Precocious Puberty and GnRH analogs: Current treatment practices and perspectives amongst US pediatric endocrinologists.

INTRODUCTION: GnRHas are used for treatment of precocious puberty. Over the last decade, several new formulations have been approved. METHODS: The Drugs & Therapeutics subcommittee of the Pediatric Endocrine Society (PES) undertook a review to ascertain the current treatment options, prescribing behaviors, and practices of GnRHas among pediatric endocrinologists practicing within the United States. The survey consisted of four main subsections: 1. Description of clinical practice; 2. Self-assessment of knowledge base of pediatric and adult GnRHa formulations; 3. Current practice for treating CPP; and 4. Utilization of healthcare resources. RESULTS: There were 223 survey respondents. Pediatric endocrine practitioners were most familiar with the pediatric one-monthly preparation, the three-month preparation, and the histrelin implant (Supprelin®) (61.9%, 71.7%, and 34.5%, respectively), with lower familiarity for 24-week triptorelin intramuscular (Triptodur®) and 22.9% and six-month subcutaneous leuprolide (Fensolvi®). Only 23% of the respondents reported being extremely familiar with the availability of adult formulations, and 25% reported being completely unaware of cost differences between pediatric and adult GnRHa preparations. The implant was the most preferred therapy (44.4%), but in practice, respondents reported a higher percentage of patients were treated with 3-month preparation. While family preference/ease of treatment (87%) was the key determinant for using a particular GnRHa preparation, insurance coverage also played a significant role in the decision (65.5%). Responses regarding assessment for efficacy of treatment were inconsistent, as were practices and criteria for obtaining an MRI. CONCLUSIONS: The survey indicated there is more familiarity with older, shorter-acting GnRHas, which are prescribed in greater numbers than newer, longer-acting formulations. There is lack of consensus on the need for CNS imaging in girls presenting with CPP between 6-8 years of age and use of laboratory testing to monitor response to treatment. Insurance requirements regarding CNS imaging and laboratory monitoring are highly variable. Despite having similar constituents and bioavailability there are substantial cost differences between the pediatric and adult formulations and lack of evidence for safe use of these formulations in children. The survey-based analysis highlights the challenges faced by prescribers, while reflecting on areas where further research is needed to provide evidence-based practice guidelines for pediatric endocrinologists.

Practice Variation among Pediatric Endocrinologists in the Dosing of Glucocorticoids in Young Children with Congenital Adrenal Hyperplasia.

A Pediatric Endocrine Society (PES) Drugs and Therapeutics Committee workgroup sought to determine the prescribing practices of pediatric endocrinologists when treating children <10 years of age with congenital adrenal hyperplasia (CAH). Our workgroup administered a 32-question online survey to PES members. There were 187 respondents (88.9% attending physicians), mostly from university-affiliated clinics (~80%). Ninety-eight percent of respondents prescribed the short-acting glucocorticoid hydrocortisone to treat young children, as per the Endocrine Society CAH Guidelines, although respondents also prescribed long-acting glucocorticoids such as prednisolone suspension (12%), prednisone tablets (9%), and prednisone suspension (6%). Ninety-seven percent of respondents indicated that they were likely/very likely to prescribe hydrocortisone in a thrice-daily regimen, as per CAH Guidelines, although 19% were also likely to follow a twice-daily regimen. To achieve smaller doses, using a pill-cutter was the most frequent method recommended by providers to manipulate tablets (87.2%), followed by dissolving tablets in water (25.7%) to create a daily batch (43.7%) and/or dissolving a tablet for each dose (64.6%). Thirty-one percent of providers use pharmacy-compounded hydrocortisone suspension to achieve doses of <2.5 mg. Our survey shows that practices among providers in the dosing of young children with CAH vary greatly and sometimes fall outside of the CAH Guidelines-specifically when attempting to deliver lower, age-appropriate hydrocortisone doses.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Monitoring for and Management of Endocrine Dysfunction in Adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a peroxisomal disorder affecting the nervous system, adrenal cortical function, and testicular function. Newborn screening for ALD has the potential to identify patients at high risk for life-threatening adrenal crisis and cerebral ALD. The current understanding of the natural history of endocrine dysfunction is limited. Surveillance guidelines for males with ALD were developed to address the unpredictable nature of evolving adrenal insufficiency. Early recognition and management of adrenal insufficiency can prevent adrenal crisis. While testicular dysfunction in ALD is described, the natural history and complications of low testosterone, as well as the management, are not well described.

MRI surveillance of boys with X-linked adrenoleukodystrophy identified by newborn screening: Meta-analysis and consensus guidelines.

BACKGROUND: Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. METHODS: To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. RESULTS: One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. CONCLUSION: Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

Pediatric Endocrinology in the Time of COVID-19: Considerations for the Rapid Implementation of Telemedicine and Management of Pediatric Endocrine Conditions.

BACKGROUND: Pediatric endocrine practices had to rapidly transition to telemedicine care at the onset of the novel coronavirus disease 2019 (COVID-19) pandemic. For many, it was an abrupt introduction to providing virtual healthcare, with concerns related to quality of patient care, patient privacy, productivity, and compensation, as workflows had to change. SUMMARY: The review summarizes the common adaptations for telemedicine during the pandemic with respect to the practice of pediatric endocrinology and discusses the benefits and potential barriers to telemedicine. Key Messages: With adjustments to practice, telemedicine has allowed providers to deliver care to their patients during the COVID-19 pandemic. The broader implementation of telemedicine in pediatric endocrinology practice has the potential for expanding patient access. Research assessing the impact of telemedicine on patient care outcomes in those with pediatric endocrinology conditions will be necessary to justify its continued use beyond the COVID-19 pandemic.

Adrenoleukodystrophy in the era of newborn screening.

PURPOSE OF REVIEW: Adrenoleukodystrophy (ALD) is a peroxisomal disorder with varying clinical presentations, including adrenal insufficiency, neurologic disease, and testicular dysfunction. The present review is intended to describe the current knowledge of the pathophysiology of ALD and provide an update regarding newborn screening, diagnosis, monitoring, and treatment. RECENT FINDINGS: New York State initiated newborn screening for ALD on December 30, 2013. Successful ALD newborn screening has led to its addition on other state newborn screens and recommendations for universal screening. Initial incidence reports, based on newborn screening, suggest ALD may be more common than previously described. The Pediatric Endocrine Society has published guidance for monitoring newborn males with ALD and case reports suggest biochemical adrenal insufficiency can be present during early infancy. Allogeneic hematopoietic stem cell transplant and gene therapy have been effective at halting the progression of cerebral ALD. SUMMARY: Early diagnosis and monitoring for progression of ALD can prevent adrenal crisis and treat the cerebral form of the disease. Initial guidelines for surveillance are likely to evolve as newborn screening not only aids in early detection and therapeutic interventions for ALD, but also expands our knowledge of the natural history of ALD.

Precocious puberty and Chiari I malformation with syrinx: a case report of an unusual presentation of Costello syndrome.

BACKGROUND: Costello syndrome (CS) is a rare RASopathy causing developmental delays, short stature and classically, delayed puberty. We present a patient with CS and central precocious puberty (CPP). CASE PRESENTATION: A female patient with CS presented at 6 years 10 months of age with breast development. CPP was biochemically confirmed at 7 years 1 month of age, no additional pituitary dysfunction was noted and puberty progressed at follow-up. Brain magnetic resonance imaging (MRI) revealed a Chiari I malformation with a syrinx, requiring surgical decompression. The patient was successfully treated with histrelin. CONCLUSIONS: Although recent publications do not recommend routine brain MRI in girls with isolated CPP over 6 years of age, in those with CS actionable MRI findings are more likely and imaging should be performed. It is unclear whether the cerebral malformation in the patient contributed to CPP or was an incidental syndromic finding.

Peak Growth Hormone Response to Combined Stimulation Test in 315 Children and Correlations with Metabolic Parameters.

BACKGROUND/AIMS: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. METHODS: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as &#x3c;10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline. RESULTS: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. CONCLUSION: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of &#x3c; 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

Early Onset Primary Adrenal Insufficiency in Males with Adrenoleukodystrophy: Case Series and Literature Review.

The lifetime risk for adrenal insufficiency in male children with adrenoleukodystrophy (ALD) is estimated at 80%-86%. Prior to newborn screening, male children with ALD were identified by family history or after symptom development. These young patients with ALD and adrenal insufficiency support newborn screening for ALD.

Adrenoleukodystrophy: Guidance for Adrenal Surveillance in Males Identified by Newborn Screen.

Context: Adrenoleukodystrophy (ALD) is a peroxisomal disorder associated with neurologic decompensation and adrenal insufficiency. Newborn screening for ALD has recently been implemented in five states with plans to expand to all 50 states in the United States. Adrenal insufficiency ultimately develops in most males with ALD, but the earliest age of onset is not well established. Objective: These clinical recommendations are intended to address screening for adrenal insufficiency in boys identified to have ALD by newborn screen. Participants: Seven members of the Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee, with clinical experience treating children with ALD and adrenal insufficiency, and a pediatric endocrinologist and laboratory director were selected to be on the working committee. Consensus Process: The authors comprised the working group and performed systematic reviews of the published literature regarding adrenal insufficiency and ALD. The recommendations were reviewed and approved by the larger Pediatric Endocrine Society Drug and Therapeutics/Rare Diseases Committee and then by the Pediatric Endocrine Society Board of Directors. Conclusions: There is limited literature evidence regarding monitoring of evolving adrenal insufficiency in male infants and children with ALD. The recommendations suggest initiating assessment of adrenal function at diagnosis with ALD and regular monitoring to identify boys with adrenal insufficiency in a timely manner and prevent life-threatening adrenal crisis. These recommendations are intended to serve as an initial guide, with the understanding that additional experience will inform future guidelines.

Thyroid Ultrasound: More Sensitive than Radioactive Iodine Imaging in Detecting Recurrence of Papillary Thyroid Cancer in Two Pediatric Patients.

BACKGROUND: Papillary thyroid cancer (PTC) is an uncommon pediatric disease with an excellent prognosis. In follow-up surveillance, neck ultrasound (US), basal and thyroid-stimulating hormone-stimulated serum thyroglobulin (Tg) levels, and diagnostic whole-body radioactive iodine scans (DxWBS) have been traditionally used in both adults and children for the detection of recurrence or metastases of PTC. METHODS: Two pediatric patients with metastatic PTC were followed after standard ablative treatment with routine neck US and serum Tg levels, as well as periodic DxWBS. RESULTS: Neck US identified recurrent and metastatic PTC which DxWBS failed to detect. CONCLUSION: Neck US was superior to DxWBS in the detection of recurrent PTC in these 2 pediatric patients. These findings are consistent with the 2015 American Thyroid Association (ATA) Guidelines that neck US is an ideal imaging modality in pediatric patients for the surveillance of PTC local recurrence or lymph node metastases.

Endocrine Dysfunction in X-Linked Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and leads to an elevation of very-long-chain fatty acids (VLCFA). The accumulation of the VLCFA and the associated oxidative stress can present with a spectrum of significant neurologic disease, adrenal insufficiency, and testicular dysfunction in males with ABCD1 gene mutations. Much of the published literature for X-ALD has focused on the associated devastating progressive neurologic conditions. The purpose of this review is to summarize the concerns for endocrine dysfunction associated with X-ALD and provide guidance for monitoring and management of adrenal insufficiency.

New-onset diabetes mellitus after pediatric liver transplantation.

In the first five yr after liver transplant, approximately one in 10 pediatric recipients will develop NODAT. Factors associated with higher risk for NODAT have been difficult to identify due to lack of uniformity in reporting and data collection. Limited studies have reported higher risk in those who are at an older age at transplant, those with high-risk ethnic backgrounds, and in those with particular underlying conditions, such as CF and primary sclerosing cholangitis. Immunosuppressive medications, including tacrolimus, cyclosporine A, GC, and sirolimus, have been implicated as contributing to NODAT, to varying degrees. Identifying those at highest risk, appropriately screening, and diagnosing NODAT is critical to initiating timely treatment and avoiding potential complications. In the pediatric population, treatment is limited primarily to insulin, with some consideration for metformin. Children with NODAT should be monitored carefully for complications of DM, including microalbuminuria, hypertension, hyperlipidemia, and retinopathy.

The role of ¹²³I imaging in the evaluation of infants with mild congenital hypothyroidism.

BACKGROUND/AIMS: Controversy exists regarding the diagnosis and treatment of mild congenital hypothyroidism (MCH). We studied the value of (123)I imaging in patients with MCH. METHODS: Retrospective chart review of infants and children <4 years of age who underwent (123)I imaging: group 1 = MCH [thyroid-stimulating hormone (TSH) <25 µIU/ml, normal free T4/T3], group 2 = severe congenital hypothyroidism (TSH ≥25 µIU/ml), and group 3 = MCH in infancy imaged after treatment withdrawal at age 3 years. Data collected included 4- and 24-hour (123)I uptake, TSH, free T4/total T3 at imaging, age at imaging, and levothyroxine (L-T4) dose at 1 year of. RESULTS: Thirty-six patients underwent (123)I imaging. In group 1 (n = 20, median TSH: 8.49 µIU/ml), 85% had abnormal imaging consistent with dyshormonogenesis. Two patients were referred after 1 year of age. The median age at imaging for the remaining 18 patients was 54 days. Median L-T4 dose at 1 year of age for these 18 patients was 2.8 µg/kg, which is consistent with dyshormonogenesis. Ninety-one percent of group 2 (n = 11, median TSH: 428.03 µIU/ml) had abnormal imaging. The median age at imaging was 13 days. Four patients in group 3 had abnormal (123)I imaging and restarted treatment. CONCLUSION: (123)I imaging is a valuable tool for evaluation, diagnosis, and treatment of MCH.