Graves' disease (GD) is the most common cause of juvenile thyrotoxicosis in children and adolescents (1, 2). Three treatment modalities are now available for the treatment of Graves' thyrotoxicosis in childhood: antithyroid drugs (ATD), surgery and radioactive iodine (RAI). However, none of these treatments has been shown to be ideal or clearly superior to the others. Physicians in different countries have different approaches concerning the optimal treatment of juvenile GD.In a European questionnaire study (3), which was conducted by the European Thyroid Association in 1993 and in which 99 individuals or groups from 22 countries participated, it was found that 22 out of 99 physicians from nine countries would consider RAI treatment as the treatment of choice for children with recurrent thyrotoxicosis after surgery, or with recurrent thyrotoxicosis 2 years after ATD. However, RAI is preferred by only a small percentage of physicians for this group of patients in Europe. Hardly any of the respondents chose RAI for the patients with a toxic adenoma or a multinodular toxic goiter (3). On the other hand, in view of the difficulties with medical therapy in children and adolescents, including poor compliance, a high rate of relapse, drug toxicity and continued thyroid enlargement, some eminent American physicians emphasize the safety, simplicity and economic advantages of (131)I ablation which should be considered more commonly in children (4, 5).We had the opportunity to conduct a similar study during a pediatric thyroidology symposium, which was organized by Professors Buyugkebiz and Laron in Izmir (Smyrna) Turkey from 30 October to 1 November 2003. During the congress a questionnaire with the following four questions was circulated among the 120 participants from eight countries who were mainly paediatric endocrinologists. Most of them were from Turkey and the rest, except for one who came from the USA, were Europeans. Sixty-one out of the 120 physicians responded.
HL Fideleff, HR Boquete, MG Suarez, GF Ruibal, PG Sobrado, M Azaretsky, AB Pujol, AM Sequera, J Giuseppucci, and R Ponzio
OBJECTIVE: To study hormonal and histological parameters of paediatric-adolescent varicocele in order to know certain aspects of its natural history, in an attempt to find prognostic markers of testicular damage. DESIGN AND METHODS: In a prospective cross-sectional study, we evaluated 93 children and adolescents with left unilateral varicocele and 29 healthy males as control group. All of them were classified according to Tanner stage. Scrotal Doppler in both testes and GnRH and human chorionic gonadotrophin (hCG) tests were performed in all subjects. Surgery was performed in 28 patients and homolateral testicular biopsy in 18. RESULTS: Hormonal measurements of patients with varicocele were compared with a control group for each Tanner stage. Testicular biopsy specimens were analysed by light and electron microscopy. We only observed statistical differences in Tanner III patients in basal FSH (median and range) controls=1.70 (1.10-3.70) IU/l vs varicocele=4.20 (1.00-7.50) IU/l, P<0.05 and in Tanner IV patients in LH post-GnRH: controls=11.0 (7.50-15.0) IU/l vs varicocele=18.0 (5.10-29.0) IU/l, P<0.05 and in testosterone post-hCG: controls=9.50 (7.7-10.0) ng/ml vs varicocele=12.0 (6.2-23.0) ng/ml, P<0.01. No correlation was found between the various clinical grades of varicocele and hormonal measurements for each Tanner stage. No statistically significant differences were found between pre- and post-operative hormonal findings, either in basal levels or in maximal responses. On the other hand, no morphological abnormalities were observed by electron microscopy in germ cells, tubular wall and interstice. CONCLUSIONS: There appears to be no reliable biochemical marker in children and adolescents that may predict impaired testicular function. A significant size discrepancy between both testes, testicular pain and a hyperresponse to GnRH stimulation should continue to be, for the time being, the indications for surgery.
Eva Al Taji, Heike Biebermann, Zdeňka Límanová, Olga Hníková, Jaroslav Zikmund, Christof Dame, Annette Grüters, Jan Lebl, and Heiko Krude
Objective: Mutations in NKX2.1, NKX2.5, FOXE1 and PAX8 genes, encoding for transcription factors involved in the development of the thyroid gland, have been identified in a minority of patients with syndromic and non-syndromic congenital hypothyroidism (CH).
Design: In a phenotype-selected cohort of 170 Czech paediatric and adolescent patients with non-goitre CH, including thyroid dysgenesis, or non-goitre early-onset hypothyroidism, PAX8, NKX2.1, NKX2.5, FOXE1 and HHEX genes were analysed for mutations.
Methods: NKX2.1, NKX2.5, FOXE1 and HHEX genes were directly sequenced in patients with syndromic CH. PAX8 mutational screening was performed in all 170 patients by single-stranded conformation polymorphism, followed by direct sequencing of samples with abnormal findings. The R52P PAX8 mutation was functionally characterized by DNA binding studies.
Results: We identified a novel PAX8 mutation R52P, dominantly inherited in a three-generation pedigree and leading to non-congenital, early-onset, non-goitre, non-autoimmune hypothyroidism with gradual postnatal regression of the thyroid size and function. The R52P PAX8 mutation results in the substitution of a highly conserved residue of the DNA-binding domain with a loss-of-function effect. Conclusions: The very low frequency of genetic defects in a population-based cohort of children affected by non-goitre congenital and early-onset hypothyroidism, even in a phenotype-focussed screening study, suggests the pathogenetic role of either non-classic genetic mechanisms or the involvement of genes unknown so far. Identification of a novel PAX8 mutation in a particular variant of non-congenital early-onset hypothyroidism indicates a key function of PAX8 in the postnatal growth and functional maintenance of the thyroid gland.
Yasmine El Allali, Coralie Hermetet, Justine Bacchetta, Cyril Amouroux, Anya Rothenbuhler, Valérie Porquet-Bordes, Marie-Alexandrine Champigny, Sabine Baron, Pascal Barat, Hélène Bony-Trifunovic, Karine Bourdet, Kanetee Busiah, Maryse Cartigny-Maciejewski, Florence Compain, Régis Coutant, Jessica Amsellem-Jager, Marc De Kerdanet, Nathalie Magontier, Brigitte Mignot, Odile Richard, Sylvie Rossignol, Sylvie Soskin, Aurélie Berot, Catherine Naud-Saudreau, Jean-Pierre Salles, Agnès Linglart, Thomas Edouard, and Anne Lienhardt-Roussie
To describe the presenting features and molecular genetics of primary hyperparathyroidism (PHPT) in the paediatric population.
Retrospective study of 63 children diagnosed with primary PHPT from 1998 to 2018.
Compared to older children, infants were often asymptomatic (54% vs 15%, P = 0.002) with a milder form of PHPT. When symptomatic, children and adolescents mostly presented with non-specific complaints such as asthenia, depression, weight loss, vomiting or abdominal pain. A genetic cause of PHPT was identified in about half of this cohort (52%). The infancy period was almost exclusively associated with mutation in genes involved in the calcium-sensing receptor (CaSR) signalling pathway (i.e. CaSR and AP2S1 genes, ‘CaSR group’; 94% of infants with mutations) whereas childhood and adolescence were associated with mutation in genes involved in parathyroid cell proliferation (i.e. MEN1, CDC73, CDKN1B and RET genes, ‘cell proliferation group’; 69% of children and adolescents with mutations). Although serum calcium levels did not differ between the two groups (P = 0.785), serum PTH levels and the urinary calcium/creatinine ratio were significantly higher in ‘cell proliferation group’ patients compared to those in the ‘CaSR group’ (P = 0.001 and 0.028, respectively).
Although far less common than in adults, PHPT can develop in children and is associated with significant morbidity. Consequently, this diagnosis should be considered in children with non-specific complaints and lead to monitoring of mineral homeostasis parameters. A genetic cause of PHPT can be identified in about half of these patients.
Roberta Ricotti, Arianna Solito, Elena Mariotti Zani, Marina Caputo, Giulia Genoni, Francesco Barone-Adesi, Valentina Mancioppi, Emanuela Agosti, Gianluca Aimaretti, Simonetta Bellone, and Flavia Prodam
Data on metabolic impairments in Cushing’s syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity.
Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity.
Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles.
We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.
Michael J O'Grady, Conor Hensey, Miriam Fallon, Hilary Hoey, Nuala Murphy, Colm Costigan, and Declan Cody
Based on adult data, a peak cortisol response ≥500 nmol/l to insulin-induced hypoglycaemia constitutes a normal. Age-specific reference ranges for basal morning cortisol have been developed for clinical use in the paediatric population. Such reference ranges are not clearly established for peak cortisol responses to insulin-induced hypoglycaemia despite limited data suggesting an effect of age on peak cortisol. The aims of this study were to assess factors affecting the cortisol response to insulin-induced hypoglycaemia in children and to determine whether the peak cortisol response was related to age.
The present study was a retrospective cohort study.
Retrospective analysis of children and adolescents aged ≤18 years undergoing the insulin tolerance test with adequate hypoglycaemia was undertaken. Patients with hypopituitarism or severe hypothalamic–pituitary–adrenal axis impairment (peak cortisol value <400 nmol/l) or using systemic glucocorticoids were excluded.
Two hundred and twenty-three tests were analysed. Peak cortisol responses ≥500 nmol/l occurred in 183 (82%) tests. Age was negatively associated with peak cortisol responses (r=−0.15, P=0.03). A peak cortisol response <500 nmol/l was significantly less common in patients aged <12 years (9/97 (9%) vs 31/126 (25%); P=0.004). In children aged <12 years, the median (5th–95th centiles) peak cortisol values were 610 (480–806) nmol/l compared with 574 (442–789) nmol/l in children aged ≥12 years (P<0.004). Similarly, median cortisol increment was significantly higher in younger patients (301 nmol/l compared with 226 nmol/l (P=0.0004)).
Use of a single peak cortisol threshold in children of all ages is not appropriate and will result in overdiagnosis of adrenal insufficiency in adolescents.
Marianne K Vihinen, Kaija-Leena Kolho, Merja Ashorn, Matti Verkasalo, and Taneli Raivio
We investigated circulating markers of bone turnover before and during systemic glucocorticoid treatment in paediatric patients with inflammatory bowel disease (IBD).
Twenty-two children (mean age, 12.3 years) with IBD necessitating peroral steroid therapy were studied, with special reference to bone formation and resorption markers amino-terminal type I collagen propeptide (PINP) and carboxyterminal telopeptide of type I collagen (ICTP) respectively. In addition, GH-related IGF-I and sex hormone-binding protein (SHBG) were measured. Bone markers were analyzed at the initiation of the glucocorticoid treatment, at 2 and 5 weeks thereafter and at 1 month following the withdrawal of the steroid. Control group comprised 22 IBD patients in remission.
PINP and IGF-I were already lower before glucocorticoid treatment serum in children with active IBD as compared with control children with IBD in remission (median PINP 271 vs 535 μg/l, P<0.05; IGF-I 23 vs 29 nmol/l, P<0.05). After 2 weeks of glucocorticoid treatment serum PINP levels had declined further, from 271 to 163 μg/l (P<0.001), serum ICTP from 14.2 to 9.6 μg/l (P<0.001), and SHBG from 54 to 35 nmol/l (P<0.001) respectively. By contrast, serum IGF-I increased from 23 to 37 nmol/l (P<0.001). One month after the withdrawal of the glucocorticoid, all bone markers restored to levels similar to the controls.
Bone formation in children with active IBD appears compromised and systemic glucocorticoid treatment further suppresses bone turnover. After the cessation of the glucocorticoid the bone markers show immediate improvement.
Raja Padidela, Miriam Fiest, Ved Arya, Virpi V Smith, Michael Ashworth, Dyanne Rampling, Melanie Newbould, Gauri Batra, Jacqueline James, Neville B Wright, Mark J Dunne, Peter E Clayton, Indraneel Banerjee, and Khalid Hussain
Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients.
We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-l-18F-fluorodihydroxyphenylalanine (18F-DOPA) PET/CT scanning) and histological data were collected.
Nine children (age range 2–14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and 18F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas.
We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.
P G Murray, A Read, I Banerjee, A J Whatmore, L E Pritchard, R A Davies, J Brennand, A White, R J Ross, and P E Clayton
Leptin deficiency caused by mutations within the leptin gene (LEP) results in severe early onset obesity, hypogonadism, pubertal delay and immune system abnormalities. Constitutional delay in growth and puberty (CDGP) is a common condition seen in paediatric clinics, in which children present with delayed growth and puberty but usually also have a slim body habitus. We hypothesized that LEP variants may play a role in the phenotype seen in CDGP.
To screen a group of children with CDGP for pathogenic sequence variants in LEP.
Patients and methods
Denaturing HPLC was used to screen for LEP sequence variants in DNA samples from 78 children with CDGP (predominantly white males) and 112 control subjects. DNA fragments with a WAVE pattern deviant from wild type were directly sequenced. A STAT3 luciferase reporter assay in human embryonic kidney (HEK293) cells transiently transfected with the leptin receptor was used to test activity of mutant leptin.
One child with CDGP was identified to be heterozygous for a novel missense variant (c.68C>G), which results in a proline to arginine substitution (p.P23R). This sequence variant was not identified in any of the other control subjects, but was identified in his mother who shared a similar phenotype of slim body habitus, reduced appetite and pubertal delay (menarche aged 15 years). The leptin variant showed similar stability in serum compared with wild type and did not demonstrate increased activity in an in vitro reporter gene assay.
This is the first report of a sequence variant within the LEP gene associated with reduced body mass index rather than obesity. We hypothesize that this variant has increased bioactivity in vivo.
Enora Le Roux, Agathe Turpin, Morgane Michel, Isabelle Tejedor, Florence Menesguen, Sabine Malivoir, Sandrine Bottuis, Hélène Mellerio, Michel Polak, and Philippe Touraine
Objective. To evaluate the effect of a new care organisation on multiple outcomes of transition success and its cost-effectiveness in patients with any endocrine or metabolic disease diagnosed during childhood and transferred to adult care.
Design. Non-randomized controlled trial in a French University Hospital.
Methods. Patients transferred to adult care during the control period (04/2014-08/2016) and the intervention period (09/2016-06/2018) were included. The intervention is based on case management involving liaising with paediatric services, personalising care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector). The primary endpoint was the percentage of patients lost to follow-up at 24 months post transfer. Other outcomes were collected from medical files, consultation software, and questionnaires. A cost analysis was performed.
Results. 202 patients were included (101 per period) , the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n=34 (17%) and n=45 (22%)) and thyroid diseases (n=21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow up in the control group versus 9 with the intervention (p=0.49). The percentage of honoured consultation among those planned during 24 months was higher with intervention (p=0.0065). Patient satisfaction, physician trust, transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up.
Conclusions. At 24 months post transfer the rate of lost to follow-up does not differ significantly, but indicators of a steadier follow-up are increased and the intervention appears to be cost-effective.