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.

Hypogonadotropic Hypogonadism.

Delayed puberty is defined as absent testicular enlargement in boys or breast development in girls at an age that is 2 to 2.5 SDS later than the mean age at which these events occur in the population (traditionally, 14 years in boys and 13 years in girls). One cause of delayed/absent puberty is hypogonadotropic hypogonadism (HH), which refers to inadequate hypothalamic/pituitary function leading to deficient production of sex steroids in males and females. Individuals with HH typically have normal gonads, and thus HH differs from hypergonadotropic hypogonadism, which is associated with primary gonadal insufficiency.

Normal Puberty.

Puberty is characterized by gonadarche and adrenarche. Gonadarche represents the reactivation of the hypothalamic-pituitary-gonadal axis with increased gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone secretion following the quiescence during childhood. Pubarche is the development of pubic hair, axillary hair, apocrine odor reflecting the onset of pubertal adrenal maturation known as adrenarche. A detailed understanding of these pubertal processes will help clarify relationships between the timing of the onset of puberty and cardiovascular, metabolic, and reproductive outcomes in adulthood. The onset of gonadarche is influenced by neuroendocrine signals, genetic variants, metabolic factors, and environmental elements.

Diagnosis of Central Precocious Puberty.

A thorough history and physical examination including Tanner staging and growth assessments can guide differential diagnosis and aid in the evaluation of precocious puberty. Basal luteinizing hormone levels measured using a highly sensitive assay can be helpful in diagnosing central precocious puberty (CPP). Brain MRI is indicated with males diagnosed with CPP and females under the age of 6 with CPP. As more information becomes available regarding the genetic etiologies of CPP, genetic testing may preclude the need for imaging studies and other hormonal testing, especially in familial cases.

Individualized care for patients with intersex (differences of sex development): Diagnosis and treatment of aphallia.

This review discusses issues and concerns in the management of aphallia, updating status of a post-pubertal individual who required further surgery after having initial surgery for aphallia as an infant. Through this case, which discusses an 18-year-old young adult who had penile agenesis, who desired further phalloplasty involving glanuloplasty and implantation of an erectile device, we highlight the importance of periodic evaluation and close follow up. Surgery during infancy or early childhood to create a penis is important for gender development in a boy, especially if there were functional testes during fetal life, even if this surgery would only be the first stage. There is a strong probability of subsequent surgery after initial phalloplasty before puberty, even with the use of currently refined techniques. Here we discuss the changing techniques that document the ongoing, continued refinement of these procedures, highlighting that further outcome data are needed to identify ways to further optimize current techniques.

The Impact of COVID-19 Pandemic on Prevalence of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes: A Single-Centre Study in Central Pennsylvania.

Objective: We conducted this study to investigate whether the COVID-19 pandemic impacted the rate of DKA and previously identified risk factors in children presenting with T1D. Methods: We performed an extension of a retrospective analysis of all paediatric patients (age ≤ 18) newly diagnosed with T1D within a tertiary care referral centre between 01/01/2017 and 09/14/2020. Demographics, insurance coverage and clinical documents 30 days before their T1D diagnosis were abstracted to assess for symptoms at diagnosis, laboratory values (blood glucose, HbA1c, venous pH and bicarbonate) and any healthcare encounters within 30 days of their diagnosis of T1D. Results: 412 patients with T1D [171 F:241 M; 370 pre-COVID era:42 post-COVID era] were included. The percentages of DKA diagnoses at admission were very similar between the pre-COVID and post-COVID groups (47% vs. 48%), as were the severity (13% vs. 14% mild DKA; 33% vs. 31% moderate or severe DKA). Conclusion: There were no fluctuations in the rate of DKA among paediatric patients newly diagnosed with T1D throughout the coronavirus pandemic in central Pennsylvania.

Prevalence and factors associated with diabetic ketoacidosis at diagnosis of type 1 diabetes: A report from a tertiary medical center in Central Pennsylvania.

Objective: To explore the rate and factors associated with diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in a single tertiary medical centre in Central Pennsylvania. Methods: Retrospective chart review of all individuals ≤ 18 years of age who were diagnosed with T1D (N = 350) at the Penn State Hershey Pediatric Diabetes Clinic from January 2017 to December 2019. We report logistic regression models for DKA at diagnosis of T1D for age, gender, race/ethnicity, BMI percentile, health insurance, outcome of any healthcare encounter 30 days prior to T1D diagnosis, HbA1c level, altered mental status at diagnosis, and diagnosis of autism spectrum disorder and a multivariable logistic regression model including all aforementioned variables. Results: Of the 350 newly diagnosed children with T1D from 2017 to 2019, 161/350 (46%) presented in DKA. Among patients with DKA, there were 45 (28%) in mild DKA and 116 (72%) in moderate/severe DKA, which represents 13% and 33% of all patients diagnosed with T1D, respectively. Variables associated with increased risk of DKA at presentation of T1D included age (<3 or 9-13), BMI percentile (<3% or > 97%), no referral during preceding healthcare encounter, HbA1c level and altered mental status. In a multivariable model, age (<3 or 9-13), no referral during preceding healthcare encounter, HbA1c level and altered mental status were associated with DKA at presentation, whereas gender, race/ethnicity, BMI percentile, health insurance and autism spectrum disorder diagnosis were not. Discussion: Our study notes an overall higher rate of DKA at diagnosis (46%) compared to the SEARCH study (approximately 30%) but a lower rate compared to a recent study in Colorado children (58%).

Individualized care for patients with intersex (differences of sex development): part 4/5.Considering the Ifs, Whens, and Whats regarding sexual-reproductive system surgery.

Issues and concerns regarding surgery of the sexual-reproductive anatomy during infancy and early childhood are discussed using four actual examples. A case of a 46, XX infant with 21 hydroxylase deficiency congenital adrenal hyperplasia (CAH) with atypical (ambiguous) genitalia is discussed regarding timing and potential harms and benefits of surgery. We present the perspective of balancing the child's rights to bodily autonomy and right to an open future versus parents' decision making authority regarding what they perceive as their child's future best interests. The second case is a newborn with complete androgen insensitivity syndrome and we discuss the harms, benefits and timing of gonadectomy. The third case examines the physical and psychological impact of penile shaft hypospadias, raising the question of whether surgery is justified to prevent what may or may not be considered a permanent disability. The fourth case involves an adult woman with classic CAH, born with a urogenital sinus and clitoromegaly, who never had genital surgery and is now requesting vaginoplasty, but not clitoral reduction. The primary message of this article, as the previous articles in this series, is to encourage patient-family centered care that individualizes treatment guided by shared decision making.

Individualized care for patients with intersex (disorders/differences of sex development): Part 3.

The focus of this article is to review the complex determinants of gender assignment in a child with a disorder of sex development using four different clinical cases. While the care of patients with DSD may be shared across several specialties and opinions regarding their management may vary, this may be further complicated by psychosocial, cultural and economic factors. In this regard, access to behavioral health specialists with experience and specialization in the treatment of patients with DSD should be a foundational component of the standard of care and can greatly assist in the complex decision-making regarding gender assignment. We recommend an individualized approach by a multidisciplinary team utilizing a range of evolving strategies, including outcome data (or lack thereof) to support families during the decision-making process.

Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium.

This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.

Occurrence of Cranial Neoplasms in Pediatric Patients with Noonan Syndrome Receiving Growth Hormone: Is Screening with Brain MRI prior to Initiation of Growth Hormone Indicated?

Noonan syndrome (NS) is associated with short stature. Growth hormone treatment has been FDA approved for use in these patients. Children with NS are at a higher risk of developing benign and malignant proliferative disorders, primary brain tumors being one of them. Since growth hormone therapy can worsen the tumor burden, screening with a brain MRI prior to growth hormone initiation in NS patients is strongly recommended. Here we present two NS patients who developed different primary brain tumors while being on growth hormone therapy.

Pragmatic approach to intersex, including genital ambiguity, in the newborn.

The evaluation and management of a newborn with ambiguous genitalia must be undertaken as quickly as possible and with great sensitivity for the child's family. Where possible, a comprehensive team approach with a pediatric urologist, endocrinologist, geneticist, neonatologist, and child psychiatrist/psychologist should work closely with the family to establish the diagnosis and determine gender. Although the preferred gender assignment is not always clear, a thorough examination of endocrine function, karyotype, and potential for fertility should guide the determination. While some disorders of sex development (DSD) sex assignments are relatively straightforward, those with more advanced genital ambiguity and unclear gonadal function represent a major challenge. A child's phenotypic sex results from the differentiation of internal ducts and external genitalia under the influence of hormones and transcription factors. Any discordance among these processes results in ambiguous genitalia or DSD. Currently, the main categories of DSD are 46,XX DSD, 46,XY DSD, sex chromosome DSD, ovotesticular DSD, and 46,XX testicular DSD. Priority is given to rule out more immediate life-threatening disorders like salt wasting CAH. Many centers in the United States lack the comprehensive "team members" and not all conditions necessitate this team approach. This article aims to provide guidance for initial workup and identify the specific conditions for which expert guidance is needed.