Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at t-cell marker CD3, is the first medication approved by the FDA to delay progression from Stage 2 to Stage 3 type 1 diabetes (T1D). To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Cushing Syndrome in Childhood.

We describe a 15-year-old boy who presented with low back pain due to vertebral compression fractures, growth deceleration, excessive weight gain, rounded facies, dorsocervical fat pad, and hypertension. He was diagnosed as having Cushing syndrome (CS) due to primary pigmented nodular adrenocortical disease resulting in excess cortisol produced by the adrenal glands, leading to disruption of the hypothalamic-pituitary-adrenal axis. The most common cause of CS is exogenous glucocorticoids, with endogenous causes being extremely rare, often leading to delay in diagnosis or misdiagnosis. Herein, we review clinical presentation, screening for hypercortisolism, and decision-making in the diagnosis of CS, as well as therapeutic approaches. The wide range of clinical presentations in pediatric CS and the rarity of the condition can lead to difficulty in the recognition, diagnosis, and subsequent management of these patients. CS can be difficult to differentiate from more common exogenous obesity, and outpatient screening of cortisol excess is challenging. Early recognition and treatment of CS is necessary to avoid multisystemic complications, and patients with suspected endogenous CS should be referred to a tertiary care center with experienced pediatric endocrinology and surgery specialists. Further confirmatory diagnostic tests are necessary to distinguish corticotropin-independent from corticotropin-dependent forms of CS, including a high-dose dexamethasone suppression test, a corticotropin-releasing hormone stimulation test, and imaging. There can be challenges to the evaluation of CS, including complex inpatient testing and difficulty with localization on imaging. Long-term sequelae of CS, including adrenal insufficiency, obesity, hypertension, and mental health disorders, may remain despite definitive surgical treatment, meriting close follow-up with the primary care clinician and subspecialists.

A Novel De Novo Frameshift Pathogenic Variant in the FAM111B Resulting in Progressive Osseous Heteroplasia Phenotype.

INTRODUCTION: Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption. CASE: A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function. CONCLUSION: This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.

A Unique Case of Aggressive Central Giant Cell Granuloma in a 10-Year-Old Boy With 16p13.11 Microdeletion Syndrome.

Central giant cell granuloma (CGCG) is a rare disease characterized by sporadic, benign, intraosseous mandibular lesions of unknown etiology. Histologically, these lesions are indistinguishable from brown tumors of hyperparathyroidism and cherubism, and occasionally have been associated with different syndromes raising a question for genetic etiology. The CGCG has varied presentation ranging from nonaggressive and indolent to aggressive, destructive, and recurrent, often posing diagnostic and therapeutic challenges. Herein, we present the first case of a 10-year-old boy with CGCG and 16p13.11 microdeletion syndrome, highlight the diagnostic challenges inherent to this heterogeneous disorder, and discuss the genetics and treatment approaches of these complex lesions.

Quantifying RANKL and OPG levels in healthy children: A large cross-sectional analysis.

BACKGROUND: There have been new advances in understanding bone remodeling on a molecular level including the RANKL-OPG pathway, leading to advancements in targeted therapeutic intervention. There is however limited data in pediatrics with little known on normative values in healthy children. This is the largest cohort to quantify RANKL, OPG, and RANKL: OPG levels in healthy children as well as study the influence of age, gender, Tanner stage, and BMI in this population. METHODS: Healthy subjects, 1-21 years of age, were recruited from general pediatric clinics affiliated with CHLA and in collaboration with samples stored from a previously completed study. Healthy children were defined as those with no chronic disease, daily medication, or fractures in the past six months. Free soluble RANKL and OPG levels were quantified using a sandwich ELISA. RESULTS: Three hundred samples were collected with overall serum concentrations of RANKL, OPG and RANKL: OPG of 0.28 pmol/L, 3.56 pmol/L and 0.08 pmol/L, respectively. Serum RANKL and RANKL: OPG concentrations were significantly different by age (p = 0.0001 and 0.0027, respectively). There was an overall downward trend by age except in the 11-15-year age group where a slight increase was noted. RANKL concentrations were also significantly different between Tanner stages, with highest concentrations seen at Tanner 3 (p = 0.0481), and zBMI (p = 0.001). OPG was inversely correlated with zBMI, but not influenced by gender, age, or Tanner stage. CONCLUSION: We showed significant difference in RANKL levels by age, Tanner stage, and zBMI. OPG was inversely correlated with zBMI. Insight into circulating levels of RANKL, OPG and RANKL: OPG in healthy children may be a potential tool to better understand disease states in pediatrics. Future studies are needed to evaluate the clinical significance of RANKL and OPG levels for diagnostic and therapeutic purposes in this population.

A case of severe TBCE-negative hypoparathyroidism-retardation-dysmorphism syndrome: Case report and literature review.

Hypoparathyroidism-retardation-dysmorphism syndrome (HRD) is a rare autosomal recessive disorder attributed to the mutations in the tubulin-specific chaperone E (TBCE) gene, which is vital for microtubule function during mitosis, organelle positioning, and neuronal cytokinesis. HRD is a congenital syndromic hypoparathyroidism associated with growth deficiency, microcephaly, intellectual disability, ocular anomalies, and facial dysmorphism. To our knowledge, there is only one published case of mild HRD-like syndrome with no identifiable genetic etiology. We report a case of severe TBCE-negative phenotypic HRD in a 4-year-old female from India presenting with hypocalcemic seizures due to congenital hypoparathyroidism, extreme microcephaly, growth deficiency, ocular anomalies, and facial dysmorphism. SNP microarray and whole exome sequencing (WES) did not detect any abnormalities in TBCE or other genes of interest. WES revealed two variants of unknown clinical significance in CASC5 gene, which codes for a protein in the kinetochore and, interestingly similar to TBCE, is essential for proper microtubule function during mitosis and cell proliferation and has been implicated in primary microcephaly disorders. However, further targeted sequencing in the parents revealed both variants inherited from the unaffected mother. Significant copy number variant noise in the proband and her parents limited further analysis. At this time the role of variants in the CASC5 gene is unclear and cannot explain our patient's phenotype. In conclusion, we report a severe case of phenotypic HRD syndrome, in which extensive genetic evaluation failed to reveal an etiology. Our case demonstrates that the pathogenesis of HRD may be genetically heterogenous, meriting further genetic investigations.

Efficacy of growth hormone replacement on anthropometric outcomes, obesity, and lipids in children with optic nerve hypoplasia and growth hormone deficiency.

BACKGROUND: Hypopituitarism and obesity are causes of major lifelong morbidity in patients with optic nerve hypoplasia (ONH). Growth hormone deficiency (GHD) affects the majority of children with ONH, though the degree of deficiency and variability of early growth patterns range from early severe retardation to normal initial growth. The utility of early GH replacement for improving anthropometric, body composition, and lipid outcomes in patients with ONH and GHD, especially those with normal initial height velocity, is unknown. This study examines the effects of GH replacement in a cohort of children with ONH and GHD. METHODS: Controlled clinical trial from 2005-2014. The study included 17 children with ONH and untreated GHD. Those meeting criteria for growth deceleration were assigned to treatment with recombinant human growth hormone (n = 5) while those with normal height velocity were randomized either to treatment (n = 5) or to observation (no intervention, n = 7). Study duration was 3 years. Primary outcome measures included stature, weight, weight-for-stature, and BMI standard deviation score (SDS) at study completion. RESULTS: Subjects on GH, irrespective of entry growth trajectory, grew more on average in stature than controls by a difference of 0.98 SDS by study end; this effect persisted after adjusting for baseline overweight status. Treatment had an effect on weight SDS only after adjusting for initial overweight status, resulting in an average increase of 0.83 SDS more than controls. Subjects who were overweight at the outset experienced greater gains in both weight and stature SDS. Treatment had no statistically significant impact on weight-for-stature or BMI SDS. A reduction in body fat percentage was observed in those treated, both before (-6.1 %) and after (-4.3 %) adjustment for initial overweight status. CONCLUSION: Early GH replacement has a positive effect on short-term statural outcomes in children with ONH and GHD, even in those exhibiting normal initial linear growth. Results were less conclusive regarding treatment effects on body composition and lipids.

Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia.

BACKGROUND/AIMS: Youth with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency develop cardiovascular disease (CVD) risk factors of obesity and hypertension. Carotid intima-media thickness (CIMT), a marker of CVD risk, is increased in CAH young adults. We examined CIMT and its relationship with androgens and obesity in adolescents/young adults with CAH. METHODS: Twenty CAH subjects (age 16 ± 3.3 years, 50% female) and 20 matched controls were studied cross-sectionally. Eight additional obese patients with CAH were included in within-group comparisons. CIMT by high-resolution ultrasound, androgens, anthropometry, bone age (BA), and metabolic/inflammatory markers were assessed. RESULTS: Within the CAH group, CIMT correlated with 17-hydroxyprogesterone (r = 0.48, p < 0.05) and androstenedione (r = 0.46, p < 0.05), and was greater in obese subjects. CIMT was greater in CAH males than females, but similar among CAH females with advanced BA, CAH males with normal BA, and control males. There was no difference in CIMT between CAH and controls, although high-density lipoprotein was inversely correlated with CIMT in both groups. CONCLUSION: CIMT is associated with increased androgens in CAH adolescents and young adults, with loss of sex differences in CAH females with excess androgen exposure. Our findings highlight the importance of hormonal control for CVD prevention in CAH.

Increased Abdominal Adiposity in Adolescents and Young Adults With Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency.

CONTEXT: Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in normal children, potentially increasing their risk of cardiovascular disease (CVD). Abdominal adiposity, in particular visceral adipose tissue (VAT), is strongly associated with metabolic syndrome and CVD. However, it remains unknown whether VAT is increased in CAH. OBJECTIVE: The objective of the study was to determine whether adolescents and young adults with classical CAH have more VAT and sc adipose tissue (SAT) than matched controls and whether VAT and SAT are associated with biomarkers of metabolic syndrome, inflammation, and hyperandrogenism in CAH. DESIGN/SETTING: This was a cross-sectional study at a tertiary center. PARTICIPANTS: CAH subjects (n = 28; 15.6 ± 3.2 y; 15 females) were matched for age, sex, ethnicity, and body mass index to healthy controls (n = 28; 16.7 ± 2.3 y; 15 females). MAIN OUTCOME MEASURES: VAT and SAT, using computed tomography imaging and serum biomarkers associated with CVD risk, were measured. Data are reported as mean ± SD. RESULTS: Both VAT (43.8 ± 45.5 cm(2)) and SAT (288.1 ± 206.5 cm(2)) were higher in CAH subjects than controls (VAT 26.4 ± 29.6 cm(2) and SAT 226.3 ± 157.5 cm(2); both P < .001). The VAT to SAT ratio was also higher in CAH subjects (0.15 ± 0.07) than controls (0.12 ± 0.06; P < .05). Within CAH, measures of obesity (waist to height ratio, fat mass) and inflammation (plasminogen activator inhibitor-1, high-sensitivity C-reactive protein, leptin) correlated strongly with VAT and SAT. In addition, homeostasis model assessment of insulin resistance, and low-density lipoprotein correlated with abdominal adiposity. There were no sex differences for VAT or SAT in CAH subjects. CONCLUSIONS: CAH adolescents and young adults have increased abdominal adiposity, with a higher proportion of proinflammatory VAT than SAT. An improved understanding of the mechanism of obesity in CAH may lead to targeted prevention and therapeutics in this high-risk population.

Decreased adrenomedullary function in infants with classical congenital adrenal hyperplasia.

CONTEXT: Classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can cause life-threatening adrenal crises as well as severe hypoglycemia, especially in very young children. Studies of CAH patients 4 years old or older have found abnormal morphology and function of the adrenal medulla and lower levels of epinephrine and glucose in response to stress than in controls. However, it is unknown whether such adrenomedullary abnormalities develop in utero and/or exist during the clinically high-risk period of infancy and early childhood. OBJECTIVE: The objective of the study was to characterize adrenomedullary function in infants with CAH by comparing their catecholamine levels with controls. Design/Settings: This was a prospective cross-sectional study in a pediatric tertiary care center. MAIN OUTCOME MEASURES: Plasma epinephrine and norepinephrine levels were measured by HPLC. RESULTS: Infants with CAH (n = 9, aged 9.6 ± 11.4 d) had significantly lower epinephrine levels than controls [n = 12, aged 7.2 ± 3.2 d: median 84 [(25th; 75th) 51; 87] vs 114.5 (86; 175.8) pg/mL, respectively (P = .02)]. Norepinephrine to epinephrine ratios were also significantly higher in CAH patients than controls (P = .01). The control infants had primary hypothyroidism, but pre- and posttreatment analyses revealed no confounding effects on catecholamine levels. CONCLUSIONS: This study demonstrates for the first time that infants with classical CAH due to 21-hydroxylase deficiency have significantly lower plasma epinephrine levels than controls, indicating that impaired adrenomedullary function may occur during fetal development and be present from birth. A longitudinal study of adrenomedullary function in CAH patients from infancy through early childhood is warranted.

Management of congenital adrenal hyperplasia in childhood.

PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) can present management challenges to the pediatric clinician. Glucocorticoid replacement remains the cornerstone of treatment; however, there are new formulations and delivery mechanisms being studied. Clinicians continue to discuss the optimal treatment of patients from the prenatal stage, through infancy to adulthood. As well, the role of genetics in the clinical care of patients with CAH, and screening for complications, remain topics of discussion. This review will highlight advances made in the past year, as they pertain to the management of pediatric patients with CAH. RECENT FINDINGS: This article covers recent studies pertaining to optimal medication regimens, including prenatal dexamethasone treatment; medication delivery; monitoring of hormonal control; and the role of genotyping and genetics in the management of children with CAH. SUMMARY: Much remains to be learned about the optimal management of children with CAH, including fludrocortisone replacement in simple-virilizing patients, frequency of specific monitoring strategies (e.g., electrolytes, bone age), catecholamine status, stress-dosing in nonclassical adrenal hyperplasia, and early screening for complications or metabolic sequelae. Further randomized and prospective studies are needed to address these issues.