Giorgio Zamboni

Effects of two different regimens of recombinant human growth hormone therapy on the bone mineral density of patients with growth hormone deficiency

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Central precocious puberty: current treatment options.

Central precocious puberty (CPP) is characterized by early pubertal changes, acceleration of growth velocity, and rapid bone maturation that often result in reduced adult height. An onset of pubertal signs before the age of 8 years in girls and 9 years in boys should always be evaluated. A combination of clinical signs, bone age, pelvic echography in girls, and hormonal data are required to diagnose CPP and make a judgment concerning progression and prognosis.Not all children with apparently true CPP require medical intervention. The main reasons for treatment are to prevent compromised adult height and to avoid psychosocial or behavioral problems. The need for treatment for auxologic reasons is based on estimation of predicted adult height, with the finding of a reduced height potential, which may require a follow-up. Indication for treatment on the basis of psychologic and behavioral anomalies has to be determined on an individual basis.The main short-term aims of therapy are to stop the progression of secondary sex characteristics and menses (in girls) and to treat the underlying cause, when known. Long-term goals are to increase final adult height and to promote psychosocial well-being.Once it has been decided that treatment is appropriate, it should be initiated immediately with depot gonadotropin-releasing hormone (GnRH) agonists. The effective suppression of pituitary gonadal function is achieved with these compounds in practically all CPP patients.Long-term data are now available from 2 decades of GnRH agonist treatment for patients with CPP. Treatment preserves height potential in the majority of patients (especially in younger patients) and improves the final adult height of children with rapidly progressing CPP, with a complete recovery of the hypothalamic-pituitary-gonadal axis after treatment. GnRH agonist treatment using depot preparations is useful and has a good safety profile, with minimal adverse effects and no severe long-term consequences. Although further data are need, there may be a role in the future for combining somatropin (growth hormone) and GnRH agonist treatment for some patients with significantly impaired growth velocity. The introduction of GnRH antagonists is likely to improve the treatment options for CPP.

Altered bone metabolism in children infected with human immunodeficiency virus.

Aim: Data on bone homoeostasis of children infected with human immunodeficiency virus (HIV), at the time of the gain in bone mass, are very rare. To determine possible alterations in bone metabolism, 13 prepubertal vertically HIV‐infected children were studied. Methods: Viral load, CD4 count, interleukin‐6 (IL‐6), growth hormone, insulin‐like growth factor‐I (IGF‐I), IGF binding protein‐3 (IGFBP‐3), acid‐labile subunit (ALS), IGFBP‐3 proteolysis, osteocalcin in blood and N‐terminal telopeptide of type I collagen in urine were determined. Lumbar spine bone mineral density was examined by dual‐energy X‐ray absorptiometry. Results: Low osteocalcin levels were found in all patients. Low IGF‐I was found in only six children, who had low CD4 count and high IL‐6 levels, with normal levels of IGFBP‐3 and ALS, absent IGFBP‐3 proteolysis and decreased bone mineral density, irrespective of viral load or growth.

Neonatal screening for glucose-6-phosphate dehydrogenase deficiency fails to detect heterozygote females.

We examined glucose-6-phosphate dehydrogenase (G6PD) deficiency in north-eastern Italian Caucasian neonates detected by neonatal screening, in order to measure the incidence of heterozygote females detected by neonatal screening, and to estimate the near-true total incidence. A total of 85,437 Caucasian neonates, born between January 2000 and December 2001, have been enclosed in the study. The total incidence of the disease, measured by fluorescent method, is 0.9‰ the total incidence, calculated by Hardy–Weinberg law, is 4.8‰. The frequency of missed females is 93% of total females expected with G6PD deficiency; most of them are very likely heterozygous females. The sensitivity of the fluorescent method might be not sufficient to detect all females. Since heterozygote females might develop the symptoms of G6PD deficiency later, these results suggest that the G6PD neonatal screening may not be helpful in preventing disease in females.

Diagnostic effectiveness of simultaneous thyroxine and thyroid-stimulating hormone screening measurements. Thirteen years' experience in the Northeast Italian Screening Programme.

Objectives: To evaluate the effectiveness of thyroid-stimulating hormone (TSH) and thyroxine [T4) measurements at neonatal screening for congenital hypothyroidism, we compared our false-negative results with those we would have obtained if we had used TSH screening alone. Subjects and methods: Between January 1989 and December 2001 745,258 newborns were screened (98.3% of total born) for congenital hypothyroidism in northeast Italy. T4 and TSH were measured simultaneously on blood spots collected after birth. Between 1989 and 1998, semiquantitative total T4 (tT4) and TSH concentrations were measured by radiolabelled immunological assay and, from 1999 to 2001, using time-resolved fluorometer Delfia instruments (EG&G Wallac Oy, Finland) and fluoroimmunometric assay (Delfia neonatal hTSH and T4 kits). Results: Ten neonates were missed by our screening programme (normal tT4 and TSH) and classified as false negatives; these infants were diagnosed later in life with central hypothyroidism. If we had measured TSH alone in our screening programme, we would have missed an additional 21 patients with low tT4 and normal TSH; of these, four were affected by central hypothyroidism and 17 were diagnosed within the second month of life as affected by primary hypothyroidism with delayed TSH rise. Conclusions: Simultaneous T4 and TSH measurements at neonatal screening can miss patients affected by central hypothyroidism. However, this screening procedure allows identification of cases of central hypothyroidism with low T4 values and those neonates affected by primary hypothyroidism with delayed TSH rise who we would have missed by using the TSH measure alone.

Influence of dietary taurine on vitamin D absorption

To evaluate the influence of dietary taurine supplementation on vitamin D absorption, we studied three groups of infants: 21 (11 preterm) were fed a taurine‐free formula, 21 (10 preterm) were fed a taurine‐supplemented formula (50 mg/100 g of powder) and 20 (9 preterm) were fed human, not heat‐treated milk. Taurine, total bile acids, glyco‐(GBA) and tauro‐(TBA) conjugated bile acids, 25–hydroxyvita‐min D3 (250HD3) and 1,25–dihydroxyvitamin D3 (1,250H2D3) were determined in all infants at birth in blood cord and at one and three months of life. In preterm infants fed a taurine‐free formula, we found lower plasma taurine levels than in infants of other groups at one and three months of life. In these infants, GBA predominated, with a G/T ratio of 1.1 and 1.4 at one and three months of life, whereas in all other infants TBA predominated with a G/T ratio always < I. Also, 250HD3 and 1,250H2D3 levels were significantly lower in preterm infants fed a taurine‐free formula than in infants fed a taurine‐enriched formula or human milk. Term infants fed a taurine‐free formula did not show differences in the parameters studied in comparison to infants of other groups. Low taurine dietary intake appears to compromise vitamin D absorption in preterm infants, and therefore taurine supplementation of preterm infant formulas should be encouraged.

Urological complications and copper replacement therapy in childhood Menkes syndrome

BACKGROUND Urological complications are frequent in Menkes syndrome, a very rare X-linked recessive disorder of copper (Cu) metabolism. AIM To evaluate the role of Cu therapy in preventing the progression of urological complications. SUBJECTS AND METHODS We retrospectively enrolled 57 patients with Menkes syndrome (55 published case reports and two of our own unpublished cases) and investigated the reported urological complications, distinguishing the patients with or without Cu replacement therapy and evaluating the efficacy of this therapy in the prevention of urological complications. RESULTS The most frequent urological complication was bladder diverticulum (38.6% of the total patients); obstruction bladder outflow and rupture of the kidney were less frequent (both 1.8% of the total). The number of congenital urological complications increased progressively by age category; in fact, 77.8% of patients did not report urological complications at the age of 0.4+/-0.2 y, and 28.6% of them displayed > or = two congenital urological complications at the age of 9.3+/-2.6 y. The percentage of urological complications found in younger patients not on Cu therapy did not differ from that of older patients treated with Cu therapy. A comparison between patients of the same age interval, who were or were not treated with Cu, showed that treated children had fewer urological complications than untreated children. CONCLUSION Our investigation suggests that Cu therapy in patients with Menkes syndrome does not prevent the progression of urological complications; however, it might delay their worsening.

Gonadal function and response to growth hormone (GH) in boys with isolated GH deficiency and to GH and gonadotropins in boys with multiple pituitary hormone deficiencies

OBJECTIVE [corrected] To evaluate spermatogenesis in patients with isolated GH deficiency and multiple pituitary hormone deficiencies. DESIGN Treatment of isolated GH-deficient patients with recombinant human GH (weekly dose of 0.7 IU/kg) for 5.3 +/- 0.4 (mean +/- SD) years and cotreatment of multiple pituitary deficient patients with GH at the same dosage for 8.0 +/- 0.4 years and hCG (2,000 IU, three times per week) and hMG (500 IU, two times per week) for 13.7 +/- 1.1 months. SETTING Endocrine Pediatric Unit. PATIENTS Eight patients affected by isolated GH deficiency and seven by multiple pituitary hormone deficiencies. MAIN OUTCOME MEASURES Serum LH, FSH, and T, testicular volume, semen volume, density, count, and motility. RESULTS Patients with isolated GH deficiency completed their pubertal development in 19.0 +/- 3.5 months and patients with multiple pituitary hormone deficiencies in 13.7 +/- 1.1 months. At the end of puberty, the two groups of patients had similar testicular volume, penis size, sperm concentration, motility, and morphology, although T levels and seminal volume were lower in isolated GH-deficient patients than in multiple pituitary deficient patients. CONCLUSIONS The two groups of patients, treated specifically for their identified hormonal deficiencies, in the end had similar satisfactory reproductive results.

Effects of 1,25-dihydroxyvitamin D3 and growth hormone therapy on serum osteocalcin levels in children with growth hormone deficiency

In order to investigate the influence on bone metabolism of growth hormone (GH), we evaluated the response to an acute load of 1,25(OH)2D3 (Rocaltrol) (1.5 micrograms/day for 4 days) in 16 growth hormone-deficient prepubertal children (11 boys and 5 girls, aged from 6.2 to 9.6 years) both before and after 1 month of human GH (hGH) therapy (0.1 IU/kg/day, 6 times per week). Before and after the 1,25(OH)2D3 load, serum IGF-I, osteocalcin, Ca, P, alkaline phosphatase (ALP) and urinary excretion of Ca and P were measured. The serum levels of osteocalcin rose significantly after the first 1,25(OH)2D3 load, without an increase in IGF-I values and with a slight non-significant increase in serum Ca and P. Almost superimposable increases of osteocalcin, Ca and P were observed after 1 month of hGH therapy, with a significant increase of IGF-I, but they did not rise further after the second 1,25(OH)2D3 load. On the basis of our results, 1,25(OH)2D3 seems to have a stimulatory action on osteoblastic activity even in the absence of normal levels of GH. However, there is no apparent additional stimulatory activity after administration of hGH. Osteocalcin level behaviour during our study might suggest that GH and 1,25(OH)2D3 have a common and easily saturable stimulatory pathway on osteoblastic function.

Neonatal screening, clinical features and genetic testing for galactosemia.

To the Editor: Neonatal screening has been introduced in many countries in order to detect neonates affected by metabolic or endocrine diseases when they are still without symptoms. The neonatal screening for metabolic diseases may include galactosemia. The hallmarks of classical galactosemia [galactose-1-phosphate uridyltransferase (GALT) deficiency] are Gram-negative sepsis, early acute hepatic dysfunction, and failure to thrive. These neonates are already symptomatic before neonatal screening results will be obtained. To diagnose most of the Letters to the editor