Incidence and prevalence rate estimation of GH treatment exposure in Piedmont pediatric population in the years 2002-2004: Data from the GH Registry.

OBJECTIVE: The aim of this study is to estimate the annual incidence and prevalence rate of the GH treatment exposure in patients under the age of 18 treated for hypopituitarism or isolated GH deficiency (GHD) in Piedmont, during the period January 1, 2002 to December 31, 2004. METHODS: The selection criteria for recombinant human GH (rhGH) treatment in childhood were approved by the Ministry of Health in Italy in the yr 1998. The present analysis is based on data from the Registry of subjects receiving GH therapy (GH Registry) made up of the 918 pediatric patients (age <18 yr) with a diagnosis of GHD (excluding Prader-Willi and Turner syndromes and other conditions), diagnosed in the period January 1, 2002 - December 31, 2004. The case series has been described as regards the number of cases per year of diagnosis; the prevalence and incidence rates, calculated per 10,000 (per ten thousand) inhabitants, are given for each year of the study period. RESULTS: The prevalence rate increases slightly from 8.62 per thousand in 2002 to 9.44 per thousand in 2004 and the incidence rates estimated were 2.49 per ten thousand, 1.86 per ten thousand and 1.97 per ten thousand in the yr 2002, 2003 and 2004, respectively. CONCLUSION: The Piedmont GH Registry represents the first database available in Italy and could set an example for the other Italian regions as well.

Retesting young adults with childhood-onset growth hormone (GH) deficiency with GH-releasing-hormone-plus-arginine test.

Within an appropriate clinical context, severe GH deficiency (GHD) in adults has to be defined biochemically by provocative testing of GH secretion. Patients with childhood-onset GHD need retesting in late adolescence or young adulthood to verify whether they have to continue recombinant human GH treatment. GHRH + arginine (GHRH+ARG) is the most reliable alternative to the insulin-induced hypoglycemia test (ITT) as a provocative test for the diagnosis of GHD in adulthood, provided that appropriate cut-off limits are assumed (normal limits, 16.5 microg/L as 3rd and 9.0 microg/L as 1st centile). We studied the GH response to a single GHRH (1 microg/kg iv) + ARG (0.5 g/kg iv) test in 62 young patients who had undergone GH replacement in childhood, based on the following diagnosis: 1) organic hypopituitarism with GHD (oGHD) In = 18: 15 male (M), 3 female (F); age, 26.8+/-2.2 yr; GH peak < 10 microg/L after two classical tests]; 2) idiopathic isolated GHD (iGHD) [n = 23 (15 M, 8 F); age, 23.0+/-1.5 yr; GH peak < 10 microg/L after two classical tests]; and 3) GH neurosecretory dysfunction (GHNSD) [n = 21 (10 M, 11 F); age, 25.1+/-1.6 yr; GH peak > 10 microg/L after classical test but mGHc < 3 microg/L]. The GH responses to GHRH+ARG in these groups were also compared with that recorded in a group of age-matched normal subjects (NS) [n = 48 (20 M, 28 F); age, 27.7+/-0.8 yr]. Insulin-like growth factor I levels in oGHD subjects (61.5+/-13.7 microg/L) were lower (P < 0.001) than those in iGHD subjects (117.2+/-13.1 microg/L); the latter were lower than those in GHNSD subjects (210.2+/-12.9 microg/L), which, in turn, were similar to those in NS (220.9+/-7.1 microg/L). The mean GH peak after GHRH+ARG in oGHD (2.8+/-0.8 microg/L) was lower (P < 0.001) than that in iGHD (18.6+/-4.7 microg/L), which, in turn, was clearly lower (P < 0.001) than that in GHNSD (31.3+/-1.6 microg/L). The GH response in GHNSD was lower than that in NS (65.9+/-5.5 microg/L), but this difference did not attain statistical significance. With respect to the 3rd centile limit of GH response in young adults (i.e. 16.5 microg/L), retesting confirmed GHD in all oGHD, in 65.2% of iGHD, and in none of the GHNSD subjects. With respect to the 1st centile limit of GH response (i.e. 9.0 microg/L), retesting demonstrated severe GHD in 94% oGHD and in 52.1% of iGHD. All oGHD and iGHD with GH peak after GHRH+ARG lower than 9 microg/L had also GH peak lower than 3 microg/L after ITT. In the patients in whom GHD was confirmed by retesting, the mean GH peak after GHRH+ARG was higher than that after ITT (3.4+/-0.5 vs. 1.9+/-0.4). In conclusion, given appropriate cut-off limits, GHRH+ARG is as reliable as ITT for retesting patients who had undergone GH treatment in childhood. Among these patients, severe GHD in adulthood is generally confirmed in oGHD, is frequent in iGHD, but never occurs in GHNSD.

Chromosomal aberrations, sister chromatid exchanges and high frequency cells in young patients with neurofibromatosis 1 (NF1).

Chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and high frequency cells (HFCs) have been assessed in peripheral blood lymphocytes of 10 neurofibromatosis (NF1) patients and 10 healthy controls. In both groups, the spontaneous rates and the induced (bleomycin for CA and MMC for SCE) frequencies were analyzed. No differences between cells from NF1 patients and controls were observed with respect to spontaneous or bleomycin induced CA. Spontaneous or MMC induced SCE frequencies were also similar in NF1 patients and controls. HFCs, on the contrary, were statistically lower in NF1 patients.

A patient with early puberty associated with Chiari 1 malformation.

A boy is described with early puberty and Chiari 1 malformation. It is not known whether there was an etiological relationship between these two conditions, or whether they were coincidental. This report emphasizes the utility of MRI when early puberty is diagnosed, particularly in males.

Longitudinal distance standards of fetal growth. Intrauterine and Infant Longitudinal Growth Study: IILGS.

BACKGROUND: Most ultrasonographic fetal growth norms are derived from cross-sectional data or from longitudinal data treated as coming from cross-sectional studies, although only longitudinal models may detect particular aspects of fetal growth shape, such as peak of growth velocity. MATERIALS AND METHODS: The sample included 238 singleton normal pregnancies. All the fetal traits under study (biparietal diameter, occipito-frontal diameter, head circumference, femur diaphysis length and abdomen circumference) were measured according to the classical ultrasound techniques by highly trained operators. Individual growth profiles (made up of 5 to 9 measures) were taken at regular intervals between the 12th and the 40th week. Growth norms were traced by means of a two-stage linear model: (I) a 3-constant fetal growth function was fitted to each individual growth profile, (II) growth centiles were based upon the weighted mean and covariance matrix of the individual growth constants. RESULTS: Fetal growth curves show a sigmoid shape with a maximum slope (i.e. a peak growth velocity) which occurs earlier for head diameters (about 18 weeks), later for femur diaphysis length (20 weeks) and abdomen circumference (22 weeks). During intrauterine growth, all traits show a progressive increase in interindividual variability, which is more prominent for abdomen circumference. CONCLUSION: The mathematical model applied to a large sample of growth profiles provided a satisfactory description of the individual fetal development and its biological variability, and allowed the construction of longitudinal distance standards useful for clinical purposes.

[Neonatal anthropometry and early differentiations in embryo-fetal growth]. / Dimensioni neonatali e differenziazione precoce della crescita embrio-fetale.

It is well known that the biologic variability in fetal size increases as pregnancy advances, although the embryonal and early fetal growth patterns as well as how early and how much the genetic, hormonal and environmental variables play a role in its modulation are still debated. It is accepted that growth in the first trimester of pregnancy is relatively uniform, with a minimal biologic variability; this variability may be underestimated, because the transversal studies do not permit the identification of the growth pattern. The aim of this work is to evaluate, by means of a longitudinal study, the time of embryo-fetal growth differentiation related at neonatal anthropometric measurements. We evaluated 238 neonates (123 female; 115 male) delivered at term after low risk, uncomplicated pregnancies. The subjects were divided into three tertles (low, mid and high) according to birth weight, length and head circumference. For each tertle, distance curves, velocity curves, and rate of increase were calculated by using respectively fetal abdominal circumference (for birth weight), fetal femural length (for neonatal length) and fetal head circumference (for neonatal circumference). The distance curves showed clear differences among the tertles only in the second period of pregnancy, whereas the velocity curves showed clear differences among tertles already in the first 12 weeks. The value of growth rates were similar for all the variables during the entire time considered. This study shows that the anthropometric differences between newborn subgroups exist already at the end of the first trimester of pregnancy and, in physiological conditions, until the end of pregnancy. The anthropometric differences observed early in our study, at twelve weeks of gestational age, are still present at the end of pregnancy and let us suppose a very early expression of the genetic potential for individual growth.

Variation of bone age progression in healthy children.

Bone age assessments were related to auxological variables in 407 Italian boys, between 7 and 12 years of age, in order to elucidate the factors that affect the rate of skeletal maturation and to examine the possibility of using measures of skeletal maturation of evaluate individual patients. Using the radius-ulna-short bones (RUS) method of assessment, bone age velocity was greater in the Italian boys than for the UK reference standards, although there was considerable interindividual dispersion around the mean. Bone age velocity and height velocity were poorly correlated, and there was little correlation between skeletal and pubertal maturation. There was a slight positive correlation between bone age velocity and height SDS and between bone age velocity and body mass index. Bone age estimations using RUS were greater than those obtained using the carpus. In conclusion, the marked interindividual deviation in measured bone ages makes it difficult to relate data on an individual basis to other measures of growth and maturation

The GH-releasing effect of Hexarelin, a synthetic hexapeptide, in newborns is lower than in young adults.

The aim of the present study was to verify the GH-releasing effect of Hexarelin, a synthetic hexapeptide, in newborns who are known to have GH hypersecretion likely due to hyperactivity of GHRH-secreting neurons while somatostatinergic activity seems not fully operative. We studied in 6 newborns (NB, 2.5 +/- 2.1 days), 12 prepubertal children (PC, 9.8 +/- 0.45 yr) and 12 young adults (YA, 28.2 +/- 0.2 yr) the GH response to Hexarelin (HEX, 2 micrograms/kg i.v.) compared to that observed after GHRH (1 microgram/kg i.v.) in 6 NB (4.2 +/- 0.4 days), 12 PC (9.9 +/- 0.6 yr) and 12 YA (31.0 +/- 1.3 yr). GH levels were assayed basally and 30 and 60 min after drug administration. In NB, mean (+/- SEM) basal GH levels were higher while IGF-I levels were lower than those recorded in PC and YA (GH: 34.8 +/- 1.9 vs 2.8 +/- 0.4 vs 1.4 +/- 0.4 micrograms/l, p < 0.0006; IGF-I: 36.3 +/- 1.9 vs 152.0 +/- 11.5 vs 175.8 +/- 15.3 micrograms/l, p < 0.0007); in the last two groups GH and IGF-I levels were similar. The mean delta GH peak after HEX in NB (32.8 +/- 4.7 micrograms/l) was similar to that in PC (34.6 +/- 4.3 micrograms/l) and lower (p < 0.01) than that in YA (56.2 +/- 7.4 micrograms/l). Delta GH peak after GHRH in NB (60.1 +/- 1.5) was higher than those in PC and YA (20.8 +/- 4.8 and 22.8 +/- 3.4 micrograms/l) (p < 0.005 and < 0.002, respectively). In NB, the GH response to HEX was lower (p < 0.005) than to GHRH while in PC and YA the somatotrope response to HEX was higher (p < 0.03 and 0.0004, respectively) than to GHRH. These data demonstrate that the GH-releasing effect of Hexarelin undergoes age-dependent variation being lower in newborns than in young adults, opposite to that observed after GHRH administration. The evidence that Hexarelin releases less GH than GHRH in newborns but not in prepubertal children and in young adults makes unlikely the hypothesis that the GH-releasing effect of this hexapeptide is mediated via endogenous GHRH release.

Is the persistence of isolated GH deficiency in adulthood predicted by anatomical hypothalamic-pituitary alterations?

The aim of this study was to verify the persistence in adulthood of GH deficiency diagnosed in childhood and treated with hGH in childhood and to study whether anatomical hypothalamic-pituitary alterations evaluated by magnetic resonance (MR) imaging could predict it. To this goal, in six GHD adults (3 males and 3 females aged 17.2-24.5 yr, BMI 21.8 +/- 1.3), we studied anterior pituitary hormone response to GHRH (1 microgram/kg iv)+pyridostigmine (120 mg po)+ GnRH (100 micrograms iv) +TRH (400 micrograms iv)+hCRH (100 micrograms iv) as well as brain MR imaging. In childhood, the diagnosis of severe isolated GHD had been done based on auxological findings as well as on GH response < 7 micrograms/L after two classical provocative stimuli. In the present study, hormonal responses showed the persistence of severe isolated GHD in 4 out of 6 patients (peak, mean +/- SEM: 3.8 +/- 0.6, range 2.6-4.8 micrograms/L). In these patients, IGF-I levels were found low or low-normal. In other 2 patients, a clear GH response to stimulation (peak: 51.3 and 43.0 micrograms/L, respectively) together with normal IGF-I levels were found. No other anterior pituitary hormone deficiency was present in all subjects. MR imaging showed pituitary hypoplasia in all patients with persistent GHD; in 2 out of them, pituitary stalk interruption and ectopic neurohypophysis was also present. On the other hand, MR imaging showed normal hypothalamo-pituitary morphology in the 2 subjects with normal somatotrope response. In conclusion, our present data indicate that testing with a potent stimulus such as GHRH+pyridostigmine is a reliable method to assess the persistence of GH deficiency which associates with anatomical hypothalamic-pituitary alterations at the MR imaging. Patients with transient GH deficiency in childhood and normal pituitary GH reserve in adulthood have normal hypothalamic-pituitary MR imaging.

Main problems associated with bone age and maturity evaluation.

In scientific papers, skeletal maturation-expressed as bone maturity scores or bone age-is often used as a quantifiable variable similar to height or weight. This paper discusses whether this approach is appropriate. The questions addressed are whether skeletal maturation can be measured on a quantitative scale, whether its use is appropriate in computing, and what the 'numbers' used represent. Reference will be made mainly to the Tanner-Whitehouse method, which, in the opinion of the authors, has been the most reliable method of assessment to date. Many of the remarks made in this paper may be extended to other methods of assessment, and have been stressed by Tanner himself. The authors are aware that, in the future, some of the remarks could be made redundant by the development of more detailed definitions of bone maturation. This is becoming feasible with the advent of expert systems for the automatic recognition of different stages of bone maturation.

Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, before and during puberty.

The objective of this study was to verify the GH-releasing activity of a synthetic hexapeptide, hexarelin (HEX), before and during puberty. Ninety-six children (54 boys and 42 girls, aged 4.1-17.4 yr) were studied. Fifty-two of the children were prepubertal, and the other 44 were in pubertal stage II-IV. The GH response to 2 micrograms/kg HEX, iv (n = 56), was higher (P < 0.001) than that induced by 1 microgram/kg GHRH, iv (n = 33). The iv dose of 2.0 micrograms/kg HEX induced a greater GH increase (P < 0.02) than the 1.0 microgram/kg dose. The GH-releasing effect of 10 mg HEX, orally, was greater (P < 0.03) than that of 1.0 microgram/kg GHRH, iv (n = 7). The iv dose of 2 micrograms/kg HEX elicited an increase in GH levels that was higher in pubertal children than in prepubertal children (77.5 +/- 8.5 vs. 39.4 +/- 4.4 micrograms/L; P < 0.001). Before puberty, there was no sex-dependent difference in the GH response to HEX. It increased during puberty (P < 0.05 and P < 0.002 for boys and girls, respectively), when it was higher (P < 0.05) in girls than in boys. In contrast, GH responses to GHRH were not related to sex differences and/or puberty. In conclusion, HEX is a potent and reproducible stimulus of GH secretion in children. The effect of HEX increases in puberty, with girls showing a more marked GH response.

Growth velocity monitoring of the efficacy of different therapeutic protocols in a group of thalassaemic children.

Since intensive chelating therapy for thalassaemic children was introduced, growth rates appear to have diminished. To investigate what factors were responsible we compared velocities of growth in length over a period of 1 year between groups distinguished by different strategies of treatment. Forty-two thalassaemic patients, 30 males aged 4-12 years, and 12 females, 4-10 years old, were assigned from their current treatment into subgroups based upon blood ferritin levels, daily dose of desferrioxamine and urinary zinc levels. CONCLUSION The results confirm that a reduction in desferrioxamine results in greater growth. If blood ferritin is low, the change effect may be greater. Secondly, any zinc deficiency should be treated. The changes in treatment convert a growth velocity of -2 to -3 SDS to a velocity of about -1 SDS.

[Magnetic resonance in the study of patients of short stature of the hypothalamo-hypophyseal origin. Report on 29 cases]. / La risonanza magnetica nello studio dei pazienti con bassa statura di origine ipotalamo-ipofisaria. Rapporto su 29 casi.

Although growth hormone (GH) deficiency is a very common cause of short stature, many cases are still diagnosed as idiopathic. Magnetic Resonance Imaging (MRI), more clearly than CT, reveals the anatomy of the hypothalamic-hypophyseal region and of the possible alterations (pituitary hypoplasia, interruption of the stalk) causing hormonal deficit. Twenty-nine patients with short stature underwent MRI examinations of the hypothalamic-pituitary region to assess the significance of the correlation between hormonal test and MR patterns. Five patients had normal variants of short stature (NVSS), 7 had multiple pituitary hormone defects (MPHD) and 17 had isolated growth hormone deficiency (IGHD). In patients with MPHD or with severe isolated growth hormone deficit MRI shows interruption of the pituitary stalk with ectopy of the neurohypophysis or a mass. In patients with less severe IGHD and in NVSS, MRI demonstrates a normal pituitary region or a slightly hypoplastic gland, the neurohypophysis being normally situated. MRI may provide an ethiological classification in short stature patients. Typical MR patterns can be demonstrated in cases of dwarfism secondary to a mass in the hypothalamic-pituitary region or to morphological changes of the pituitary stalk, while in transient GH deficit no anatomical abnormalities are observed.

Turner's syndrome in Italy: familial characteristics, neonatal data, standards for birth weight and for height and weight from infancy to adulthood.

In 1990, the Italian Study Group for Turner's Syndrome (ISGTS) undertook a nationwide survey, involving the retrospective collection of cross-sectional data and longitudinal growth profiles of 772 girls with Turner's syndrome born between 1950 and 1990. The study was carried out in 29 pediatric endocrinological centers. In this first report, the familial characteristics and neonatal data of Turner girls are described, compared to those of the general population, and related to postnatal somatic development. Furthermore, charts for birth weight and growth standards for height and weight from infancy to adulthood are presented (these are the first charts based on a large sample from the Mediterranean area). The main findings were: (1) incidence of Turner births increases with parental age or parity; (2) most of the neonates are small for dates; (3) girls with normal birth weight tend to be both taller and heavier than girls with low birth weight during the whole growth period; and (4) a 10-cm difference in midparental height leads to a 6.5-cm difference in adult stature.

Final height in sexually precocious girls after therapy with an intranasal analogue of gonadotrophin-releasing hormone (buserelin).

Twenty-two girls affected by sexual precocity with impaired final height prognosis were followed until they achieved final height. Twelve of them were treated with an intranasal (D-Ser6)-gonadotrophin-releasing hormone (GnRH) analogue (buserelin) administered at a mean dose of 25 micrograms/kg/day (range 20-32) for a mean period of 14 months (range 8-18). Ten girls refused treatment. Mean final height of the treated girls was 157.3 +/- 8.2 cm, significantly (p = 0.03) higher than the 149.7 +/- 5.5 cm of untreated patients. Treated girls surpassed midparental height (+1.7 cm) while untreated girls reached the lower part of target zone (-3.5 cm). Our data suggest that intranasal buserelin treatment preserves final height in girls with sexual precocity and initially impaired height prognosis.

Dose-dependent effects of deflazacort and prednisone on growth and skeletal maturation.

Deflazacort (DFZ), a new glucocorticoid which has recently become available, is expected to have less negative effects on growth and skeletal maturation than conventional steroids, in children treated long term. To verify this hypothesis, a multicentre trial was organized to evaluate the effects of DFZ vs prednisone (PDN) on statural growth and skeletal maturation in a group of prepubertal children requiring glucocorticoid therapy for at least 6 months/year. The results of an analysis of 55 children (aged 3-12 years, 24 with connective tissue disease and 31 with kidney glomerular disorders) treated randomly with either DFZ (31 patients) or PDN (24 patients) and followed for a mean period of about 22 months (16 months under steroid therapy) are presented. The observation period was split up into the following phases according to dose and administration regimen: daily, high-dose therapy; alternate-day, high-dose therapy; low-dose therapy; suspension of treatment. The height, statural age, skeletal age and body weight velocities (i.e. the increase/year) were considered. In spite of large intra-individual and inter-individual variability, the results suggest that DFZ has a lower negative impact on indicators of growth. During high-dose daily administration, the height velocity tended to be lower in the PDN group and the impairment of skeletal maturity was significantly less for DFZ than for PDN. During an alternate-day regimen, height velocity was slightly higher in the PDN group and skeletal age velocity was higher in the DFZ group. It seems that steroid effects on statural growth and bone maturation occur in parallel.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance and the diagnosis of short stature of hypothalamic-hypophyseal origin.

Magnetic resonance imaging was performed in 23 patients with short stature (7 had multiple pituitary hormone defect, 11 had isolated growth hormone deficiency and 5 had normal variant short stature) to investigate if there is a relation between magnetic resonance findings and results of endocrine tests. Magnetic resonance imaging of patients with multiple pituitary hormone deficiency or with serious isolated growth hormone deficiency (growth hormone < 3 micrograms/l) revealed an interrupted pituitary stalk and ectopic neurohypophysis or a mass. In patients with less serious isolated growth hormone deficiency (growth hormone > 3 micrograms/l) or with normal variant short stature, the technique revealed a normal or hypoplastic hypophysis. Magnetic resonance appears to be a useful second-level diagnostic tool in defining the type of alteration in growth defects of endocrine origin.