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While there is considerable overlap in the treatment of patients with intersex traits and differences in sex development (I/DSD) with transgender and gender diverse (TGD) youth, the initial medical evaluation varies significantly. I/DSD youth often present due to differences in genitalia development in infancy or pubertal development in adolescence, and this leads to comprehensive biochemical, radiologic, and genetic evaluation. TGD youth, however, tend to have typical development noted at birth and during puberty, but present with a gender identity that does not align with their sex assigned at birth and do not require evaluation for underlying pathology. For both I/DSD and TGD youth, the mainstays of treatment are to better align one's physical appearance to their gender identity. This review discusses the non-medical and medical interventions utilized in gender affirming care. A multidisciplinary team of mental health providers, pediatric medical providers, and surgeons is recommended for providing gender affirming care to both I/DSD youth and TGD youth and their families. Radiologists have an important role in initial evaluation of I/DSD youth and in ongoing monitoring of growth and bone mineral density during puberty induction in I/DSD and TGD youth., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To explore transgender and nonbinary (TNB) young adults' (1) interest in receiving gender-affirming medications through telemedicine before age 18 years and (2) willingness to initiate this care with primary care providers (PCPs). Methods: Data were from a survey of TNB young adults who had not received gender-affirming medications before age 18 years. Chi-square and Wald tests identified demographic differences in telemedicine interest and willingness to initiate medications with their PCP as minors. Results: Among 280 respondents, 82.5% indicated interest in telemedicine and 42.0% were willing to initiate medications with their PCP. Black/African American respondents were more likely to indicate interest in telemedicine than White and multiracial respondents. Respondents from rural areas were more likely to indicate willingness to initiate medications with their PCP than those from urban areas. Conclusions: Telemedicine expansion and further support for PCPs may represent critical opportunities to promote equitable access to adolescent gender-affirming care.

Objective: This study aimed to evaluate the serum estradiol levels in gender-diverse youth to compare the efficacy of different estradiol routes in achieving therapeutic blood levels and suppressing serum testosterone levels., Methods: This was a retrospective chart review of patients who initiated estradiol at an adolescent gender clinic between 2010 and 2019. Data on the route of estradiol administration and antiandrogen use (spironolactone or gonadotropin-releasing hormone agonist) were collected, and laboratory data were analyzed. Scatterplots were used to visualize the relationship between the estradiol dose and testosterone and estradiol laboratory values., Results: A total of 118 patients were included, with a mean (standard deviation [SD]) age of 17.2 (1.6) years. The most common route of estradiol administration was oral only (62.7%), followed by transdermal only (23.7%), multiple routes excluding subcutaneous (8.5%), and any subcutaneous (5.1%). Notable variability was observed in the serum estradiol levels, with means (SDs) of 131.9 (120.4) pg/mL for those on oral estrogen 6 to 8 mg per day, 62.6 (40.3) pg/mL for those on transdermal estrogen 0.1 to 0.15 mg every 24 hours, and 53.6 (42.4) pg/mL for those on subcutaneous estradiol. In patients who received spironolactone, transdermal estradiol was associated with lower testosterone levels than estradiol administered orally or subcutaneously., Conclusion: Oral, transdermal, and subcutaneous administrations of estrogen all lead to increased serum estradiol levels and are effective for use in gender-affirming care for youth. Patients on transdermal estrogen tended to have lower serum estradiol levels but also had more suppression of serum testosterone levels., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Background: An electronic consultation (e-consult) platform was implemented to support pediatric primary care providers (PCPs) in providing gender-affirming care to transgender and nonbinary (TNB) adolescents. Following implementation, a study was conducted to (1) explore how access to this e-consult platform impacts PCP confidence and referral patterns, (2) describe the content of questions, and (3) evaluate PCP's perspectives regarding platform usability. Methods: Following each submission, providers completed a 17-item survey. A total of 20 providers submitted 38 e-consults and 26 follow-up surveys between October 2021 and December 2022. Results: All PCPs reported a high overall value and increased confidence caring for TNB adolescents. Nearly one in five (19%) felt it allowed them to avoid submitting a specialty referral. Mean System Usability Scale score was 78.2 indicating good usability. Conclusion: This e-consult platform shows great promise in increasing PCP confidence providing gender-affirming care adolescents. More widespread utilization could help improve access to care and decrease specialty care referrals.

Transgender and gender diverse (TGD) youth have high rates of health disparities and face significant barriers to accessing medical care. Primary care providers (PCPs) are often the first health care providers that TGD youth seek out to discuss gender identity and find support. Thus, it is crucial for PCPs to have an understanding of gender diversity and knowledge to support TGD youth with gender-affirming care. The purpose of this article is to offer strategies PCPs can implement to increase their comfort and capacity in providing care for TGD people. Key steps to support TGD youth in the primary care setting include creating affirming clinical environments, discussing gender identity at routine visits, supporting parents and families, supporting social transition, and providing menstrual suppression for those who desire it. Multidisciplinary gender clinics can partner with PCPs to support adolescents in accessing gender-affirming medical care and to provide additional education and support. [ Pediatr Ann . 2023;52(12):e442-e449.] .

Gender diverse adolescents have low pretreatment bone mineral density (BMD), with variable changes in BMD after initiation of gender-affirming treatment. We aimed to assess factors associated with low BMD in gender diverse youth. Sixty-four patients were included in our analysis (73% assigned male at birth). Subtotal whole-body BMD Z -scores were low in 30% of patients, and total lumbar spine BMD Z -scores low in 14%. There was a positive association with body mass index, and no association with vitamin D level. Male sex assigned at birth was associated with lower pretreatment BMD, with lower average BMD Z -scores compared to previous studies., Competing Interests: P.S. is involved in clinical research funded by Soleno Therapeutics, Inc., and Millendo Therapeutics, Inc. The other authors have no conflicts of interest to disclose., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Nonbinary individuals, or those who identify outside of the traditional gender binary, are currently present in up to 9% of the general population of youth or up to 55% of gender-diverse youth. Despite the high numbers of nonbinary individuals, this population continues to experience barriers to healthcare due to providers' inability to see beyond the transgender binary and lack of competence in providing nonbinary care. In this narrative review, we discuss using embodiment goals to individualize care of nonbinary individuals, and review hormonal and nonhormonal treatment options for gender affirmation. Hormonal treatments include those often used in binary transgender individuals, such as testosterone, estradiol, and anti-androgens, but with adjustments to dosing or timeline to best meet a nonbinary individual's embodiment goals. Less commonly used medications such as selective estrogen receptor antagonists are also discussed. For nonhormonal options, alterations in gender expression such as chest binding, tucking and packing genitalia, and voice training may be beneficial, as well as gender-affirming surgeries. Many of these treatments lack research specific to nonbinary individuals and especially nonbinary youth, and future research is needed to ensure safety and efficacy of gender-affirming care in this population., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

Purpose: To compare the efficacy of intramuscular Lupron and subcutaneous Eligard, two formulations of leuprolide, for puberty suppression in transgender and gender diverse (TGD) youth., Methods: A retrospective chart review of TGD youth receiving Lupron or Eligard 22.5 mg every 3 months was conducted to determine hormone levels obtained 1 hour after an injection (1hrPost) and patient-reported clinical puberty suppression., Results: Forty eight patients were analyzed: 33% assigned female at birth of which 25% were premenarchal, mean age at first injection 13.7 years, and 50% received concurrent gender affirming hormones. Of these, 13% received Lupron, 52% Eligard, and 35% initially received Lupron then transitioned to Eligard due to drug shortages. There were 55 incidents of 1hrPost levels, 42 after Eligard and 13 after Lupron. Clinical puberty suppression occurred in all patients; however, biochemical suppression occurred in 90% of Eligard and 69% of Lupron (p = .06)., Discussion: Eligard and Lupron were both effective in suppressing clinical puberty progression in our population of TGD youth, of which 50% were receiving concurrent gender affirming hormones., (Copyright © 2022 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Acne vulgaris is among the most common skin disorders afflicting adolescents worldwide, and though well-established guidelines of care exist for acne management, these guidelines do not uniformly consider or address the unique psychosocial and medical needs of transgender and gender diverse (TGD) youth. Part 2 of this two-part review provides guidance on a stepwise approach to the medical treatment of acne in TGD youth, with an emphasis on safety, efficacy, and the delivery of medical care in a culturally humble, thoughtful, and gender-affirming manner., (© 2022 Wiley Periodicals LLC.)

Acne vulgaris is among the most common skin disorders afflicting adolescents worldwide, and though well-established guidelines of care exist for acne management, these guidelines do not uniformly consider or address the unique psychosocial and medical needs of transgender and gender diverse (TGD) youth. TGD youth may possess distinct goals of therapy when treating their acne; the use of medicines routinely employed to treat acne may also expose TGD adolescents receiving gender affirming medical therapy to greater risk of adverse events. Part 1 of this two-part review provides dermatologists an understanding of gender affirming care and its timing, as well as its potential impacts on the development of acne in TGD youth., (© 2022 Wiley Periodicals LLC.)

Increasing numbers of transgender and gender diverse (TGD) youth are presenting for medical care, including seeking more information and access to services from gynecologic and reproductive health experts. Such experts are well positioned to provide affirming, comprehensive services, including education, hormonal interventions, menstrual management, contraception, and various gynecological procedures. Early medical guidance and support for the TGD community has been associated with long-term positive emotional and physical health outcomes. In this article medical interventions that reproductive health experts can offer to their TGD patients are discussed., (Copyright © 2020 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To discuss treatments used to enhance growth in pediatric patients with short stature., Recent Findings: New data confirm the known efficacy of recombinant human growth hormone (rhGH) in growth hormone deficiency (GHD) and idiopathic short stature. The latest data from the Safety and Appropriateness of Growth hormone Treatment in Europe cohort did not indicate a long-term risk of malignancy in those treated for isolated GHD, but possibly increased risk in those with other diagnoses. Recombinant human insulin-like growth factor 1 is effective in treating patients with pregnancy-associated plasma protein A2 deficiency. Gonadotropin-releasing hormone agonists or aromatase inhibitor treatment to delay puberty remains controversial. They are more likely to augment adult height if combined with rhGH treatment in children already receiving rhGH. Preliminary data indicate that recombinant C-type natriuretic peptide (CNP) is safe in children and increases growth velocity upon 42 months of treatment in achondroplasia., Summary: Recent data confirms previous data on rhGH efficacy and safety. Therapies to delay growth plate closure have greatest efficacy to augment height if combined with GH in select diagnoses. Recombinant CNP holds promise as a medical treatment for short stature associated with achondroplasia.

Transgender and gender-diverse youth and their families are increasingly presenting to adolescent gynecological providers for education, care, and referrals. These youth more often face mental health and social disparities that frequently go unrecognized or unaddressed by providers. A gender-affirmative approach focuses on providing emotional validation, psychological safety, and support to young patients and their families. With better understanding of the unique needs of transgender and gender-diverse populations, gynecological care can be personalized and delivered in a nuanced fashion to better address the sexual and reproductive needs of gender minority patients. In this article we review essential psychological and social considerations in caring for transgender and gender-diverse youth, including concepts relating to gender identity, affirmative approaches, means of assessing for risk and resiliency, and family dynamics. Ultimately, adolescent gynecological providers have an important role in promoting the emotional health and positive development of transgender and gender-diverse youth., (Copyright © 2019 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Background The American Thyroid Association (ATA) recommendations for the follow-up of thyroid nodules with benign fine needle aspiration (FNA) cytology in children are largely based on adult data, despite well-characterized differences between thyroid nodules in adults and children. We aimed to determine the optimal time interval for repeat evaluation of an FNA-benign thyroid nodule in a pediatric patient. Methods This is a retrospective chart review of patients <19 years of age from 2003 to 2013 with a benign thyroid nodule by FNA cytology. Results We identified 43 patients with benign thyroid nodule cytology on FNA. The average age at diagnosis was 15.6 years, with female predominance (91%). Initial ultrasound (US) findings showed an average nodule size of 2.5 cm, 10% with calcifications, 37% hyperemia, 29% hypoechogenicity and 7% lymphadenopathy. Follow-up US was done in 42%. The first follow-up US occurred on average at 15 months after the initial US. Four patients had nodules with significant growth over time. One patient with papillary thyroid carcinoma (PTC) on final pathology initially had a decreasing nodule size, and then a subsequent increase in the nodule size after 4.5 years. Thyroid nodules were surgically removed in 33% with the final pathology showing a benign cytology in four patients, follicular adenoma in eight patients and PTC in two patients. Conclusions The majority of patients with benign thyroid nodules had no significant increase in nodule size in the first year of follow-up, including one patient who was subsequently found to have PTC. We recommend follow-up US at 1 year after initial presentation in low-risk pediatric patients with benign thyroid nodule cytology.

Aggrecan is an integral component of the extracellular matrix in cartilaginous tissues, including the growth plate. Heterozygous defects in the aggrecan gene have been identified as a cause of autosomal dominant short stature, bone age acceleration, and premature growth cessation. The mechanisms accounting for this phenotype remain unknown. We used ATDC5 cells, an established model of chondrogenesis, to evaluate the effects of aggrecan deficiency. ATDC5 aggrecan knockdown cell lines (AggKD) were generated using lentiviral shRNA transduction particles. Cells were stimulated with insulin/transferrin/selenium for up to 21 days to induce chondrogenesis. Control ATDC5 cells showed induction of Col2a1 starting at day 8 and induction of Col10a1 starting at day 12. AggKD cells had significantly reduced expression of Col2a1 and Col10a1 (p<0.0001) with only minimal increases in expression over time, indicating that chondrogenesis was markedly impaired. The induction of Col2a1 and Col10a1 was not rescued by culturing of AggKD cells in wells pre-conditioned with ATDC5 extracellular matrix or in co-culture with wild-type ATDC5 cells. We interpret our studies as indicating that aggrecan has an integral role in chondrogenesis that may be mediated through intracellular mechanisms., Competing Interests: The authors have declared that no competing interests exist.

Interleukin-6 (IL-6) is implicated in the pathogenesis of both systemic juvenile idiopathic arthritis (SJIA) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but the 2 have not been previously described as occurring together. We report a case of a 6-year-old girl with symptoms of arthralgia, daily fevers, evanescent rash, lymphadenopathy, and laboratory evaluation showing elevated inflammatory markers, consistent with SJIA. At presentation, the patient had hyponatremia with a sodium level of 128 mEq/L. She had low serum osmolality with elevated urine osmolality, consistent with SIADH. Hyponatremia improved temporarily during times of fluid restriction as expected in SIADH, but did not resolve until SJIA was treated successfully with tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity. The positive response to treatment with tocilizumab supports the role of IL-6 in the pathogenesis of both SJIA and SIADH. Patients with SJIA should be monitored for SIADH to avoid complications of untreated hyponatremia., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Glycogen storage disease (GSD) type IX and growth hormone (GH) deficiency cause ketotic hypoglycemia via different mechanisms and are not known to be associated. We describe a patient presenting with severe ketotic hypoglycemia found to have both GSD IX and isolated GH deficiency., Case Presentation: A 3-year-and-11-month-old boy with a history of prematurity, autism, developmental delay, seizures, and feeding difficulty was admitted for poor weight gain and symptomatic hypoglycemia. He was nondysmorphic, with a height of 93.8 cm (2%, -1.97 SDS), and has no hepatomegaly. He developed symptomatic hypoglycemia, with a serum glucose level of 37 mg/dL after 14 h of fasting challenge. Critical sample showed a GH of 0.24 ng/mL. GH provocative stimulation testing was done with a peak GH of 2.8 ng/mL. Brain magnetic resonance imaging showed a hypoplastic pituitary gland. Given the clinical symptoms, suspicion for mitochondrial disease was high. Dual Genome Panel by Massively Parallel Sequencing revealed a hemizygous variant c.721A>G (p1241V) in the X-linked PHKA2 gene, a causative gene for GSD IX. Red blood cell PhK enzyme activity testing was low, supporting the diagnosis., Conclusions: Given the patient's developmental delays that were not explained by GH deficiency alone, further investigation showed two unrelated conditions resulting in deranged metabolic adaptation to fasting leading to severe hypoglycemia.

Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.

Objective: This study evaluates the clinical characteristics, workup, treatment, and outcomes of pediatric patients diagnosed with an autonomously functioning thyroid nodule (AFTN) in a large cohort of patients presenting for evaluation of a thyroid nodule. There are few prior studies on AFTN in pediatrics, with limited data on treatment and outcomes. Rates of malignancy in AFTN are perceived as low, but prior studies have varying reports., Methods: This is a retrospective chart review of patients less than 21 years of age at Rhode Island Hospital over an 11-year period (2003-2013). We reviewed 354 charts, which yielded 242 patients with a diagnosis of thyroid nodule and 17 patients with AFTN., Results: The prevalence of AFTN in patients presenting with thyroid nodules was 7%. Mean age of patients was 15.8 years at diagnosis, and mean nodule size was 3.3 cm. There was female predominance. Thyroid-stimulating hormone levels were suppressed at diagnosis in 87% of patients. Six patients were treated with surgery, 5 patients with radioactive iodine therapy (RAI), 2 patients with medication, and 1 patient was observed without treatment. Three patients treated with RAI required subsequent treatment for hypothyroidism or continued hyperthyroidism. One patient had papillary thyroid carcinoma based on final surgical pathology., Conclusion: Our study found a higher prevalence of AFTN compared to the reported prevalence in adults. We concur with the new guidelines on management of thyroid nodules in recommending surgery for treatment of AFTN, based on the variability of outcomes after treatment with RAI.