Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

A quality improvement project for managing hypocalcemia after pediatric total thyroidectomy.

Objectives Hypocalcemia following total thyroidectomy (TT) is relatively common. It may result in significant morbidity, prolonged hospital stay, and increased costs. Treatment with intravenous (IV) calcium gluconate may also carry significant risks. In pediatrics, management consensus guidelines are lacking. Methods At Phoenix Children's Hospital, a team of pediatric endocrinologists, surgeons and otolaryngologists developed a clinical pathway for patients undergoing TT. It was a Quality Improvement (QI) project with the primary aim of decreasing IV calcium gluconate use from a baseline of 68% to less than 40% over 15 months. Secondary aims included reducing hypocalcemia and length of hospitalization. Interventions included sending weekly pathway reminder emails, starting pre-operative calcium, and pathway implementation into the electronic health record. Results Twenty-seven patients underwent TT over 15 months. IV calcium gluconate use dropped to 48%. Hypocalcemia and length of hospitalization were 96% and 52.7 h (range 21.1-115.7) respectively. Pathway adherence improved after targeted interventions. Eleven (73%) of the 15 patients whose post-operative parathyroid hormone (PTH) nadir was below 15 pg/mL required IV calcium gluconate vs. two (17%) out of 12 with levels above this threshold. Conclusions Standardizing care allowed for objective outcome analysis. We learned that post-operative serum PTH level was the main risk factor for requiring IV calcium gluconate. Implementing the pathway as a QI project allows for revisions based on outcomes, ultimately resulting in a pathway that best utilizes our infrastructure to optimize care. Other pediatric institutions may face similar challenges and can potentially learn from our experience.

Severe early onset obesity and hypopituitarism in a child with a novel SIM1 gene mutation.

SUMMARY: Single-minded homolog 1 (SIM1) is a transcription factor that plays a role in the development of both the hypothalamus and pituitary. SIM1 gene mutations are known to cause obesity in humans, and chromosomal deletions encompassing SIM1 and other genes necessary for pituitary development can cause a Prader-Willi-like syndrome with obesity and hypopituitarism. There have been no reported cases of hypopituitarism linked to a single SIM1 mutation. A 21-month-old male presented to endocrinology clinic with excessive weight gain and severe obesity. History was also notable for excessive drinking and urination. Endocrine workup revealed central hypothyroidism, partial diabetes insipidus, and central adrenal insufficiency. Genetic evaluation revealed a novel mutation in the SIM1 gene. No other genetic abnormalities to account for his obesity and hypopituitarism were identified. While we cannot definitively state this mutation is pathogenic, it is notable that SIM1 plays a role in the development of all three of the patient's affected hormone axes. He is now 6 years old and remains on treatment for his pituitary hormone deficiencies and continues to exhibit excessive weight gain despite lifestyle interventions. LEARNING POINTS: Mutations in SIM1 are a well-recognized cause of monogenic human obesity, and there have been case reports of Prader-Willi-like syndrome and hypopituitarism in patients with chromosomal deletions that contain the SIM1 gene. SIM1 is expressed during the development of the hypothalamus, specifically in neuroendocrine lineages that give rise to the hormones oxytocin, arginine vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin. Pituitary testing should be considered in patients with severe obesity and a known genetic abnormality affecting the SIM1 gene, particularly in the pediatric population.

Epidemiology of Pediatric Traumatic Brain Injury and Hypothalamic-Pituitary Disorders in Arizona.

Traumatic brain injury (TBI) in children can result in long-lasting social, cognitive, and neurological impairments. In adults, TBI can lead to endocrinopathies (endocrine system disorders), but this is infrequently reported in children. Untreated endocrinopathies can elevate risks of subsequent health issues, such that early detection in pediatric TBI survivors can initiate clinical interventions. To understand the risk of endocrinopathies following pediatric TBI, we identified patients who had experienced a TBI and subsequently developed a new-onset hypothalamic regulated endocrinopathy (n = 498). We hypothesized that pediatric patients who were diagnosed with a TBI were at higher risk of being diagnosed with a central endocrinopathy than those without a prior diagnosis of TBI. In our epidemiological assessment, we identified pediatric patients enrolled in the Arizona Health Care Cost Containment System (AHCCCS) from 2008 to 2014 who were diagnosed with one of 330 TBI International Classification of Diseases (ICD)-9 codes and subsequently diagnosed with one of 14 central endocrinopathy ICD-9 codes. Additionally, the ICD-9 code data from over 600,000 Arizona pediatric patients afforded an estimate of the incidence, prevalence, relative risk, odds ratio, and number needed to harm, regarding the development of a central endocrinopathy after sustaining a TBI in Arizona Medicaid pediatric patients. Children with a TBI diagnosis had 3.22 times the risk of a subsequent central endocrine diagnosis compared with the general population (±0.28). Pediatric AHCCCS patients with a central endocrine diagnosis had 3.2-fold higher odds of a history of a TBI diagnosis than those without an endocrine diagnosis (±0.29). Furthermore, the number of patients with a TBI diagnosis for one patient to receive a diagnosis of a central endocrine diagnosis was 151.2 (±6.12). Female subjects were more likely to present with a central endocrine diagnosis after a TBI diagnosis compared to male subjects (64.1 vs. 35.9%). These results are the first state-wide epidemiological study conducted to determine the risk of developing a hypothalamic-pituitary disorder after a TBI in the pediatric population. Our results contribute to a body of knowledge demonstrating a TBI etiology for idiopathic endocrine disorders, and thus advise physicians with regard to TBI follow-up care that includes preventive screening for endocrine disorders.

Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity.

The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor α[TGFα) and (2) γ-aminobutyric acid (GABA)-mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention.

Endocrine and pubertal disturbances in optic nerve hypoplasia, from infancy to adolescence.

BACKGROUND: Endocrinologic abnormalities are a common co-morbidity in patients with optic nerve hypoplasia (ONH), however the impact on puberty is unknown. The purpose of this study was to examine rates of endocrine dysfunction and pubertal disturbances in a pediatric population of ONH. METHODS: A retrospective chart review was conducted on a cohort of children with ONH between January 2005 and March 2013. Endocrine dysfunction was determined based on laboratory evidence of hormone deficiency or hormone replacement. Pubertal disturbances were characterized based on presence of micropenis, tanner staging, menarche and hormone replacement. Pituitary abnormalities were classified using MRI findings. Descriptive statistics were used, and comparisons between groups were performed using the chi-square test. RESULTS: During the study period, 101 patients underwent an endocrine evaluation (median age: 2.3 years [0.76 - 6.5]). Hypopituitarism was present in 73% of patients with growth hormone deficiency (56%) and hypothyroidism (54%) being the most common. Pubertal disturbances (n = 19) were common; micropenis in 31% (13/42) of males and 2% with precocious puberty. Half of adolescents (n = 4/8) were diagnosed with gonadotropin deficiency. Patients with MRI pituitary abnormalities were more likely to have endocrine dysfunction than those without (p = 0.004). The sensitivity and specificity of MRI pituitary abnormalities for hypopituitarism was 54% and 92%, respectively. CONCLUSIONS: A significant proportion of children with ONH have endocrine dysfunction. The high frequency of pubertal disturbances in this study emphasizes the need for long-term monitoring of developing endocrinopathy. While pituitary gland abnormalities are a good predictor of endocrine dysfunction, a normal pituitary gland does not rule out endocrinopathy.