Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other ...conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents.
When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise.
Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion.
Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement.
The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely.
Abstract
Context
Central precocious puberty (CPP) can have a familial form in approximately one-quarter of the children. The recognition of this inherited condition increased after the identification ...of autosomal dominant CPP with paternal transmission caused by mutations in the MKRN3 and DLK1 genes.
Objective
We aimed to characterize the inheritance and estimate the prevalence of familial CPP in a large multiethnic cohort; to compare clinical and hormonal features, as well as treatment response to GnRH analogs (GnRHa), in children with distinct modes of transmission; and to investigate the genetic basis of familial CPP.
Methods
We retrospectively studied 586 children with a diagnosis of CPP. Patients with familial CPP (n = 276) were selected for clinical and genetic analysis. Data from previous studies were grouped, encompassing sequencing of MKRN3 and DLK1 genes in 204 patients. Large-scale parallel sequencing was performed in 48 individuals from 34 families.
Results
The prevalence of familial CPP was estimated at 22%, with a similar frequency of maternal and paternal transmission. Pedigree analyses of families with maternal transmission suggested an autosomal dominant inheritance. Clinical and hormonal features, as well as treatment response to GnRHa, were similar among patients with different forms of transmission of familial CPP. MKRN3 loss-of-function mutations were the most prevalent cause of familial CPP, followed by DLK1 loss-of-function mutations, affecting, respectively, 22% and 4% of the studied families; both affected exclusively families with paternal transmission. Rare variants of uncertain significance were identified in CPP families with maternal transmission.
Conclusion
We demonstrated a similar prevalence of familial CPP with maternal and paternal transmission. MKRN3 and DLK1 loss-of-function mutations were the major causes of familial CPP with paternal transmission.
Concerns with pubertal development are common and can cause considerable distress to patients and their carers. Many presentations reflect normal variations of pubertal timing and primarily require ...reassurance, although patients may opt for interventions. Other presentations need active management to avoid significant adverse effects on growth and psychosocial development. All should undergo careful assessment, particularly as some children or adolescents presenting with abnormalities in pubertal timing may have serious pathology which requires urgent investigations and treatment. This review describes the appropriate investigations and their interpretation for young people presenting with disorders in pubertal timing.
This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic ...challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.
This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in ...GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.
Precocious puberty is defined as the appearance of secondary sex characteristics before 8 years of age in girls and before 9 years of age in boys. Central precocious puberty (CPP) is diagnosed when ...activation of the hypothalamic–pituitary axis is identified. It is a rare disease with a clear female predominance. A background of international adoption increases its risk, with other environmental factors such as endocrine disruptors also being associated with CPP.
The causes of CPP are heterogeneous, with alterations of the CNS being of special interest. Physical injuries of the CNS are more frequent in boys, while idiopathic etiology is more prevalent among girls. However, in the last decade the number of idiopathic cases has diminished thanks to the discovery of mutations in different genes, including KISS1, KISS1R, MKRN3, and DLK1 that cause CPP.
For the diagnosis of CPP, hormone studies are needed in addition to the clinical data regarding signs of pubertal onset. For this purpose, the GnRH test continues to be the gold standard. Imaging analyses, such as bone age and brain MRI, are also very useful. Furthermore, genetic testing must be incorporated in the diagnosis of CPP, especially in familial cases.
Early puberty has been related to various consequences in the medium and long term such as behavioral problems, breast cancer, obesity, and metabolic comorbidities. However, there are few studies that have exclusively analyzed patients with CPP.
GnRH analogs are the most frequent treatment election with the main objective being to improve adult height. Currently, there are new formulations that are being investigated.
Whether children, especially girls, are entering and progressing through puberty earlier today than in the mid-1900s has been debated. Secular trend analysis, based on available data, is limited by ...data comparability among studies in different populations, in different periods of time, and using different methods. As a result, conclusions from data comparisons have not been consistent. An expert panel was asked to evaluate the weight of evidence for whether the data, collected from 1940 to 1994, are sufficient to suggest or establish a secular trend in the timing of puberty markers in US boys or girls. A majority of the panelists agreed that data are sufficient to suggest a trend toward an earlier breast development onset and menarche in girls but not for other female pubertal markers. A minority of panelists concluded that the current data on girls' puberty timing for any marker are insufficient. Almost all panelists concluded, on the basis of few studies and reliability issues of some male puberty markers, that current data for boys are insufficient to evaluate secular trends in male pubertal development. The panel agreed that altered puberty timing should be considered an adverse effect, although the magnitude of change considered adverse was not assessed. The panel recommended (1) additional analyses of existing puberty-timing data to examine secular trends and trends in the temporal sequence of pubertal events; (2) the development of biomarkers for pubertal timing and methods to discriminate fat versus breast tissue, and (3) establishment of cohorts to examine pubertal markers longitudinally within the same individuals.
Abstract
Context
The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In ...population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown.
Objective
This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
Methods
We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort.
Results
MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 2.2%; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 0.6%; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07).
Conclusion
We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
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