Andrea Corrias

Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis

OBJECTIVE To investigate the association between juvenile autoimmune thyroiditis (JAT) and thyroid cancer in pediatric patients. DESIGN We conducted a retrospective study among children and adolescents affected by JAT. SETTINGS Data from 6 Italian pediatric endocrinology centers were collected. PARTICIPANTS Three hundred sixty-five children and adolescents affected by JAT diagnosed at 3.6 to 17.0 years of age. INTERVENTIONS All patients underwent clinical examination and thyroid function test every 6 to 12 months and thyroid echography every 12 to 24 months. Fine-needle aspiration biopsy was performed in 39 patients with nodule diameter of 1 cm or larger, as well as in 4 patients with nodule diameter of less than 1 cm and echographic findings suspicious for neoplasm. Twenty-three patients underwent surgery. MAIN OUTCOME MEASURES Thyroid function, echographic pattern, nodule diameter, the presence of lymphadenopathy, and cytologic and histologic diagnoses were considered. RESULTS Thyroid nodules were found in 115 patients; findings in 11 of these were consistent with papillary carcinoma, with 5 exhibiting lymph node metastasis. The prevalence of male sex among patients with cancer was greater than that among patients with JAT (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.44-6.20). The growth of nodules during levothyroxine sodium therapy (OR, 15.60; 95% CI, 1.87-181.90) and the finding of lymphadenopathy (OR, 5.44; 95% CI, 1.05-30.50) were statistically significantly associated with the presence of cancer, while uninodularity and hypoechogenicity were not. CONCLUSIONS The observed prevalences of thyroid nodules and thyroid cancer in our JAT case series were 31.5% and 3.0%, respectively. Papillary carcinoma was the only histotype detected. The finding of lymphadenopathy, a lack of response to levothyroxine therapy, and nodule hypoechogenicity suggested malignancy. Fine-needle aspiration biopsy was reliable in selecting patients for referral to surgery.

Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty.

We reviewed the hospital records of 45 boys, followed in 13 pediatric departments throughout Italy, who had undergone computed tomography and/or magnetic resonance imaging for central precocious puberty (CPP). Twenty-seven patients (60%) had idiopathic CPP and 18 (40%) neurogenic CPP. A hamartoma of the tuber cinereum was found in six patients (33%). All patients with hypothalamic hamartoma had earlier onset of symptoms than patients with idiopathic CPP. Five patients (27%) were affected by type 1 neurofibromatosis, two had ependymoma and five patients had an intracranial anomaly. Basal LH and basal and peak LH/FSH ratio were greater, but not significantly, in boys with neurogenic CPP than in boys with idiopathic CPP. The highest LH peak levels were observed in patients with hamartoma; however, no correlation was observed between LH peak and the size of the hamartomas. In addition, bone age at diagnosis was more advanced in patients with hamartoma than in patients with other conditions. In conclusion, gonadotrophin-dependent precocious puberty may be of idiopathic origin or may occur in association with any CNS disorder. Further studies are needed in order to evaluate the effects of nutritional, environmental and psychosocial factors on the timing of sexual maturation, to explain the high incidence of idiopathic CPP in our male patients.

Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved.

OBJECTIVE The aim of the study was to examine clinical characteristics, biochemical parameters, and TSH-R gene variations in children and adolescents with subclinical hypothyroidism (SH) in order to evaluate their pattern of distribution in SH. PATIENTS We enrolled 88 patients, each having at least two TSH measurements above the upper limit of the reference range with normal free thyroid hormones and negative thyroid autoantibodies. MAIN OUTCOME MEASURES Clinical characteristics included height, weight, family history of thyroid diseases, thyroid volume, and echogenicity at ultrasonography. Biochemical parameters included TSH, free thyroid hormones, thyroid autoantibodies, and adjusted daily urinary iodine excretion (UIE). Genetic variations in the TSH-R gene were assessed. RESULTS The prevalence of overweight/obesity, positive family history of thyroid diseases, and thyroid hypoechogenicity was 28.4, 45.5, and 22.7%, respectively. Median TSH was higher in overweight/obese patients than in normal-weight ones (7.4 vs. 5.7 muIU/ml; P = 0.04) and in overweight/obese patients with hypoechogenicity than in those with normal ultrasound pattern (8.5 vs. 6.8 muIU/ml; P = 0.04). Adjusted daily UIE was lower in subjects without than in those with a positive family history of thyroid diseases (81 vs. 120 mug/d; P = 0.001). The prevalence of a positive family history of thyroid diseases was 1.9-fold higher in patients with nonsynonymous mutations in the TSH-R gene than in patients without any mutation (80 vs. 42%; P = 0.03). A novel mutation at position 1559 in exon 10 (W520X) was detected in one child. CONCLUSIONS Overweight/obesity, thyroid hypoechogenicity, and nonsynonymous mutations in the TSH-R gene are characterizing features of a large portion of SH children.

The natural history of the normal/mild elevated TSH serum levels in children and adolescents with Hashimoto’s thyroiditis and isolated hyperthyrotropinaemia: a 3‐year follow‐up

Objective  The natural history of Hashimoto’s thyroiditis (HT) and isolated hyperthyrotropinaemia (IH) is not well defined. We therefore studied the natural course of patients with HT and IH and looked for possible prognostic factors.

Ultrasound Screening for Thyroid Carcinoma in Childhood Cancer Survivors: A Case Series

CONTEXT Childhood cancer survivors need regular monitoring into young adulthood and beyond, because they are at risk for developing late-onset complications of cancer therapy, including second malignancies. OBJECTIVE This study focuses on the use of thyroid ultrasound to screen for thyroid carcinoma in a population of childhood cancer survivors. PATIENTS A total of 129 subjects who had received radiotherapy to the head, neck, or upper thorax for a pediatric cancer were studied in the setting of a long-term follow-up unit. DESIGN Thyroid ultrasound usually began 5 yr after radiotherapy and was repeated every third year, if negative. Median follow-up time since childhood cancer diagnosis was 15.8 yr (range 6.1-34.8 yr). Solid thyroid nodules were found in 35 patients. Fine-needle aspiration was performed in 19 patients, of which 14 had nodules above 1 cm. MAIN OUTCOME MEASURE The main outcome measure was the finding of not palpable thyroid cancers. RESULTS Cytological examination of specimens diagnosed papillary carcinoma in five patients who underwent surgery. The cytological diagnosis of papillary thyroid carcinoma was confirmed in all cases by histological examination. Notably, only two of these patients had palpable nodules; the other three were smaller than 1 cm and were detected only by ultrasound. However, histological examination showed nodal metastases in two of these. CONCLUSIONS Although ultrasound screening for thyroid cancer in the general population is not cost effective and could lead to unnecessary surgery, due to false positives, we believe that in childhood cancer survivors who received radiotherapy involving the head, neck, or upper thorax, it would be worthwhile.

GH/IGF-I axis in Prader-Willi syndrome: Evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli

Basal IGF-I levels and the GH response to at least two among provocative stimuli such as clonidine (CLO, Catapresan, 150 mcg/m2 po), GHRH (1 mcg/kg iv)+arginine (ARG, 0.5 g/kg iv infusion during 30 min) and GHRH+pyridostigmine (PD, Mestinon cpr 60 mg po) have been evaluated in 43 children with Prader-Willi syndrome (PWS, 17 males and 26 females, age 3–22 yr, 7 normal weight and 36 obese PWS), in 25 normal short children (NC, 17 males and 8 females, 7.7–18.5 yr) and in 24 children with simple obesity (OB, 14 males, 10 females, 7.7–21.5 yr). Both normal weight and obese PWS had mean IGF-I levels lower than those recorded in NC (p<0.001) and OB (p<0.001). The GH responses to GHRH+ARG and GHRH+PD in NC were similar and higher than that to CLO (p<0.001). In PWS the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.001) which, in turn, was higher than that to CLO (p<0.001); these responses in PWS were lower than those in normal children (p<0.02) and similar to those in OB. In normal weight PWS the GH responses to GHRH+ARG and to GHRH+PD were similar and higher than to CLO (p<0.05); however, each provocative stimulus elicited a GH rise lower than that in NC (p<0.05). In obese PWS as well as in OB the GH response to GHRH+ARG was higher than that to GHRH+PD (p<0.02) which, in turn, was higher than that to CLO (p<0.001); all GH responses in obese PWS and OB were lower than those in NC (p<0.001) but similar to those in normal weight PWS. In conclusion, patients with PWS show clear reduction of IGF-I levels as well as of the somatotroph responsiveness to provocative stimuli independently of body weight excess. These results strengthen the hypothesis that PWS syndrome is frequently connoted by GH insufficiency.

Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics

BACKGROUND Survival rates among childhood cancer survivors (CCS) have enormously increased in the last 40 years. However, this improvement has been achieved at the expense of serious late effects that frequently involve the endocrine system. AIM To evaluate the cumulative incidence of endocrine diseases in a cohort of long-term CCS. MATERIALS AND METHODS We analyzed the clinical data of 310 adults, followed for a median time of 16.0 years after the first cancer diagnosis. The monitoring protocols applied to each patient were personalized on the basis of cancer diagnosis and previous treatments, according to the Childrens Oncology Group guidelines. RESULTS The cumulative incidence of endocrine late effects steadily increased over time. At the last follow-up visit available, 48.46% of females and 62.78% of males were affected by at least one endocrine disease. The most common disorders were gonadal dysfunction, primary hypothyroidism, and GH deficiency (GHD). The main risk factors for endocrine disease were male sex (hazard ratio (HR)=1.45, 95% confidence interval (95% CI) 1.05-1.99), radiotherapy (HR=1.91, 95% CI 1.28-2.84), hematopoietic stem cells transplantation (HR=3.11, 95% CI 2.23-4.34), and older age at cancer diagnosis (HR=1.89, 95% CI 1.25-2.85). Male sex was associated with a higher risk of gonadal disorders, whereas radiotherapy specifically increased the risk of GHD and thyroid dysfunction. CONCLUSIONS Endocrine disorders among CCS have a high prevalence and increase over time. Thus, endocrinologists need to cope with an increasing demand for health care in a field that is still little developed and that, in perspective, could also be extended to some selected types of adult cancer survivors.

Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes

Objective  TSH resistance ranges from overt nonautoimmune hypothyroidism to subclinical hypothyroidism, defined as mild hyperthyrotrophinaemia but a euthyroid state clinically. To date, 23 inactivating mutations of the TSH receptor (TSHR) gene have been proven responsible for the clinical condition, but an absence of mutations in the TSHR gene has been reported for several cases of TSH resistance as well. In this paper, we aimed to investigate the actual role of the TSHR gene in the development of both subclinical and congenital hypothyroidism.

The Italian National Survey for Prader-Willi syndrome: an epidemiologic study.

Twenty‐five medical centers and the Prader–Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4–46.7). Two hundred thirty‐eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity‐related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death.

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541.