A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience.

Background: Androgen blockers are an essential part of gender affirming care in post-pubertal transfeminine patients. Bicalutamide is a highly potent androgen receptor blocker that is used primarily in adults. We aimed to review our experience with the use of bicalutamide in transgender adolescents who were assigned male at birth. Methods: A retrospective review of medical records of transfeminine patients treated with bicalutamide during an 8-year period was conducted. Results: Forty patients, aged 15.5 ± 1.55 years were identified, of whom 21 (53%) were started on bicalutamide alone and 19 were started concurrently on estrogen. In patients on bicalutamide alone, 90.4% reported breast development at their first follow up visit, which occurred at a median of 7.1 months. Patients were treated for 29.4 ± 18.2 months. No episodes of liver toxicity related to bicalutamide were seen. Conclusions: Although these results are preliminary, bicalutamide appears to be a safe option for androgen blockade in transgender girls.

Treatment of Central Precocious Puberty with a Focus on Girls.

The age of thelarche has declined in the past few decades but not the age of menarche. This is important when assessing girls who present with breast development between 6 and 8 years because not all of them will need treatment. The decision for treatment depends on age, bone age (BA), rate of pubertal progression, height velocity, psychosocial factors, and predicted adult height (PAH), with the caveat that height predictions are not precise and BA interpretation is variable.

Diagnostic Conundrum of a Sertoli Cell Tumor in a 2-Year-Old Girl with Peripheral Precocious Puberty and a Café-au-Lait Macule: A Case Report.

INTRODUCTION: Ovarian Sertoli cell tumors represent a subset of sex cord stromal tumors and are exceedingly rare in prepubertal children. Here, we report a girl with vaginal bleeding due to a Sertoli cell tumor who was originally thought to have McCune-Albright syndrome (MAS). CASE PRESENTATION: A previously healthy girl presented at age 2 years 6 months with breast development and vaginal bleeding. On exam, she had Tanner 4 breasts, Tanner 1 pubic hair, estrogenized vaginal mucosa, and a café-au-lait macule. Laboratory studies revealed an elevated estradiol with suppressed gonadotropins and negative tumor markers. Her bone age was advanced by more than 3 years. Pelvic ultrasound (US) revealed an enlarged uterus and a slightly larger left compared to right ovary. She was started on tamoxifen for presumed MAS. A repeat pelvic US 1 month later showed a heterogenous mass in the left ovary which was subsequently resected. Pathology revealed a Sertoli cell tumor, lipid-rich variant. Germline sequencing revealed a pathogenic STK11 variant, diagnostic for Peutz-Jeghers syndrome (PJS). CONCLUSION: The findings in our patient were strikingly similar to those encountered in MAS. To our knowledge, our patient is the youngest ever reported to present with precocious puberty due to a Sertoli cell tumor in the setting of PJS.

Presentation and Care for Children with Peripheral Precocious Puberty.

Peripheral precocious puberty (PPP) refers to the early onset of sexual maturation that is independent of central nervous system control. The extensive differential diagnosis includes congenital and acquired causes. Presenting features depend on which class of sex steroids is involved, and diagnosis rests on hormonal and, if indicated, imaging and/or genetic studies. Effective treatment exists for nearly all causes of PPP. Ongoing research will advance our therapeutic armamentarium and understanding of the pathophysiologic basis of these conditions.

Characteristics of patients with classic congenital adrenal hyperplasia missed on the newborn screen.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) has been in place in the USA for over 20 years. However, not all patients with classic CAH are diagnosed as neonates. OBJECTIVES: Our aim was to characterize patients with classic CAH who were missed on the newborn screen (NBS) in Indiana and determine if discriminating features were present that might have led to earlier detection. METHODS: Medical records of children diagnosed with classic CAH due to 21-hydroxylase deficiency seen at Riley Hospital for Children in Indiana between January 2005 and December 2020 were reviewed. Patient characteristics, visit information and lab results were collected. Statistical analysis was performed using SPSS version 28. RESULTS: A total of 64 patients were identified of whom 12 (19%) were missed on the NBS. Mean age at diagnosis was 21.7 months (range: 2-74 months), 67% were girls and 66% were salt wasters. Eight (67%) presented with clinical evidence of hyperandrogenism, including clitoromegaly (n=7), posterior labial fusion (n=5) and pubic hair (n=2). Screening was pursued due to a family history of CAH in the remaining 4. Genetic confirmation was present in 50%. There was no history of antenatal steroid exposure in any of the missed patients. No differences were seen with regard to sex, ethnicity, gestational age, birth weight, type of CAH or serum 17-hydroxyprogesterone (17OHP) level at diagnosis in patients who were missed compared with those diagnosed on the NBS (14,948 ng/dL vs 16,701 ng/dL, p=0.74). However, the mean testosterone level at diagnosis was lower in patients who were missed compared with those who were diagnosed earlier (68 ± 60.28 vs 196.2 ± 206.0, p=0.02). Positive family history of CAH was present in 42% of the missed patients. Timing of the NBS collection was not different between the two groups, p=0.36. CONCLUSION: Nearly one-fifth of our patients with classic CAH were missed on the NBS. No specific features were identified that distinguished these children from those who were detected at birth. It is critical to maintain a high index of suspicion for CAH in order to recognize these patients as early as possible so as to avoid adverse effects and potential life-threatening adrenal crises.

Central precocious puberty: a review of diagnosis, treatment, and outcomes.

Central precocious puberty (CPP) refers to early activation of the hypothalamic-pituitary-gonadal (HPG) axis and is manifested by breast development in girls or testicular enlargement in boys before the normal physiological age ranges. CPP can be precipitated by intracranial pathology, exposure to high levels of sex steroids, or environmental risk factors, but most cases are idiopathic. Monogenic causes have also been identified. In this Review, we summarise pathophysiology, risk factors, diagnosis, and management of CPP. Concern for CPP should prompt referral to paediatric endocrinology where diagnosis is confirmed by clinical, biochemical, radiological, and genetic testing. CPP is treated with a gonadotropin-releasing hormone analogue, the primary aims of which are to increase adult height and postpone development of secondary sexual characteristics to an age that is more commensurate with peers. Although long-term outcomes of treatment with gonadotropin-releasing hormone analogues are reassuring, additional research on the psychological effect of CPP is needed.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Rhabdomyolysis: A Rare Presentation of Hashimoto Thyroiditis in an Adolescent Boy and Review of the Literature.

INTRODUCTION: Hypothyroidism-induced rhabdomyolysis without precipitating factors is extremely rare, particularly in pediatric patients. We describe a previously healthy adolescent boy who came to our institution with vague symptoms and was found to have rhabdomyolysis secondary to hypothyroidism due to Hashimoto thyroiditis. We also summarize previously published cases in children and adolescents. CASE PRESENTATION: A 16-year-old boy presented to the emergency department at Riley Hospital for Children with a 2-week history of bilateral eye and lip swelling, fatigue, and slowing of speech initially attributed to angioedema. His laboratory studies were significant for acute kidney injury secondary to rhabdomyolysis. Additional evaluation revealed profound primary hypothyroidism and positive TPO antibodies. Although his free T4 was undetectable, his TSH was only 32.2 mcU/mL. He received IV hydration and thyroid replacement, and his symptoms improved after several months of treatment. DISCUSSION: Rhabdomyolysis without any risk factors is very rare, especially in children. Our patient was not on any medications, had no family history of neuromuscular disorders, and no history of trauma, infection, or strenuous exercise. The reason behind the disproportionately mild elevation of TSH in the setting of an undetectable free T4 is unclear. CONCLUSION: It is important for clinicians to be aware that rhabdomyolysis may be a presenting sign of severe hypothyroidism, as delay in diagnosis and treatment can be detrimental.

Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia.

BACKGROUND: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. OBJECTIVE: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. METHODS: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher's exact test was used to determine statistical significance. RESULTS: Of 123 responders, 14 were males with CAH (range 16-54 years) and 109 were parents of males with CAH (son's age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. CONCLUSIONS: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.

Long-term experience with the use of a single histrelin implant beyond one year in patients with central precocious puberty.

OBJECTIVES: The histrelin implant has been used to treat central precocious puberty (CPP) for more than 15 years. Although approved for annual use, limited published reports suggest that a single implant is efficacious well beyond a year. Our objective was to report our long-term experience using a single histrelin implant for more than 12 months in children with CPP. METHODS: We performed a retrospective study of 170 children with central precocious puberty treated with a single histrelin implant for more than 1 year. RESULTS: Implants were left in situ for an average of 24 months. Pubertal development regressed or remained stable in the vast majority of patients and biochemical suppression was maintained. No correlation between time since an implant was placed and complications such as implant breakage or a second incision was seen. CONCLUSIONS: A single histrelin implant provides excellent pubertal suppression well beyond a year. Extended use of a single histrelin implant should be considered standard of care in children with CPP.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

History of Puberty: Normal and Precocious.

Spanning from bench to bedside, the history of normal and precocious puberty is characterized by a series of remarkable advances that have illuminated reproductive physiology and profoundly impacted clinical care. Early recognition of the hypothalamic and pituitary control of ovarian and testicular function led to the identification of GnRH as the key driver of pubertal onset. Decades later, discovery of the kisspeptin system further refined our understanding of human reproductive neuroendocrinology. Development of long-acting analogs of GnRH revolutionized the treatment of precocious puberty worldwide and ushered in the current era of an ever-expanding therapeutic armamentarium. Identification of monogenic etiologies of precocious puberty has further illustrated the exquisite complexity that comprises neurosecretory modulation of the hypothalamic GnRH neuron and may well lead to exciting novel targeted therapies.

Gonadotropin-releasing hormone analog therapies for children with central precocious puberty in the United States.

Gonadotropin-releasing hormone agonists (GnRHa's) are the standard treatment for children with central precocious puberty (CPP). We aim to present data on available GnRHa options with an easy-to-review table and discuss factors that influence treatment selection. Five GnRHa's are currently FDA-approved and prescribed in the US and published data suggest similar safety and efficacy profiles over the first year of treatment. One- and 3-month intramuscular (IM) leuprolide acetate (LA) have long-term safety and efficacy data and allow for flexible dosing. Six-month IM triptorelin pamoate offers a longer duration of treatment, but without long-term efficacy and outcome data. Six-month subcutaneous (SQ) LA combines a SQ route of injection and long duration of action but lacks long-term efficacy and outcome data. The 12-month SQ histrelin acetate implant avoids injections and offers the longest duration of action, but requires a minor surgical procedure with local or general anesthesia. Factors in treatment selection include route of administration, needle size, injection volume, duration of action, and cost. The current GnRHa landscape provides options with varying benefits and risks, allowing physicians and caregivers to select the most appropriate therapy based on the specific needs and concerns of the child and the caregiver. Agents have different advantages and disadvantages for use, with no one agent displaying superiority.

Do All Patients with Congenital Adrenal Hyperplasia Need to Be on Hydrocortisone Three Times a Day in Order to Have Normal Growth?

BACKGROUND: Three times daily (TID) hydrocortisone (HC) is recommended as the optimal glucocorticoid regimen in growing children with congenital adrenal hyperplasia (CAH). However, a variety of other treatment schemes are used in the clinical setting. OBJECTIVE: The aim of this study was to determine whether there are clinical differences between children being treated with TID HC versus those receiving other glucocorticoid regimens. Furthermore, we sought to determine whether there was evidence of a deleterious effect on growth in children receiving treatment with alternate regimens. METHODS: Medical records of children followed in our pediatric endocrinology outpatient clinic for classic CAH secondary to 21-hydroxylase deficiency during the last 10 years were reviewed. Variables analyzed included sex, age at the most recent visit, glucocorticoid type, frequency and dose (mg/m2/day), height z-score, BMI z-score, ethnicity, most recent bone age, growth velocity z-score, and provider's impression of compliance (good or poor). RESULTS: Of 104 children (51% boys) with CAH, 50 (48%) were on TID HC, 43 (41%) were on prednisone or prednisolone, and 5 (5%) were on dexamethasone. An additional 6 (6%) were on HC administered either 2 or 4 times daily. No differences were seen between TID HC and alternate regimen groups with respect to sex, height z-score, BMI z-score, ethnicity, provider assessment of compliance, ratio of bone age to chronologic age, or growth velocity. The average height z-score was -0.40 ± 1.31 in the TID HC group compared to -0.87 ± 1.33 in the alternate regimen group (p = 0.075). Patients receiving TID HC were younger (p = 0.027) and on a lower glucocorticoid dose (p = 0.001) than those on alternate regimens. CONCLUSIONS: Less than half of our patients with CAH were receiving TID HC. Reassuringly, growth parameters and other indices of disease control were equivalent between patients on conventional HC dosing and other therapeutic approaches. These results suggest that a range of glucocorticoid treatment regimens may be equally viable in children with CAH.

Outcome of Dopamine Agonist Therapy Withdrawal in Children with Prolactinomas.

BACKGROUND: Prolactinomas are rare in children and adolescents. As in adults, dopamine agonists (DAs) are the treatment of choice in the majority of patients. However, at what point children should be taken off of therapy and what the recurrence risk of hyperprolactinemia is following treatment withdrawal is not well described. OBJECTIVE: Our objective was to systematically review our experience with DA treatment withdrawal in children and adolescents with prolactinomas. METHODS: A retrospective review of patients followed for prolactinomas during the last 12 years was conducted. Variables analyzed included age, gender, initial serum prolactin levels, tumor characteristics, cabergoline dose, and results of treatment withdrawal. Clinical characteristics of patients who met eligibility criteria for DA withdrawal were compared with those who did not. Patients who underwent surgery were excluded. RESULTS: Of 47 patients identified, 42 were included in the study. Of those, DA withdrawal was attempted in 13 (31%) and was initially successful in 3 (21%). Patients who did not meet eligibility criteria for treatment withdrawal had higher baseline prolactin levels (p = 0.018) as well as larger (p = 0.03) and more invasive (p = 0.002) tumors. CONCLUSIONS: Less than half of our patients were eligible for DA treatment withdrawal and less than one-fourth achieved remission of hyperprolactinemia following cessation of therapy. This suggests that the overall recurrence rate of prolactinomas in pediatric patients may be higher than has been reported in adults.

Gonadotropin-Releasing Hormone Analogs for Treatment of Central Precocious Puberty in Children Younger than 2 Years of Age.

Although gonadotropin-releasing hormone analogs are the standard of care for the treatment of central precocious puberty, they are not approved for children/< age 2 years. We reviewed experience with the use of gonadotropin-releasing hormone analogs in 47 children younger than age 2 years, which revealed efficacy and safety comparable with that in older children.

Variability in Oral Desmopressin Dose Requirements in Children with Central Diabetes Insipidus.

There is inconsistency in the amount of oral desmopressin that children with central diabetes insipidus require. We investigated whether clinical characteristics influenced desmopressin dose requirements in 100 children with central diabetes insipidus. Extremely large doses were associated with acquired etiology (P = .04), greater body mass index z score, intact thirst, and additional pituitary hormone deficiencies (P < .001).

Non-GH Agents and Novel Therapeutics in the Management of Short Stature.

Short stature is one of the most common reasons for referral to pediatric endocrinologists. The vast majority of short children do not have growth hormone (GH) deficiency or another pathologic process that is interfering with normal growth. While GH has been approved in the US for several etiologies of non-GH deficient short stature, its high cost and need for daily injections represent barriers for many families. Alternative agents for the management of short stature include the use of gonadotropin releasing hormone analogs (GnRHas) to delay puberty, and aromatase inhibitors (AIs) in boys to postpone epiphyseal fusion. The results of studies employing GnRHas as either monotherapy or combined with GH are mixed, and there is a dearth of rigorously designed clinical trials that have followed patients to adult height. While AIs have been found to result in modest increases in adult height in some studies, important questions about their long-term safety exist. The C-type natriuretic peptide analog vosoritide is an experimental agent that is emerging as a potential treatment for a few specific conditions including achondroplasia, although its efficacy in attenuating disproportionality is as yet unproven. While each of these therapeutic strategies holds promise, none are currently considered standard of care and several important questions remain. These include the impact of these interventions on quality of life as well as long-term outcomes.