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Mariacarolina Salerno, Nicola Improda, and Donatella Capalbo

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

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Manuela Cerbone, Donatella Capalbo, Malgorzata Wasniewska, Sara Alfano, Giuseppina Mattace Raso, Ugo Oliviero, Antonio Cittadini, Filippo De Luca, and Mariacarolina Salerno

Objective

To investigate the effect of levothyroxine (L-T4) treatment on early markers of atherosclerotic disease in children with mild idiopathic subclinical hypothyroidism (SH).

Design

Two-year, open, case–control prospective study.

Methods

A total of 39 children, aged 9.18±3.56 years, with SH and 39 healthy controls were enrolled in the study. Waist-to-height ratio (WHtR), blood pressure, triglycerides, total cholesterol (total-C), HDL-C, LDL-C, non-HDL-C, triglycerides/HDL-C, atherogenic index (AI), homocysteine (Hcy), asymmetric dimethylarginine (ADMA), flow-mediated dilation (FMD) and intima–media thickness (IMT) were evaluated at baseline and after 2 years of L-T4 treatment in SH children and after 2 years of follow-up in controls.

Results

At study entry WHtR was higher in SH subjects compared with controls (0.56±0.08 vs 0.49±0.07, P=0.04) and significantly decreased after 2 years of treatment (0.50±0.06, P<0.0001). Mean HDL-C levels (50.47±11.43 vs 61.06±13.83mg/dL, P=0.002) were lower, while triglycerides/HDL-C (1.63±1.07 vs 1.19±0.69, P=0.05), AI (3.32±0.90 vs 2.78±0.68, P=0.005), and Hcy (9.35±2.61 vs 7.71±1.94μmol/L, P=0.01) were higher in SH subjects compared with controls and improved after 2 years of treatment (HDL-C 56.26±13.76mg/dL, P<0.0001; triglycerides/HDL-C 1.23±0.78, P=0.006; AI 2.82±0.68, P<0.0001; and Hcy 8.25±2.09μmol/L, P=0.06). ADMA concentrations at baseline were higher in SH subjects compared with controls (0.77±0.21 vs 0.60±0.16μmol/L, P=0.001) and decreased after therapy (0.58±0.13μmol/L, P<0.0001). FMD, IMT and other metabolic parameters were not different among SH subjects and controls at baseline and after 2 years.

Conclusions

Children with SH may have subtle pro-atherogenic abnormalities. Although L-T4 treatment exerts some beneficial effects, the long-term impact of therapy on metabolic outcomes in SH children still remains unclear.

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Ugo Oliviero, Antonio Cittadini, Giorgio Bosso, Manuela Cerbone, Antonio Valvano, Donatella Capalbo, Valentina Apuzzi, Fabrizia Calabrese, Teresa Lettiero, and Mariacarolina Salerno

Objective

Patients with congenital hypothyroidism (CH) display subclinical abnormalities of the cardiovascular system that are related to unphysiological fluctuations of TSH levels and occur despite careful replacement therapy.

Design

The aim of the present case–control study was to evaluate the effects of long-term levothyroxine (l-T4) replacement therapy on the vascular district in CH patients by assessing endothelial function with flow-mediated dilation (FMD) and brachial artery distensibility with the measurement of the coefficient of distensibility (DC).

Methods

Thirty-two young adults with CH aged 18.9±0.2 years and 32 age- and sex-matched controls underwent brachial Doppler ultrasound examination to measure FMD and DC at the time of the study. Hypothyroidism was diagnosed by neonatal screening, and l-T4 treatment was initiated within the first month of life.

Results

Compared to healthy controls, CH patients had significantly reduced brachial artery reactivity with lower FMD values (8.9±5.7 vs 14.1±5.1% P=0.003) and decreased vascular distensibility (24.6±1.6 vs 27.3±3 kPa−1×10−3, P<0.0002). Linear regression analysis revealed that both total and pubertal mean TSH and number of episodes of undertreatment were independent determinants of FMD and DC. Pubertal mean TSH was the best predictor of both FMD and DC (r=0.81 and r=0.87 respectively, P<0.001).

Conclusions

Young adults with CH treated with long-term l-T4 replacement therapy may have significant impairment of both FMD and DC. Our data suggest that high TSH levels, inadequately corrected by l-T4 replacement therapy in CH patients especially during puberty, can exert significant effects on the elastic and functional vessel properties.

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Malgorzata Wasniewska, Tommaso Aversa, Mariacarolina Salerno, Andrea Corrias, Maria Francesca Messina, Alessandro Mussa, Donatella Capalbo, Filippo De Luca, and Mariella Valenzise

Aim

To follow-up for 5 years thyroid status evolution in 127 girls with mild (TSH 5–10 mU/l) subclinical hypothyroidism (SH) of different etiologies.

Patients

The population was divided into two age-matched groups of 42 and 85 girls with either idiopathic (group A) or Hashimoto's thyroiditis (HT)-related SH (group B). Group B was in turn divided into three subgroups, according to whether SH was either isolated or associated with Turner syndrome (TS) or Down syndrome (DS).

Results

At the end of follow-up the rate of girls who became euthyroid was higher in group A (61.9% vs 10.6%), whereas the rates of patients who remained SH (55.3% vs 26.2%), became overtly hypothyroid (30.6% vs 11.9%) or required levothyroxine (l-T4) therapy (63.5% vs 23.8%) were higher in group B. Among the girls of group B, the risk of remaining SH or developing overt hypothyroidism was higher in the subgroups with TS or DS than in those with isolated HT.

Conclusions

Long-term prognosis of mild and idiopathic SH is frequently benign, even though a l-T4 treatment may be needed throughout follow-up in almost a quarter of cases; long-term prognosis is different in the girls with either idiopathic or HT-related SH; and the association with either TS or DS impairs the outcome of HT-related SH.

Free access

Malgorzata Wasniewska, Mariacarolina Salerno, Alessandra Cassio, Andrea Corrias, Tommaso Aversa, Giuseppina Zirilli, Donatella Capalbo, Milva Bal, Alessandro Mussa, and Filippo De Luca

Objective

To prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH.

Design

Clinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1±3.0 years) with idiopathic SH.

Results

During the study, mean TSH levels showed a trend toward a progressive decrease while FT4 levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT4 levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT4 at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period.

Conclusions

(a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT4 values or clinical status or auxological parameters.

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Filippo De Luca, Andrea Corrias, Mariacarolina Salerno, Malgorzata Wasniewska, Roberto Gastaldi, Alessandra Cassio, Alessandro Mussa, Tommaso Aversa, Giorgio Radetti, and Teresa Arrigo

Objective

To compare the presentation and clinical course of Graves' disease (GD) in two pediatric populations consisting of 28 patients with Down's syndrome (DS) and 109 controls without DS respectively.

Design and methods

The evolution over time of GD was determined in both groups according to the clinical changes and the variations in TSH, free thyroxine, and TSH receptor autoantibodies serum levels during the entire follow-up.

Results

Female prevalence (50 vs 81.6%; χ 2=12.0, P<0.0005) and average age at GD presentation (9.9±4.4 vs 11.5±3.5 years, P<0.05) were significantly lower in DS group than in controls. Clinical responsiveness to methimazole therapy was significantly better in DS patients, as demonstrated by both the lower relapse rates after the first cycle withdrawal (7.1 vs 31.2%; χ 2=7.4, P<0.005) and the higher persistent remission rates after definitive therapy withdrawal (46.4 vs 26.7%; χ 2=4.1, P<0.05). Moreover, in DS group, no patients needed surgery or radioiodine ablation, whereas non-pharmacological treatment was necessary in 11% of controls (χ 2=3.8, P<0.05). Antecedents of Hashimoto's thyroiditis (HT) were documented in 21.4% of DS patients and in 3.7% of controls (χ 2=10.4, P<0.005). Association with other autoimmune diseases was detected in 32.1% of DS cases and in 12.8% of controls (χ 2=5.94, P<0.025).

Conclusions

GD in DS children and adolescents is characterized by several peculiarities: i) earlier presentation; ii) no gender predominance; iii) less severe clinical course; iv) higher frequency of documented HT antecedents; v) more frequent association with other autoimmune diseases.

Free access

Manuela Cerbone, Carmela Bravaccio, Donatella Capalbo, Miriam Polizzi, Malgorazata Wasniewska, Daniela Cioffi, Nicola Improda, Mariella Valenzise, Dario Bruzzese, Filippo De Luca, and Mariacarolina Salerno

Objective

The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine.

Design and methods

Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4–18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0–9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls.

Results

At study entry, height (−0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI −0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (−0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (−0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up.

Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH.

Conclusions

Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.

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Ginevra Corneli, Carolina Di Somma, Flavia Prodam, Jaele Bellone, Simonetta Bellone, Valentina Gasco, Roberto Baldelli, Silvia Rovere, Harald Jörn Schneider, Luigi Gargantini, Roberto Gastaldi, Lucia Ghizzoni, Domenico Valle, Mariacarolina Salerno, Annamaria Colao, Gianni Bona, Ezio Ghigo, Mohamad Maghnie, and Gianluca Aimaretti

Objective

To define the appropriate diagnostic cut-off limits for the GH response to GHRH+arginine (ARG) test and IGF-I levels, using receiver operating characteristics (ROC) curve analysis, in late adolescents and young adults.

Design and methods

We studied 152 patients with childhood-onset organic hypothalamic–pituitary disease (85 males, age (mean±s.e.m.): 19.2±0.2 years) and 201 normal adolescents as controls (96 males, age: 20.7±0.2 years). Patients were divided into three subgroups on the basis of the number of the other pituitary hormone deficits, excluding GH deficiency (GHD): subgroup A consisted of 35 panhypopituitary patients (17 males, age: 21.2±0.4 years), subgroup B consisted of 18 patients with only one or with no more than two pituitary hormone deficits (7 males, age: 20.2±0.9 years); and subgroup C consisted of 99 patients without any known hormonal pituitary deficits (60 males, age: 18.2±0.2 years). Both patients and controls were lean (body mass index, BMI<25 kg/m2). Patients in subgroup A were assumed to be GHD, whereas in patients belonging to subgroups B and C the presence of GHD had to be verified.

Results

For the GHRH+ARG test, the best pair of highest sensitivity (Se; 100%) and specificity (Sp; 97%) was found choosing a peak GH of 19.0 μg/l. For IGF-I levels, the best pair of highest Se (96.6%) and Sp (74.6%) was found using a cut-off point of 160 μg/l (SDS: −1.3). Assuming 19.0 μg/l to be the cut-off point established for GHRH+ARG test, 72.2% of patients in subgroup B and 39.4% in subgroup C were defined as GHD. In patients belonging to group B and C and with a peak GH response <19 μg/l to the test, IGF-I levels were lower than 160 μg/l (or less than 1.3 SDS) in 68.7 and 41.6% of patients respectively predicting severe GHD in 85.7% of panhypopituitary patients (subgroup A).

Conclusions

In late adolescent and early adulthood patients, a GH cut-off limit using the GHRH+ARG test lower than 19.0 μg/l is able to discriminate patients with a suspicion of GHD and does not vary from infancy to early adulthood.

Free access

Dominique Simon, Ibrahima Ba, Nancy Mekhail, Emmanuel Ecosse, Anne Paulsen, Delphine Zenaty, Muriel Houang, Monique Jesuran Perelroizen, Gian-Paolo de Filippo, Mariacarolina Salerno, Gilbert Simonin, Rachel Reynaud, Jean-Claude Carel, Juliane Léger, and Nicolas de Roux

Context and objective

Idiopathic central precocious puberty (iCPP) is defined as early activation of the hypothalamic–pituitary–gonadal axis in the absence of identifiable central lesions. Mutations of the makorin RING finger 3 (MKRN3) gene are associated with iCPP. We aimed to assess the frequency of MKRN3 mutations in iCPP and to compare the phenotypes of patients with and without MKRN3 mutations.

Design

An observational study was carried out on patients recruited at pediatric hospitals in France and Italy. Forty-six index CPP cases were screened for mutations in the MKRN3 coding sequence: 28 index cases of familial cases and 18 cases did not report any familial history of CPP. The endocrine phenotype was compared between MKRN3 mutated and non-mutated patients.

Results

MKRN3 mutations were identified in one sporadic and 13 familial cases. We identified five new heterozygous missense mutations predicted to be deleterious for protein function and two frameshift mutations, one new and the other recurrent, predicted to result in truncated proteins. Age at puberty onset varied very little among patients with MKRN3 mutations and puberty occurred earlier in these patients than in those without MKRN3 mutations (6.0 years (5.4–6.0) vs 7.0 years (6.0–7.0), P=0.01).

Conclusions

MKRN3 mutations are common in familial iCPP. MKRN3 is one of the gatekeepers of the postnatal activation of the gonadotropic axis.

Restricted 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.