Publications by authors named "Donatella Capalbo"

50 Publications

Growth Hormone Receptor (GHR) 6Ω Pseudoexon Activation: a Novel Cause of Severe Growth Hormone Insensitivity.

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute, London EC1M 6BQ, UK.

Context: Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.

Objective: This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.

Methods: A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Growth Hormone Receptor (Ghr) 6ω Pseudoexon Activation: A Novel Cause Of Severe Growth Hormone Insensitivity (Ghi).

J Clin Endocrinol Metab 2021 Jul 28. Epub 2021 Jul 28.

Centre for Endocrinology, William Harvey Research Institute: Barts and The London School of Medicine and Dentistry William Harvey Research Institute.

Context: Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.

Objective: Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.

Design: A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.

Results: We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.

Conclusion: Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
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http://dx.doi.org/10.1210/clinem/dgab550DOI Listing
July 2021

Differences of sex development in the newborn: from clinical scenario to molecular diagnosis.

Minerva Pediatr (Torino) 2021 Jun 21. Epub 2021 Jun 21.

Unit of Endocrinology, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy.

Differences/disorders of sex development (DSD) are defined as a group of congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. The incidence of DSD is 1:4500 births. The current classification divides DSDs into 3 categories according to chromosomal sex: 46,XX DSD, 46,XY DSD and sex chromosome DSD. DSD phenotypes can be concordant with the genotype (apparently normal external genitalia associated with gonadal dysgenesis), or can range from simply hypospadias to completely masculinised or feminised genitalia with a discordant karyotype. Numerous genes implicated in genital development have been reported. The search of genetic variants represents a central element of the extended investigation, as an improved knowledge of the genetic aetiology helps the immediate and long-term management of children with DSDs, in term of sex of rearing, hormone therapy, surgery, fertility and cancer risk. This review aims to assess the current role of molecular diagnosis in DSD management.
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http://dx.doi.org/10.23736/S2724-5276.21.06512-5DOI Listing
June 2021

Primary Adrenal Insufficiency in Childhood: Data From a Large Nationwide Cohort.

J Clin Endocrinol Metab 2021 03;106(3):762-773

Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University of Naples Federico II, Endo-ERN Center for Rare Endocrine Conditions, Naples, Italy.

Context: Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children.

Objective: To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI.

Patients And Methods: Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected.

Results: The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was -0.70 ± 1.20 standard deviation score.

Conclusions: We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.
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http://dx.doi.org/10.1210/clinem/dgaa881DOI Listing
March 2021

Growth Trajectory and Adult Height in Children with Nonclassical Congenital Adrenal Hyperplasia.

Horm Res Paediatr 2020 18;93(3):173-181. Epub 2020 Aug 18.

Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari "A. Moro", Bari, Italy.

Background: Children with nonclassical congenital adrenal hyperplasia (NCCAH) often present increased growth velocity secondary to elevation of adrenal androgens that accelerates bone maturation and might compromise adult height (AH).

Objective: The aim of the study was to analyze prognostic factors affecting growth trajectory (GT) and AH in children with NCCAH.

Methods: The study was a retrospective, multicentric study. The study population consisted of 192 children with a confirmed molecular diagnosis of NCCAH, followed by pediatric endocrinology centers from diagnosis up to AH. Clinical records were collected and analyzed. AH (standard deviation score; SDS), pubertal growth (PG) (cm), GT from diagnosis to AH (SDS), and AH adjusted to target height (TH) (AH-TH SDS) were evaluated as outcome indicators using stepwise linear regression models.

Results: The stepwise linear regression analysis showed that AH and AH-TH were significantly related to chronological age (CA) (p = 0.008 and 0.016), bone age (BA)/CA ratio (p = 0.004 and 0.001), height (H) (p < 0.001 for both parameters) at NCCAH diagnosis, and TH (p = 0.013 and <0.001). PG was higher in males than in females (22.59 ± 5.74 vs. 20.72 ± 17.4 cm, p = 0.002), as physiologically observed, and was positively related to height (p = 0.027), negatively to BMI (p = 0.001) and BA/CA ratio (p = 0.001) at NCCAH diagnosis. Gender, genotype, biochemical data, and hydrocortisone treatment did not significantly impair height outcomes of these NCCAH children.

Conclusions: The results of this study suggest that AH and GT of NCCAH patients are mainly affected by the severity of phenotype (CA, BA/CA ratio, and H) at the time of diagnosis.
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http://dx.doi.org/10.1159/000509548DOI Listing
July 2021

MANAGEMENT OF ENDOCRINE DISEASE Subclinical hypothyroidism in children.

Eur J Endocrinol 2020 Aug;183(2):R13-R28

Department of Mother and Child, Paediatric Endocrinology Unit, University Hospital 'Federico II', Naples, Italy.

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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http://dx.doi.org/10.1530/EJE-20-0051DOI Listing
August 2020

Cognitive Function in Children With Idiopathic Subclinical Hypothyroidism: Effects of 2 Years of Levothyroxine Therapy.

J Clin Endocrinol Metab 2020 03;105(3)

Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University Federico II, Naples, Italy.

Background: Long-term consequences of mild subclinical hypothyroidism (SH) in children are still unclear, and the need for levothyroxine (L-T4) supplementation remains controversial. We designed a 2-year, case-control, prospective study of a cohort of children with SH to evaluate the effects of L-T4 therapy on neurocognitive outcome.

Methods: Thirty-four children, age 9.1 ± 2.6 years, with long-lasting, idiopathic, and mild SH, and 34 healthy matched controls, were enrolled. Twenty SH children underwent a 2-year L-T4 treatment (group A), whereas 14 refused treatment and were reevaluated after a 2-year-follow-up (group B). IQ and specific cognitive domains were evaluated in all children at study entry and after 2 years of therapy (group A) or observation (group B) in SH individuals.

Results: In SH children baseline IQ scores were normal and comparable to controls (full-scale IQ [FSIQ] 100.4 ± 11.3 vs 101.8 ± 14.2, verbal IQ [VIQ] 99.7 ± 13.7 vs 98.3 ± 14.9 and performance IQ [PIQ] 101.2 ± 10.4 vs 105 ± 10.4).In group A, L-T4 treatment was associated with normalization of thyrotropin (6.3 ± 1.0 mIU/L at baseline vs 2.8 ± 1.4 mIU/L at 2 years, P < .001). However, 2-year L-T4 therapy was not associated with a change in IQ scores (FSIQ 104.4 ± 13.8 vs 102.7 ± 11.0; VIQ 101.8 ± 14.9 vs 102.3 ± 11.9; and PIQ 106.5 ± 13.9 vs 102.7 ± 10.7) or in verbal or performance subtest scores. No significant differences were found in IQ scores after 2 years of treatment in group A compared to group B after a 2-year follow-up.

Conclusions: Our data suggest neurocognitive function in children is not impaired by persistent, mild, untreated SH and is not significantly modified by 2-year L-T4 supplementation.
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http://dx.doi.org/10.1210/clinem/dgaa046DOI Listing
March 2020

Accuracy and Limitations of the Growth Hormone (GH) Releasing Hormone-Arginine Retesting in Young Adults With Childhood-Onset GH Deficiency.

Front Endocrinol (Lausanne) 2019 31;10:525. Epub 2019 Jul 31.

Department of Pediatrics, IRCCS Istituto Giannina Gaslini Institute, University of Genova, Genova, Italy.

Re-testing for GH secretion is needed to confirm the diagnosis of GH deficiency (GHD) after adult height achievement in childhood-onset GHD (COGHD). To define the cut-off of GH peak after retesting with GH-releasing hormone plus arginine (GHRHarg) in the diagnosis of permanent GHD in COGHD of different etiology. Eighty-eight COGHD (median age 17.2 y), 29 idiopathic GHD (IGHD), 44 cancer survivors (TGHD) and 15 congenital GHD (CGHD) were enrolled in the study; 54 had isolated GHD (iGHD) and 34 had multiple pituitary hormone deficiencies (MPHD). All were tested with insulin tolerance test (ITT) and GHRHarg. IGHD with a GH response to ITT ≥6μg/L were considered true negatives and served as the control group, and patients with a GH response <6μg/L as true positives. Baseline IGF-I was also measured. The diagnostic accuracy of GHRHarg testing and of IGF-I SDS in patients with GHD of different etiologies was evaluated by ROC analysis. Forty-six subjects with a GH peak to ITT ≥6μg/L and 42 with GH peak <6 μg/L showed a GH peak after GHRHarg between 8.8-124μg/L and 0.3-26.3μg/L, respectively; 29 IGHD were true negatives, 42 were true positives and 17 with a high likelihood GHD showed a GH peak to ITT ≥6μg/L. ROC analysis based on the etiology indicated the best diagnostic accuracy for peak GH cutoffs after GHRHarg of 25.3 μg/L in CGHD, 15.7 in TGHD, and 13.8 in MPHD, and for IGF-1 SDS at -2.1 in CGHD, -1.5 in TGHD, and -1.9 in MPHD. Our findings indicate that the best cut-off for GH peak after retesting with GHRHarg changes according to the etiology of GHD during the transition age. Based on these results the diagnostic accuracy of GHRHarg remains questionable.
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http://dx.doi.org/10.3389/fendo.2019.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684745PMC
July 2019

Cardiovascular Health in Children and Adolescents With Congenital Adrenal Hyperplasia Due to 21-Hydroxilase Deficiency.

Front Endocrinol (Lausanne) 2019 11;10:212. Epub 2019 Apr 11.

Pediatric Section, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.

Increasing evidence indicates that adults with Congenital Adrenal Hyperplasia (CAH) may have a cluster of cardiovascular (CV) risk factors. In addition, ongoing research has highlighted that children and adolescents with CAH are also prone to developing unfavorable metabolic changes, such as obesity, hypertension, insulin resistance, and increased intima-media thickness, which places them at a higher risk of developing CV disease in adulthood. Moreover, CAH adolescents may exhibit subclinical left ventricular diastolic dysfunction and impaired exercise performance, with possible negative consequences on their quality of life. The therapeutic management of patients with CAH remains a challenge and current treatment regimens do not always allow optimal biochemical control. Indeed, overexposure to glucocorticoids and mineralocorticoids, as well as to androgen excess, may contribute to the development of unfavorable metabolic and CV abnormalities. Long-term prospective studies on large cohorts of patients will help to clarify the pathophysiology of metabolic alterations associated with CAH. Meanwhile, further efforts should be made to optimize treatment and identify new therapeutic approaches to prevent metabolic derangement and improve long-term health outcomes of CAH patients.
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http://dx.doi.org/10.3389/fendo.2019.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470198PMC
April 2019

Mild Hypothyroidism in Childhood: Who, When, and How Should Be Treated?

J Endocr Soc 2018 Sep 25;2(9):1024-1039. Epub 2018 Jul 25.

Department of Translational Medical Sciences-Pediatric Section, University of Naples Federico II, Naples, Italy.

Mild hypothyroidism, also known as subclinical hypothyroidism (SH), is biochemically defined as serum TSH levels above the upper limit of the reference range, in the presence of normal serum concentrations of total T4 and free T4 (FT4). In the neonatal period, mild hypothyroidism can be defined by the presence of a TSH value between 6 and 20 mIU/L and normal FT4 levels. After the neonatal period, SH can be defined mild if TSH ranges between 4.5 and 10 mIU/L. The management of mild hypothyroidism in childhood is challenging. The major concern is to establish whether this condition should always be considered an expression of mild thyroid dysfunction. Indeed, the effects of untreated mild hypothyroidism are still not completely defined. In the neonatal period, concern exists about neurocognitive outcome; in children, although there is no clear evidence of alterations in growth or neurocognitive development, subtle cardiovascular abnormalities have been documented. Therefore, there is still uncertainty about the need of treatment across all ages, and the management should be based on the age of the child, the etiology, and the degree of TSH elevation, as well as on other patient factors. This review updates current evidences on diagnosis and management of mild hypothyroidism in childhood.
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http://dx.doi.org/10.1210/js.2017-00471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117400PMC
September 2018

Growth Hormone Improves Cardiopulmonary Capacity and Body Composition in Children With Growth Hormone Deficiency.

J Clin Endocrinol Metab 2017 11;102(11):4080-4088

Department of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, 80131 Naples, Italy.

Context: Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking.

Objectives: Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents.

Design: Prospective, case-control study.

Patients And Methods: Twenty-one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual-energy x-ray absorptiometry, before and after 12 months of GH therapy. Twenty-one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year.

Results: At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function.

Conclusion: Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short-term GH replacement therapy.
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http://dx.doi.org/10.1210/jc.2017-00871DOI Listing
November 2017

Glucose homeostasis in GHD children during long-term replacement therapy: a case-control study.

Endocrine 2018 03 5;59(3):643-650. Epub 2017 Sep 5.

Department of Translational Medical Sciences Pediatric Endocrinology Section, University "Federico II" of Naples, Naples, Italy.

Purpose: To evaluate glucose homeostasis in children with growth hormone (GH) deficiency (GHD) receiving long-term replacement therapy.

Methods: We evaluated glucose, insulin, HOmeostasis Model Assessment (HOMA-IR), and HbA1c in 100 GHD children at diagnosis and during 5 years of therapy. One hundred healthy children comparable to patients were evaluated at baseline and after 1 and 5 years.

Results: No difference was detected at baseline between GHD patients and controls in glucose (79.58 ± 9.96 vs. 77.18 ± 8.20 mg/dl), insulin (4.50 ± 3.24 vs. 4.30 ± 2.60 µU/ml), HbA1c (5.20 ± 0.31 vs. 5.25 ± 0.33%) levels, and HOMA-IR (0.93 ± 0.72 vs. 0.86 ± 0.61). One year of GH was associated with a significant increase in insulin (7.21 ± 4.84, p < 0.001) and HOMA-IR (1.32 ± 0.98, p < 0.001) in GHD children, which became different from controls (p < 0.001 and p = 0.004). These parameters did not change further during the following years of treatment in GHD subjects. In contrast, controls did not show significant changes in insulin (4.40 ± 2.60) and HOMA-IR (0.82 ± 0.60) during the first year; however, at the fifth year of the study a significant increase in insulin (6.50 ± 3.50, p = 0.004) and HOMA-IR (1.29 ± 0.54, p < 0.001) was documented, making these parameters comparable between patients and controls.

Conclusions: Our results suggest that growth hormone (GH) treatment is not associated with significant impairment of insulin sensitivity in GHD children. The slight impairment observed in GHD adolescents after long-term GH is comparable to that physiologically occurring in healthy pubertal subjects.
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http://dx.doi.org/10.1007/s12020-017-1408-0DOI Listing
March 2018

HYDROCORTISONE THERAPY AND GROWTH TRAJECTORY IN CHILDREN WITH CLASSICAL CONGENITAL ADRENAL HYPERPLASIA.

Endocr Pract 2017 May 22;23(5):546-556. Epub 2017 Feb 22.

Objective: Poor linear growth is one of the main concerns in children with congenital adrenal hyperplasia (CAH). We aimed to analyze factors affecting growth trajectory in children with classical CAH.

Methods: Clinical records of children followed from infancy up to the end of growth at two Italian tertiary referral hospitals were reviewed. Fifty-seven patients (31 males), treated with hydrocortisone and fludrocortisone only, were included. Clinical observations were divided into three groups: 0 to 2 years, 172 observations; from 2 years to puberty onset, 813 observations; after puberty onset, 527 observations. Height velocity, pubertal growth spurt, and final height were evaluated as outcomes.

Results: Final height standard deviation score (SDS) was lower than target height SDS (-0.74 ± 1.1 versus -0.31 ± 1.01; P<.001). Target-adjusted final height SDS was -0.44 ± 1.8 in males and -0.13 ± 1.1 in females (P = .001). Total pubertal growth was 21.9 ± 7.3 cm in males and 19.2 ± 8.2 cm in females (P = .19). Hydrocortisone dose increased and height-velocity SDS decreased during puberty. At multivariable analysis, height-velocity SDS was adversely affected by hydrocortisone dose (P = .038) and directly related to adrenocorticotropic hormone (ACTH) levels (P = .023). Target-adjusted final-height SDS was adversely affected by hydrocortisone dose (P<.001) and positively related to mineralocorticoid therapy (P = .001) and ACTH levels (P = .02). Total pubertal growth (cm) was positively related to ACTH levels (P = .01).

Conclusion: Height outcome of CAH patients is now better than previously reported. During puberty, the lowest effective dose of hydrocortisone should be used to optimize pubertal growth spurt and final height.

Abbreviations: 17-OHP = 17-alpha-hydroxyprogesterone ACTH = adrenocorticotropic hormone BMI = body mass index CAH = congenital adrenal hyperplasia GH = growth hormone HPA = hypothalamus-pituitary-adrenal PRA = plasma renin activity SDS = standard deviation score SV = simple virilizing SW = salt-wasting.
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http://dx.doi.org/10.4158/EP171751.ORDOI Listing
May 2017

Muscle and skeletal health in children and adolescents with GH deficiency.

Best Pract Res Clin Endocrinol Metab 2016 Dec 25;30(6):771-783. Epub 2016 Nov 25.

Department of Medical Translational Sciences, Paediatric Endocrinology Section, Federico II University, Via S. Pansini 5, 80131 Naples, Italy. Electronic address:

In addition to promoting linear growth, GH plays a key role in the regulation of bone and muscle development and metabolism. Although GH deficiency is frequently listed among the causes of secondary osteoporosis in children, its impact on bone and muscle health and on fracture risk is still not completely established. Current data suggest that childhood-onset GH deficiency can affect bone and muscle mass and strength, with GH replacement therapy exerting beneficial effects. Moreover, GH withdrawal at final height can result in reduced peak bone and muscle mass, potentially leading to increased fracture risk in adulthood. Thus, the muscle-bone unit in GH deficient subjects should be monitored during childhood and adolescence in order to prevent osteoporosis and increased fracture risk and GH replacement should be tailored to ensure an optimal bone and muscle health.
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http://dx.doi.org/10.1016/j.beem.2016.11.012DOI Listing
December 2016

Subclinical hypothyroidism in childhood - current knowledge and open issues.

Nat Rev Endocrinol 2016 12 1;12(12):734-746. Epub 2016 Jul 1.

Department of Pediatric, Gynecology, Microbiological and Biochemical Sciences, University of Messina, Messina, 98125, Italy.

Subclinical hypothyroidism is defined as serum levels of TSH above the upper limit of the reference range, in the presence of normal concentrations of total T or free T. This biochemical profile might be an indication of mild hypothyroidism, with a potential increased risk of metabolic abnormalities and cardiovascular disease recorded among adults. Whether subclinical hypothyroidism results in adverse health outcomes among children is a matter of debate and so management of this condition remains challenging. Mild forms of untreated subclinical hypothyroidism do not seem to be associated with impairments in growth, bone health or neurocognitive outcome. However, ongoing scientific investigations have highlighted the presence of subtle proatherogenic abnormalities among children with modest elevations in their TSH levels. Although current findings are insufficient to recommend levothyroxine treatment for all children with mild asymptomatic forms of subclinical hypothyroidism, they highlight the potential need for assessment of cardiovascular risk among children with this condition. Increased understanding of the early metabolic risk factors associated with subclinical hypothyroidism in childhood will help to improve the management of affected individuals.
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http://dx.doi.org/10.1038/nrendo.2016.100DOI Listing
December 2016

Unbalanced Immune System: Immunodeficiencies and Autoimmunity.

Front Pediatr 2016 6;4:107. Epub 2016 Oct 6.

Department of Translational Medical Sciences, Federico II University of Naples , Naples , Italy.

Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained.
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http://dx.doi.org/10.3389/fped.2016.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052255PMC
October 2016

Novel Findings into AIRE Genetics and Functioning: Clinical Implications.

Front Pediatr 2016 22;4:86. Epub 2016 Aug 22.

Pediatric Section, Department of Translational Medical Sciences, Federico II University , Naples , Italy.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), formerly known as autoimmune polyendocrine syndrome type 1, is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE's function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications.
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http://dx.doi.org/10.3389/fped.2016.00086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992815PMC
September 2016

In children with autoimmune thyroid diseases the association with Down syndrome can modify the clustering of extra-thyroidal autoimmune disorders.

J Pediatr Endocrinol Metab 2016 Sep;29(9):1041-6

Background: It is known that the association with Down syndrome (DS) can affect the phenotypic expression of autoimmune thyroid diseases (AITDs), whilst is unknown whether the clustering of extra-thyroidal autoimmune diseases (ETADs) may also be atypical in DS children.

Methods: The aim of this study was to investigate the clustering of ETADs in 832 children with AITDs divided in two groups with or without DS (A and B, respectively) and in four subgroups of patients aged either <6 or ≥6 years.

Results: The rate of children with ETADs was significantly higher in Group A; in particular, alopecia areata (p=0.00001) and vitiligo (p=0.00001) were found more often in Group A irrespective of age, whilst the distribution of T1 diabetes mellitus was not different in the two groups. Celiac disease prevalence was significantly higher in DS patients only in the older subgroup.

Conclusions: The association with DS may be able to modify the clustering of ETADs in the children with AITDs by favoring the aggregation of some specific diseases such as alopecia areata and vitiligo.
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http://dx.doi.org/10.1515/jpem-2016-0073DOI Listing
September 2016

Predictors of Insulin-Like Growth Factor-I Responses to Growth Hormone Replacement in Young Adults with Growth Hormone Deficiency.

Horm Res Paediatr 2016 13;85(6):379-88. Epub 2016 May 13.

Department of Paediatrics, University of Cambridge, Cambridge, UK.

Background/aims: Physiological growth hormone (GH) secretion and insulin-like growth factor-I (IGF-I) levels are greater in young compared to older adults. We evaluated IGF-I levels and predictors of IGF-I responses in young adults on GH replacement.

Design: From the KIMS database, 310 young adults (age 15-26 years) with severe GH deficiency related to childhood-onset disease and commenced on 'adult GH replacement' were identified. 'IGF-I responses' were estimated from first-year increments in IGF-I standard deviation scores (SDS) and adjusted for GH dose. Body composition was assessed by bioimpedance in 143 patients.

Results: IGF-I levels increased markedly from baseline to 1 year of replacement (-3.75 ± 1.94 vs. -1.36 ± 1.86 SDS, p < 0.0001), but remained low compared to normative data despite dose titration. In multivariate models, IGF-I responses were positively associated with age [B (SE) SDS/(mg/m2); 0.52 (0.15), p = 0.0007] and BMI SDS [1.06 (0.25), p < 0.0001] and inversely associated with female gender [-4.45 (0.79), p < 0.0001] and baseline IGF-I SDS [-1.44 (0.20), p < 0.0001]. IGF-I responses were positively associated with first-year increases in lean body mass (r = 0.19, p = 0.003) and haemoglobin A1c (r = 0.15, p = 0.031).

Conclusions: Low IGF-I levels in young adults on treatment may reflect suboptimal GH replacement. Identification of predictors for IGF-I responses could lead to a more appropriate replacement strategy. Association between IGF-I responses and lean body mass suggests that maintaining age-appropriate IGF-I levels is important during therapy.
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http://dx.doi.org/10.1159/000445832DOI Listing
April 2017

Effects of L-thyroxine treatment on early markers of atherosclerotic disease in children with subclinical hypothyroidism.

Eur J Endocrinol 2016 Jul 11;175(1):11-9. Epub 2016 Apr 11.

Pediatric Endocrinology UnitDepartment of Translational Medical Sciences, University "Federico II" of Naples, Naples, Italy

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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http://dx.doi.org/10.1530/EJE-15-0833DOI Listing
July 2016

Long-term effects of growth hormone (GH) replacement therapy on hematopoiesis in a large cohort of children with GH deficiency.

Endocrine 2016 Jul 28;53(1):192-8. Epub 2015 Oct 28.

Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University of Naples "Federico II", via Sergio Pansini 5, 80131, Naples, Italy.

The aim of our prospective case-control study was to evaluate long-term effects of GH replacement therapy on erythrocytes parameters, leukocytes, and platelets numbers in a large cohort of children with isolated GH deficiency (GHD). Hemoglobin (Hb) concentration, hematocrit (Hct), mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, number of erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes and platelets, ferritin, and C-reactive protein were evaluated in 85 children with isolated GHD (10.20 ± 3.50 years) before and annually during the first 5 years of GH replacement therapy and in 85 healthy children age and sex comparable to patients during 5 years of follow-up. Compared with controls, GHD children at study entry showed lower Hb (-1.18 ± 0.87 vs. -0.40 ± 0.90 SDS, p < 0.0001), red cells number (-0.24 ± 0.81 vs. 0.25 ± 1.14 SDS, p < 0.0001), and Hct (-1.18 ± 0.86 vs. -0.68 ± 0.99 SDS, p < 0.0001). Twelve GHD patients (14 %) showed a normocytic anemia. GH therapy was associated with a significant increase in Hb, Hct, and red cells number which became all comparable to controls within the first 2 years of treatment. Moreover, hemoglobin levels normalized in all anemic GHD patients after 5 years of therapy. No difference between patients and controls was found in leukocytes and platelets numbers neither at baseline nor during the study. GHD in childhood is associated with an impairment of erythropoiesis which causes a normocytic anemia in a considerable percentage of patients. GH replacement therapy exerts a beneficial effect leading to a significant increase of erythrocytes parameters and recovery from anemia. Neither GHD nor GH replacement treatment exerts effects on leukocytes or platelets numbers.
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http://dx.doi.org/10.1007/s12020-015-0781-9DOI Listing
July 2016

Five-year prospective evaluation of thyroid function in girls with subclinical mild hypothyroidism of different etiology.

Eur J Endocrinol 2015 Dec 15;173(6):801-8. Epub 2015 Sep 15.

Department of PediatricGynecological, Microbiological and Biomedical Sciences, University of Messina, Via Consolare Valeria, 98125 Messina, ItalyPediatric Endocrinology UnitDepartment of Translational Medical Sciences, University 'Federico II', Naples, ItalyDepartment of PediatricsUniversity of Turin, Turin, Italy.

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.
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http://dx.doi.org/10.1530/EJE-15-0484DOI Listing
December 2015

Cardiovascular abnormalities and impaired exercise performance in adolescents with congenital adrenal hyperplasia.

J Clin Endocrinol Metab 2015 Feb 18;100(2):644-52. Epub 2014 Nov 18.

Internal Medicine (A.M.M., A.S., A.D.P., A.C.) and Pediatric (N.I., D.C., M.Al., M.S.) Sections, Department of Translational Medical Sciences, "Federico II" University School of Medicine, 80131 Naples, Italy; Department of Cardiac Surgery (M.Ar.), Instituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, 20097 Milan, Italy; and Department of Experimental Medicine (A.L., A.M.I.), "Sapienza" University, 00186 Rome, Italy.

Context: PATIENTS with classic congenital adrenal hyperplasia (CAH) are treated with lifelong glucocorticoids (GCs). Cardiovascular and metabolic effects of such therapy in adolescents have never been quantified.

Objective: Our objective was to investigate left ventricular (LV) morphology, function, and exercise performance in adolescents with CAH.

Design And Setting: We conducted a cross-sectional and controlled study conducted at a tertiary referral center.

Patients: Twenty patients with classic CAH (10 females) aged 13.6 ± 2.5 years and 20 healthy controls comparable for sex and pubertal status were enrolled in the study and compared with a group of 18 patients without CAH receiving a similar dose of GCs for juvenile idiopathic arthritis.

Main Outcomes Measures: Echocardiographic assessment and symptom-limited exercise testing were performed. Anthropometric, hormonal and biochemical parameters were also measured.

Results: Compared with healthy controls, patients with CAH exhibited an increased body mass index (P < .001), waist-to-height ratio (P < .001), and percent body fat (P < .001) as well as higher insulin concentrations and homeostasis model assessment of insulin resistance index even after adjustment for body mass index (P = .03 and P = .05, respectively). Moreover, CAH patients exhibited an impaired exercise capacity as shown by reduced peak workload (99 ± 27 vs 126 ± 27 W, P < .01) and higher systolic blood pressure response at peak (156 ± 18 vs 132 ± 11 mm Hg, P < .01; Δ = 45 ± 24 vs 22 ± 10 mm Hg, P = .05) with respect to healthy controls. CAH males displayed mild LV diastolic dysfunction as documented by significant prolongation of both isovolumic relaxation time (118 ± 18 vs 98 ± 11 milliseconds, P < .05) and mitral deceleration time (138 ± 25 vs 111 ± 15 milliseconds, P < .01). No significant differences in cardiovascular function were found between CAH and juvenile idiopathic arthritis patients.

Conclusion: Adolescents with CAH exhibit impaired exercise performance and enhanced systolic blood pressure response during exercise. In our population, such abnormalities appear related to GC therapy rather than CAH per se. CAH males, but not females, present mild LV diastolic dysfunction that correlates with testosterone concentrations suggesting a sex hormone-related difference.
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http://dx.doi.org/10.1210/jc.2014-1805DOI Listing
February 2015

Cutaneous vasculitis in patients with autoimmune polyendocrine syndrome type 1: report of a case and brief review of the literature.

BMC Pediatr 2014 Nov 1;14:272. Epub 2014 Nov 1.

Unit of Pediatric Endocrinology, Department of Traslational Medical Sciences, "Federico II" University of Naples, Naples, Italy.

Background: Autoimmune polyendocrine syndrome type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy, is a rare autosomal recessive disease due to pathogenic variants in the AIRE gene. Classic features of the syndrome are mucocutaneous candidiasis, chronic idiopathic hypoparathyroidism and Addison disease. However, other endocrine and non-endocrine components, may occur with a different prevalence. In addition to ectodermal features, which are quite common features of the disease, APS 1 patients may experience other types of skin alterations, such as vasculitic skin rash. An early diagnosis of APS 1 can be very challenging, due to the high clinical heterogeneity, and a considerable delay may occur between the appearance of symptoms and the diagnosis.

Case Presentation: We report on a girl affected by APS 1 who presented with cutaneous vasculitis when she was seven-months old, some years before the onset of the common components of the disease.

Conclusion: Clinical picture of APS 1 may be characterized by isolated rare or atypical autoimmune or immune-mediated manifestations, even years before the onset of the classic components of the disease. Among these uncommon features, skin rashes of variable form and duration may occur, most of them being associated with histopathological features of vasculitis. Our case suggests that cutaneous vasculitis may represent a first sign of APS 1. The clinical significance of cutaneous vasculitis in the context of APS 1 is still debated. It may represent a rare, unusual, early component of the disease or a clinical manifestation secondarily related to the typical APS 1 components (i.e. autoimmune thyroid disease), which are frequently associated with rheumatologic-like signs and symptoms. Alternatively, it may be the expression of an independent disease co-occuring with APS 1. In conclusion, our case suggests that children presenting with unexplained vasculitic skin rash should be followed-up in order to early identify APS 1.
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http://dx.doi.org/10.1186/1471-2431-14-272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286916PMC
November 2014

Cardiovascular risk factors in children with long-standing untreated idiopathic subclinical hypothyroidism.

J Clin Endocrinol Metab 2014 Aug 19;99(8):2697-703. Epub 2014 May 19.

Pediatric Endocrinology Unit (C.M., D.C., S.A., M.S.), Department of Translational Medical Sciences, and Department of Experimental Pharmacology (G.M.R., R.M.), University "Federico II" of Naples, 80131 Naples, Italy; Department of Pediatrics (M.W., F.D.L.), University of Messina, 98121 Messina, Italy.

Context: Subclinical hypothyroidism (SH), defined as increased TSH serum levels and normal serum free T4 concentrations, has been associated with an increased risk of coronary heart disease in adults. Data in children and adolescents are scanty.

Objective: The objective of the study was to investigate the clinical and biochemical cardiovascular risk factors in children with mild SH (serum TSH concentrations 4.5-10 mU/L).

Design And Setting: This is a cross-sectional and controlled study conducted at a tertiary referral center on patients with persistent idiopathic long-standing (3.2 ± 0.4 y) mild SH. At study entry patients and controls underwent a clinical and biochemical assessment for cardiovascular risk.

Participants: Forty-nine children aged 8.5 ± 0.5 years with SH and 49 controls were enrolled in the study.

Main Outcome Measure: Systolic and diastolic blood pressure, body mass index (BMI), waist to height ratio, lipid profile, homocysteine, high-sensitivity serum C-reactive protein, fibrinogen, adiponectin, insulin, and homeostasis model assessment index were measured.

Results: Waist to height ratio (P < .0001), atherogenic index (P = .001), triglycerides to high-density lipoprotein-cholesterol ratio (P = .01), and homocysteine levels (P = .002) were significantly higher and high-density lipoprotein-cholesterol significantly lower (P = .003) in SH subjects compared with controls. No significant differences were found in the other clinical and biochemical cardiovascular risk factors analyzed. Multivariate regression model revealed that BMI and thyroid status were the main independent factors affecting dependent variables. Even after an adjustment for BMI, most of the variables still remained significantly associated with mean TSH levels or SH duration.

Conclusions: Mild long-lasting untreated idiopathic SH may be associated with subtle proatherogenic abnormalities. Although it is difficult to establish whether these mild abnormalities represent the early steps in the initiation of atherogenesis, these children need to be carefully monitored for metabolic complications.
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http://dx.doi.org/10.1210/jc.2014-1761DOI Listing
August 2014

Low circulating levels of IGF-1 in healthy adults are associated with reduced β-cell function, increased intramyocellular lipid, and enhanced fat utilization during fasting.

J Clin Endocrinol Metab 2014 Jun 11;99(6):2198-207. Epub 2014 Mar 11.

Department of Paediatrics (A.T., D.C., M.L.M., K.M., D.B.D.) and Wolfson Brain Imaging Centre (A.S.), University of Cambridge, CB2 0QQ, Cambridge, United Kingdom; Medical Research Council (MRC) Metabolic Diseases Unit (G.S.H.Y.), University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom; MRC Human Nutrition Research of Growth and Reproduction (L.B.); and National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre (D.B.D.), Cambridge, CB1 9NL, United Kingdom; Department of Endocrinology (S.W.J., A.V.), Rigshospitalet and Copenhagen University, DK-2100 Denmark; Oxford Centre for Diabetes, Endocrinology, and Metabolism (N.R.H.), University of Oxford, Oxford, OX3 7LE, United Kingdom; and Department of Growth and Reproduction (A.J.), Rigshospitalet, Faculty of Health and Medical Sciences, DK-2100 Denmark.

Context: Low serum IGF-1 levels have been linked to increased risk for development of type 2 diabetes. However, the physiological role of IGF-1 in glucose metabolism is not well characterized.

Objective: Our objective was to explore glucose and lipid metabolism associated with variations in serum IGF-1 levels.

Design, Setting And Participants: IGF-1 levels were measured in healthy, nonobese male volunteers aged 18 to 50 years from a biobank (n = 275) to select 24 subjects (age 34.8 ± 8.9 years), 12 each in the lowest (low-IGF) and highest (high-IGF) quartiles of age-specific IGF-1 SD scores. Evaluations were undertaken after a 24-hour fast and included glucose and glycerol turnover rates using tracers, iv glucose tolerance test to estimate peripheral insulin sensitivity (IS) and acute insulin and C-peptide responses (indices of insulin secretion), magnetic resonance spectroscopy to measure intramyocellular lipids (IMCLs), calorimetry, and gene expression studies in a muscle biopsy.

Main Outcome Measures: Acute insulin and C-peptide responses, IS, and glucose and glycerol rate of appearance (Ra) were evaluated.

Results: Fasting insulin and C-peptide levels and glucose Ra were reduced (all P < .05) in low-IGF compared with high-IGF subjects, indicating increased hepatic IS. Acute insulin and C-peptide responses were lower (both P < .05), but similar peripheral IS resulted in reduced insulin secretion adjusted for IS in low-IGF subjects (P = 0.044). Low-IGF subjects had higher overnight levels of free fatty acids (P = .028) and β-hydroxybutyrate (P = .014), increased accumulation of IMCLs in tibialis anterior muscle (P = .008), and a tendency for elevated fat oxidation rates (P = .058); however, glycerol Ra values were similar. Gene expression of the fatty acid metabolism pathway (P = .0014) was upregulated, whereas the GLUT1 gene was downregulated (P = .005) in the skeletal muscle in low-IGF subjects.

Conclusions: These data suggest that serum IGF-1 levels could be an important marker of β-cell function and glucose as well as lipid metabolic responses during fasting.
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http://dx.doi.org/10.1210/jc.2013-4542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413372PMC
June 2014

Cluster of cardiometabolic risk factors in children with GH deficiency: a prospective, case-control study.

Clin Endocrinol (Oxf) 2014 Jun 16;80(6):856-62. Epub 2014 Jan 16.

Pediatric Endocrinology Unit, Department of Translational Medical Sciences, University "Federico II" of Naples, Naples, Italy.

Objective: Growth hormone (GH) deficiency (GHD) in adults is associated with increased cardiovascular (CV) risk. Although some authors have documented the presence of early CV risk factors in untreated GHD children, results are still inconsistent. Aim of this study was to evaluate the effects of GHD and GH therapy on early cardiometabolic risk factors in a large cohort of children.

Subjects And Methods: Waist-to-height ratio (WHtR), triglycerides, total-, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol, atherogenic index (AI = total /HDL cholesterol), homocysteine, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP) and fibrinogen were evaluated in seventy-one GHD children (9·8 ± 3·6 years) before and after 2 years of GH therapy. Seventy-one healthy controls comparable with patients for age, sex and body mass index (BMI) were enrolled.

Results: Compared with controls, GHD children at study entry had higher WHtR (0·52 ± 0·05 vs 0·45 ± 0·19, P = 0·004), triglycerides (0·44 ± 0·98 vs -0·03 ± 0·73 SDS, P = 0·012), total cholesterol (0·28 ± 1·08 vs -0·46 ± 0·98 SDS, P < 0·001), LDL cholesterol (0·20 ± 0·90 vs -0·39 ± 1·06 SDS, P = 0·007), AI (3·19 ± 0·73 vs 2·77 ± 0·53, P = 0·001), homocysteine (8·45 ± 1·8 vs 7·72 ± 1·6 μm, P = 0·003), leptin (8·03 ± 4·2 vs 5·09 ± 1·9 ng/ml, P = 0·001) and fibrinogen (292·6 ± 33 vs 268 ± 31·4 mg/dl, P = 0·011). No differences were found in adiponectin or hsCRP. GH therapy was associated with a significant reduction in WHtR (P < 0·001), total cholesterol (P < 0·001), LDL cholesterol (P = 0·002), homocysteine (P = 0·044) leptin (P = 0·022) and fibrinogen (P = 0·001). Moreover, GH therapy was associated with a significant increase in adiponectin levels (P = 0·001).

Conclusions: Our data suggest that children with untreated GHD exhibit a cluster of early cardiovascular risk factors and that GH treatment exerts beneficial effects on these abnormalities.
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http://dx.doi.org/10.1111/cen.12393DOI Listing
June 2014

APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors.

Front Immunol 2013 Oct 23;4:331. Epub 2013 Oct 23.

Pediatric Section, Department of Translational Medical Sciences, "Federico II" University , Naples , Italy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease.
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http://dx.doi.org/10.3389/fimmu.2013.00331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805967PMC
October 2013

Serum thyrotropin concentration in children with isolated thyroid nodules.

J Pediatr 2013 Nov 22;163(5):1465-70. Epub 2013 Aug 22.

Division of Pediatric Endocrinology, Department of Pediatrics, University of Torino, Torino, Italy. Electronic address:

Objective: To investigate the correlation between serum thyroid-stimulating hormone (TSH) concentration and nodule nature in pediatric patients with thyroid nodules, with the aim of identifying a marker able to differentiate benign and malignant nodules.

Study Design: This was a retrospective analysis of serum TSH concentrations in a multicentric case series of 125 pediatric patients with benign and malignant thyroid nodules.

Results: Of the 125 patients, 99 had benign thyroid nodules and 26 had differentiated thyroid cancer (24 papillary and 2 follicular). Final diagnosis was based on surgery in 57 cases and on a benign cytology plus clinical follow-up in 68 cases. Serum TSH concentration was significantly higher in patients with thyroid cancer compared with those with benign nodules (3.23 ± 1.59 mU/L vs 1.64 ± 0.99 mU/L; P < .001). Binary logistic regression analysis revealed that serum TSH was the sole predictor of malignancy (P < .001). Dividing the patient cohort into 5 groups based on serum TSH quintiles (TSH cutoffs 0.40, 1.00, 1.50, 1.80, and 2.80 mU/L), we observed that cancer prevalence increased in parallel with serum TSH (P < .001), with respective rates of 0%, 4%, 16%, 32%, and 52% in the 5 quintile groups.

Conclusion: Because cases with malignant nodules are most likely seen in the upper normal serum TSH range (ie, >2.8 mU/L), serum TSH concentration can serve as a predictor of thyroid cancer in pediatric patients with thyroid nodules and can inform the decision of when to submit patients to further investigation by cytology.
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http://dx.doi.org/10.1016/j.jpeds.2013.07.003DOI Listing
November 2013

Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model.

Expert Rev Clin Immunol 2013 Jan;9(1):43-51

Department of Pediatrics, Federico II University, S Pansini 5, 8013 Naples, Italy.

Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Central tolerance within the thymus and peripheral tolerance in peripheral lymphoid organs lead to immunologic nonresponsiveness against self-components. The central tolerance represents the mechanism by which T cells binding with high avidity to self-antigens are eliminated through the so-called negative selection. Thymic medullary epithelial cells and medullary dendritic cells play a key role in this process, through the expression of a large number of tissue-specific self-antigens involving the transcription factor autoimmune regulator (AIRE). Mutations of AIRE result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, a rare autosomal recessive disease (OMIM 240300), which is the paradigm of a genetically determined failure of central tolerance and autoimmunity. This review focuses on recent advances in the molecular mechanisms of central tolerance, their alterations and clinical implication.
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http://dx.doi.org/10.1586/eci.12.88DOI Listing
January 2013
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