Characterization of Spontaneous and Induced Puberty in Girls with Turner Syndrome

OBJECTIVE: To characterize puberty in girls with Turner syndrome (TS) and determine whether specific patient characteristics are associated with the timing of menarche. We also sought to compare spontaneous versus induced puberty in these patients. METHODS: Medical records of girls followed in our Pediatric Endocrine clinic for TS from 2007 to 2015 were reviewed. RESULTS: Fifty-three girls were included, of whom 10 (19%) achieved menarche spontaneously and 43 (81%) received hormone replacement therapy (HRT). Of girls receiving HRT, a younger age at estrogen initiation correlated with a longer time to menarche (P = .02), and a mosaic karyotype was associated with a shorter time to menarche (P = .02), whereas no relationship was seen for body mass index, estrogen regimen, or maternal age at menarche. Nineteen girls (44%) receiving HRT had bleeding on estrogen alone at a wide dose range and were more likely to be on transdermal than oral preparations (P = .01). Girls with spontaneous puberty achieved menarche at a younger age (P<.01) and were more likely to have mosaic TS (P = .02). CONCLUSION: Significant variability in the timing of menarche exists among girls with TS. However, age at pubertal induction and karyotype were significantly correlated with age at menarche in our patients. A wide range of estrogen doses is seen in girls who bleed prior to progesterone, suggesting extreme variability in estrogen sensitivity among patients with TS. Girls achieving spontaneous menarche are younger and more likely to have a mosaic karyotype than those with induced menarche. Large-scale prospective studies are needed to confirm these results

Methimazole Desensitization in a 4-Year-Old With Refractory Graves Disease

Objective: To describe a 4-year-old girl with Graves disease and methimazole allergy who underwent desensitization, allowing continued methimazole use when other treatments were contraindicated. Methods: We formulated a desensitization plan utilizing cetirizine and prednisone for a patient with previously diagnosed Graves disease who developed urticaria and arthralgias from methimazole. She was admitted for monitoring of rash, urticaria, angioedema, and anaphylaxis. Her methimazole dose was increased as tolerated and then titrated as an outpatient. Results: A 4-year-old girl presented with a heart rate of 195 beats/minute, blood pressure of 145/108, and subsequent labs of undetectable thyroid stimulating hormone (TSH), free T4 5.8 ng/dL, thyroid peroxidase antibody 11.5 IU/ml, and TSH receptor antibody 39.03 IU/L, consistent with Graves disease. She developed urticaria and arthralgias after 2.5 weeks on methimazole, which resolved with drug cessation. Because of her age, the risks of radioactive iodine ablation and surgery were concerning; therefore, methimazole desensitization was attempted. Prednisone (1 mg/kg/day) and cetirizine (5 mg/day) were started prior to low-dose methimazole reintroduction and continued for 7 days. Methimazole was then gradually increased to a final dose of 15 mg daily (0.8 mg/kg/day). Free T4 normalized within a month (1.12 ng/dL), and her TSH normalized within 10 months (4.61 mcU/mL). Except for 2 possible breakthrough allergic responses that resolved with pulse steroids, she continues to tolerate methimazole. Conclusion: We describe a case of methimazole desensitization. In this patient, pretreatment with prednisone, coupled with daily cetirizine, successfully induced methimazole tolerance when other treatment modalities were contraindicated

Differential effects of hydrocortisone, prednisone, and dexamethasone on hormonal and pharmacokinetic profiles: a pilot study in children with congenital adrenal hyperplasia

BACKGROUND: Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. METHODS: Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. RESULTS: Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BMI. SNP analysis revealed significant associations between hormone concentrations, pharmacokinetic parameters, and variants in several glucocorticoid pathway genes (ABCB1, NR3C1, IP013, GLCCI1). CONCLUSIONS: DEX resulted in marked adrenal suppression suggesting that its potency relative to hydrocortisone and prednisone was underestimated. SNPs conferred significant differences in responses between subjects. Although preliminary, these pilot data suggest that incorporating pharmacogenetics has the potential to eventually lead to targeted therapy in children with CAH

Testotoxicosis with an episodic course: an unusual case within a series

Objective: To describe an unusual case of familial male precocious puberty (FMPP) characterized by periodic remission compared to a series of boys with typical testotoxicosis. Methods: Medical records of boys with FMPP followed at our institution from 2001–2017 were reviewed. Variables analyzed included age, family history, physical exam, hormone levels, bone age, and treatment. Results: A boy of age 2 years 10 months presented with growth acceleration and masturbatory behaviors. On exam, he had 6-mL testes, an enlarged phallus (10.5 × 2.5 cm), and Tanner 2 pubic hair. Testosterone was 242 ng/dL (normal level, ≤30 ng/dL). Genetic testing revealed an Asp578Gly luteinizing hormone receptor mutation confirming FMPP. Anastrozole 1 mg and bicalutamide 50 mg daily were started. During 7.5 years of follow-up, two periods of spontaneous remission occurred lasting >3 years and 10 months, respectively. Both were characterized by prepubertal testosterone levels (10 to 28 ng/dL) and arrested pubertal development off therapy. Relapses were marked by elevated testosterone, growth acceleration, and pubertal progression. Ten additional boys aged 3.46 ± 0.72 years with FMPP were identified, one of whom also had an Asp578Gly mutation. Average testosterone at presentation was 335 ± 193 ng/dL (range, 146 to 778 ng/dL) and average bone age/chronologic age was 2.02 ± 0.47. All were treated with bicalutamide and anastrozole or letrozole. Conclusion: We report a case of intermittent FMPP in contrast to a series of boys with a characteristic clinical course. To our knowledge, a similar case has not previously been reported. Our case expands the clinical spectrum of this rare condition

Testotoxicosis with an episodic course: an unusual case within a series

Objective: To describe an unusual case of familial male precocious puberty (FMPP) characterized by periodic remission compared to a series of boys with typical testotoxicosis. Methods: Medical records of boys with FMPP followed at our institution from 2001–2017 were reviewed. Variables analyzed included age, family history, physical exam, hormone levels, bone age, and treatment. Results: A boy of age 2 years 10 months presented with growth acceleration and masturbatory behaviors. On exam, he had 6-mL testes, an enlarged phallus (10.5 × 2.5 cm), and Tanner 2 pubic hair. Testosterone was 242 ng/dL (normal level, ≤30 ng/dL). Genetic testing revealed an Asp578Gly luteinizing hormone receptor mutation confirming FMPP. Anastrozole 1 mg and bicalutamide 50 mg daily were started. During 7.5 years of follow-up, two periods of spontaneous remission occurred lasting >3 years and 10 months, respectively. Both were characterized by prepubertal testosterone levels (10 to 28 ng/dL) and arrested pubertal development off therapy. Relapses were marked by elevated testosterone, growth acceleration, and pubertal progression. Ten additional boys aged 3.46 ± 0.72 years with FMPP were identified, one of whom also had an Asp578Gly mutation. Average testosterone at presentation was 335 ± 193 ng/dL (range, 146 to 778 ng/dL) and average bone age/chronologic age was 2.02 ± 0.47. All were treated with bicalutamide and anastrozole or letrozole. Conclusion: We report a case of intermittent FMPP in contrast to a series of boys with a characteristic clinical course. To our knowledge, a similar case has not previously been reported. Our case expands the clinical spectrum of this rare condition

Characterization of Spontaneous and Induced Puberty in Girls with Turner Syndrome

OBJECTIVE: To characterize puberty in girls with Turner syndrome (TS) and determine whether specific patient characteristics are associated with the timing of menarche. We also sought to compare spontaneous versus induced puberty in these patients. METHODS: Medical records of girls followed in our Pediatric Endocrine clinic for TS from 2007 to 2015 were reviewed. RESULTS: Fifty-three girls were included, of whom 10 (19%) achieved menarche spontaneously and 43 (81%) received hormone replacement therapy (HRT). Of girls receiving HRT, a younger age at estrogen initiation correlated with a longer time to menarche (P = .02), and a mosaic karyotype was associated with a shorter time to menarche (P = .02), whereas no relationship was seen for body mass index, estrogen regimen, or maternal age at menarche. Nineteen girls (44%) receiving HRT had bleeding on estrogen alone at a wide dose range and were more likely to be on transdermal than oral preparations (P = .01). Girls with spontaneous puberty achieved menarche at a younger age (P<.01) and were more likely to have mosaic TS (P = .02). CONCLUSION: Significant variability in the timing of menarche exists among girls with TS. However, age at pubertal induction and karyotype were significantly correlated with age at menarche in our patients. A wide range of estrogen doses is seen in girls who bleed prior to progesterone, suggesting extreme variability in estrogen sensitivity among patients with TS. Girls achieving spontaneous menarche are younger and more likely to have a mosaic karyotype than those with induced menarche. Large-scale prospective studies are needed to confirm these results

An Online Resident-as-Teacher Curriculum Improves First-Year Residents’ Self-Confidence Teaching in the Clinical Learning Environment

We implemented an online Resident-as-Teacher curriculum for all incoming residents (PGY1s) to provide them with a basic foundation for effective teaching in the clinical learning environment. The curriculum consisted of 5 asynchronous modules delivered via the web from 2017-2021. Prior to starting the course, the PGY1s completed a self-assessment of their teaching ability (pre-test) and then again 7-8 months after completing the course (post-test). Analysis of the paired data from 421 PGY1s showed a statistically significant improvement in the self-ratings of their teaching from pre-test to post-test (p < 0.001). Our findings suggest that an online Resident-as-Teacher curriculum can produce lasting benefits in new residents’ self-confidence as educators

Advancing Equity in Graduate Medical Education Recruitment Through a Diversity Equity and Inclusion (DEI) Toolkit for Program Directors

Objectives To increase diversity and inclusion in graduate medical education (GME), the Accreditation Council for Graduate Medical Education (ACGME) issued new diversity standards requiring programs to engage in practices that focus on systematic recruitment and retention of a diverse workforce of trainees and faculty. The literature on how program directors (PDs) can incorporate and prepare for this standard is limited. Methods We developed a diversity, equity, and inclusion (DEI) toolkit for PDs as an example of an institutional GME-led effort to promote inclusive recruitment and DEI awareness among residency and fellowship programs at a large academic center. Results A survey was sent to 80 PDs before the launch of the toolkit and 6 months afterwards with response rates of 27% (22/80) and 97% (78/80), respectively. At baseline, 45% (10/22) anticipated that the DEI toolkit might provide better resources than those currently available to them and 41% (9/22) perceived that the toolkit might improve recruitment outcomes. At 6 months, 63% (49/78) found the toolkit helpful in the 2021-2022 recruitment season. By contrast, 2% (2/78) of PDs did not find the toolkit helpful, and 33% (26/78) said they did not access the toolkit. When asked if a PD changed their program's recruitment practices because of the toolkit, 31% (24/78) responded yes. Programs that changed recruitment practices started to require unconscious bias training for all faculty and residents involved in the residency interviews and ranking. Others worked on creating a standardized scoring rubric for interviews focused on four main domains: Experiences, Attributes, Competencies, and Academic Metrics. Conclusion There is a need to support PDs in their DEI journey and their work to recruit a diverse workforce in medicine. Utilizing a DEI toolkit is one option to increase DEI knowledge, skills, awareness, and self-efficacy among PDs and can be adopted by other institutions and leaders in academic medicine