Renuka Ramakrishnan

Testosterone Therapy Improves the First Year Height Velocity in Adolescent Boys with Constitutional Delay of Growth and Puberty

Background Constitutional delay of growth and puberty (CDGP) can cause significant psychological distress in adolescent boys. Although testosterone usage in this group has not been shown to affect the final adult height, the effect on the first year height velocity has not been widely reported. Objectives The aim is to determine whether testosterone treatment improves the first year height velocity in boys with CDGP when compared to boys with CDGP who go through puberty spontaneously Methods Retrospective data from 23 adolescent boys with CDGP was analysed. Ten out of 23 boys (43%) received testosterone injection (testosterone enanthate, 125 mg), once every 6 weeks for 3 doses in total. Both the groups (treated and untreated) had their height, bone age and testicular volume measured at the baseline, The height velocity and final predicted adult height were compared at the end of one year between both the groups. Results In the testosterone-untreated group, the mean (± SD) chronological age, bone age, height standard deviation scores (SDS) and testicular volume were 14.3 years (± 0.3),12.1 years (± 1.6), -1.9 (± 0.8) and 4.7 mL (± 1.1) respectively. Within the testosterone-treated group the mean (± SD) chronological age, bone age, height SDS and testicular volume at presentation were 14.4 years (± 0.4), 11 years (± 1.6), -2.1 SD(± 0.6) and 4.5 mL (± 1.2) respectively. The mean age of treatment with testosterone was 14.4 years (± 0.44). The mean height velocity one year after treatment was 8.4 cm/year (± 1.7) in the testosterone treated group when compared to 6.1 cm/year (± 2.1) in the patients who did not receive treatment (P = 0.01). There was no significant difference in the final predicted height between the 2 groups (P = 0.15). Conclusions Testosterone therapy improves the first year height velocity in boys with CDGP, without influencing their final predicted height.

Recovery of hypothalamo–pituitary–adrenal axis suppression during treatment with inhaled corticosteroids for childhood asthma

Objective To describe recovery of adrenal insufficiency in asthmatic children treated with inhaled corticosteroids (ICS) and cortisol replacement therapy. Design Retrospective, observational study. Patients A 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). Measurements Change 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). Results Baseline 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. Conclusion Recovery of adrenal function is common and occurs during continued ICS and cortisol replacement therapy.

An unusual case of hereditary nephrogenic diabetes insipidus (HNDI) affecting mother and daughter

Abstract Hereditary nephrogenic diabetes iInsipidus (HNDI) is an uncommon disorder due to a resistance to anti-diuretic hormone leading to a reduced urinary concentrating ability. The X-linked form is fully expressed in hemizygous male patients, but diabetes insipidus may also present in heterozygous females where it must be distinguished from autosomal and other secondary causes. We report a mother and daughter in the same family with HNDI due to a heterozygous deletion in exon 1 of the AVPR2 gene, not previously described in the literature. A 5-year-old girl was referred for investigation of polyuria and polydipsia. The patient had a water deprivation test elsewhere at the age of 3 that was inconclusive. A degree of water restriction was imposed leading to headaches. The thyroid, cortisol, renal, and calcium profiles were normal. Her mother showed similar symptoms that had not been previously investigated. AQP2 (Aquaporin) and initial AVPR2 gene sequencing had not identified a mutation, but subsequent quantitative polymerase chain reaction analysis revealed a heterozygous large exon 1 deletion of the AVPR2 gene. The same deletion was also found in the child’s mother. The patient’s symptoms have significantly improved on appropriate treatment. Further analysis revealed skewed X inactivation in mother and daughter.

Hypercalcaemic Pancreatitis, Adrenal Insufficiency, Autoimmune Thyroiditis and Diabetes Mellitus in a girl with Probable Sarcoidosis

Introduction Sarcoidosis is a multisystemic granulomatous disease with diverse and often non-specific symptoms during childhood. The clinical manifestations sometimes include endocrinopathies related to sarcoid infiltration of various endocrine organs, but more commonly due to the associated autoimmune endocrine disorders. There are only a few reports of multiple autoimmune and non-autoimmune endocrine problems occurring simultaneously in patients with sarcoidosis. We report a girl with probable sarcoidosis who also had Hashimoto’s thyroiditis, Type 1 diabetes (T1D) and secondary adrenal insufficiency. Case Presentation A 9-year-old girl previously diagnosed with autoimmune hypothyroidism and vitamin D deficiency, presented with hypercalcemic pancreatitis after initiating vitamin D supplementation that lead to a diagnosis of probable sarcoidosis. Secondary adrenal insufficiency and T1D were subsequently diagnosed. Her angiotensin converting enzyme levels on 2 occasions were 106 and 135 nmol/mL/min (normal range 10 - 43). All investigations conducted to exclude several infectious and malignant conditions that may mimic sarcoidosis were negative. The patient showed a good response to treatment with hydrocortisone, levothyroxine, insulin and methotrexate. Conclusions To our knowledge, ours is the youngest ever patient reported in the literature with sarcoidosis to develop multiple autoimmune and non-autoimmune endocrinopathies.

G462(P) Outcome of equivocal Cortisol responses to Insulin tolerance and Glucagon stimulation tests performed in children with idiopathic short stature (ISS) and idiopathic isolated growth hormone deficiency (IIGHD)

Introduction The insulin tolerance (ITT) and glucagon stimulation (GST) tests are used most frequently to assess growth hormone reserve. These tests also stimulate cortisol release. It is not uncommon for patients, with no clinical suggestion of cortisol deficiency, to have equivocal cortisol responses (peak cortisol <500 nmol/L) which may cause unnecessary parental anxiety, further testing and treatment. Aim To explore the outcome of children with idiopathic short stature and isolated idiopathic short stature who had peak cortisol levels <500 nmol/l in the ITT or GST during the period January 2008 to December 2014. Results Data from 189 (130 M) patients, age 12.0 years ± 4.4 (mean±SD) were studied. 94 underwent a GST and 95 underwent an ITT. In 38 patients (20.1%), age 12.1yrs (1.7–19.2 yrs), peak cortisol levels were <500 nmol/L, of whom 24 patients, (median age 7.7 yrs, 1.7–16.8 yrs) underwent GST (peak cortisol levels 396 nmol/L, 231–491) and 14 patients (median age 14.0 yrs, 5. 2–19.2 yrs) underwent ITT (peak cortisol 461 nmol/L, 408–497). Outcome of these patients who had peak cortisol <500 nmol/l is given in the following Table.Abstract G462(P) Table 1 Number of patients n = 38 Test, Peak cortisol – median (range) (nmol/l) Outcome 16 GST, N=15, 364 (238–464) ITT, N=1, 486 Passed LDSST 6 451 (422–486) All had ITT and were treated with hydrocortisone on sick days only. 3 patients had LDSST of whom 2 had peak cortisol levels <500 nmol/L. 13 GST, N=7, 414 (345–491) ITT, N=6, 482 (408–497) Observation only, remained clinically well. Median period of observation 2.5yrs (range 0.9–7.8 yrs) 1 469 on ITT Morning cortisol was 457nmol/l 1 301 on GST Passed ITT after GST with peak of 541nmol/l 1 428 on GST Did not attend 3 appointments LDSST: low dose short Synacthen test Conclusion Our observations support previous reports that cortisol levels in healthy children may be <500nmol/L on the GST and ITT, and strengthen recommendations for a review in the definitions of ‘normal’ and ‘abnormal’ results.

G474(P) Role of low dose short synacthen test (LDSST) in the assessment of adrenal reserve in children with chronic Asthma

Background The 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. Aims To describe recovery of adrenal function in children with abnormal cortisol responses to the LDSST during treatment with ICS for asthma. Methodology The 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. Results Data 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). Conclusions 1) 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.

G439 Mode of clinical presentation and delayed diagnosis of turner syndrome

Background Early diagnosis of girls with Turner syndrome (TS) is essential to provide timely intervention and support. The screening guidelines for TS suggest karyotype evaluation in patients presenting with short stature, webbed neck, lymphoedema, coarctation of aorta or > two dysmorphic features (nail dysplasia, high arched palate, short fourth metacarpal or strabismus). Objectives The aim of the study was to determine the age and clinical features at the time of presentation to identify potential delays in diagnosis of TS. Methods Retrospective data on age at diagnosis, reason for karyotype analysis and presenting clinical features was collected from the medical records of 67 girls with TS. Results The mean age of diagnosis was 5.89 (±5.3) years and ranged from prenatal to 17.9 years. 10% were diagnosed antenatally, 16% in infancy, 54% in childhood (1–12 years) and 20% in adolescence (12–18 years). Only 42% of girls were diagnosed before 5 years of age. Lymphoedema (27.3%) and dysmorphic features (27.3%) were the main signs that triggered screening in infancy. Short stature was the commonest presenting feature in both childhood (52.8%) and adolescent (38.5%) years. 23% were screened because of delayed puberty and 15% due to irregular periods in the adolescence. At least 12% of girls fulfilled the criteria for earlier screening but were diagnosed only at a later age (mean age= 8.78 years). The actual duration of delay in children presenting with short stature could not be ascertained due to lack of height measurements prior to seeking specialist opinion. The karyotype for each patient was also analysed. 13.4% of patients had classical 45XO karyotype and 52.3% of girls had a variant karyotype (mosaic pattern etc). The mean age of diagnosis for both groups was 5.3 years. Conclusion Majority of girls with TS were diagnosed only after the age of 5 years. Short stature triggered evaluation for most patients diagnosed in childhood and adolescence. Lack of community height-screening programme and lack of awareness could have led to potential delays in diagnosing TS. New strategies for earlier detection of TS are needed.