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Context: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. Objective: To assess whether gene panel testing can assist with clinical differential diagnosis, to allow accurate and timely management of delayed puberty patients. Design: Retrospective study Methods: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rare, predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. Results: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only 3 patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. Conclusion:This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.

ObjectiveTo describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy.DesignRetrospective, observational study.PatientsA total of 113 patients, 74 male; age 10.4 (3.3–16.5) years; beclomethasone-equivalent ICS dose, 800 μg, (100–1,000), tested by low dose short Synacthen (tetracosactide) test (LDSST), were studied. Test results were classified by basal and peak cortisol concentration: “normal” (basal >100 nmol/L, peak >500 nmol/L), “suboptimal” (basal >100 nmol/L, peak 350–499 nmol/L), “abnormal” (basal <100 nmol/L and/or peak <350 nmol/L). Patients with suboptimal results received hydrocortisone during periods of stress only, and those with abnormal responses received daily hydrocortisone, increased during periods of stress. A total of 73 patients (68%) had ≥2 LDSSTs over 2.2 years (0.2–7.7).MeasurementsChange in cortisol response to repeat LDSST (movement between diagnostic groups, difference in basal and peak cortisol >15% [2× the inter-assay coefficient of variation]), change in BMI and height standard deviation score (SDS).ResultsBaseline test results were abnormal in 17 patients (15%) and all of them had repeat tests. In 13 patients (76%), test results improved (normal in six, suboptimal in seven) and four (24%) remained abnormal. Baseline tests results were suboptimal in 54 patients (48%), of whom 50 (93%) were retested. Repeat tests were normal in 36 patients (72%), remained suboptimal in 11 (22%), and were abnormal in three (6%). Baseline tests results were normal in 42 patients, of whom six patients (14%) were retested. Results remained normal in three (50%), were suboptimal in two (33%), and abnormal in one (17%). Basal and peak cortisol levels increased by >15% in 33/73 (45%) and 42/73 (57%) patients, respectively, and decreased by >15% in 14/73 (19%) and 7/73 (10%), respectively. There was no significant change in height or BMI SDS.ConclusionRecovery of adrenal function is common and occurs during continued ICS and cortisol replacement therapy.

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BackgroundThe role of inhaled corticosteroids (ICS) is undisputable in the management of chronic asthma. However, the regular or recurrent use of ICS results in suppression of hypothalamic-pituitary–adrenal (HPA) axis, that could be asymptomatic or results in adrenal crisis. The Low Dose Short Synacthen Test (LDSST) has been shown to be a sensitive test of adrenal function during ICS therapy.AimsTo describe recovery of adrenal function in children with abnormal cortisol responses to the LDSST during treatment with ICS for asthma.MethodologyThe result of LDSST’s performed in children treated with ICS for asthma between 2011–2014 was studied. Results of previous and subsequent LDSST were also collected. Age, gender, cumulative corticosteroid dosage and the outcome of LDSST were analysed. Patients were classified as having normal (>500nmol/L), suboptimal (350–499nmol/L) and abnormal (<350nmol/L) cortisol responses from the results of their first LDSST. Baseline cortisol levels <100nmol/L at 9am were considered abnormal. The repeat LDSST test results were also analysed to assess the movement of patients between the groups and time period for that shift.ResultsData are shown as median (range) 184 LDSSTs were carried out in 81 patients (51M), age 10.6 years (0.7–17.1). Duration of follow up was 1.6 years (0–6.3), and the number of LDSST’s was 2.3/patient (1–6). Recovery of adrenal function was observed in 65% and 50% of patients with suboptimal and abnormal group respectively. Test results worsened in 25% of patients including patients in normal group. 13/52 patients with impaired, and 4/14 patients with abnormal tests were not tested further. 10 patients (12%) had basal cortisol levels <100nmol/l, of which 4 became normal and 6 still remained abnormal after 1.9 years (0–6.3) of follow-up. The total daily dose of inhaled corticosteroid (Beclomethasone equivalent) in suboptimal and abnormal group was 780 mcg/day, which was 35% higher than the patients in normal group (p = 0.01).Conclusions1) Adrenal suppression is common in chronic asthma patients receiving ICS 2) Adrenal function could worsen in patients who were tested normal previously and hence high index of suspicion is required to diagnose this early. 3) Higher dose of inhaled corticosteroid dose is likely to result in suboptimal or abnormal LDSST.