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Biomedical subjects

P Pirazzoli

Publications and source records attributed to P Pirazzoli.

At least 19 recordsLinked to original sources
PubMed2006

Functional studies of two novel and two rare mutations in the 21-hydroxylase gene.

Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency and presents with a wide spectrum of clinical manifestations, from prenatal virilization and salt-wasting in the neonatal period to precocious pubarche and late-onset hyperandrogenic symptoms during adulthood. A limited number of mutations account for the majority of all mutated alleles, but a growing number of rare mutations are responsible for the disease in some patients. By sequence analysis of the CYP21A2 gene, we identified two novel (I171N and L446P) and two rare (R341P and R426H) mutations in seven Italian patients with CAH. One of the patients was diagnosed with mild non-classical CAH and was found to be a compound heterozygote (I171N/V281L), while all other patients showed severe phenotypes with latent or manifest salt-wasting. The residual activities measured after expression of the four mutant enzymes in COS-1 cells were all below 1% towards both natural substrates (17-OH-progesterone and progesterone) compared with the wild-type protein. All four mutations are, thus, associated with severe enzyme deficiency and are predicted to cause classic CAH if found in trans with other mutations causing severe enzyme deficiency.

17-alpha-Hydroxyprogesterone↗
PubMed2005

Final height in a patient with Laron syndrome after long-term therapy with rhlGF-I and short-term therapy with LHRH-analogue and oxandrolone during puberty.

OBJECTIVE: To report our experience on long-term treatment with recombinant-human-IGF-I (rhIGF-I) of a female patient with Laron syndrome (mutation G223G in the GH receptor gene), who received short-term treatment (1 yr) with LHRH analogue at the start of puberty and subsequently with oxandrolone. CASE REPORT: The patient started IGF-I therapy (dose 40 microg/kg bid for 9 months, 80 microg/kg bid until 13.7 yr of age and 120 microg/kg bid thereafter) when she was 7.6 yr old (height -6 sds), and was treated for 9.4 yr until final height (cm 129.7; -5.5 sds). At first signs of puberty (age 12.7 yr; height 116.3; -5.3 sds), LHRH analogue was started (3.75 mg/28 days) and bone age progressed by 6 months in the 12-month period. Growth velocity decreased in the 6-12th month of combined treatment (0.9 cm/6 months), and treatment was suspended. At age 14.8 (height 124.5; -6.6 sds), oxandrolone was added (0.1 mg/kg/day), but after 12 months (height 128 cm; -5.7 sds) bone age increased from 11.5 to 13.5 yr and the drug was stopped. No side effects occurred during the various treatments. Body segments progressed harmonically: there was a tendency towards improvement in the upper to lower body segment ratio and in cranial growth. Only biiliac diameter did not increase during LHRH treatment. During the 9-yr period, body mass index (BMI), subscapular and triceps skinfold centiles did not show any significant variations. CONCLUSIONS: Our patient with Laron syndrome after long-term treatment showed a final result below the initial expectations, confirming that IGF-I used with the present schedule is less effective than GH in GH-deficient patients. LHRH analogue therapy at puberty was associated with a slower bone age maturation but with an almost complete arrest of growth. On the contrary, oxandrolone sustained growth but caused an excessive maturation of bone age. Other strategies are necessary to improve final height in these patients.

Age Determination by Skeleton↗
PubMed2004

Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency and presents a wide spectrum of clinical manifestations from a severe classical form to a milder late-onset form with a variable severity of hyperandrogenic symptoms. A limited number of mutations account for the majority of the mutated alleles, but additional rare mutations are responsible for the symptoms in some patients. By CYP21 gene analysis, we identified a chimeric CYP21P/CYP21 gene with the fusion breakpoint downstream of the common P30L mutation as well as a GCC to ACC change at codon 15 (A15T) in two subjects with classical CAH and a CCC to TCC change at codon 482 (P482S) in seven subjects referred for nonclassical CAH, precocious pubarche, menstrual irregularities, or hypertrichosis. The two amino acid substitutions were reconstructed by in vitro site-directed mutagenesis, the proteins were transiently expressed in COS-1 cells, and enzyme activity toward the two natural substrates (17-hydroxyprogesterone and progesterone) was determined. The A15T mutant exhibited no significant difference in activity compared with the wild-type protein, whereas the P482S mutation reduced enzyme activity to 70% of normal. This impairment of activity was confirmed in vivo by detection of heterozygote carriers by the ACTH test.

Adolescent↗
PubMed2003

Gonadal function and pubertal development after treatment of a childhood malignancy.

As survival rates for childhood cancer have improved, the importance of assessing gonadal dysfunction caused by alkylating agents and radiotherapy in children treated for cancer has increased. Infertility is the major long-term side effect of chemotherapy (CT) in males, whereas Leydig cell function is less affected. Our studies confirm that prepuberty does not protect the male gonad from the late effects of CT and that protocols less gonadal-lesive (such as ABVD regimens) should be preferred. Ovaries are less affected, but early depletion of follicles and premature menopause may occur. High-dose busulfan conditioning regimens cause ovarian failure in young females. The role of gonadal irradiation is discussed: high dosages (>2000 cGy) provoke sterility, impaired testosterone secretion in males and estradiol release in females. High dosage hypothalamic-pituitary irradiation causes delayed puberty and hypogonadism in males and females, whereas lower dosages may be associated with early puberty, particularly in females.

Antineoplastic Agents↗
PubMed2000

CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia-Romagna region.

OBJECTIVES: We have genotyped the patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency identified from March 1980 to December 1997 through a combined program of neonatal screening and case survey in the Emilia-Romagna Region (Italy). We have also analysed retrospectively the possible advantages of genotypical neonatal classification. DESIGN: A 'phase A' of screening and clinical monitoring (March 1980-September 1983 and March 1991-December 1997) and a 'phase B' of clinical monitoring only (October 1983-February 1991) were taken into account. PATIENTS: A total of 61 patients (20 salt wasting, nine simple virilizing and 32 nonclassical forms) were genotyped, HLA typed and hormonally tested to understand better the genotype/phenotype relationship and the epidemiology and geographical distribution of associated mutations. The fully genotyped patients were classified into four mutation groups according to the degree of enzymatic activity ('null' and 'A' to 'C'). RESULT: The most frequent genotype alterations were deletion (24.1% classical, 3.3% nonclassical forms), large gene conversion (9.2% classical, 1.7% nonclassical forms), In2 splice (27.7% classical, 15.0% nonclassical forms), I172N (5.5% classical, 10.0% nonclassical forms), V281L (3.7% classical, 43.3% nonclassical forms), P453S (5.0% nonclassical forms). A significant difference (chi2 = 5.101; P < 0.025) in the distribution of classical genotypes was found in Romagna (south-east; incidence 1 : 7437 newborns) compared to Emilia (north-west; incidence 1 : 25 090 newborns). Two putative new mutations were found in our population. Little discrepancy was found between genotype and phenotype. CONCLUSIONS: The high frequency of genotypes 'null' or 'A' in the 'phase A' vs. 'phase B' of our study confirms the usefulness of neonatal screening in preventing the death of male patients with salt wasting forms. The substantial similarity in the mutational spectrum of classical forms found in our study, based on the detection of all the classical patients of a specific area, leads us to believe that the distribution of mutations is due to the inherent characteristics of the gene locus, and that regional effects play a minor role. Prompt neonatal genotyping can be of valuable diagnostic assistance in neonatal screening for the confirmation of the diagnosis in newborns with moderately elevated 17 hydroxyprogesterone levels.

Adolescent↗
PubMed1999

Birth weight affects final height in patients treated for growth hormone deficiency.

OBJECTIVE: Birth weight influences both postnatal growth and the initial response to GH therapy in GH-deficient subjects, but its relationship to final height is uncertain. Therefore, we examined final height results in a group of subjects treated for GH deficiency who were born small, appropriate or large for gestational age (GA). DESIGN: Retrospective study. PATIENTS: 108 GH-treated patients (age at diagnosis 11.1 +/- 2.0 years) affected by idiopathic and isolated GH deficiency (peak < 8 microg/l after pharmacological and/or nocturnal mean GH concentration </= 3.3 microg/l) were examined. Twenty-four had a birth weight < 3rd centile (2300 g +/- 268 - small for GA), 77 between the 3rd and 90th centile (3216 g +/- 317: appropriate for GA) and 7 above the 90th centile (4193 g +/- 143: large for GA). MEASUREMENTS: All subjects reached final height (growth velocity < 0.5 cm/year in the last year of treatment) after hGH treatment (range 33-96 months) at a dose of 20 U/m2/week. The 3 groups of subjects started therapy at a similar height for chronological and bone age. RESULTS: Final height in the small for GA group was - 1.71 +/- 0.93 standard deviation score (SDS), significantly lower than that of both appropriate (- 1.14 +/- 0.83 (P < 0.01)) and large (- 0.70 +/- 0.89 (P < 0.01)) for GA groups. Similarly, the small for GA group had a significantly lower height SDS increment from the start of therapy to adult height (0.54 +/- 0.84) than both the appropriate (0.99 +/- 0.78 (P < 0.05)) and the large (1.49 +/- 0.84 (P < 0.01)) for GA groups. The percentage of subjects with final height above target height was significantly different in the 3 groups: 21% for the small, 38% for the appropriate and 71% for the large for GA groups (P < 0.05). In the whole group of patients there was a positive correlation between birth weight and final height (r = 0.38; P < 0.0001). CONCLUSIONS: The present study showed that our patients, affected by isolated and idiopathic GH deficiency but with different birth weights, despite starting treatment with a similar height and bone age delay, had different auxological outcomes. It seems, therefore, that final height is strongly influenced by birth weight which penalizes the smaller newborns and assists the larger ones.

Adolescent↗
PubMed1999

Reduced spontaneous growth hormone secretion in patients with Turner's syndrome.

We evaluated growth hormone (GH) secretion in 81 patients with Turner's syndrome (TS) (mean age 10.7+/-3.6 y) with respect to karyotype, auxological characteristics and growth response to GH treatment (1 IU/kg/wk). None of the patients had spontaneous puberty or had started replacement therapy with estrogens. Thirty-nine patients (48%) had monosomia 45X, 29 (36%) structural abnormalities of the X chromosome and 13 (16%) X mosaicism. Before the start of GH therapy, each patient underwent an evaluation of mean nocturnal GH concentration (MGHC) and 75 patients also underwent 2 pharmacological tests. MGHC of the TS patients did not differ from that of 29 prepubertal GH-deficient girls (GH peaks < 8 microg/l after pharmacological tests) and both groups were lower (p < 0.0001 and p < 0.0005, respectively) than MGHCs of 27 short normal girls (GH peak > 8 microg/l). MGHC of the patients with TS was negatively correlated (p < 0.001) with bodyweight excess (BWE) at multiple regression analysis. MGHC of the TS patients with BWE < 20% was significantly higher (p < 0.02) than that of the TS patients with BWE > 20%, but again did not differ from that of the GH-deficient patients and was lower (p < 0.001) than that of the short normal girls. MGHC did not significantly differ between the 3 groups subdivided according to karyotype. Forty-four percent of the TS patients showed GH responses to pharmacological tests < 8 microg/l. Height velocity SDS at first and second year of therapy was not influenced by MGHC levels, chronological or bone age, target height or BWE. In conclusion, spontaneous secretion in our patients with TS was lower than that of the short normal prepubertal girls and did not differ from that of GH-deficient subjects, even if we excluded overweight patients. The level of GH secretion was unable to predict GH response to treatment.

Adolescent↗
PubMed1999

Helicobacter pylori and type 1 diabetes mellitus in children.

BACKGROUND: Helicobacter pylori is a recognized gastroduodenal pathogen and H. pylori infection is one of the most common bacterial infections, usually acquired during childhood. However, diabetes mellitus is characterized by an increased susceptibility to infections. METHODS: We compared the prevalence of H. pylori infection as well as cytotoxin-associated gene A-CagA-and vacuolating cytotoxin gene A-VacA-positivity in 103 children and adolescents with type 1 diabetes mellitus and in 236 nondiabetic children. We used a novel Recombinant ImmunoBlot Assay-Strip (RIBA SIA) with individual band for whole H. pylori lysate and recombinant CagA and VacA. RESULTS: H. pylori-positive subjects, both diabetics and controls, were significantly older than negative subjects. In the whole group of diabetic patients the prevalence of each of the three reactivities was higher than in control subjects, reaching significance only for lysate. Only diabetic patients over 12 years of age, with a longer disease duration, had a higher prevalence of positive cases, although not significantly so. CONCLUSIONS: In the first few years of disease, diabetic children do not differ from the nondiabetic population. Subsequently they show an H. pylori seroprevalence tendentially higher than that of controls of the same age. Therefore, H. pylori infection acquired in childhood and lasting several years, could be one of the causes of chronic atrophic gastritis, which is more frequent in longstanding diabetes mellitus.

Adolescent↗
PubMed1998

Outcome of premature thelarche: relation to puberty and final height.

BACKGROUND: There is a debate about the possible progression of idiopathic premature thelarche towards precocious or early puberty. OBJECTIVE: To evaluate height and age at onset of puberty in a group of girls with a history of idiopathic premature thelarche. STUDY DESIGN: The height and age at onset of puberty of 42 girls now over 10 years of age who were diagnosed with isolated premature thelarche before the age of 3 years were evaluated. RESULTS: Menarche was reached before or at 11 years of age in 13.5% of this group of girls. This percentage of early menarche was higher than would be expected from historical controls in the general population, but was consistent with maternal age of menarche. The mean (SD) height of the girls (n = 15) who achieved adult height was 162.9 (6.3) cm, which was slightly higher than the mean (SD) relative mid-parental height (160.7 (6.7) cm). CONCLUSIONS: Isolated premature thelarche with onset before 3 years of age progresses towards precocious puberty, although this was consistent with the maternal age of menarche. Furthermore, adult height was normal when compared with population norms in all patients.

Adolescent↗
PubMed1998

Low growth hormone-binding protein in infants with congenital hypothyroidism.

We evaluated the circulating levels of GH, insulin-like growth factor I (IGF-I), GH-binding protein (GHBP), and IGF-binding protein-3 (IGFBP-3) before L-T4 therapy in 19 infants with congenital hypothyroidism (CH), aged 12-29 days, diagnosed by neonatal screening and in a group of age- and sex-matched control infants. The same parameters were reevaluated after several months of treatment. Serum GHBP was measured by the high performance liquid chromatography-gel filtration method; serum GH, IGF-I, and IGFBP-3 levels were determined by commercial kits. The hypothyroid patients, before beginning therapy, presented significantly lower GHBP values than controls (P < 0.0001); during treatment, these values increased significantly; however, after 6 months they were still significantly lower than control values (P < 0.01). The pretreatment levels of GH were not significantly different from control values; after 1 month of treatment, GH did not show the decrease observed in controls and, therefore, was significantly higher (P < 0.01). The pretreatment levels of IGF-I were not significantly different from control values, but were lower in patients with severe than in those with mild hypothyroidism. They decreased at about 4 months of life and became significantly lower than control values at about 7 months of age (P < 0.05). In conclusion, it may be hypothesized that the condition of CH induces a change in GHBP expression, perhaps beginning in fetal life. The intrauterine production of IGF-I seems to be independent of the levels of GHBP and partially affected by fetal thyroid function.

Carrier Proteins↗
PubMed1997

Developmental pattern of fetal growth hormone, insulin-like growth factor I, growth hormone binding protein and insulin-like growth factor binding protein-3.

AIMS: To evaluate the developmental pattern of fetal growth hormone (GH), insulin-like growth factor I (IGF-I), GH binding protein (GHBP) and IGF binding protein-3 (IGF-3); to determine the implications for fetal growth. METHODS: Serum GH, IGF-I, GHBP and IGFBP-3 were measured in 53 fetuses, 41 aged 20-26 weeks (group A) and 12 aged 31-38 weeks (group B). Fetal blood samples were obtained by direct puncture of the umbilical vein in utero. Fetal blood samples were taken to rule out beta thalassaemia, chromosome alterations, mother to fetus transmissible infections, and for maternal rhesus factor. GHBP was determined by gel filtration chromatography of serum incubated overnight with 125I-GH. GH, IGF-I and IGFBP-3 were determined by radioimmunoassay. RESULTS: Fetal serum GH concentrations in group A (median 29 micrograms/l, range 11-92) were significantly higher (P < 0.01) than those of group B (median 16.7 micrograms/l, range 4.5-29). IGF-I in group A (median 20 micrograms/l, range 4.1-53.3) was significantly lower (P < 0.01) than in group B (median 75.2 micrograms/l, range 27.8-122.3). Similarly, IGFBP-3 concentrations in group A (median 950 micrograms/l, range 580-1260) were significantly lower than those of group B (median 1920 micrograms/l, range 1070-1770). There was no significant difference between GHBP values in group A (median 8.6%, range 6.6-12.6) and group B (median 8.3%, range 6-14.3). Gestational age correlated positively with IGF-I concentrations (P < 0.0001) and IGFBP-3 (P < 0.0001) and negatively with GH (P < 0.0001). GHBP values did not correlate with gestational age. Multiple regression analysis showed a negative correlation between GH:IGF-I ratio and fetal growth indices CONCLUSIONS: The simultaneous evaluation of fetal GH, IGF-I, IGFBP-3 and GHBP suggests that the GH-IGF-I axis might already be functional in utero. The progressive improvement in the efficiency of this axis in the last part of gestation does not seem to be due to an increase in GH receptors.

Biomarkers↗
PubMed1997

Final height of patients treated for isolated GH deficiency: examination of 83 patients.

The aim of the present study was to evaluate retrospectively the influence of various auxological and laboratory parameters on final height in a group of GH-deficient children after replacement therapy and to compare their final height with that of a group of short children with normal GH secretion and hence not treated. The final height was evaluated of 83 patients (51 males and 32 females) affected by idiopathic isolated GH deficiency and treated with recombinant human GH (hGH) for 2-7 years. Inclusion criteria at the start of treatment were short stature (mean height for chronological age in standard deviation score (SDS) -2.21) due to idiopathic isolated GH deficiency (GH peak < 8 micrograms/l after two pharmacological tests and/or mean GH concentration < 3.3 micrograms/l during the night) and treatment with recombinant hGH for at least 2 years at a dose of 15-20 U/m2 per week by s.c. injection for 6 or 7 days/ week. Mean chronological age at diagnosis was 12.2 +/- 1.7 years; 35 were prepubertal and 48 pubertal. The final height of 51 untreated short stature (mean height for chronological age in SDS -2.13 at diagnosis) subjects (42 males and 9 females: 29 prepubertal and 22 pubertal at diagnosis with mean chronological age 11.6 +/- 2.4 years) with normal GH secretion was also evaluated. In the treated subjects final height SDS was higher than that of the untreated group (-1.3 vs -1.7 SDS; P = 0.01). Both treated and untreated subjects showed a final height lower than target height, but 39% of the treated subjects vs only 20% of the untreated group (P = 0.035) had a final height greater than target height. In the treated subjects this percentage was higher in the patients improving their height for bone age in the first years of therapy. While treated females showed a positive correlation only between target and final height (P = 0.0001), in treated males final height correlated with the Bayley-Pinneau prediction at diagnosis, height for chronological age and bone age at diagnosis and target height. Patients who started therapy before puberty also showed these correlations with data calculated at the onset of puberty, together with a correlation with chronological age at the onset of puberty. When considering the influence of GH response at tests on final height, the percentage of subjects exceeding target height increased progressively according to the severity of the GH deficiency. There was no difference in height gain between the patients starting therapy before or during puberty. The height gain, however modest, obtained by our treated patients, the number of patients with final height greater than target height and the favourable comparison with the untreated short-stature subjects represent a promising result, which could be improved by personalizing treatment.

Adolescent↗
PubMed1996

Urinary growth hormone estimation in diagnosing severe growth hormone deficiency.

Urinary growth hormone was measured in 54 children with short stature who had growth hormone deficiency that was initially diagnosed pharmacologically (arginine and L-dopa) and physiologically (mean growth hormone concentration during sleep evaluated twice). Based on the growth hormone response to pharmacological tests the subjects were subdivided into three groups: group A, 20 subjects with normal response (peak concentration > 8 micrograms/l); group B, 20 subjects with response between 4 and 8 micrograms/l; and group C, 14 subjects with response < 4 micrograms/l. In group A four subjects had an abnormally low nocturnal mean growth hormone concentration (< or = 3.3 micrograms/l). In group C seven subjects had multiple pituitary hormone deficiency and abnormal magnetic resonance imaging. All subjects had urine collected from 8.00 pm to 8.00 am for 4-5 consecutive nights. A positive correlation was found between serum nocturnal mean growth hormone values and urinary growth hormone in all subjects. Mean (SD) concentrations of urinary growth hormone were similar in groups A (18.0 (9.5) ng/g creatinine) and B (13.6 (5.9) ng/g creatinine), but significantly higher than that of group C (3.4 (3.7) ng/g creatinine). Considering as abnormal urinary growth hormones below the lower limit of the range in group A, specificity and sensitivity of urinary growth hormone was 100% and 35% respectively. Sensitivity for groups B and C were 5% and 78% respectively. When considering only the subjects of group C with pathological magnetic resonance findings, sensitivity increased to 100%. In the four subjects of group A with mean growth hormone concentration < or = 3.3 micrograms/l, specificity decreased to 80%. It is concluded that urinary growth hormone assay is characterised by a sensitivity too low to be regarded as improving the traditional diagnostic approach to define growth hormone deficiency, unless it is used to identify subjects with the most severe deficiencies.

Adolescent↗
PubMed1996

Congenital adrenal hyperplasia: neonatal mass screening compared with clinical diagnosis only in the Emilia-Romagna region of Italy, 1980-1995.

OBJECTIVE: Comparative study of the incidence of classic 21-hydroxylase deficiency congenital adrenal hyperplasia (21ase-def CAH) and clinical findings of affected infants diagnosed via newborn screening versus case survey only in the Emilia-Romagna region of Italy. METHODS: Neonatal mass screening (from March 1980 to September 1983-Period A, and from March 1991 to August 1995-Period C) and case survey study (from 1980 to June 1995; case survey alone from October 1983 to February 1991--Period B) were performed by the Regional Referral Center for Neonatal Screening for Endocrine-Metabolic Disease with a laboratory (Central Laboratory, S. Orsola Hospital, Bologna) and clinical (First Pediatric Clinic, University of Bologna, S. Orsola Hospital, Bologna) component. A population-based sample of 420 960 newborns consecutively born in the Emilia-Romagna region from March 1980 to August 1995 were studied. Spot 17-OH-progesterone (nmol/L blood) was tested by the radioimmunoassay method after sample extraction during Period A and by fluoroimmunometric time resolved method without sample extraction during Period C. Serum 17-OH-progesterone (ng/dL or nmol/L) was tested by the radioimmunoassay method (Diagnostic Product Corporation Kit, Los Angeles, CA). The case survey was performed by means of a questionnaire sent to all regional centers dealing with pediatrics, neonatology, endocrinology, and pediatric surgery. RESULTS: Thirteen classic 21ase-def CAH were diagnosed by means of neonatal screening (combined A and C periods). One true and one questionable false-negative cases were identified. The incidence of classical 21-hydroxylase deficiency for the white population was 1:15 518 (95% confidence limits 1:9249-1:28 400) by neonatal screening plus case survey, 1:18 105 (95% confidence limits 1:10 365-1:35 041) by neonatal screening alone and 1:25 462 (95% confidence limits 1:12 925-1:59 043) by case survey alone. The sensitivity and specificity of screening for classic CAH were 83% and 99.8% for Period A and 90% and 99.2% for Period C, respectively. The percentage of salt-wasting forms and the male/female ratio were higher during the neonatal screening period than during the case survey only. Sixty-one percent of classic CAH patients benefited from a prompt diagnosis. Nonclassical 21ase-def CAH cases detected via screening and case survey were also reported. CONCLUSIONS: Even in a region with adequate neonatal services, clinical diagnosis alone of classic CAH might be delayed or misinterpreted and salt-wasting crises could cause neonatal deaths. CAH screening is thus an effective tool for diagnosing affected male infants without a family history of CAH and for preventing salt loss. However, to achieve maximal benefit from screening, quick procedures are necessary for notification of positive results and beginning prompt treatment. The possibility of false-negative cases indicates that clinical observation should never be abandoned, even with ongoing screening programs.

17-alpha-Hydroxyprogesterone↗
PubMed1995

Follow-up of antibodies to growth hormone in 210 growth hormone-deficient children treated with different commercial preparations.

The aim of the study was to evaluate the immunogenicity of different commercial recombinant-growth hormone preparations. The presence of antibodies to growth hormone was tested in 210 growth hormone-deficient children at 6-month intervals during treatment for 6-66 months. The patients were treated with three preparations (groups A, B and C of 70 cases each) having the authentic growth hormone sequence. Groups A and B received hormone synthesized by the recombinant DNA technique in E. coli, while the group C preparation was produced in a mammalian cell line. The preparations showed poor immunogenicity and antibodies were found as follows: 1.4% in patients of group A (1 case: binding capacity 0.2 mg/l and Ka 3.5 10(7) l M-1), 2.8% in patients of group B (2 cases; case 1 binding capacity 0.7 mg/l and Ka 1.5 10(7) l M-1; case 2 binding capacity 0.04 mg/l and Ka of 1.8 10(8) and 6.5 10(6) l M-1), and 8.5% in group C (6 cases; binding capacity from 0.4 to less than 0.02 mg/l, Ka from 1.6 10(7) to 3.8 10(8) l M-1). Only two patients of group C presented the antibodies in two subsequent examinations; in the other patients the positivity was found once. In all patients positive samples were found at intervals of 6-24 months after the start of therapy. In all antibody-positive patients growth velocity presented no decrease at the time of antibody detection and was never different to that of negative patients. We conclude that the three commercial preparations examined showed poor immunogenicity without clinical relevance.

Adolescent↗
PubMed1994

Long-term follow-up and final height in girls with central precocious puberty treated with luteinizing hormone-releasing hormone analogue nasal spray.

OBJECTIVE: To evaluate clinical, hormonal, and auxologic features in a group of girls with central precocious puberty during and after long-term treatment with luteinizing hormone-releasing hormone analogue nasal spray. DESIGN: Clinical survey, before-after trial. SETTING: Pediatric Clinic, Endocrinological Center, University of Bologna (Italy). PATIENTS: Forty-one girls with central precocious puberty were treated for 28 months (range, 12 to 60 months); 25 of them discontinued therapy at a mean chronological age of 10.0 +/- 0.9 years and were followed up for 25 months (range, 6 to 50 months). Twelve patients achieved adult height. INTERVENTION: Buserelin acetate (D-Ser [TBU] LHRH A1-9EA) nasal spray; 1800 micrograms/d subdivided into six intranasal administrations of 300 micrograms each. MEASUREMENTS/MAIN RESULTS: Basal follicle-stimulating hormone, peak gonadotropin values (fluoro-immunoenzymatic method, Eurogenetics, Tessenderlo, Belgium; sensitivity was 0.5 IU/L for luteinizing hormone and 1 IU/L for follicle-stimulating hormone), and estradiol (radioimmunoassay method, DPC Kit, Los Angeles, Calif; sensitivity was 11.01 pmol/L) were significantly suppressed (P < .0001) as of the third month of treatment and increased significantly (P < .01) to pretreatment levels 6 months after discontinuation of therapy. Uterine and mean ovarian volumes, which were stable throughout treatment, appeared significantly higher (P < .05) than before treatment at only 6 months after stopping therapy. In patients with more advanced bone age (according to Greulich and Pyle) at onset of treatment, we observed a more significant improvement of SD score for height (Tanner). Mean adult height in our patients was 159.5 +/- 6.1 cm, and the variables that were significantly associated with final height were height age/bone age ratio at onset and target height (according to Tanner). CONCLUSIONS: Long-term buserelin treatment administered nasally is effective because of completeness of inhibition, quick reversibility after treatment is stopped, and lack of side effects. Its auxologic results are different depending on bone age advancement at onset, which represents a predictor of "therapeutic success." Further follow-up would be useful.

Administration, Intranasal↗
PubMed1994

Molecular study of human growth hormone gene cluster in three families with isolated growth hormone deficiency and similar phenotype.

The growth hormone (GH) gene (hGH-N) cluster was analysed using polymerase chain reaction, Southern and polymorphism analysis in five patients (including two pairs of siblings) with extreme short stature and absence of GH secretion. Patients 1 and 2 (siblings) were homozygous for a large deletion removing four genes of the cluster: hGH-N, hCS-L, hCS-A and hGH-V. Both siblings produced high anti-GH antibody levels in response to exogenous GH therapy, followed by growth arrest a few months after starting replacement therapy. In patient 3 we detected a heterozygous deletion which involved three genes of the cluster (hCS-A, hGH-V, hCS-B) and left an intact hGH-N gene. Direct sequencing of hGH-N specific amplified fragments excluded the presence of any point mutations in exons and splicing regions. In patients 4 and 5 (sisters) our study did not demonstrate any gene deletions. Analysis of polymorphic restriction patterns in this family demonstrated that both sisters inherited the same alleles from the father but different alleles from the mother, suggesting that the defect was not linked to the hGH-N gene. These results confirm the difficulty of clinical identification of subjects with hGH-N deletion and underline the importance of DNA analysis in patients with absence of GH secretion and extreme growth retardation.

Adolescent↗