Background: Delphian (level VI) lymph nodes are often linked to head and neck malignancy, but their relationship with thyroiditis is less well described. Ultrasound is used in the assessment and workup for thyroiditis, but thyroid appearances can be variable and non-specific. The presence of a Delphian lymph node may help to determine the aetiology of inflammatory thyroid disease. Objective: To investigate whether assessing Delphian lymph nodes on ultrasound can help predict the diagnosis of thyroiditis in children. Methods: Retrospective review of scans from 70 children (1-17 years old) carried out by a single radiologist at a tertiary paediatric centre. The presence or absence of Delphian lymph nodes was assessed, as well as the thyroid size/volume, echogenicity and vascularity. Biochemical markers, where applicable, and clinical diagnoses were obtained and matched up to radiological findings. Markers included thyroid function tests (TFTs) as well as serum thyroid peroxidase antibody and thyroid receptor antibody. Results: Twenty-four patients had Delphian lymph nodes identified on ultrasound. There was statistical significance between the presence of Delphian lymph nodes and heterogeneous thyroid architecture (p < 0.001), thyroid enlargement (p = 0.002) and increased thyroid vascularity (p < 0.001). Although no significant association was identified between the size of the Delphian lymph node and the thyroid appearances on ultrasound or the biochemical results, there was a significant association between the presence of Delphian lymph nodes and the clinical diagnosis. Conclusion: There is a significant association between the presence of Delphian lymph nodes on ultrasound with findings in thyroiditis. These include the presence of key biochemical markers and abnormal thyroid appearances on ultrasound - increased heterogeneity, size and vascularity.

CONTEXT:Congenital Hyperinsulinism (CHI) is associated with inappropriately high levels of C-peptide in the context of hypoglycemia. OBJECTIVE:We aimed to better clarify a diagnostic threshold value of C-peptide for children presenting with CHI. DESIGN:This was a retrospective case-control analysis, examining all hypoglycemia screens, undertaken between 2009 and 2019 at a quaternary paediatrics unit. Plasma C-peptide, insulin, free fatty acid (FFA) and B-hydroxybutyrate (BHOB) concentrations in children diagnosed with CHI were compared with concentrations in children diagnosed with other conditions. PATIENTS:All patients requiring hypoglycaemic screens at the quaternary children's hospital were analysed. RESULTS:Median [C-peptide] were statistically significantly different between CHI (147) and non-CHI (72) patients, p < 0.05. The Youden Index indicated that a [C-peptide] value of 291.5 pmol/L would give the greatest optimization of sensitivity (82%) and specificity (99%) for detecting CHI. Median [insulin] differed significantly between the cohorts with a level of 64 pmol/L for CHI patients compared with 0 pmol/L with non-CHI patients (p < 0.01). Median [BOHB] was 0 μmol/L in CHI patients as compared with 2378 μmol/L for non-CHI patients (p < 0.01). Median [FFA] levels were 1910 μmol/L in the non-CHI cohort, compared with 0 in the CHI cohort (p < 0.01). CONCLUSIONS:This study suggests that a C-peptide concentration greater than 291.5 pmol/L is diagnostic of CHI in children. C-peptide appears to offer the greatest utility as a biochemical diagnostic test for CHI and could be prioritised for laboratory analysis.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

BACKGROUND:Daily recombinant human growth hormone (rhGH) is approved and marketed worldwide to treat children and adults with GH deficiency and other conditions. Efficacy of rhGH therapy is influenced by several variables. Drop of treatment adherence over time has been recognized as a cause of reduced rhGH efficacy and has driven considerable efforts from pharmaceutical companies and scientists to develop long-acting rhGH (LAGH) formulations in order to relieve patients and their families from the burden of daily injections.SUMMARY:Different technologies to manipulate drug release have been produced allowing weekly, biweekly, or monthly rhGH administration. The LAGH formulations developed at present have demonstrated a comparable or even higher efficacy as compared with daily rhGH in most of the cases and no major safety issues in phase 3 studies. A greater incidence of injection-site reactions has been reported but mainly of mild and transient nature.KEY MESSAGES:Despite LAGH analogs appearing promising, potential drawbacks still need to be addressed. Long-term consequences of nonphysiological GH profile and its consequences on metabolism and risk of cancer, optimal therapeutic monitoring, immunogenicity of LAGH molecules, and potential novel side effects related to the technologies used to develop these molecules are among the major concerns that require answers from long-term surveillance. Finally, increased acceptance of LAGH formulations from patients and their caregivers is yet to be demonstrated and cost-effectiveness evaluated consequently.

Context:In focal congenital hyperinsulinism (CHI), localized clonal expansion of pancreatic β-cells causes excess insulin secretion and severe hypoglycemia. Surgery is curative, but not all lesions are amenable to surgery.Objective:We describe surgical and nonsurgical outcomes of focal CHI in a national cohort.Methods:Patients with focal CHI were retrospectively reviewed at 2 specialist centers, 2003-2018.Results:Of 59 patients with focal CHI, 57 had heterozygous mutations in ABCC8/KCNJ11 (51 paternally inherited, 6 de novo). Fluorine-18 L-3,4 dihydroxyphenylalanine positron emission tomography computed tomography scan identified focal lesions in 51 patients. In 5 patients, imaging was inconclusive; the diagnosis was established by frozen section histopathology in 3 patients, a lesion was not identified in 1 patient, and 1 declined surgery. Most patients (n = 56) were unresponsive to diazoxide, of whom 33 were unresponsive or partially responsive to somatostatin receptor analog (SSRA) therapy. Fifty-five patients underwent surgery: 40 had immediate resolution of CHI, 10 had persistent hypoglycemia and a focus was not identified on biopsy in 5. In the 10 patients with persistent hypoglycemia, 7 underwent further surgery with resolution in 4 and ongoing hypoglycemia requiring SSRA in 3. Nine (15% of cohort) patients (1 complex surgical access; 4 biopsy negative; 4 declined surgery) were managed conservatively; medication was discontinued in 8 children at a median (range) age 2.4 (1.5-7.7) years and 1 remains on SSRA at 16 years with improved fasting tolerance and reduction in SSRA dose.Conclusion:Despite a unifying genetic basis of disease, we report inherent heterogeneity in focal CHI patients impacting outcomes of both surgical and medical management.

ContextMeta-analyses report that the low dose short Synacthen test (LDSST) is more sensitive but less specific than the standard dose test for the diagnosis of adrenal insufficiency, and there are concerns regarding the accuracy of dosing in the LDSST.ObjectivePerform a retrospective, observational study to review the outcomes of LDSSTs performed in a tertiary endocrine service from 2008 to 2014 (N = 335) and 2016 to 2020 (N = 160), and examine for relationships between cortisol measurements and indication for testing, age and sex.MethodsLDSST were performed by endocrine nurses. Synacthen 500 ng/1.73m2 administered as IV bolus, sampling at 0, 15, 25, and 35 minutes.ResultsMean (± 1SD) baseline cortisol was 221 ± 120 nmol/L, peak 510 ± 166 nmol/L and increment 210 ± 116 nmol/L. 336 (70%) patients had a normal response (baseline cortisol >100 nmol/L, peak >450 nmol/L), 78 (16%) a suboptimal response (peak cortisol 350-450 nmol/L) and were prescribed hydrocortisone to during periods of stress only, 67 (14%) an abnormal response (baseline <100nmol/L or peak <350nmol/L) and were prescribed daily hydrocortisone. Basal, peak, and incremental increases in cortisol were higher in females (P = .03, P < .001, P = .03, respectively). Abnormal results occurred most frequently in patients treated previously with pharmacological doses of glucocorticoids or structural brain abnormalities (P < .001).ConclusionThe low prevalence and strong association of abnormal results with indication for testing, suggests that over diagnosis occurred infrequently in this clinical setting.

BACKGROUND:Noonan syndrome is an autosomal dominant condition with an incidence of 1:1000 to 1:2500. The disorder is associated with distinct dysmorphic features, cardiac anomalies, developmental delay and delayed puberty. Short stature is a recognised feature of Noonan syndrome.OBJECTIVES:The aim of this study is to assess the effect of growth hormone treatment in patients with Noonan syndrome.METHODS:Retrospective data was collected from patients with Noonan syndrome treated with growth hormone. The results were analysed with variables expressed as mean values and standard deviation scores.RESULTS:Twelve Noonan syndrome patients (M: F = 10:2) treated with growth hormone were identified. The mean age of starting growth hormone was 8 years, with baseline height standard deviation score of -2.96 (range: -1.64 to -5.54). The height standard deviation score significantly improved to -2.50 (P = 0.0035) and then -2.22 (P = 0.0025), following one and two years of treatment, respectively. The average height velocity for the patients prior to starting treatment was 5.16cm/year (range: 2.4 - 8.2 cm/year), which significantly improved to 7.76cm/year (ranging from 4.1 to 12.8 cm/year) after one year of growth hormone treatment (P = 0.020) and to 6.51cm/year at the end of two years.CONCLUSIONS:Our study has shown that growth hormone treatment significantly improves the height standard deviation score of patients with Noonan syndrome over a two-year course of growth hormone therapy without any side effects. Further research is required to analyse the long-term effect of growth hormone therapy in patients with Noonan syndrome, including the impact on final adult height.

OBJECTIVE:There is a paucity of data describing long-term outcomes of paediatric patients with pituitary adenoma. In this report, we describe clinical features, treatment and outcomes of a paediatric cohort. DESIGN:Retrospective cohort study. PATIENTS:Twenty-four white Caucasian patients aged <16 years from a single tertiary care centre in the United Kingdom at diagnosis followed for (median, range) 3.3, 0.7-8.4 years. MEASUREMENTS:Clinical and radiological data at diagnosis and follow-up. RESULTS:Thirteen patients had prolactinomas (54.1%, age: 15.2 years, 13.2-15.8 years; all females), including ten macroadenomas (11.0-35.0 mm). Patients presented with menstrual disorders (91%), headache (46%), galactorrhoea (46%) and obesity (body mass index [BMI] SDS > 2): (38%). Ten patients with prolactinoma were treated with dopamine agonist alone, 3 also required surgery and 2 patients, cabergoline, surgery plus radiotherapy. Five patients had Cushing's disease (20.8%, age: 14.0, 4.0-15.7 years; 2 female), including one macroadenoma (24 mm). Patients presented with obesity (100%), short stature (60%) and headache (40%). Transsphenoidal resection resulted in biochemical cure (09.00 cortisol < 50 nmol/L). Two patients relapsed 3- and 6 years following surgery, requiring radiotherapy. One patient also required bilateral adrenalectomy. Six patients had nonfunctioning pituitary adenoma (25.0%, age: 15.8, 12.5-16.0 years; 2 female), including two macroadenomas (20.0-53.0 mm). Patients presented with obesity (67%), visual field defects (50%) and headache (50%). Four required surgical resections; two recurred following surgery and required radiotherapy. On latest follow-up; 13 (54.1%) patients were obese (BMI 3.09 SDS; range: 2.05-3.73 SDS). CONCLUSION:Obesity is common at diagnosis of pituitary adenoma in childhood and may persist despite successful treatment. Adenomas were larger, more resistant to treatment, and more likely to recur than in adult populations.

Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.

Congenital hyperinsulinism is a rare but significant cause of severe and persistent hypoglycaemia in infancy. Although a biphasic phenotype of congenital hyperinsulinism in infancy followed by Maturity-Onset Diabetes of the Young (MODY) in later life has been established for HNF4A, the existence of a similar phenotype for a related MODY gene, HNF1A, is less clear. We describe two cases of congenital hyperinsulinism in association with dominantly inherited variants in HNF1A. They presented in the early neonatal period with unequivocal biochemical evidence of congenital hyperinsulinism and persistence into childhood with ongoing need for medical therapy. Both cases inherited HNF1A variants from a parent with a diabetes phenotype consistent with MODY, without obesity, insulin resistance or other metabolic syndrome features. In the first case, a paternally inherited novel c.-230_-101del variant was found that deletes the minimal promoter region presumably required for HNF1A expression. In the second case, a maternally inherited missense variant (c.713G>T, p.(Arg238Met)) was identified. This variant is predicted to cause haploinsufficiency via aberrant splicing and has previously been associated with MODY but not congenital hyperinsulinism. Our cases further strengthen the evidence for HNF1A as a CHI-causing gene requiring long-term follow-up.

Background There is limited data on adrenal function in the early days after birth in extremely premature infants. The relationship between plasma adrenocorticotrophic (ACTH) and cortisol hormone is central to the integrity of the hypothalamic-pituitary-adrenal (HPA) axis yet there are no studies examining this relationship in prematurity. Methods The aim of this study was to examine the relationship between early morning plasma cortisol and ACTH concentrations during the first 5 days after birth in infants born at less than 28 weeks' gestation and to identify any independent factors that determine plasma cortisol levels in these infants during extreme prematurity. We prospectively studied early morning plasma ACTH and cortisol concentrations in infants born below 28 weeks' gestation during the first 5 days of birth. Plasma cortisol was measured without extraction, using DPC Immulite® 2000 using a solid phase 2 site chemiluminescent immunometric assay. ACTH was measured using a radioimmunoassay. Spearman's correlation was used to examine the relationship between cortisol and ACTH. Multiple regression analysis was used to examine the relationship between plasma cortisol and clinical risk index for babies (CRIB) score, antenatal dexamethasone, mode of delivery and gestation. Results There were 95 infants (53 males) of mean gestation 25.3 ± 1.3 standard deviation (SD) (range 23-27 + 6) weeks. The mean birth weight was 809 ± 17.0 g. The mean plasma cortisol was 400.5 ± 42.6 nmol/L and the mean plasma ACTH was 4.5 ± 0.9 pmol/L. Early morning plasma cortisol correlated significantly with gestation (R = 0.4, p = 0.005). Early morning plasma ACTH did not correlate with early morning plasma cortisol (R = -0.12, p = 0.7). Multiple regression analysis showed that gestation was the only independent determinant of early morning plasma cortisol concentration (beta coefficient = -0.4, p = 0.04). Conclusions The relationship between early morning plasma ACTH and plasma cortisol is either not established or is impaired in infants of less than 28 weeks' gestation in the first 5 days after birth. The plasma cortisol level is mainly determined by gestation and is not directly related to illness severity, antenatal steroids or plasma ACTH in these infants in the first 5 days after birth.