Ida Pucarelli

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.

Growth Hormone Treatment in Noonan Syndrome: Report of Four Cases Who Reached Final Height

Final height of 4 patients with Noonan syndrome and short stature treated with growth hormone (GH) is reported. Four prepubertal girls (chronological age 12.3-15.1 years, bone age 11.0-11.5 years) were treated with recombinant human growth hormone (0.5 IU/kg/week s.c.) for at least 3 years. Stimulated GH secretion was normal, spontaneous nocturnal GH secretion was low in 1 patient. Final height, as standard deviation score according to Ranke-specific standards for Noonan syndrome, improved in 3 patients and 2 of the exceeded their corrected midparental height.

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.

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.

GH Assessment and Three Years’ hGH Therapy in Girls with Turner Syndrome

Fifteen girls with Turner syndrome (TS) were submitted to GH secretion assessment before undergoing hGH therapy. In the first 9 months, hGH was given at a dose of 0.5 IU/kg/week s.c. daily; afterward, the dose was increased to 1 IU/kg/week s.c. daily. The girls were prepubertal, with a mean (SD) chronological age (CA) of 12.5 (2.6) years, and a mean (SD) bone age of 10.5 (1.8) years. A clonidine stimulation test, 1-29 GHRH test and GH spontaneous nocturnal secretion assessment were performed in all patients. Results showed a variable pattern of GH secretion in 10 patients, in only 2 did we find all values definitely normal, and in 3 we found a total GH deficiency. Height velocity, expressed as standard deviation scores (SDS) for CA according to Turner references, during the first year of treatment increased significantly: 0.36 (1.15) -3.30 (2.87) (p < 0.001), and the increment remained quite unchanged during both the second and third years: 3.16 (2.96) and 2.55 (3.87), respectively (n.s.). Height, expressed in SDS for CA for Turner references, increased significantly throughout the whole period of treatment and reached the highest value at the end of the third year of therapy. GH secretion parameters poorly correlated with pretreatment auxological data or response to treatment. Our long-term study confirms that in TS GH measurement is not useful in indicating hGH therapy or in predicting the response.

Thyroid C-cell hyperplasia in an adolescent with neurofibromatosis type 1.

Background: Subjects with neurofibromatosis type 1 (NF1) show an increased risk of endocrine tumors, especially pheochromocytoma, whereas thyroid C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) are very rare events described only in adult patients. Method: A case of CCH diagnosed in a 14-year-old girl affected with NF1 is reported. Calcitonin serum level after pentagastin was elevated (286 pg/ml). Genetic testing was performed in order to rule out mutations in the RET proto-oncogene. Result: No germline mutation previously reported in MEN2 was detected. Multifocal and bilateral CCH was demonstrated by immunohistochemistry. Conclusion: It is suggested that in such a genetic background of high risk for malignancy, CCH could be considered as an extremely rare condition likely preceding MTC.

Acute suppurative thyroiditis treated avoiding invasive procedures in a child.

Acute suppurative thyroiditis is uncommon in children (1). Acute suppurative thyroiditis is a potentially life-threatening endocrine emergency. The management of this condition has recently been reviewed (2–4), but the optimal treatment is still debated. Surgery is the traditional treatment of this condition, but a nonsurgical management has also been reported (5). This case illustrates a successful conservative approach monitored by ultrasound (US) in a 4-yr-old girl. She came to our observation for a lump of more than 2 cm in the left side of the neck (Fig. 1A1). Ten days before she was admitted to a different institution for a left anterior neck mass. The mass was painful, tender, with erythema and warmth. She presented with fever (39 C) and leucocytosis (white blood cells, 22.100; neutrophils 85%) and was treated for acute suppurative thyroiditis with iv ampicillin and gentamicyn for a week. At our first observation she presented with a firm, painless lump of more than 2 cm in the left side of the neck (Fig. 1A1). At US (Fig. 1B1), the left lobe of thyroid was enlarged, and the parenchyma looked subverted, with a large irregular hypoechoic area and effacement of the planes between prethyroid muscles and soft tissues surrounding the lobe. Adjacent to the lump, a hypoechoic area in the soft tissue, presumably an abscess, was found (arrow). She was treated with amoxicillin and clavulanic acid (100 mg/kg/d per os) for 55 d. The lump disappeared (Fig. 1A2). At US (Fig. 1B2), nearly normal parenchyma was visible as well as muscles and soft tissues. The hypoechoic area was substituted with hyperechoic tissue (arrow). After 6 months she is well, and thyroid function is normal. A transnasal laryngoscopy to evaluate a possible pyriform sinus fistula is planned if a recurrence occurs.