrome (PCS) typically causes chronic non-cyclical abdominal pain with a considerable negative effect on the quality of life of women. However, pediatric cases with PCS are limited and non-invasive therapy for adolescent patients has not been reported. We report here a 13-year-old girl who presented with intermittent abdominal pain since the age of 2 years and her symptoms further deteriorated after breast development at 6 years and 9 months old. PCS and coexistent idiopathic central precocious puberty were finally diagnosed on the basis of tortuous ovarian and pelvic veins, and a pubertal response to a gonadotropin-releasing hormone (GnRH) test without hypothalamic–pituitary lesions. After treatment with the GnRH agonist, the pain score was greatly reduced and there was increased prediction of adult height. This case highlights the occurrence of PCS in adolescents and also indicates the role of non-invasive GnRH agonists in young patients with PCS before surgical intervention.

Thelarche variant: A new syndrome of precocious sexual maturation?

1990 ◽  
Vol 123 (5) ◽  
pp. 481-486 ◽  
Author(s):  
Richard Stanhope ◽  
Charles C. D. Brook
Keyword(s):  
Precocious Puberty ◽  
Sexual Maturation ◽  
Central Precocious Puberty ◽  
Clinical Findings ◽  
Breast Development ◽  
Gnrh Analogue ◽  
Gonadotropin Secretion ◽  
Premature Thelarche ◽  
Isolated Premature Thelarche ◽  
Depot Injections

Abstract. We describe 10 girls (mean age 3.7 years, range 1.9-6.9) with precocious sexual maturation and clinical findings intermediate between those of premature thelarche and central precocious puberty. Studies of spontaneous gonadotropin secretion and ovarian ultrasound morphology also revealed findings intermediate between those of isolated premature thelarche and central precocious puberty. There was no response in 6 of the girls treated with GnRH analogue, whether administered intranasally, sc, or by monthly depot injections. We have called this condition thelarche variant because the gonadotropin independence and cyclical nature of breast development may well be due to a lesion of folliculogenesis.

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