Pituitary dysfunction is now well recognised after traumatic brain injury (TBI) in adults; however, little except anecdotal evidence is known about this potential complication in childhood and adolescence. Histopathological evidence exists for both hypothalamic and pituitary damage, but few data specific to children have been published. We review the available paediatric data, which shows that after both mild and severe TBI, hypopituitarism may occur, with GH and gonadotrophin deficiencies appearing to be most common. Precocious puberty has also been documented. Road-traffic accidents, falls, sport and child abuse are the most common aetiological factors for paediatric TBI. There are no published data on the incidence or prevalence, neither within a population of children with TBI, of hypopituitarism, nor on its natural history or response to hormone replacement. We urge paediatric endocrinologists, in collaboration with adult endocrinologists, to perform formal prospective research studies in patients suffering from TBI to clarify these questions.
Carlo L Acerini, Robert C Tasker, Simonetta Bellone, Gianni Bona, Christopher J Thompson and Martin O Savage
Alice Monzani, Flavia Prodam, Anna Rapa, Stefania Moia, Valentina Agarla, Simonetta Bellone and Gianni Bona
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.
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.
Mohamad Maghnie, Gianluca Aimaretti, Simonetta Bellone, Gianni Bona, Jaele Bellone, Roberto Baldelli, Carlo de Sanctis, Luigi Gargantini, Roberto Gastaldi, Lucia Ghizzoni, Andrea Secco, Carmine Tinelli and Ezio Ghigo
Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 μg/l based on a cohort of subjects with a mean age of 45 years.
Design and methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic–pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8±2.3 years, range 17–25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2±4.4 years, range 15.1–30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals.
Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8±2.0 μg/l, range 0.1–6.1 μg/l) compared with the 39 controls (18.5±15.5 μg/l, range 6.1–84.0 μg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 μg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 μg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of −1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I ≤ − 2.0 SDS showed a sensitivity of 62%.
Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 μg/l or 5 μg/l and of IGF-I of less than −2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic–pituitary abnormalities.
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
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.
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).
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.
Daniela Vivenza, Michela Godi, Maria Felicia Faienza, Simona Mellone, Stefania Moia, Anna Rapa, Antonella Petri, Simonetta Bellone, Stefania Riccomagno, Luciano Cavallo, Mara Giordano and Gianni Bona
Mutations in HESX1 represent a rare cause of GH deficiency (GHD) associated with a broad spectrum of other anomalies. We searched for causative mutations in a cohort of 244 Italian patients affected by combined and isolated GHD (IGHD).
The HESX1 gene-coding region and exon–intron boundaries were screened by denaturing HPLC scanning.
A novel mutation adjacent to the invariant donor splice site of intron 2 (c.357+3G>A) was identified at the heterozygous state in an IGHD patient. The in vitro and in vivo mRNA analysis of the wild-type HESX1 allele revealed the presence of the whole cDNA and two isoforms lacking exon 2 and exons 2–3 respectively. The mutant HESX1 allele yielded only two splicing products, the whole cDNA and the cDNA missing exons 2–3, whereas the mRNA lacking exon 2 was absent. An in vitro assay demonstrated that the exon 2-deleted mRNA, predicting a prematurely truncated protein, is subjected to nonsense-mediated mRNA decay (NMD).
The c.357+3G>A mutation prevents the generation of one of the alternative isoforms normally produced by the wild-type allele, predicting a truncated HESX1 protein. The mutation is likely to cause IGHD in the heterozygous patient by interfering with the downregulation of HESX1 expression mediated by alternative splicing and NMD.
Our results open new insight into the mechanism of HESX1 regulation suggesting that the coupling of alternative splicing and NMD might play a fundamental role in directing the HESX1 expression, and that the alteration of this process might lead to severe consequences.
Roberta Ricotti, Arianna Solito, Elena Mariotti Zani, Marina Caputo, Giulia Genoni, Francesco Barone-Adesi, Valentina Mancioppi, Emanuela Agosti, Gianluca Aimaretti, Simonetta Bellone and Flavia Prodam
Data on metabolic impairments in Cushing’s syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity.
Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity.
Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles.
We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.