Maria Segni

Progression of premature thelarche to central precocious puberty

To evaluate whether girls with premature thelarche progress to central precocious puberty (CPP) and to analyze their clinical and hormonal characteristics, we retrospectively examined 100 girls with premature thelarche who were followed for several years. Fourteen of the patients with characteristics diagnostic of premature thelarche (isolated breast development before age 8 years, bone age advancement within 2 SD of normal, normal growth velocity, follicle-stimulating hormone-predominant response to luteinizing hormone-releasing hormone) progressed during follow-up to precocious or early central puberty (progressive breast size increase, bone age acceleration, and significant decrease in predicted adult height). The chronologic age of this group of 14 girls was 5.1 +/- 2.0 years at the onset of premature thelarche and 7.8 +/- 0.6 years (mean +/- SD) after progression to central early or precocious puberty. Pelvic ultrasonography showed significant differences in measurements between the time of diagnosis of premature thelarche and progression to CPP. Nine of these patients required treatment, three with cyproterone acetate and six with luteinizing hormone-releasing hormone analogs, and all responded as expected for classic CPP. At baseline evaluation, no clinical or hormonal characteristics could be established that separated the 14 children who progressed to precocious or early puberty from the 86 girls who did not. We conclude that premature thelarche is not always a self-limited condition and may sometimes accelerate the timing of puberty.

Final height in Turner syndrome patients treated with growth hormone.

Growth hormone (GH), alone or in combination with anabolic steroids, seems to improve the growth rate in Turner syndrome, but to exert a less striking effect on the final height (FH). Reports on the FH usually lack a control group, and the GH effect is determined using the gain in centimeters over projected height. Out of a cohort of 32 Turner syndrome girls under recombinant human GH (rhGH) therapy (0.5 IU/kg/week during the 1st year and 1 IU/kg/week subsequently), 18 (treated for 3-6 years) attained FH. The mean chronological age at the first examination was 9.6 +/- (SD) 2.1 years and at the start of GH therapy 13.0 +/- 2.0 (range 8.8-17.2) years. Eighteen untreated subjects matched for chronological age and karyotype served as control group. The FH as SDS according to Lyon and to unpublished Italian Turner syndrome girl standards was not significantly different as compared with pretreatment. In comparison with Italian cross-sectional Turner syndrome standards (FH 142.5 +/- 7.0 cm), the FH of the control group was quite similar (142.2 +/- 4.9 cm), whereas the rhGH-treated group showed a FH of 147.6 +/- 7.3 cm with a mean increment of about 5 cm. The height gain during therapy (as delta height in SDS either according to Lyon or to Italian SDS standards) was compared for each girl with that of a matched girl of the control group during a comparable observation period. A significantly different delta height was observed in the treated versus control groups: 0.3 +/- 1.1 vs. -1.0 +/- 0.8 according to Lyon (p < 0.001) and 0.8 +/- 0.7 vs -0.3 +/- 0.5 according to Italian standards (p < 0.001). If we compared the FH with the projected height according to Lyon standards, the height gain (as delta height in cm) was significantly higher than in the untreated subjects (-1.1 +/- 4.8 vs. -6.2 +/- 3.9 cm; p < 0.05). It seems worthwhile to undertake GH treatment in Turner syndrome girls who represent a very short stature population, even though the response is less significant than in classic GH deficiency and shows a striking variability, probably due to a sort of peripheral resistance.

Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution.

Out of 35 girls with idiopathic central precocious puberty (CPP) treated with gonadotropin-releasing hormone agonist (GnRHa) (depot-triptorelin) at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 years whose growth velocity fell below the 25th percentile for chronological age (CA), 17 received growth hormone (GH) in addition at a dose of 0.3 mg/kg/week, s.c., 6 days per week, for 2-4 years. The other 18, matched for bone age (BA), CA and duration of GnRHa treatment, who showed the same growth pattern but refused GH treatment, remained on GnRHa alone, and were used as a control group to evaluate GH efficacy. No patient was GH deficient. Both groups discontinued treatment at a comparable BA (mean +/- SD): BA 13.4 +/- 0.6 in GnRHa plus GH group vs 13.0 +/- 0.5 years in the GnRHa alone group. The 35 patients have reached adult height (i.e. growth during the preceding year was less than 1 cm, with a BA of over 15 years). Patients of the group treated with GH plus GnRHa showed an adult height (161.2 +/- 4.8 cm) significantly higher (p < 0.001) than pre-treatment predicted adult height (PAH) calculated according to tables either for accelerated girls (153.2 +/- 5.0 cm) or for average girls (148.6 +/- 4.3 cm). The adult height of the GnRH alone treated group (156.6 +/- 5.7) was not significantly higher than pre-treatment PAH if calculated on Bayley and Pinneau tables for accelerated girls (153.9 +/- 3.8 cm), whilst it remained significantly higher if calculated on tables for average girls (149.6 +/- 4.0 cm) (p < 0.001). The gain between pre-treatment PAH and final height was 8.2 +/- 4.8 cm according to tables for accelerated girls and 12.7 +/- 4.8 cm according to tables for average girls in patients treated with GH plus GnRHa; while in patients treated with GnRH alone the gain calculated between pre-treatment PAH for accelerated girls was just 2.3 +/- 2.9 cm and 7.1 +/- 2.7 cm greater than pre-treatment PAH for average girls. The difference between the gain obtained in the two groups (about 6 cm) remained the same, however PAH was calculated. The addition of GH to GnRHa in a larger cohort of patients with CPP with a longer follow-up confirms the safety of the combined treatment and the still significant but more variable gain in the group with the combined treatment, probably due to the larger number of patients analyzed. Caution is advised in using such an invasive and expensive treatment, and there is need for further studies before widespread clinical use outside a research setting.

Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group

The main clinical feature of Turner syndrome (TS) is growth failure, with a mean spontaneous adult height ranging between 136 and 147 cm, according to the specific curves of various populations. Though a classical deficiency of GH has not been generally demonstrated, GH has been administered since 1980 in trials, using replacement doses just initially, with a subsequent trend to increase it. We report the outcome of GH therapy given at the fixed dose of 0.33 mg/kg/week in 60 TS girls observed until adult height; 59 untreated TS girls, matched for auxological, karyotypical characteristics and time of observation, born within the same decade served as controls to evaluate GH efficacy. The calculation of the gain in cm over PAH was performed on specific Italian Turner curves, as well as height evaluation as SD score and growth velocity. The same calculations were made using Lyon references and Tanner standards. The mean CA at the beginning of GH treatment was 10.9±2.76 yr (range 4.5–15.9). Mean adult height of treated group was 151±6.1 cm with a gain over the PAH calculated at start of therapy (142.9±5.3 cm) of 8.2±3.9 cm. Ns change was observed between the PAH at first observation (143.6±7.0 cm) and adult height (144.3±5.6 cm) in the control group. Treatment was well tolerated, no relevant side effects were observed, glucose metabolism resulted no more affected than in untreated subjects, IGF-I levels remained within 2 SD. Our results in 60 TS girls, though the dose remained unchanged throughout the treatment, show a good response, characterized by a striking variability in each patient (mean gain in cm over PAH at adult height of 8.17±3.9, range 3–21 cm), and significant also in comparison with the control group. As the chronological age at start of therapy ranged between 4.5 to 15.9 yr, the results were further evaluated dividing the patients into two groups, according to the age, < or >11 yr. Thirty girls were <11 yr (mean 8.7±1.76 yr) and 30 were >11 yr (mean 13.2±1.4 yr). The gain in cm over the PAH in each group was, respectively, 8.1±3.4 and 8.2±4.3 cm without any significant difference between the two groups, showing no negative correlation between the CA at the beginning of GH and the response to treatment.

Combined therapy with GnRH analog plus growth hormone in central precocious puberty.

GnRH analogues (GnRHa) arrest pubertal development, and slow growth velocity (GV) and bone maturation, thus improving adult height in central precocious puberty (CPP). In some patients, however, GV decreases to such an extent that it compromises the improvement in predicted adult height (PAH) and therefore the addition of GH is suggested. Of 20 patients with idiopathic CPP (treated with GnRHa [depot-triptorelin] at a dose of 100 microg/kg every 21 days i.m. for at least 2-3 yr) whose GV fell below the 25th percentile for chronological age (CA), ten received, in addition to the GnRHa, GH at a dose of 0.3 mg/kg/wk, s.c. 6 days weekly, for 2-4 yr. Ten patients matched for BA, CA, and duration of GnRHa treatment who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of the addition of GH. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 yr in GnRHa + GH vs 13.0 +/- 0.1 yr in the control group. At the conclusion of the study all the patients had achieved adult height. Adult height was considered to be attained when the growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients of the group treated with GH + GnRHa showed an adult height significantly higher (p<0.001) than pretreatment PAH (160.6 +/- 1.3 vs 152.7 +/- 1.7 cm). Height SDS for BA significantly increased from -1.5 +/- 0.2 at start of GnRHa to -0.21 +/- 0.2 at adult height (p<0.001). Target height was significantly exceeded. The GnRH alone treated group reached an adult height not significantly higher than pretreatment PAH (157.1 +/- 2.5 vs 155.5 +/- 1.9 cm). Height SDS for BA did not change (from -1.0 +/- 0.3 at start of GnRHa to -0.7 +/- 0.4 at adult height). Target height was just reached but not significantly exceeded. The gain in centimeters obtained calculated between pretreatment PAH and final height was 7.9 +/- 1.1 cm in patients treated with GH combined with GnRH analogue while in patients treated with GnRH analogue alone the gain was just 1.6 cm +/- 1.2 (p=0.001). Furthermore, no side effects, bone age progression, or ovarian cysts, were observed in GnRHa + GH treated patients. In conclusion, a gain of 7.9 cm in adult height represents a significant improvement which justifies the addition of GH for 2-3 yr to conventional treatment with GnRH analogues in patients with central precocious puberty, and with a decrease in growth velocity so marked as to impair predicted adult height to below the third percentile.

HLA DQ2 and/or DQ8 Is Associated With Celiac Disease–Specific Autoantibodies To Tissue Transglutaminase in Families With Thyroid Autoimmunity

TO THE EDITOR: Celiac disease (CD) is characterized by a T cell–mediated destruction of intestinal architecture that can lead to global malabsorption but presents with atypical symptoms in the majority of patients. In CD the ingestion of dietary gluten and related cereals drives intestinal inflammation and a mucosal autoimmune response to the ubiquitous enzyme tissue transglutaminase (tTG) (1, 2). Interestingly, tTG can potentiate gluten antigen presentation and immunogenicity in genetically predisposed individuals bearing the CD-predisposing major histocompatibility complex human leukocyte antigen (HLA) DQ2 or DQ8, which is found in 95% and 5% of patients, respectively (2, 3). Long-lasting CD is associated with a variety of autoimmune diseases, mainly type 1 diabetes and dermatitis herpetiformis (4). Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are the most common autoimmune disorders. They affect more than 2% of the female population in the US. These autoimmune endocrinopathies occur frequently in patients and relatives with other autoimmune diseases, such as type 1 diabetes mellitus or CD, sharing immunogenetic susceptibility loci on chromosome 6p. Thus the haplotype allele DQA1*0501 of the HLA DQ2 heterodimer DQA1*0501/ DQB1*0201, and the HLA DQ8 heterodimer DQA1*0301/ DQB1*0302, characteristic for CD patients, are also frequently found in patients with type 1 diabetes mellitus or GD (5). An association of CD with thyroid autoimmunity has been reported in patients from Italy, Finland, and the US (6–9). Because IgA autoantibodies to tTG (tTG-Ab) are a sensitive, highly specific tool for detecting atypical or subclinical CD, we measured the prevalence of these autoantibodies in patients and families with thyroid autoimmune diseases and correlated the findings with HLA DQ status. We enrolled 105 patients with thyroid autoimmune disorders (81 with GD, 24 with HT) and 95 of their first degree relatives (43 fathers, 43 mothers, and nine siblings). The diagnosis of GD was based on hyperthyroidism with thyroid stimulating hormone receptor autoantibodies, and that of HT on hypothyroidism with thyroid peroxidase autoantibodies. tTG-Ab were measured as described (10), and HLA DQA1 and DQB1 alleles determined by polymerase chain reaction (5). There was one patient with HT and known CD who also suffered from type 1 diabetes. This patient displayed high titer tTG-Ab (93 U). Another patient with HT showed a slightly elevated titer (12 U). With these two patients a prevalence of 8% among the studied patients with HT was found, whereas we did not detect tTG-Ab among patients with GD. However, five of 43 fathers (12%) and one mother (2%) of the patients with GD had slightly or clearly elevated tTG-Ab (n 5 5, 10–17 U; n 5 1, 41 U, respectively). Three of the six (50%) tTG-Ab positive parents had the HLA DQ2 specificity, as compared with only 20 of 80 (25%) of the tTG-Ab negative parents (reflecting the frequency in the normal population) (Table 1). Furthermore, these alleles were inherited by their children who had GD. In addition, HLA DQ2 and/or DQ8 were found in all five tTG-Ab positive fathers, as compared with only 17 of 38 (45%) tTG-Ab negative fathers (p 5 0.02). Remarkably, the single patient who displayed both HLA DQ2 and HLA DQ8 suffered from triple autoimmunity (type I diabetes, GD, and CD). The finding that unaffected parents of patients with autoimmune disorders transmit the susceptibility genes to their

Ectopic Intrathyroidal Thymus in Children: A Long-Term Follow-Up Study

Background: Ectopic intrathyroidal thymus has recently been reported in children as a cause of surgery and/or invasive diagnostic procedures when mistaken for a thyroid nodule. Thymus has a unique appearance at ultrasound (US). Methods: We report a follow-up study (mean 34 months, range 6–84) performed by US on 9 children (5 females) with a mean age of 6.3 ± 3.2 years with intrathyroidal thymic inclusions diagnosed by US as ‘incidentalomas’. None has palpable nodules. Results: Intrathyroidal thymic inclusions appeared on US as a hypoechoic area, with regular linear or punctuate internal hyperechoic echoes. The 2 oldest patients (13 and 17 years) showed a regression in both size and hypoechogenicity of thymic inclusions over time – reflecting the normal thymic involution with advancing age. Conclusions: Indeed, the lack of progression seen in our 9 patients over a mean time of 34 months confirmed the substantially benign and self-limited nature of this process. The increasing use of thyroid ultrasonography in children may result in an increased detection of intrathyroidal thymic inclusions – an embryologic anomaly that should be considered in the differential diagnosis of thyroid nodules in children and adolescents.

Levothyroxine treatment in pediatric benign thyroid nodules.

Aim: To evaluate the effectiveness of levothyroxine therapy in benign thyroid nodules in pediatrics. Methods: Data from 78 euthyroid children and adolescents with benign thyroid nodules were retrospectively collected. Subjects were divided into 2 groups: levothyroxine treated (n = 36) and nontreated (n = 42), and the clinical, laboratory and sonographic features of the 2 groups were compared. Nodules were considered benign according to histology, fine-needle aspiration biopsy or by features suggestive for benignity. The groups were followed up for 2.4 ± 1.3 years, and treated patients received a mean dose of levothyroxine of 1.69 ± 0.66 µg/kg/day. Results: Patients in the treated and nontreated groups were comparable for age, sex and follow-up. A reduction in nodule diameter from 2.24 ± 0.94 to 1.86 ± 1.17 cm (p = 0.039) was observed in treated patients, whereas the nodule diameter increased from 1.66 ± 0.86 to 1.78 ± 0.91 cm in nontreated patients (p = 0.024). In the treatment group, 11 patients (30.6%) had a reduction greater than 50% and significantly decreased palpable nodules (p < 0.001). A nonsignificant reduction in reported symptoms was observed, too. The change in nodule size was directly correlated with thyroid-stimulating hormone levels (r = 0.640, p < 0.001) and inversely with levothyroxine dose (r = –0.389, p = 0.009). In nontreated subjects, both palpable nodules and symptoms increased. Conclusion: This study supports levothyroxine treatment effectiveness in shrinking benign nodules.

BREG cells in Hashimoto's thyroiditis isolated or associated to further organ-specific autoimmune diseases

Hashimoto thyroiditis (HT) may occur isolated or associated with other non-endocrine autoimmune disorders (NEAD). No data are available about Breg cells in these disorders and this represented the aim of the study. Th17 and Breg cells subset were characterized on peripheral blood mononuclear cells isolated from 18 healthy donors (HD), 19 patients with isolated HT and 26 patients with HT+NEAD. Th17 were higher in patients with isolated HT than in HD but no further changes were seen in patients with HT+NEAD. CD24hiCD38hi unstimulated Breg cells were similar in HT patients and in HD, but significantly higher in patients with HT+NEAD than in both HT and in HD. CD19+CD24hiCD27+ Breg memory phenotype was similar in HD and in HT patients, but decreased in patients with HT+NEAD (23.4%vs38.5%). Upon CpG-stimulation, CD24hiCD38hi IL-10+ Breg cells were higher in HT patients than in HD (3.9%vs1.8%) but similar in patients with HT+NEAD (2.4%).

Seizures and epilepsy in Sotos syndrome: Analysis of 19 Caucasian patients with long-term follow-up

Sotos syndrome (SS) is an overgrowth syndrome characterized by typical facial appearance, learning disability, and macrocephaly as cardinal diagnostic features. Febrile (FS) and afebrile seizures are reported in 9–50% of cases. There is no evidence that patients with SS and FS later develop epilepsy, and no studies have investigated the electroclinical features and the long‐term outcome in epileptic SS patients. The authors report a series of 19 SS patients with FS and/or epilepsy during childhood and a long‐term follow‐up. More than half of FS evolved to epilepsy. Temporal lobe seizures were recorded in 40% of patients with SS. Seizures were easy to control with common antiepileptic drugs in almost all patients. A careful neurologic evaluation is useful for SS patients, since seizures are an important finding among people with this overgrowth syndrome.