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I V Wagner, C Paetzold, R Gausche, M Vogel, A Koerner, J Thiery, C G Arsene, A Henrion, B Guettler, E Keller, W Kiess, R Pfaeffle, and J Kratzsch

Context

Cutoff limits of GH stimulation tests to diagnose GH deficiency (GHD) in children and adolescents are not sufficiently validated by clinical studies due to discrepancies in the performance of GH immunoassays and lack of available study populations.

Objective

We aimed to establish new cutoff limits for GH stimulation tests based on clinical evidence and compared these immunoassay-based values with an antibody-independent mass spectrometric method.

Design and setting

In a retrospective study, GH cutoff limits for eight different immunoassays and isotope dilution mass spectrometry (ID-MS) were calculated from hGH peak concentrations of short-statured children with and without GHD.

Patients

We compared the serum GH peak concentrations at GH stimulation test of 52 short-statured children and adolescents, who have normal GH secretion at initial workup and normal growth in the follow-up, with the serum GH peak concentrations of 44 GHD patients in the same age range, in order to optimize the cutoff limit calculation.

Results

Discriminant analysis of re-measured GH led to a new cutoff limit of 7.09 μg/l using the iSYS assay (IDS) and the limits for the other seven hGH assays varied between 4.32 and 7.77 μg/l. For ID-MS, cutoffs of 5.48 μg/l (22k GH) and 7.43 μg/l (total GH) were ascertained.

Conclusion

The establishment of method-specific clinical evidence-based GH cutoff limits is of importance to ensure adequate clinical diagnosis and treatment of children and adolescents with GHD. ID-MS may become an important tool for providing both reliable and sustainable SI traceability of GH measurements in the future.

Free access

Paolo Cavarzere, Rossella Gaudino, Marco Sandri, Diego Alberto Ramaroli, Angelo Pietrobelli, Marco Zaffanello, Alessandra Guzzo, Gian Luca Salvagno, Giorgio Piacentini, and Franco Antoniazzi

Objectives

To report the frequency and characteristics of growth hormone (GH) deficiency (GHD) in adolescents who had normalized GH secretion at mid-puberty and to identify possible factors predictive for GH sufficiency at puberty.

Design

Clinical analysis of children affected by GHD at five time points: diagnosis; first year of therapy; intermediate stage of puberty; retesting and end of growth phase.

Methods

The study population was 80 children with idiopathic GHD and treated with GH for at least 2 years. Treatment was discontinued at the intermediate stage of puberty. Retesting with an arginine test was performed 12 weeks later. If GH peak at retesting was ≥8 μg/L, the therapy was definitively discontinued, otherwise it was restarted and continued until achievement of near-final height.

Results

GH therapy was discontinued in 44 children (55%), and restarted in 36 (45%). No evidence of differences in definitive height and in the delta height between the genetic target and the definitive height was found between the two groups. The only predictive factor for GHD at mid-puberty was the insulin growth factor-1 (IGF-1) level at 1 year of GH treatment.

Conclusions

GH secretion should be retested at mid-puberty. Retesting at puberty may reduce potential side effects and minimize costs, without impairing growth potential and final height.

Free access

Andrew J Beamish and Thomas Reinehr

Adolescent obesity has markedly increased worldwide in both its extent and prevalence in recent decades and obesity prevention strategies are failing. As a result, effective treatment strategies are urgently needed. As behavioral and pharmacological treatment approaches have only moderate effects in severe obesity, bariatric surgery has begun to emerge as a treatment option. In this debate article, we offer arguments opposing and supporting bariatric surgery in the treatment of severe obesity in adolescents. Bariatric surgery has superior therapeutic outcomes with respect to weight loss and resolution of comorbid diseases over other existing treatments. However, long-term outcomes after bariatric surgery in adolescents are only just beginning to emerge. Furthermore, the procedures are generally considered irreversible, apart from gastric banding. Most importantly, not all adolescents seem to benefit greatly from bariatric surgery and we are not yet able to reliably identify those who stand to gain the greatest benefit. The authors agree that adolescent bariatric surgery should be offered exclusively within formal adolescent obesity programs, delivered by specialist multidisciplinary child/adolescent obesity teams, and within specialist centers, in order to optimize outcomes and minimize potential detrimental effects. Patients and their family/carers must be educated regarding the benefits and risks, potential side effects, expected changes in eating behavior and the lifelong requirement for regular medical follow-up after surgery. Before embarking upon a surgical treatment pathway in adolescents with severe obesity, it may also be beneficial to ensure compliance to treatment is demonstrated, in order to minimize the risk of nutritional deficiencies and associated potential complications.

Restricted access

D. C. L. Savage, Constance C. Forsyth, Eileen McCafferty, and Jenny Cameron

ABSTRACT

The excretion of 7 individual 17-oxosteroids and 7 individual corticosteroids in 24 h urine samples from 62 normal infants, children and adolescents, based on an accurate and specific paper chromatographic method for their separation and quantitation, is reported. The excretion of the 11-deoxy-17-oxosteroids gradually increases from 7 years of age and the increase becomes more rapid 2 or 3 years before the clinical signs of puberty appear. The rise continues throughout puberty and beyond it until the adult level is reached. The increase far exceeds that which would be accounted for by the growth of the individual. The increase in the excretion of the 11-oxy-17-oxosteroids with age is much more gradual. Androgens favour the formation of 5α metabolites and the 5α:5β ratio of the total 5α 17-oxosteroids and the total 5β 17-oxosteroids shows a statistically significant increase with age. In addition, a relatively high 5α:5β ratio is noted in male infants, which is likely to be related to their relatively high plasma testosterone levels. The excretion of the 17-hydroxycorticosteroids and the α-ketolic metabolites of cortisol gradually rises with age and correlates with body weight. The α-ketolic metabolites of corticosterone are relatively high in infancy, but after the age of 4 years their excretion also correlates with body weight. An increase in the 5α:5β ratio of allo-THF to THF is noted at puberty similar to that found with the 5α:5β ratios of the 17-oxosteroids.

Free access

A Verrotti, G Loiacono, A Mohn, and F Chiarelli

Diabetic autonomic neuropathy (DAN) represents a major complication of diabetes mellitus but there is considerable uncertainty about its incidence, prevalence, pathogenesis, diagnosis, and prognosis. There are conflicting opinions about the pathogenesis of DAN: the ‘classical hypothesis’ has been supplemented by some new insights. Clinical symptoms of autonomic neuropathy do not generally occur until long after the onset of diabetes. DAN seems to be detectable even in asymptomatic children and adolescents with diabetes and is associated with the most serious consequences, such as cardiovascular dysfunction. Because of its association with a variety of adverse outcomes, including cardiovascular deaths, cardiovascular autonomic neuropathy is the most clinically important and well-studied form of DAN. No form of therapy in DAN has been identified that provides unequivocal, safe, and effective stabilization or reversal of the condition, just a near normal control of blood glucose in the early years after the onset of diabetes that may delay the development of clinically significant nerve impairment. This article reviews recent developments in knowledge of epidemiology, pathogenesis, clinical symptoms, diagnosis, and therapy of DAN.

Free access

Giorgia Pepe, Domenico Corica, Luisa De Sanctis, Mariacarolina Salerno, Maria Felicia Faienza, Daniele Tessaris, Gerdi Tuli, Iris Scala, Laura Penta, Angela Alibrandi, Giovanni Battista Pajno, Tommaso Aversa, Malgorzata Wasniewska, and the Thyroid Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED)

Objective

To evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents.

Design

Prospective multicenter study.

Methods

For the study, 101 DS patients with SH (TSH 5–10 mIU/L; FT4 12–22 pmol/L), aged 2–17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, and L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up.

Results

Thirty-seven out of 101 patients displayed autoantibody positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, P = 0.001; 32.4% vs 7.8%, P = 0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, P = 0.028). Gender, median BMI (SDS), height (SDS), FT4, and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (P = 0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (P = 0.02); and 37.8% of group A vs 51.5% of group B still had SH condition (P = 0.183). Logistic regression suggested autoimmunity (OR = 3.2) and baseline TSH values (OR = 1.13) as predictive factors of the evolution from SH to OH.

Conclusions

In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

Free access

Alice Monzani, Flavia Prodam, Anna Rapa, Stefania Moia, Valentina Agarla, Simonetta Bellone, and Gianni Bona

Objective

Subclinical hypothyroidism (SH) is quite common in children and adolescents. The natural history of this condition and the potential effects of replacement therapy need to be known to properly manage SH. The aim of this review is to analyze: i) the spontaneous evolution of SH, in terms of the rate of reversion to euthyroidism, the persistence of SH, or the progression to over hypothyroidism; and ii) the effects of replacement therapy, with respect to auxological data, thyroid volume, and neuropsychological functions.

Methods

We systematically searched PubMed, Cochrane, and EMBASE (1990–2012) and identified 39 potentially relevant articles of which only 15 articles were suitable to be included.

Results and conclusions

SH in children is a remitting process with a low risk of evolution toward overt hypothyroidism. Most of the subjects reverted to euthyroidism or remained SH, with a rate of evolution toward overt hypothyroidism ranging between 0 and 28.8%, being 50% in only one study (nine articles). The initial presence of goiter and elevated thyroglobulin antibodies, the presence of celiac disease, and a progressive increase in thyroperoxidase antibodies and TSH value predict a progression toward overt hypothyroidism. Replacement therapy is not justified in children with SH but with TSH 5–10 mIU/l, no goiter, and negative antithyroid antibodies. An increased growth velocity was observed in children treated with levothyroxine (l-T4; two articles). l-T4 reduced thyroid volume in 25–100% of children with SH and autoimmune thyroiditis (two studies). No effects on neuropsychological functions (one study) and posttreatment evolution of SH (one study) were reported.

Free access

Ge Li, Yu Li, Lanwen Han, Dongmei Wang, Qian Zhang, Xinhua Xiao, Lu Qi, Steven M Willi, Ming Li, Jie Mi, and Shan Gao

Objective

A subset of normal-weight individuals appears predisposed to obesity-related cardiometabolic abnormalities. Studies of this metabolically obese, normal weight (MONW) phenotype in youth are scarce. We aimed to identify early environmental and genetic factors associated with MONW in children.

Methods

Overall, 1475 normal-weight Chinese children aged 6–18 were recruited from the Beijing Children and Adolescents Metabolic Syndrome study cohort. Birthweight, childhood lifestyle, socio-economic factors, and 20 genetic variants previously shown to be associated with BMI or glucose metabolism in East Asian adults were examined for their association with the MONW phenotype. MONW was defined by exhibiting any metabolic syndrome component.

Results

After adjusting for covariates including BMI, low birthweight and low levels of physical activity, fruit consumption, parental education and household income, as well as CDKAL1 rs2206734 genotype were independent predictors of the MONW phenotype (all P < 0.05). Moreover, rs2206734 interacted with birthweight to predict the MONW phenotype (P interaction = 0.0008). Among high (>75th percentile) birthweight individuals, each C allele at this locus was associated with a 62% reduced risk of MONW (OR = 0.38; 95% CI = 0.26-0.58; P = 5.71 × 10−6), while no such genetic associations were found in intermediate or low birthweight individuals (P > 0.1). This CDKAL1-MONW relationship in high birthweight individuals was especially strong in the presence of favorable childhood environmental factors (high levels of physical activity, fruit consumption, parental education and household income) (P interaction = 0.013).

Conclusions

Our findings provided the novel evidence that early environment (especially birthweight) and genetics, along with their interaction with one another, play important roles in predicting the MONW phenotype among children.

Free access

G E Krassas, M Segni, and W M Wiersinga

Objective: Evaluation of the frequency of Graves’ ophthalmopathy (GO) and its management in children and adolescents up to 18 years old with Graves’ hyperthyroidism.

Study design: This was a questionnaire study (QS) among members of the European Thyroid Association and the European Society for Paediatric Endocrinology. Approximately 300 QS were sent to members with electronic addresses and 110 QS were returned from 25 countries: 52 respondents said they had no experience with Graves’ disease in this age group, but 67 respondents (23 paediatric and 44 adult endocrinologists) completed the QS.

Results: Out of 1963 patients with juvenile Graves’ hyperthyroidism seen by respondents in the last 10 years, 641 (33%) had GO; about one-third of GO cases were ≤10 years old, and two-thirds were 11–18 years old. The prevalences of GO among juvenile Graves’ hyperthyroidism were 36.6, 27.3 and 25.9% in countries in which the smoking prevalence among teenagers was ≥25, 20–25 and <20% respectively (P < 0.0001 by χ2 test). When confronted with the standard case of a 13-year-old girl with Graves’ hyperthyroidism and moderately severe active GO, the diagnostic approach included on average 4.9 biochemical tests (TSH, free thyroxine (FT4) and TSH.R-Ab, 100-88% of respondents) and 2.4 specific investigations (thyroid ultrasound by 69%, orthopsy/visual fields/visual acuity by 64% and orbital magnetic resonance imaging or computed tomography by 63%). Antithyroid drugs were the treatment of choice for 94% of respondents; 70% recommended a wait-and-see policy and 28% corticosteroids for the co-existing GO. In variants of the standard case, a younger age did not affect therapeutic approach very much. Recurrent hyperthyroidism would still be treated with antithyroid drugs by 66%, and with 131I by 25%. Worsening of GO or active GO when euthyroid would convince about two-thirds of respondents to initiate treatment of GO, preferably with steroids.

Conclusion: GO occurs in 33% of patients with juvenile Graves’ hyperthyroidism; its prevalence is higher in countries with a higher prevalence of smoking among teenagers. The diagnostic approach to the standard case of a 13-year-old with Graves’ hyperthyroidism and moderately severe active GO involves on average five biochemical tests; thyroid as well as orbital imaging is done in 84% of cases. Antithyroid drugs remain the treatment of choice for 94% of respondents, and even so in case of recurrences (66%). For GO, 70% recommend a wait-and-see policy; intervention, preferably with steroids, is advocated by two-thirds of respondents in cases of worsening or still-active eye disease despite euthyroidism.

Free access

Helen L Storr and Martin O Savage

Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised.