Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to ...systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants.
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.
The risk of venous thromboembolism (VTE) with gender-affirming hormone therapy (GAHT) in transgender and gender non-binary (TNB) youth is unclear.BACKGROUNDThe risk of venous thromboembolism (VTE) ...with gender-affirming hormone therapy (GAHT) in transgender and gender non-binary (TNB) youth is unclear.To identify the rate of VTE in a cohort of TNB youth followed in the transgender health clinic at Boston Children's Hospital, and to investigate the impact of congenital thrombophilia diagnosis on the use of GAHT.OBJECTIVETo identify the rate of VTE in a cohort of TNB youth followed in the transgender health clinic at Boston Children's Hospital, and to investigate the impact of congenital thrombophilia diagnosis on the use of GAHT.ICD-9 and ICD-10 codes were used to identify eligible individuals, defined as (i) having a diagnosis of gender dysphoria and (ii) venous thromboembolism (VTE). Data were abstracted from a review of medical records. A second data query assessed TNB individuals who had an associated thrombophilia diagnosis.METHODSICD-9 and ICD-10 codes were used to identify eligible individuals, defined as (i) having a diagnosis of gender dysphoria and (ii) venous thromboembolism (VTE). Data were abstracted from a review of medical records. A second data query assessed TNB individuals who had an associated thrombophilia diagnosis.The primary analysis included 1860 individuals. Total 942 individuals (50.6%) had started GAHT at the time of data analysis. Mean age (±SD) at GAHT initiation was 16.8 (±1.9) years. Five thrombotic events were identified in three (0.13%) individuals, all in the setting of additional VTE risk factors. Only two of five thrombotic events occurred while receiving GAHT. The rate of VTE in the GAHT cohort did not statistically differ from the rate of VTE in the non-GAHT cohort (0.1% vs. 0.2%, p = .62). Of the 10 individuals diagnosed with a congenital thrombophilia, two transmasculine individuals received prophylactic anticoagulation prior to GAHT. No VTE has been reported to date in this cohort.RESULTSThe primary analysis included 1860 individuals. Total 942 individuals (50.6%) had started GAHT at the time of data analysis. Mean age (±SD) at GAHT initiation was 16.8 (±1.9) years. Five thrombotic events were identified in three (0.13%) individuals, all in the setting of additional VTE risk factors. Only two of five thrombotic events occurred while receiving GAHT. The rate of VTE in the GAHT cohort did not statistically differ from the rate of VTE in the non-GAHT cohort (0.1% vs. 0.2%, p = .62). Of the 10 individuals diagnosed with a congenital thrombophilia, two transmasculine individuals received prophylactic anticoagulation prior to GAHT. No VTE has been reported to date in this cohort.In our cohort, VTE was rare in the TNB youth and was not associated with GAHT use. TNB youth with congenital thrombophilia have not developed VTE in the setting of GAHT use to date.CONCLUSIONSIn our cohort, VTE was rare in the TNB youth and was not associated with GAHT use. TNB youth with congenital thrombophilia have not developed VTE in the setting of GAHT use to date.
Abstract
Makorin ring finger protein 3 (MKRN3) is an important neuroendocrine player in the control of pubertal timing and upstream inhibitor of gonadotropin-releasing hormone secretion. In mice, ...expression of Mkrn3 in the hypothalamic arcuate and anteroventral periventricular nucleus is high early in life and declines before the onset of puberty. Therefore, we aimed to explore if the persistence of hypothalamic Mkrn3 expression peripubertally would result in delayed puberty. Female mice that received neonatal bilateral intracerebroventricular injections of a recombinant adeno-associated virus expressing Mkrn3 had delayed vaginal opening and first estrus compared with animals injected with control virus. Subsequent estrous cycles and fertility were normal. Interestingly, male mice treated similarly did not exhibit delayed puberty onset. Kiss1, Tac2, and Pdyn mRNA levels were increased in the mediobasal hypothalamus in females at postnatal day 28, whereas kisspeptin and neurokinin B protein levels in the arcuate nucleus were decreased, following Mkrn3 overexpression, compared to controls. Cumulatively, these data suggest that Mkrn3 may directly or indirectly target neuropeptides of Kiss1 neurons to degradation pathways. This mouse model suggests that MKRN3 may be a potential contributor to delayed onset of puberty, in addition to its well-established roles in central precocious puberty and the timing of menarche.
Abstract
Context
The management of youth with delayed puberty is hampered by difficulty in predicting who will eventually progress through puberty and who will fail to attain adult reproductive ...endocrine function. The neuropeptide kisspeptin, which stimulates gonadotropin-releasing hormone (GnRH) release, can be used to probe the integrity of the reproductive endocrine axis.
Objective
We sought to determine whether responses to kisspeptin can predict outcomes for individuals with pubertal delay.
Design, Setting, and Participants
We conducted a longitudinal cohort study in an academic medical center of 16 children (3 girls and 13 boys) with delayed or stalled puberty.
Intervention and Outcome Measures
Children who had undergone kisspeptin- and GnRH-stimulation tests were followed every 6 months for clinical evidence of progression through puberty. Inhibin B was measured in boys. A subset of participants underwent exome sequencing.
Results
All participants who had responded to kisspeptin with a rise in luteinizing hormone (LH) of 0.8 mIU/mL or greater subsequently progressed through puberty (n = 8). In contrast, all participants who had exhibited LH responses to kisspeptin ≤ 0.4 mIU/mL reached age 18 years without developing physical signs of puberty (n = 8). Thus, responses to kisspeptin accurately predicted later pubertal outcomes (P = .0002). Moreover, the kisspeptin-stimulation test outperformed GnRH-stimulated LH, inhibin B, and genetic testing in predicting pubertal outcomes.
Conclusion
The kisspeptin-stimulation can assess future reproductive endocrine potential in prepubertal children and is a promising novel tool for predicting pubertal outcomes for children with delayed puberty.
Roberts et al discuss the considerations for providing pediatric gender-affirmative care during the COVID-19 pandemic. Parental support has been demonstrated to reduce rates of negative health ...outcomes and prevent against suicidality. Additionally, mental health providers have the opportunity to create new services, such as telemedicine group psychotherapy experiences, to provide supportive experiences to gender diverse youth. It is of the utmost importance that all providers, across disciplines, stress that GAC is "essential," even during a pandemic. Unfortunately, many gender diverse youth have experienced delays in medically necessary treatment (e.g., pubertal suppression, hormone therapy, surgeries, etc.) and potentially have received the unintended, yet damaging message, that GAC is not a priority; therefore, it is important that multidisciplinary professionals working with gender diverse youth and their families counter this narrative.
Abstract
Context:
Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal axis. Few genetic causes of CPP have been identified, with the most common ...being mutations in the paternally expressed imprinted gene MKRN3.
Objective:
To identify the genetic etiology of CPP in a large multigenerational family.
Design:
Linkage analysis followed by whole-genome sequencing was performed in a family with five female members with nonsyndromic CPP. Detailed phenotyping was performed at the time of initial diagnosis and long-term follow-up, and circulating levels of Delta-like 1 homolog (DLK1) were measured in affected individuals. Expression of DLK1 was measured in mouse hypothalamus and in kisspeptin-secreting neuronal cell lines in vitro.
Setting:
Endocrine clinic of an academic medical center.
Patients:
Patients with familial CPP were studied.
Results:
A complex defect of DLK1 (∼14-kb deletion and 269-bp duplication) was identified in this family. This deletion included the 5′ untranslated region and the first exon of DLK1, including the translational start site. Only family members who inherited the defect from their father have precocious puberty, consistent with the known imprinting of DLK1. The patients did not demonstrate additional features of the imprinted disorder Temple syndrome except for increased fat mass. Serum DLK1 levels were undetectable in all affected individuals. Dlk1 was expressed in mouse hypothalamus and in kisspeptin neuron-derived cell lines.
Conclusion:
We identified a genomic defect in DLK1 associated with isolated familial CPP. MKRN3 and DLK1 are both paternally expressed imprinted genes. These findings suggest a role of genomic imprinting in regulating the timing of human puberty.
Through a combination of linkage analysis and whole genome-sequencing, a mutation in the paternally expressed imprinted gene DLK1 in a family with central precocious puberty is identified.
The sexually dimorphic trait of height is one aspect of the experience of transgender and gender‐diverse (TGD) individuals that may influence their gender dysphoria and satisfaction with their ...transition. In this article, we have reviewed the current knowledge of the factors that contribute to one's final adult height and how it might be affected in TGD youth who have not experienced their gonadal puberty in the setting of receiving gonadotropin‐releasing hormone analog (GnRHa) and gender‐affirming hormonal treatment. Additional research is needed to characterize the influence of growth and final adult height on the lived experience of TGD youth and adults and how to best assess their growth, predict their final adult height, and how medical transition can be potentially modified to help them meet their goals.