Headache prevalence in transgender and gender diverse youth: A single-center case-control study.

OBJECTIVE: Assess the prevalence of headache in transgender and gender-diverse adolescents, comparing prevalence with and without exposure to gender-affirming hormone therapy. BACKGROUND: Transgender and gender-diverse youth are an understudied group in whom we can study the effects of sex steroids on adolescents' development of headache. We hypothesized that transfeminine adolescents treated with estrogen would have higher odds of headache than those not treated, and that transmasculine adolescents treated with testosterone would have lower odds of headache than those not treated. METHODS: This retrospective case-control study analyzed all patients seen at the Boston Children's Hospital Gender Multispecialty Service clinic from 2007 to 2017. Cases were defined as patients with headache, controls as those without headache, and exposure as treatment with gender-affirming hormone therapy (i.e., estrogen or testosterone). A computerized search identified cases that were then validated by chart review. RESULTS: Fifty-two of the 763 transgender and gender-diverse patients seen were confirmed to have headache. Of 273 transfeminine patients 45% (123/273) received estrogen treatment. Transfeminine patients receiving estrogen were more likely to have headache than those not receiving estrogen (7% [9/123] vs. 1% [2/150]; odd ratio [OR] 5.84 (95% confidence interval [CI] 1.24-27.6), p = 0.026). Of 490 transmasculine patients, 46% (227/490) received testosterone. Transmasculine patients receiving testosterone were more likely to have headache than those not receiving testosterone (12% [28/227] vs. 5% (13/263); OR 2.71 (95% CI 1.37-5.4), p = 0.005). CONCLUSION: Among transfeminine and transmasculine youth, those who received gender-affirming hormone therapy had higher odds of headache compared to those not taking gender-affirming hormone therapy. Further prospective studies to guide headache care of transgender and gender-diverse youth and adults are needed. Our results could be generalizable to other pediatric gender management clinics and may be worth discussing with patients considering treatment.

Pneumomediastinum in COVID-19: a phenotype of severe COVID-19 pneumonitis? The results of the United Kingdom (POETIC) survey.

BACKGROUND: There is an emerging understanding that coronavirus disease 2019 (COVID-19) is associated with increased incidence of pneumomediastinum. We aimed to determine its incidence among patients hospitalised with COVID-19 in the United Kingdom and describe factors associated with outcome. METHODS: A structured survey of pneumomediastinum and its incidence was conducted from September 2020 to February 2021. United Kingdom-wide participation was solicited via respiratory research networks. Identified patients had SARS-CoV-2 infection and radiologically proven pneumomediastinum. The primary outcomes were to determine incidence of pneumomediastinum in COVID-19 and to investigate risk factors associated with patient mortality. RESULTS: 377 cases of pneumomediastinum in COVID-19 were identified from 58 484 inpatients with COVID-19 at 53 hospitals during the study period, giving an incidence of 0.64%. Overall 120-day mortality in COVID-19 pneumomediastinum was 195/377 (51.7%). Pneumomediastinum in COVID-19 was associated with high rates of mechanical ventilation. 172/377 patients (45.6%) were mechanically ventilated at the point of diagnosis. Mechanical ventilation was the most important predictor of mortality in COVID-19 pneumomediastinum at the time of diagnosis and thereafter (p<0.001) along with increasing age (p<0.01) and diabetes mellitus (p=0.08). Switching patients from continuous positive airways pressure support to oxygen or high flow nasal oxygen after the diagnosis of pneumomediastinum was not associated with difference in mortality. CONCLUSIONS: Pneumomediastinum appears to be a marker of severe COVID-19 pneumonitis. The majority of patients in whom pneumomediastinum was identified had not been mechanically ventilated at the point of diagnosis.

Utility of plasma beta-hydroxybutyrate to define resolution of diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common, life-threatening complication of type 1 diabetes (T1D) characterized by unregulated ketogenesis caused by relative or absolute insulin deficiency. DKA management requires frequent biochemical monitoring. Plasma ß-hydroxybutyrate (BOHB) has not been included in traditional definitions of DKA resolution. OBJECTIVE: The aim of this study was to determine a cut-point level of BOHB to define DKA resolution in patients with T1D treated with intravenous (IV) insulin. SUBJECTS: We identified patients with T1D receiving IV insulin for DKA treatment at a quaternary children's hospital from January 1, 2017 through December 31, 2020 who had plasma measurements of BOHB after DKA onset and whose DKA resolved by traditional laboratory criteria (venous pH (vpH) ≥ 7.3, serum bicarbonate (HCO3 ) ≥ 15 mmol/L, and/or anion gap (AG) ≤ 14 mmol/L). METHODS: Associations between plasma BOHB and vpH, HCO3 , and AG were evaluated via scatterplots. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to evaluate BOHB cut-points to predict DKA resolution. RESULTS: We analyzed 403 patients with 471 unique encounters. Plasma BOHB showed the most robust relationship with AG. The ROC curve comparing plasma BOHB to the accepted definition of DKA resolution, AG ≤14 mmol/L, had an AUC of 0.92. A BOHB value of <1.5 mmol/L had a sensitivity of 83% and specificity of 87%; this cut-point correctly classified 86% of the observations. CONCLUSIONS: A plasma BOHB value of <1.5 mmol/L can be used to define resolution of DKA.

Hyperglycemia during induction therapy for acute lymphoblastic leukemia is temporally linked to pegaspargase administration.

BACKGROUND: Chemotherapy regimens containing glucocorticoids and pegaspargase are associated with hyperglycemia; however, the pattern and underlying risk factors are not well characterized. We determined the pattern of hyperglycemia and associated factors in children with acute lymphoblastic leukemia (ALL) receiving glucocorticoids and pegaspargase during induction. METHODS: Retrospective analysis of patients treated between 2010 and 2020 at a single institution. Pretreatment data, glucose values, and insulin regimens were abstracted from the record. Hyperglycemia was defined as two or more random glucose measurements ≥200 mg/dl. Analyses of demographic and clinical factors were conducted with logistic regression. RESULTS: Two hundred thirteen patients, median age 6 years (range 1.0-18.9 years), 47% female, were included. The prevalence of hyperglycemia was 23% (n = 48). Mean glucose levels peaked 3 days following administration of pegaspargase. In multivariable analysis, age ≥10 years (odds ratio [OR] 6.2, 95% confidence interval [CI]: 2.9-13.4), female sex (OR 2.7, 95% CI: 1.2-6.2), and family history of diabetes (OR 3.2, 95% CI: 1.4-7.3) were predictive of hyperglycemia. Age ≥10 years (OR 19.4, 95% CI: 5.5-68.4), family history of diabetes (OR 8.2, 95% CI: 2.7-25.3), and higher body mass index (BMI) (OR 1.8, 95% CI: 1.1-2.9) were associated with insulin treatment. CONCLUSIONS: Onset of hyperglycemia in children receiving induction chemotherapy for ALL is temporally linked to administration of pegaspargase. Older age, female sex, and family history of diabetes are predictive of hyperglycemia during induction; older age, family history of diabetes, and higher BMI are associated with insulin treatment. Frequent glucose monitoring is indicated during induction therapy for ALL.

The effect of gender-affirming hormone treatment on serum creatinine in transgender and gender-diverse youth: implications for estimating GFR.

BACKGROUND: Equations for estimated glomerular filtration rate (eGFR) based on serum creatinine include terms for sex/gender. For transgender and gender-diverse (TGD) youth, gender-affirming hormone (GAH) treatment may affect serum creatinine and in turn eGFR. METHODS: TGD youth were recruited for this prospective, longitudinal, observational study prior to starting GAH treatment. Data collected as part of routine clinical care were abstracted from the medical record. RESULTS: For participants designated male at birth (DMAB, N = 92), serum creatinine decreased within 6 months of estradiol treatment (mean ± SD 0.83 ± 0.12 mg/dL to 0.76 ± 0.12 mg/dL, p < 0.001); for participants designated female at birth (DFAB, n = 194), serum creatinine increased within 6 months of testosterone treatment (0.68 ± 0.10 mg/dL to 0.79 ± 0.11 mg/dL, p < 0.001). Participants DFAB treated with testosterone had serum creatinine similar to that of participants DMAB at baseline, whereas even after estradiol treatment, serum creatinine in participants DMAB remained higher than that of participants DFAB at baseline. Compared to reference groups drawn from the National Health and Nutritional Examination Survey, serum creatinine after 12 months of GAH was more similar when compared by gender identity than by designated sex. CONCLUSION: GAH treatment leads to changes in serum creatinine within 6 months of treatment. Clinicians should consider a patient's hormonal exposure when estimating kidney function via eGFR and use other methods to estimate GFR if eGFR based on serum creatinine is concerning.

A serous borderline ovarian tumour in a transgender male adolescent.

Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.

Plasma ß-Hydroxybutyrate for the Diagnosis of Diabetic Ketoacidosis in the Emergency Department.

OBJECTIVE: Diabetic ketoacidosis (DKA) is a common emergency department presentation of both new-onset and established diabetes mellitus (DM). ß-Hydroxybutyrate (BOHB) provides a direct measure of the pathophysiologic derangement in DKA as compared with the nonspecific measurements of blood pH and bicarbonate. Our objective was to characterize the relationship between BOHB and DKA. METHODS: This is a cross-sectional retrospective study of pediatric patients with DM presenting to an urban pediatric emergency department between January 1, 2016, and September 30, 2018. Analyses were performed on each patient's initial, simultaneous BOHB and pH. Diagnostic test characteristics of BOHB were calculated, and logistic regression was performed to investigate the effects of age and other key clinical factors. RESULTS: Among 594 patients with DM, with median age of 12.3 years (interquartile range, 8.7-15.9 years), 176 (29.6%) presented with DKA. The inclusion of age, transfer status, and new-onset in the statistical model did not improve the prediction of DKA beyond BOHB alone. ß-Hydroxybutyrate demonstrated strong discrimination for DKA, with an area under the curve of 0.95 (95% confidence interval, 0.93-0.97). A BOHB value of 5.3 mmol/L predicted DKA with optimal accuracy (90.6% of patients were correctly classified). The sensitivity, specificity, and positive and negative predictive values of this cut point were 76.7% (95% confidence interval, 69.8%-82.7%), 96.4% (94.2%-98.0%), 90.0% (84.0%-94.3%), and 90.8% (87.7%-93.3%), respectively. CONCLUSIONS: ß-Hydroxybutyrate accurately predicts DKA in children and adolescents. More importantly, because plasma BOHB is the ideal biochemical marker of DKA, BOHB may provide a more optimal definition of DKA for management decisions and treatment targets.

Co-existence of Type 1 Diabetes Mellitus and Myasthenia Gravis: A Case Report and Review of the Literature.

Background/Objective: Type 1 diabetes (T1D) and myasthenia gravis (MG) are autoimmune conditions that rarely co-occur. Here, we report a child with MG who subsequently developed T1D. Case report: An 11-year-old girl with seropositive MG diagnosed at 4 years of age presented with muscle pain, cramps, and weight loss of 3.5 kg over 4 months. Her MG was in remission on daily pyridostigmine. She denied polyuria, polydipsia, recent illnesses, or other medications. She was prepubertal and had stable vitals with normal systemic examination. Initial work up for a probable diagnosis of rhabdomyolysis showed hyperglycemia and glucosuria. She had ketosis without acidosis. Diabetes autoantibodies were positive (anti-glutamic acid decarboxylase antibody 113.5 IU/mL (reference range < 5 IU/mL), anti-zinc transporter 8 antibody > 500 U/mL (reference range < 15 IU/mL)). Screening for autoimmune thyroid disease and celiac disease was negative. Patient was diagnosed with T1D and was started on subcutaneous insulin. Discussion: The co-existence of MG and T1D is rare. All the 4 prior reported patients from Europe were diagnosed with T1D prior to or concurrently with MG. In contrast, our patient was first diagnosed with MG and subsequently diagnosed with T1D 7 years later. Conclusions: Consider screening for T1D in patients with MG and offering treatment to those above 8 years and older with stage 2 T1D to delay its onset. Along with other causes, T1D should also be considered when patients with MG present with nonspecific symptoms such as fatigue and weight loss.

Laboratory Changes During Gender-Affirming Hormone Therapy in Transgender Adolescents.

OBJECTIVES: Guidelines for monitoring of medications frequently used in the gender-affirming care of transgender and gender-diverse (TGD) adolescents are based on studies in adults or other medical conditions. In this study, we aimed to investigate commonly screened laboratory measurements in TGD adolescents receiving gender-affirming hormone therapy (GAHT). METHODS: TGD adolescents were recruited from 4 study sites in the United States before beginning GAHT. Hemoglobin, hematocrit, hemoglobin A1c, alanine transaminase, aspartate aminotransferase, prolactin, and potassium were abstracted from the medical record at baseline and at 6, 12, and 24 months after starting GAHT. RESULTS: Two-hundred and ninety-three participants (68% designated female at birth) with no previous history of gonadotropin-releasing hormone analog use were included in the analysis. Hemoglobin and hematocrit decreased in adolescents prescribed estradiol (-1.4 mg/dL and -3.6%, respectively) and increased in adolescents prescribed testosterone (+1.0 mg/dL and +3.9%) by 6 months after GAHT initiation. Thirteen (6.5%) participants prescribed testosterone had hematocrit > 50% during GAHT. There were no differences in hemoglobin A1c, alanine transaminase, or aspartate aminotransferase. There was a small increase in prolactin after 6 months of estradiol therapy in transfeminine adolescents. Hyperkalemia in transfeminine adolescents taking spironolactone was infrequent and transient if present. CONCLUSIONS: Abnormal laboratory results are rare in TGD adolescents prescribed GAHT and, if present, occur within 6 months of GAHT initiation. Future guidelines may not require routine screening of these laboratory parameters beyond 6 months of GAHT in otherwise healthy TGD adolescents.

Care for Transgender Young People.

Clinicians of all disciplines, including pediatric endocrinologists, are likely to encounter transgender and gender-diverse (TGD) young people in their practice regardless of whether they specialize in gender-affirming medical care. Because of this, it is important to be aware of the ways in which medical professionals can affirm these individuals. Although gender-affirming therapy should always include affirmation including proper use of names and pronouns, the transition journey will look different for each patient. The gender-affirming care of TGD young people may include both medical and nonmedical interventions (e.g., social transition). Therapies utilized for medical gender transition such as gonadotropin-releasing hormone agonists and/or gender-affirming hormones have implications for growth, bone health, cardiovascular health, and fertility, although these impacts are not yet completely understood. This review provides an overview of the care of transgender young people as well as a summary of what is known about the outcomes of these therapies. Clinicians should advise TGD young people and their families of the known and unknown risks and work together with patients to decide upon a treatment and follow-up regimen that aligns with their individual gender affirmation and health goals.

Growth in Transgender/Gender-Diverse Youth in the First Year of Treatment With Gonadotropin-Releasing Hormone Agonists.

PURPOSE: Transgender/gender-diverse (TGD) youth are treated with gonadotropin-releasing hormone agonists (GnRHas) to halt endogenous puberty and prevent the development of secondary sex characteristics discordant with their gender identity. This treatment may have significant impact on growth and height velocity (HV). METHODS: Participants were recruited prior to GnRHa initiation from four gender specialty clinics in the U.S. Anthropometric, laboratory, and Tanner-stage data were abstracted from medical records. RESULTS: Fifty-five TGD youth (47% designated male at birth) with a mean ± standard deviation age of 11.5 ± 1.2 years were included in the analysis. HV in the first year of GnRHa use was median (interquartile range) 5.1 (3.7-5.6) cm/year. Later Tanner stage at GnRHa initiation was associated with lower HV: 5.3 (4.4-5.6) cm/year for Tanner stage II, 4.4 (3.3-6.0) cm/year for Tanner stage III, and 1.6 (1.5-2.9) cm/year for Tanner stage IV (p = .001). When controlled for age, there was not a significant difference in mean HV between TGD youth and prepubertal youth; however, when stratified by Tanner stage individuals starting GnRHa at Tanner stage IV had an HV below that of prepubertal youth, 1.6 (1.5-2.9) versus 6.1 (4.3-6.5) cm/year, p = .006. CONCLUSIONS: Overall, TGD youth treated with GnRHa have HV similar to that of prepubertal children, but TGD youth who start GnRHa later in puberty have an HV below the prepubertal range. Ongoing follow-up of this cohort will determine the impact of GnRHa treatment on adult height.

Expansion of the clinical and neuroimaging spectrum associated with NDUFS8-related disorder.

Biallelic pathogenic variants in NDUFS8, a nuclear gene encoding a subunit of mitochondrial complex I, result in a mitochondrial disorder characterized by varying clinical presentations and severity. Here, we expand the neuroimaging and clinical spectrum of NDUFS8-related disorder. We present three cases from two unrelated families (a girl and two brothers) homozygous for a recurrent pathogenic NDUFS8 variant [c.460G>A, p.(Gly154Ser)], located in the [4Fe-4S] domain of the protein. One of the patients developed auto-antibody positive diabetic ketoacidosis. Brain MRIs performed in two of the three patients demonstrated diffuse cerebral and cerebellar white matter involvement including corticospinal tracts, but notably had sparing of deep gray matter structures. Our report expands the neuroimaging phenotype of NDUFS8-related disorder to include progressive leukodystrophy with increasing brainstem and cerebellar involvement, with relative sparing of the basal ganglia. In addition, we describe autoimmune diabetes in association with NDUFS8-related disorder, though the exact mechanism of this association is unclear. This paper provides a comprehensive review of case presentation and progressive neuroimaging findings of three patients from two unrelated families that have an identical pathogenic NDUFS8 variant, which expands the clinical spectrum of NDUFS8-associated neurological disease.

Lipoprotein subtypes after testosterone therapy in transmasculine adolescents.

Differences in lipoprotein-particle subclasses between men and women start in puberty and narrow after menopause, suggesting a role for sex steroids. In this cross-sectional cohort study, we examined lipoprotein subtype profiles in transmasculine adolescents treated with testosterone. Transmasculine adolescents (n = 17) had lipoprotein profiles that were similar to those of cisgender males (n = 33) and more atherogenic than those of cisgender females (n = 32), with higher concentrations of small low-density lipoprotein (LDL) particles (435 ± 222 nmol/L vs. 244 ± 163 nmol/L, p = 0.008) and lower concentrations of large high-density lipoprotein (HDL) particles (1.5 ± 1.3 µmol/L vs 2.7 ± 1.2 µmol/L, p = 0.003) when compared to cisgender females. Thus, testosterone appears to be a major contributor to differences in lipoprotein profiles, a surrogate for cardiovascular disease risk, between cisgender women and both transgender and cisgender men.

Greater Than Expected Prevalence of Type 1 Diabetes Mellitus Found in an Urban Gender Program.

The prevalence of type 1 diabetes mellitus among transgender and gender diverse (TGD) youth is nearly five times higher than in the general pediatric population (9.9 per 1000 people vs. 1.93 per 1000 people). We hypothesize that minority stress experienced by TGD youth may lead to a higher prevalence of diabetes.

Physiological and Metabolic Characteristics of a Cohort of Transgender and Gender-Diverse Youth in the United States.

PURPOSE: The purpose of this study was to describe baseline physical and laboratory characteristics of participants in the largest prospective study of transgender and gender-diverse (TGD) youth in the United States. METHODS: Participants were recruited from four clinics which specialize in the care of TGD youth before starting either GnRH analogs for pubertal suppression or gender-affirming hormone treatment. Anthropometric and laboratory measurements were abstracted from the medical chart. Baseline characteristics including height, weight, body mass index, blood pressure, and laboratory measurements were compared with those of age-matched National Health and Nutritional Examination Survey comparison group. RESULTS: Seventy-eight TGD youth with a median age of 11 years (range 8-14 years) were recruited before pubertal suppression, of whom 41 (53%) were designated male at birth, and 296 participants with a median age of 16 years (range 12-20 years) were recruited before beginning gender-affirming hormones, of whom 99 (33%) were designated male at birth. The mean high-density lipoprotein cholesterol was lower in the study participants when compared with that of National Health and Nutritional Examination Survey participants (50.6 ± 12.3 mg/dL vs. 53.3 ± 13.3 mg/dL, p = .001). Otherwise, the study cohorts were similar in terms of body mass index, proportion of overweight and obesity, blood pressure, and baseline laboratory variables. CONCLUSIONS: Before starting gender-affirming treatment, TGD youth are physiologically similar to the general population of children and adolescents in the United States, with the exception of slightly lower high-density lipoprotein cholesterol. Evaluation of this cohort over time will define the physiological effects of pubertal blockade and gender-affirming hormone treatment.

Case Series: Minocycline-Associated Thyroiditis.

INTRODUCTION: Minocycline, a member of the tetracycline class of antibiotics, has been associated with benign thyroid pigmentation but reports of thyroid dysfunction are sparse. METHODS: Cases were selected via an inquiry of the electronic medical records for patients with thyroid dysfunction and the use of a tetracycline antibiotic. Non-autoimmune thyroiditis was defined as abnormally low or suppressed thyroid-stimulating hormone (TSH, <0.3 µIU/mL), elevated free thyroxine or total thyroxine, and undetectable antithyroid antibodies. RESULTS: Nine cases of thyroiditis without autoimmunity were identified out of 423 reviewed patients. Cases of thyroiditis occurred in adolescents ages 14-17 years who had been taking minocycline for 6 months to 4 years. In all cases, minocycline was prescribed for the treatment of acne. Four of the 9 received treatment for thyrotoxicosis with a ß-blocker (in 3 cases) and/or antithyroid drug (in 2 cases). Thyroiditis was symptomatic in all but one individual who presented with painless goiter. All thyroiditis was transient and resolved after a median of 4.5 months (range 2-5 months). In one case, thyroiditis was followed by transient hypothyroidism. DISCUSSION: Minocycline is known to cause thyroid abnormalities, although it has not been definitively linked to thyroid dysfunction. Here, we report 9 cases of non-autoimmune thyroiditis in adolescents receiving minocycline for acne. We recommend that minocycline exposure be considered in the differential diagnosis for thyroiditis and that patients receiving minocycline be counseled regarding the risk of thyroid dysfunction.

The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone.

CONTEXT: Current guidelines recommend close monitoring of electrolytes in transgender patients using spironolactone given the risk of hyperkalemia from mineralocorticoid antagonism. In patients taking spironolactone for other conditions, the rate of hyperkalemia is low, and the utility of frequent monitoring has been questioned. OBJECTIVE: We hypothesized that the rate of hyperkalemia in gender-diverse adolescents taking spironolactone is low and, when present, clinically insignificant. DESIGN AND OUTCOMES: A retrospective chart review of adolescents seen in a specialty gender clinic at a tertiary care pediatric hospital over 10 years identified patients prescribed spironolactone for gender transition. Study outcomes were the incidence of hyperkalemia, defined as serum potassium concentration >5.0 mmol/L, and the relationship between potassium levels and spironolactone dose and duration. RESULTS: Records were reviewed for 85 subjects with a mean ± SD age of 16.6 ± 1.7 years. There were a total of 269 potassium measurements (80 prior to spironolactone initiation and 189 during spironolactone treatment). Six potassium measurements in five subjects were >5.0 mmol/L, indicating a rate of hyperkalemia of 2.2%. None of the subjects had symptoms of hyperkalemia, and all elevated measurements were normal when repeated. Only one subject discontinued spironolactone after an elevated potassium measurement. There was no relationship between hyperkalemia and spironolactone dose. Potassium measurements decreased with increasing treatment duration. CONCLUSIONS: Hyperkalemia in patients taking spironolactone for gender transition is rare and when present is transient and asymptomatic. In the absence of other medical comorbidities, routine electrolyte monitoring in this population may be unnecessary.

11-year old boy with facial hair, acne and deepened voice.

11-year old twin boy found to have idiopathic precocious puberty after routine well-child examination revealed discordant pubertal growth between the two brothers.