Prediction of response to growth hormone treatment in pre-pubertal children with growth hormone deficiency.

BACKGROUND: GH therapy response varies substantially among patients. Several models were developed to predict the efficacy of GH therapy in children. AIM: To evaluate the accuracy of a growth prediction model using data from an Italian pediatric GH deficiency (GHD) cohort (GeNeSIS, Growth Prediction Sub-study). METHODS: Open-label, multicenter study in 22 Italian pre-pubertal GH treatment- naïve patients with GHD (8 female, 14 male, 0.5 to 12.2 yr), 18 isolated GHD, 4 multiple pituitary hormone deficiency given recombinat human GH therapy (0.025-0.035 mg/kg/day) for 12 months. Growth prediction was performed, after 3 months of treatment, using baseline data [bone age (BA) and IGF-I], a urinary marker of bone turnover [deoxypyridinoline crosslinks (DPD)] at 4 weeks, and height velocity (HV) at 3 months. Results were expressed as 1st-yr HV using the following equation: 1-yr HV (cm) = 3.543 - (2.337 × BA) - (0.010 × IGF-I) + (0.100 × DPD) + (0.299 × 3-month HV). Predictions were compared to the 1st-yr HV and accuracy was calculated as percentage of the difference between mean calculated HV and the real 1st-yr HV. RESULTS: For females predicted HV was 12.98 ± 4.82 cm/yr and actually was 13.05 ± 3.91 cm/yr after the 1st year; for males predicted HV was 13.95 ± 5.39 cm/yr and actually was 12.93 ± 5.02 cm/yr. CONCLUSIONS: In this paediatric Italian cohort with GHD, a growth prediction model seems to be a valid tool to assess 1st-yr response to GH treatment in Italian children.

Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome.

The incidence of spontaneous puberty in Turner's syndrome is reported to be between 5-10% and, more recently in some series, as high as 20%. In an Italian retrospective multicenter study, of 522 patients older than 12 yr with Turner's syndrome, 84 patients (16, 1%) presented spontaneous pubertal development with menarche that occurred at a chronological age of 13.2 +/- 1.5 yr (mean +/- SD) and a bone age of 12.9 +/- 1.9 yr. Karyotype distribution in the whole group was as follows: 52.1% (272 patients) X-monosomy (45,X), 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X. Menstrual cycles were still regular in 30 patients at 9.2 +/- 5.0 yr after menarche, 12 developed secondary amenorrhea 1.6 +/- 2.0 yr after menarche, and 19 had irregular menstrual cycles 0.9 +/- 1.8 yr after menarche. As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X seems to have a cardinal influence on the appearance of spontaneous puberty. Spontaneous pregnancy occurred in 3 patients (3.6%). The presence of chromosomal abnormalities and malformations in 2 of 3 pregnancies led us to agree with other investigators in discouraging unassisted pregnancies. Treatment with GH does not seem to exert any influence on either the age of onset or the prevalence of spontaneous pubertal development in Turner's syndrome. The increased percentage of spontaneous menarche is Turner's syndrome reported in the recent literature might be due to increased ascertainment by diligent screening for Turner's syndrome in girls with short stature and mild or no Turner's syndrome stigmata, even though they may be menstruating.

Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone.

Combined treatment with GH and GnRH analogs (GnRHa) has been proposed to improve final adult height in true precocious puberty, GH deficiency, and short normal subjects with early or normal timing of puberty with still controversial results. We treated 12 girls with idiopathic short stature and normal or early puberty with GH and GnRHa and followed them to adult height; 12 girls comparable for auxological and laboratory characteristics treated with GH alone served to better evaluate the efficacy of addition of GnRHa. At the start of combined treatment, the chronological age of the girls (CA; mean +/- SD) was 10.2 +/- 0.9 yr, bone age (BA) was 10.6 +/- 1.9 yr, height SD score for BA was - 1.81 +/- 0.8, PAH was 146.3 +/- 5.0 cm. PAH was significantly lower than target height (TH 152.7 +/- 3.6 cm; P < 0.005). GH was given at a dose of 0.3 mg/kg x week, sc, 6 days weekly, and GnRHa (depot-triptorelin) was given at a dose of 100 microg/kg every 21 days, im. The 12 girls were treated with GH alone at the same dose; at the start of therapy their CA was 10.7 +/- 1.0, BA was 10.1 +/- 1.4 yr, height SD score for BA was - 1.65 +/- 0.8, PAH was 145.6 +/- 4.4 cm, and TH was 155.8 +/- 4.6 cm. Pubertal Tanner stage in both groups was B2P2 or B3P3. LHRH test and pelvic ultrasound showed the beginning of puberty. The GH response to standard provocative tests was 10 g/L or more. The mean period of treatment was 4.6 +/- 1.7 yr in the group treated with GH plus GnRHa and 4.9 +/- 1.4 yr in the group treated with GH alone; both groups discontinued treatment at comparable CA and BA. Adult height was considered to be attained when growth during the preceding year was less than 1 cm, with a BA of over 15 yr. Patients in the group treated with GH plus GnRHa showed an adult height significantly higher (P < 0.001) than the pretreatment PAH (156.3 +/- 5.9 vs. 146.3 +/- 5 cm); the gain in centimeters calculated between pretreatment PAH and adult height was 10 +/- 2.9 cm, and 7 of 12 girls had a gain over 10 cm. Target height was significantly exceeded. Height SD score for BA increased from - 1.81 +/-0.8 to -0.85 +/- 1.0. The GH alone group reached an adult height higher than the pretreatment PAH (151.7 +/- 2.7 vs. 145.6 +/- 4.4 cm); the gain in final height vs. pretreatment PAH was 6.1 +/- 4.4 cm, and 5 of 12 girls did not gain more than 4 cm. TH was even not reached. The height SD score did not significantly change. No adverse effects were observed in either group. All of the girls showed good compliance and were satisfied with the results. Our experience suggests that the combination of GH and GnRHa is significantly more effective in improving adult height than GH alone in girls with idiopathic short stature, early or normal onset of puberty, and low PAH well below the third percentile and TH. As the cost-benefit of such invasive treatment must be seriously considered, further studies are needed due to the small sample of our patients as well as in other studies reported to date.

Combined treatment with gonadotropin-releasing hormone analog and growth hormone in central precocious puberty.

GnRH analogs (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). Fourteen children (10 girls and 4 boys) with idiopathic CPP whose GV during GnRHa treatment decreased below the 25th percentile for chronological age with no improvement in PAH received GH at a dose of 0.3 mg/kg week, sc, 6 days/week for 2-3 yr. Fourteen children (10 girls and 4 boys) with idiopathic CPP, matched for bone age (BA), chronological age, and duration of GnRHa treatment, who showed the same growth deceleration but refused GH treatment, served as the control group. In girls, GV as so score for BA improved from -3.4 +/- 0.5 to -2.5 +/- 0.5 after 3 yr of combined treatment; PAH significantly improved from 152.7 +/- 1.7 cm (before GnRHa) and 153.5 +/- 1.7 cm (before GnRHa and GH) to 167.1 +/- 3.0 cm after 3 yr of combined treatment (P < 0.01 vs. pretreatment with GnRHa plus GH). In boys, GV as SD score for BA remained unchanged from -2.0 +/- 1.0 to -2.2 +/- 1.2 after 2 yr of combined treatment; PAH increased from 166.6 +/- 4.8 cm (before GnRHa) and 166.2 +/- 4.9 (before GnRHa plus GH) to 171.1 +/- 6.1 cm after 2 yr (P = NS). In the control group, in girls after 6 yr of GnRHa treatment, height in SD score for BA improved from -1.0 +/- 0.3 to -0.1 +/- 0.4 (P = NS), and PAH significantly improved from 155.5 +/- 2.0 to 161.5 +/- 2.1 cm (P < 0.05); in boys after 4 yr of GnRHa treatment, height in SD score for BA improved from -1.1 +/- 0.3 to -0.3 +/- 0.4 (P = NS), and PAH changed from 172.6 +/- 3.6 to 170.3 +/- 3.6 cm (P = NS). Eight of 10 girls receiving GH plus GnRHa treatment had an actual height higher than PAH and their target height. The results of our long term study indicate that in children with CPP who show a marked decrease in GV during GnRHa treatment, GH administration remarkably improves growth velocity and predicted adult height, especially in girls.

Adult height in girls with central precocious puberty treated with gonadotropin-releasing hormone analogues and growth hormone.

GnRH analogues (GnRHa) represent the treatment of choice in central precocious puberty (CPP), because arresting pubertal development and reducing either growth velocity (GV) or bone maturation (BA) should improve adult height. However, in some patients, GV decrease is so remarkable that it impairs predicted adult height (PAH); and therefore, the addition of GH is suggested. Out of twenty subjects with idiopathic CPP (treated with GnRHa depot-triptorelin, at a dose of 100 microg/kg im every 21 days, for at least 2-3 yr), whose GV fall below the 25th percentile for chronological age, 10 received, in addition to GnRHa, GH at a dose of 0.3 mg/kg x week s.c., 6 days weekly, for 2-4 yr; and 10 matched for BA, chronological age, and duration of GnRHa treatment, who showed the same growth pattern but refused GH treatment, served to evaluate the efficacy of GH addition. No patient showed classical GH deficiency. Both groups discontinued treatment at a comparable BA (mean +/- SEM): 13.2 +/- 0.2 in GnRHa plus 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 plus GnRHa showed an adult height significantly higher (P < 0.001) than pretreatment PAH (160.6 +/- 1.3 vs. 152.7 +/- 1.7 cm). Target height (TH) was significantly exceeded. The group treated with GnRH alone reached an adult height not significantly higher than pretreatment PAH (157.1 +/- 2.5 vs. 155.5 +/- 1.9 cm). TH 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 GnRHa; whereas in patients treated with GnRHa alone, the gain was just 1.6 +/- 1.2 cm (P = 0.001). Furthermore, no side effects have been observed either on bone age progression or ovarian cyst appearance and the gynecological follow-up in the GH-treated patients (in comparison with those treated with GnRHa alone). 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 during the conventional treatment with GnRHa, especially in patients with CPP, and a decrease in GV so marked as to impair PAH, not allowing it to reach even the third centile.

Urinary pyridinium collagen cross-links predict growth performance in children with idiopathic short stature and with growth hormone (GH) deficiency treated with GH. Skeletal metabolism during GH treatment.

GH is able to promote longitudinal growth in children with GH-deficiency (GHD) and in some children with idiopathic short stature (ISS). The objectives of this study were to evaluate the predictive value of bone and collagen markers on the growth response to GH therapy in children with ISS and with GHD, and to characterize the effects of GH treatment on bone and collagen turnover in children with ISS and with GHD. Twenty prepubertal short, slowly growing, children treated with GH, 15 IU/m2 per week, were studied; of them 13 (10 males) had ISS and 7 (5 males) had GHD. An overnight 12-h urinary collection and a fasting morning blood sample were obtained at baseline, 1, 3, 6, and 12 months of treatment. Urinary levels of collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), and circulating levels of osteocalcin, intact PTH, calcitonin, procollagen type III aminoterminal propeptide (PIIINP), insulin-like growth factor-I, and alkaline phosphatase were determined. Urinary collection was also obtained from 127 healthy children (51 males) aged 6-13 yr. In children with ISS, the changes in Dpd over 1 month of GH therapy were related to the changes in height velocity (HV) over 1 yr of therapy (r = 0.67; P < 0.05); the changes in Pyd after 1 month of GH treatment were related to the changes in HV at 6 months of GH treatment (r = 0.57; P < 0.05). All the other markers evaluated were not related to the HV changes in children with ISS. In children with GHD, the changes in Pyd and in Dpd after 1 month of GH treatment were positively related to the changes in HV after 12 months of therapy (r = 0.82; P < 0.05, and r = 0.82; P < 0.05, respectively). The changes in Pyd after 1 month were also related to the HV changes after 6 months of GH (r = 0.77; P < 0.05). Positive relationships between the HV after 6 months of GH and the increases of PIIINP (r = 0.80; P < 0.05) and osteocalcin (r = 0.77; P < 0.05) after 3 months of GH therapy were observed. All patients showed urinary Dpd and Pyd excretions in the normal range. In patients with ISS, Pyd (P < 0.05), Dpd (P < 0.05), osteocalcin (P < 0.01), PIIINP (P < 0.01), and alkaline phosphatase (P < 0.01) increased longitudinally during the GH treatment and the increments reached a maximum after 3-6 months of therapy. Patients with GHD showed an increase of the same markers but the increases occurred earlier, after 1 month of GH therapy. The collagen cross-links, Pyd and Dpd, could be helpful early markers in predicting the responsiveness to GH therapy in children with ISS and with GHD. GH treatment stimulates bone and collagen metabolism.

Accuracy of fine needle aspiration biopsy of thyroid nodules in detecting malignancy in childhood: comparison with conventional clinical, laboratory, and imaging approaches.

In childhood the traditional diagnostic approach to thyroid nodules consists of clinical, laboratory, and imaging evaluations. A safe and accurate procedure is needed to promptly identify patients who require surgery. In regard to the usefulness of fine needle aspiration biopsy, the data in the literature concerning children and adolescents are scanty. The aim of this study was to evaluate and compare the diagnostic accuracies of clinical, laboratory, and imaging data collected retrospectively in a group of pediatric patients with thyroid nodules submitted to fine needle aspiration biopsy. Forty-two patients who underwent surgery for thyroid nodules, recruited in 9 Italian pediatric endocrine units, were retrospectively studied. According to histological diagnosis, they were divided into 2 groups, 22 patients with benign lesions and 20 patients with malignant lesions. From clinical records we obtained data about 1) symptoms of neck compression; 2) cervical adenopathy; 3) thyroid function, calcitonin level, and antithyroid antibody titers; 4) ultrasonography; 5) (99m)Tc scintiscanning; and 6) cytology obtained with fine needle aspiration biopsy. Patients and nodule characteristics were analyzed statistically for associations with the presence of thyroid cancer. Among clinical findings, only adenopathy was significantly higher in the group with cancer (8 of 22 benign lesions vs. 16 of 20 malignant lesions; P = 0.006). Thyroid function and antibody titers were similar in the 2 groups, whereas the serum calcitonin level was elevated only in 1 patient with malignant lesions. Among ultrasonography findings, no significant statistical difference was found between the 2 groups with regard to number, dimensions, growth progression, or hypoechogenic pattern of the nodules. Regarding scintigraphic findings, no significant difference was found between the 2 groups. However, a positive correlation (r = 0.90; P < 0.0001) was found between fine needle aspiration biopsy cytological findings and histological diagnoses. The sensitivity, specificity, and accuracy of fine needle aspiration biopsy were 95%, 86.3%, and 90.4%, respectively. A multiple regression analysis showed that only fine needle aspiration biopsy (beta coefficient = 0.963; P < 0.0001) significantly contributed to detecting malignancy (multiple r = 0.973; P < 0.0001). This study provides strong evidence that fine needle aspiration biopsy is a safe technique even in childhood and adolescence, offering the best sensitivity, specificity, and accuracy in detecting malignancy compared with conventional approaches.

Recommendations for the diagnosis and management of Turner syndrome.

Comprehensive recommendations on the diagnosis of Turner syndrome (TS) and the care of affected individuals were published in 1994. In the light of recent advances in diagnosis and treatment of TS, an international multidisciplinary workshop was convened in March 2000, in Naples, Italy, in conjunction with the Fifth International Symposium on Turner Syndrome to update these recommendations. The present paper details the outcome from this workshop. The genetics and diagnosis of the syndrome are described, and practical treatment guidelines are presented.

Clinical and roentgenographic findings in a patient with primordial microcephalic dwarfism type Caroline Crachami.

We describe a patient with primordial microcephalic dwarfism with severe intrauterine growth retardation and severe and progressive postnatal deficit in length, weight and head circumference. The patient was extroverted and sociable but mildly mentally retarded. He had marked delay of bone maturation and an enlargement of the sella turcica. This child and two previously reported patients [Boscherini et al., Eur J Pediatr 137:237-242, 1981] have many characteristics in common with Caroline Crachami, the famous "Sicilian dwarf". We think that these patients belong to a separate category of microcephalic primordial dwarfism.

Bone turnover and bone mineral density in young adult patients with panhypopituitarism before and after long-term growth hormone therapy.

We examined the effects of biosynthetic growth hormone (GH) on biochemical indices of bone turnover and on bone mineral density in a group of GH-deficient adults. Thirteen patients (eight males and five females) aged 24 +/- 5 years (range 16-35) were studied before and 12 and 24 months after GH treatment (0.1 IU.kg-1 day-1, 6 days a week). Serum levels of insulin-like growth factor I (IGF-I), calcitonin, parathyroid hormone, alkaline phosphatase, intact osteocalcin, fasting urinary hydroxyproline/creatinine ratio and bone mineral density (BMD), measured at the lumbar spine by dual-photon absorptiometry, were evaluated. After 12 months of treatment, IGF-I, alkaline phosphatase, osteocalcin and the fasting urinary hydroxyproline/creatinine ratio increased significantly. However, after 24 months of therapy, serum levels of osteocalcin decreased to pretreatment values while IGF-I, fasting urinary hydroxyproline/creatinine ratio and alkaline phosphatase remained elevated significantly. No changes were found in parathyroid hormone and calcitonin plasma levels or in BMD either after 12 or 24 months of treatment. These data demonstrate that GH, at the dosage that we used, activates bone turnover during 24 months of therapy in adults with panhypopituitarism, even if a downward trend for osteocalcin became apparent at 24 months. However, this activation in bone turnover was not accompanied by an increase in BMD. We can hypothesize that GH, at the relatively high dosage used, may stimulate osteoclastic activity to a greater extent than osteoblastic activity. It is probable that the dose of GH replacement therapy in adults plays a key role.

Analysis of the factors affecting auxological response to GnRH agonist treatment and final height outcome in girls with idiopathic central precocious puberty.

The aim of this retrospective study was to analyze the factors which affected the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP) who had been treated with the same therapy protocol (Decapeptyl Depot, 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0+/-1. 3 (S.D.) years of age) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: (a) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, P<0.01); (b) a striking deceleration of bone age (BA), revealed by the subnormal DeltaBA:Deltachronological age (CA) ratio (0.2+/-0.1); (c) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, P<0.0005). Treatment interruption was followed by an important catch-down growth, with an FH (158.4+/-5.8 cm) lower (P<0.025) than that predicted at the end of therapy. However, FH fell within the population norm and the target range in respectively 87.3 and 90% of the patients. The tallest FH was recorded in the patients who started therapy at less than 6 years of age and in those who discontinued treatment at a BA of 12.0--12.5 years. At stepwise regression analysis, FH in the whole study population was positively affected by the following independent factors: (a) height at the end of therapy (F=45.45, P<0.0001); (b) pretreatment height (F=13.91, P<0.0005); (c) treatment duration (F=8. 51, P<0.005); (d) target height (TH) (F=7.70, P<0.01). We conclude that: (i) most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; (ii) the height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; (iii) the most favorable height prognosis with respect to TH is generally observed in the subjects with the tallest height at the end of treatment and the lowest BA2:CA2 ratio, due to the important deterioration of height prognosis which frequently follows therapy interruption; (iv) FH is also significantly conditioned by both TH and treatment duration; (v) in order to strengthen the weak therapeutic effect of GnRH agonists in CTPP this treatment should be started as early as possible and discontinued at a BA of 12.0--12.5 years.

Comparison of nephelometric and hemolytic techniques for determination of antistreptolysin O antibodies.

The sensitivity of a newly devised nephelometric method for determining antistreptolysin O antibodies was compared with the hemolytic inhibition assay. Three hundred-thirty single serum samples from children with and without evidence of group A streptococcal infection were analyzed by the two techniques. The nephelometric method results correlated well with those of the reference test (concordance: r = 0.88). Furthermore, 134 pairs of acute and convalescent phase sera from patients with culture-proven GAS infection and 50 pairs from children who served as control subjects were examined. The nephelometric assay was more sensitive in detecting significant ASO antibody rises than the hemolytic assay. The automated nephelometric method appears to be a much simpler and sensitive procedure for testing ASO antibodies.

Is obesity-related insulin status the cause of blunted growth hormone secretion in Turner's syndrome?

Growth hormone (GH) secretion is reduced in girls with Turner's syndrome (TS) at pubertal age. We have recently proposed that the impairment of GH release in TS girls might be secondary to obesity. In the present study, we assessed the influence of overweight-related insulin status on spontaneous GH secretion in a group of 15 TS girls. Eighteen age-matched short normal subjects and six short obese prepubertal children were chosen as controls. Anthropometry, spontaneous GH secretion, insulin-like growth factor-I (IGF-I) serum levels, basal fasting insulin, and glucose concentrations were determined. The percentage of ideal body weight (IBW) was used as an index of nutritional status. Baseline fasting glucose (milligrams per deciliter) to insulin (milliunits per liter) ratio (G/I) was chosen as an index of insulin resistance. GH secretion was significantly lower in TS girls than in non-obese children (P < .005), whereas no significant difference was seen between TS and obese subjects. IGF-I levels were not statistically different in all groups. GH secretion was confirmed to be related to the degree of overweight (r = -.52, P < .05 in TS girls and r = -.74, P < .0001 in control group). G/I was closely related to both the percentage of IBW (r = -.59, P = .02) and GH level (r = .57, P = .03) in TS patients. These results confirm that the blunted GH secretion in TS patients is dependent on nutritional status, and suggest that insulin resistance secondary to overweight might represent the pathophysiologic link between the obesity-related metabolic status and impaired GH secretion.

Special features of Graves' disease in early childhood.

Graves' disease (GD) is extremely rare in children younger than 4 years of age, but if not recognized and treated it can seriously interfere with growth and development. We report three unrelated children, all females, in whom GD occurred before the age of 3. These children presented with goiter, exophthalmos, tachycardia, and hyperactivity. Moreover, one showed a severe psychomotor delay, and had previously undergone surgery due to craniosynostosis; the other two manifested a language delay. All had high thyroid hormones and thyrotropin receptor antibody (TRAb) serum levels that clearly indicated autoimmune hyperthyroidism. In all of them, the disease presumably had developed during the first or second year of life. No maternal history of GD was present in two. The third child was born to a mother affected with GD during pregnancy, but it is likely that her GD began to develop after 6 months of life. These children are being treated with methimazole, and treatment is still necessary after 32 months. TRAb levels were persistently high at follow-up. Psychological evaluation including language development at follow-up was appropriate for age in two children; the third child improved, but severe mental retardation is still evident. GD assessment in early childhood also needs to focus on psychological evaluation. Pediatricians should be aware of the possibility of permanent brain damage and craniosynostosis due to hyperthyroidism in infancy.

Italian cross-sectional growth charts for height, weight and BMI (6-20 y).

OBJECTIVE: To trace growth charts for height, weight and body mass index (BMI) that apply to the whole Italian population. Different charts were drawn for central-north and south Italy since children in central-north regions are known to be taller and leaner. DESIGN: Cross-sectional study. SETTING: A sample of schoolchildren covering 16 of the 20 Italian regions, with data collected between 1994 and 2000. SUBJECTS: A total of 27 421 girls and 27 374 boys, aged 6-20 y. METHODS: Height and weight were measured using portable Harpenden stadiometers and properly calibrated scales, respectively. SIEDP references are presented both as centiles and as LMS curves for the calculation of standard deviation scores. According to International Obesity Task Force, SIEDP charts for BMI include the limits for overweight and obesity, ie the centiles having, at 18 y of age, the value of 25 and 30 kg/m(2), respectively. RESULTS: The comparison between SIEDP and Tanner et al's charts for height, still in use among most Italian paediatricians, shows that before puberty Italian children are 2-4 cm taller than their English peers. Because of these differences, Tanner's charts fail to detect, when applied to Italian children, 50-90% of short children aged 6-11 y, ie with stature below the 3rd centile of their reference population. Rolland-Cachera et al's centiles for BMI are lower than those of SIEDP standards, mainly during adolescence (up to 6.6 kg/m(2) for the 97th centile), and apply poorly to Italian children. The prevalence of overweight is 27 (boys) and 19% (girls) in south Italy vs 17 (boys) and 10% (girls) in central-north Italy. CONCLUSIONS: These references intend to supply Italian paediatricians with a tool that avoids the use of outdated or inadequate charts, and thus should be suitable for monitoring their patients' growth. SPONSORSHIP: Italian Society for Pediatric Endocrinology and Diabetes (SIEDP).

Clustering of autoimmune thyroid diseases in children and adolescents: a study of 66 families.

Autoimmune thyroid diseases (AITD) are known to be clustered in families, but to what extent this occurs in childhood and adolescence is not well defined. In order to establish the prevalence of AITD in the siblings of affected children and adolescents, we examined 73 siblings from 66 families selected on the basis of a pediatric index patient. Sixty-six families, including a total of 146 offspring, were selected on the basis of diagnosis of chronic lymphocytic thyroiditis (CLT) (n = 55) or Graves' disease (GD) (n = 11). Among the 73 siblings examined, 20 new cases of CLT (27%) were detected. L-Thyroxine therapy was required in 4/20. History of AITD was recorded in 24/66 mothers (36%), and in two fathers. Overall in these families, considering both the index patients and the new patients, 86/141 (61%) children and adolescents were affected with AITD, with a female/male ratio of 3.3:1. Our study confirms that AITD clusters in families with a high prevalence in the siblings of affected children and adolescents. These children should be followed in order to avoid undiagnosed hypothyroidism. Prospective studies are warranted to identify predictive factors for overt thyroid disease.

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.

When to stop GnRH analog therapy: the experience of the Italian Study Group for Physiopathology of Puberty.

Data reported in this study have been recently published elsewhere. The authors retrospectively analyzed the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP), who had been treated with the same therapy protocol (Decapeptyl Depot at the dose of 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0 +/- 1.3 yr) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: A) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, p<0.01); B) a striking deceleration of BA, revealed by the subnormal deltaBA:deltaCA ratio (0.2 +/- 0.1); C) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, p<0.0005). Treatment interruption was followed by notable catchdown growth, with FH (158.4 +/- 5.8 cm) lower (p < 0.025) with respect to that predicted at the end of therapy. However FH fell within the population norm and the target range in 87.3% and 90% of patients, respectively. The tallest FH was recorded in the patients who discontinued treatment at a BA of 12.0-12.5 years. We conclude that: 1) Most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; 2) The height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; 3) The most favorable height prognosis with respect to target height (TH) is generally observed in the patients with the tallest H2 and the lowest BA2:CA2 ratio, due to the notable deterioration of height prognosis which frequently follows therapy interruption; 4) In order to strengthen the weak therapeutic effect of GnRH agonists in CTPP, this treatment should be discontinued at a BA of 12-12.5 years.

End results in central precocious puberty with GnRH analog treatment: the data of the Italian Study Group for Physiopathology of Puberty.

We report some end results with GnRH agonist (GnRHa) treatment in central precocious puberty (CPP), in terms of final height (FH), ovarian function, peak bone mass, body composition and psychological problems. The two studies reported (Study I and II) are part of the activity of the Italian Study Group for Physiopathology of Puberty. Study L Growth data were analyzed of three groups of patients: treated with i.n. spray buserelin, i.m. triptorelin and untreated. Both GnRHa administration modes were effective in arresting pubertal development and all girls had complete recovery of the reproductive axis after therapy. Treated patients showed an improvement in final height in comparison with untreated patients and compared to predicted height at the start of treatment with both agonist treatments. However, patients treated with the long-acting slow release preparation had a better improvement in adult height and reached or exceeded the genetic height potential. Study II. In a retrospective evaluation of the outcome in 71 girls with idiopathic CPP treated with triptorelin, we found that FH fell within the population norm and the target range in 87.3% and 90% of the patients respectively. The tallest FH was recorded in the patients who started therapy at less than 6 years of age and in those who discontinued treatment at a bone age of 12.0-12.5 yr. Finally, we and other groups have recently found normal values of bone mineral density in girls at the end of GnRHa treatment in the great majority of patients.

Factors influencing final/near-final height in 12 boys with central precocious puberty treated with gonadotrophin-releasing hormone agonists. Italian Study Group of Physiopathology of Puberty.

Gonadotrophin-releasing hormone agonists (GnRHa) have been demonstrated as the therapy of choice for central precocious puberty (CPP). Few studies have provided male patients' adult height data. In our multicenter study we evaluated long-term effects of different GnRHa preparations and final/near-final height (FH) in 12 boys with CPP and analyzed the factors influencing FH. Patients' mean chronological age at the time of diagnosis was 7.6 +/- 0.9 yr. Three patients were treated only with triptorelin at a mean dose of 90 microg/kg i.m. every 28 days. Nine patients initially received buserelin (at a mean initial dose of 53.4 microg/kg/day i.n. divided into 3-6 equal doses) or buserelin (at a mean dose of 36.7 microg/kg/day s.c.) and were subsequently switched to triptorelin. The GnRHa therapy was continued for 4.1 +/- 0.6 yr (range 2.9-5.4). The mean predicted adult height increased from 169.9 +/- 4.2 cm at diagnosis to 180.7 +/- 6.0 cm at the end of treatment. Mean FH was 176.1 +/- 6.1 cm (170.1-190.7), corresponding to mean SDS(CA) 0.4 +/- 0.8 (-0.6/2.5), mean SDSBA 0.2 +/- 0.9 (-0.6/2.4) and mean corrected SDS for target height of 0.4 +/- 0.6 (-0.8/1.2). Multiple regression analysis revealed that FH was mainly influenced by target height and height at discontinuation of GnRHa therapy. The present data indicate that GnRHa therapy significantly improves growth prognosis in boys with CPP and fully restores genetic height potential.