Central precocious puberty: treatment with triptorelin 11.25 mg.

BACKGROUND: Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). AIM: To assess the efficacy of triptorelin 11.25 mg in children with CPP. PATIENTS: 17 patients (16 females) with CPP (7.9 ± 0.9 years) were treated with triptorelin 11.25 mg/90 days. METHODS: Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7 ± 16.5 IU/L at baseline to 0.9 ± 0.5 IU/L at M3 (P < 0.0001); they did not significantly changed at M6 and M12. CONCLUSIONS: Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Are IGF-I and IGF-BP3 useful for diagnosing growth hormone deficiency in children of short stature?

BACKGROUND: The diagnosis of growth hormone deficiency (GHD) is based on clinical and auxological characteristics combined with the results of growth hormone provocation tests. AIM: To evaluate the utility of IGF-I and IGF-BP3 serum levels in the diagnosis of GHD among children of short stature. SUBJECTS/METHODS: We recruited 207 short pre-pubertal children and divided them into two groups. One group consisted of 70 children (mean age 7.93 +/- 2.35 SD) with a growth hormone (GH) response on two provocative tests of < or = 8 ng/ml, while the other group contained 137 children (mean age 7.92 +/- 2.11 SD) with a peak GH value of > 8 ng/ml. Serum IGF-1 and IGF-BP3 levels were determined in the two groups. RESULTS: The difference in serum IGF-I between the two groups was not significant (p= 0.26), while the difference in IGF-BP3 between the two groups was statistically significant (p= 0.004). The performance of serum IGF-1 and IGF-BP3 as a diagnostic tool, expressed as AUC by ROC analyses, was quite low. CONCLUSION: Neither IGF-I nor IGF-BP3 are an adequate substitute for the stimulus test in the diagnosis of growth hormone deficiency among children of short stature.

Diagnosis of growth hormone deficiency by using the arginine provocative test: is it possible to shorten testing time without altering validity?

BACKGROUND: The arginine test is used for the diagnosis of growth hormone deficiency (GHD), but its duration is not uniform and varies from 180 to 90 min. SUBJECTS AND METHODS: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the arginine test in 208 children evaluated for short stature (height less than -2 SD); 67 were diagnosed with idiopathic short stature (ISS) and 141 with GHD. We calculated the frequency distribution of the GH peaks to arginine in GHD and in ISS at various times and the percentage of GH peaks to arginine before and after 90 min in all and in ISS children. RESULTS: The GH peak distribution varied between 30 and 120 min, even though the vast majority of peaks occurred between 30 and 90 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 95.2% in all children and 100% in ISS. CONCLUSION: The arginine test can be administered for only 90 min without significantly changing its validity, in order to reduce the discomfort of patients and the cost of the test.

Partial growth hormone deficiency and changed bone quality and mass in type I trichorhinophalangeal syndrome.

The trichorhinophalangeal syndromes (TRPSs) are syndromes due to haploinsufficiency of genes in the chromosome 8q24.12 region. Type I TRPS is characterized by typical facial features including sparse, brittle and fine hair, bulbous nose, and a long philtrum, as well as skeletal abnormalities. Growth retardation is a feature frequently found in these patients, who commonly are of short stature; however, only one case with growth hormone deficiency has been described in a TRPS patient and that patient had type II TRPS. Skeletal morphological abnormalities have been studied, but investigation of bone metabolism and quality in this kind of patients are not available. In this report we describe two cases of type I TRPS with partial growth hormone deficiency and significant bone mass and quality impairment, which was unresponsive to GH treatment.

Precocious puberty in a girl with floating-harbor syndrome.

Floating-Harbor syndrome (FHS) is a rare genetic disorder characterized by short stature, delayed bone age, mild to moderate mental retardation, speech problems, and peculiar craniofacial features. In these patients pubertal development has been reported to be normal. In this paper, we describe a girl with FHS who developed precocious puberty. FHS diagnosis was made at 2 years 5 months on the basis of peculiar clinical features. At 7 years 7 months, the girl began pubertal development; her height was 112.5 cm (-2.42 SDS) and pubertal staging was B2 PH2 AH1. LHRH test underlined LH and FSH peak values of 11.7 mIU/ml and 6.2 mIU/ml, respectively. Plasma levels of 17beta-estradiol were normal (8.5 pg/ml). Ophthalmological and neurological examinations, including nuclear magnetic resonance imaging of the brain, were normal. Treatment with gonadotrophin-releasing hormone analogue was begun. At 10 years 1 month, because of reduced height velocity, her growth hormone secretion was evaluated with diagnosis of neurosecretory dysfunction; hGH therapy was begun. The patient showed a good response to hGH treatment, reaching a normal adult height (156.1 cm; -1.20 SDS). This report suggests that, in patients with FHS, precocious puberty should be taken into consideration; in these patients, a careful endocrinological followup for the possible presence of growth and pubertal disorders is needed.

Osteoprotegerin serum levels in children with type 1 diabetes: a potential modulating role in bone status.

OBJECTIVE: Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption. DESIGN: We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications. METHODS: Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1-13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihy-droxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children. RESULTS: Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student's t-test, P < 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student's t-test, P < 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student's t-test, r = -0.62; P = 0.001), and HbA1c (r = -0.59; P = 0.007). OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003). CONCLUSIONS: Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.

Reduction of baseline body mass index under gonadotropin-suppressive therapy in girls with idiopathic precocious puberty.

OBJECTIVE: To investigate longitudinally body mass index (BMI) evolution and obesity prevalence in a large and very homogeneous study population consisting only of girls with non-organic central precocious puberty (CPP) who were treated with gonadotropin-releasing hormone agonists (GnRHa) for at least two years. PATIENTS AND DESIGN: The 101 girls with idiopathic CPP who were selected for this study fulfilled the following inclusion criteria: (a) suppression of gonadotropin and gonadal sex steroid secretion during the overall GnRHa treatment period; (b) adequate compliance with the therapy regimen. All the girls were treated for 44+/-14 months and were followed-up for 15.7+/-7.8 months after therapy withdrawal. RESULTS: At the start of therapy, 23.8% of the girls had a BMI exceeding 2 standard deviation scores (SDS) and were therefore classified as obese; both average BMI-SDS and obesity prevalence significantly decreased during the treatment period (chi(2)=16.6, P<0.0005) and only 4% of the patients, all with pre-existing obesity, were still obese at the end of therapy; during the therapy period, BMI-SDS increased in none of the patients. Both average BMI-SDS and obesity prevalence (from 4 to 0%; chi(2)=4.0, P<0.05) further decreased during the period that followed therapy withdrawal. CONCLUSIONS: (a) girls with idiopathic CPP are frequently obese at the onset of GnRHa therapy (23.8%), probably due to the hormonal changes which accompany the start of puberty; (b) their obesity is neither long-lasting nor related to GnRHa administration; (c) on the contrary, GnRHa therapy may have a favourable effect on BMI decrease, provided that treatment is performed for at least two years and is accompanied by a complete suppression of gonadotropin secretion; (d) this unexpected effect, which has never been reported hitherto, might represent a further indication for GnRHa administration in idiopathic CPP.

Thyroid hypoplasia of the left lobe in two girls affected by Williams syndrome.

Williams syndrome is a well-recognized disorder, having an incidence of 1 in 20,000 live births. However, thyroid function in these patients is rarely studied. This paper reports thyroid hypoplasia of the left lobe in two girls affected by Williams syndrome, suggesting that it may be a feature of this syndrome.

Refinement of the 12q14 microdeletion syndrome: primordial dwarfism and developmental delay with or without osteopoikilosis.

In their studies on the molecular basis of osteopoikilosis, Menten et al have identified three individuals with microdeletions on chromosome 12q14.4, which removed several genes including LEMD3, the osteopoikilosis gene. In addition to osteopoikilosis, affected individuals had growth retardation and developmental delay. We now report a smaller 12q14.4 microdeletion in a boy with severe pre and postnatal growth failure, and mild developmental delay; the patient was small at birth and presented with poor feeding and failure to thrive during the first 2 years of life, similar to the phenotype of primordial dwarfism or severe Silver-Russell syndrome (SRS). The 12q14 deletion did not include LEMD3, and no signs of osteopoikilosis were observed on skeletal radiographs. Among the deleted genes, HMGA2 is of particular interest in relationship to the aberrant somatic growth in our patient, as HMGA2 variants have been linked to stature variations in the general population and loss of function of Hmga2 in the mouse results in the pygmy phenotype that combines pre and postnatal growth failure, with resistance to the adipogenic effect of overfeeding. Sequencing of the remaining HMGA2 allele in our patient showed a normal sequence, suggesting that HMGA2 haploinsufficiency may be sufficient to produce the aberrant growth phenotype. We conclude that the 12q14.4 microdeletion syndrome can occur with or without deletion of LEMD3 gene; in LEMD3-intact cases, the phenotype includes primordial short stature and failure to thrive with moderate developmental delay, but osteopoikilosis is absent. Such cases will likely be diagnosed as Silver-Russell-like or as primordial dwarfism.

Oral clonidine provocative test in the diagnosis of growth hormone deficiency in childhood: should we make the timing uniform?

INTRODUCTION: Oral clonidine is one of the most frequent drugs used for the diagnosis of growth hormone deficiency (GHD), but the duration of the test, depending on which European centres use it, is not uniform and can vary from 120 to 150 min or even 180 min. SUBJECTS AND METHODS: To standardize this test, evaluating the possibility to shorten it to 90 min, we investigated the response of GH to the oral clonidine test in 291 children evaluated for short stature (height <-2 SD). Of these, 164 were diagnosed as idiopathic short stature (ISS) and 127 as GHD. In these patients, we calculated: (1) the frequency distribution of the GH peaks to clonidine in GHD and in ISS at various times; (2) the percentage of GH peaks to clonidine before and after 90 min in all and in ISS children; (3) the percentage of the first GH value >or=10 ng/ml before 90 min and after 90 min in ISS. RESULTS: GH peak distribution varied between 30 and 180 min, even though the vast majority of peaks occurred between 30 and 60 min. There was no significant difference (p > 0.05) in the peak distribution between ISS and GHD children. The percentages of GH peaks within 90 min were 92.1% in all children and 95.7% in ISS. If considering the first value of GH >or=10 ng/ml this last percentage reaches 96.3%. CONCLUSION: Our study suggests that the oral clonidine test can be administered for only 90 min without significantly changing its validity. This test should be standardized at 90 min in European protocols just as in those currently used in the USA in order to reduce the discomfort of patients and the cost of this diagnostic procedure.

Undetectable serum IgA and low IgM concentration in children with congenital hypothyroidism.

Some studies suggest thyroid hormones may regulate the human immune system. In order to evaluate the effect of thyroid hormone deficiency on antibody production, we evaluated serum IgA and IgM concentrations in 83 children with congenital hypothyroidism (CH), diagnosed by neonatal screening. Patients were compared to two healthy, age-matched control groups. Patients with permanent CH had a significantly higher frequency of undetectable IgA concentrations (thyroid agenesis, P<10(-5); thyroid ectopy, P=0.013) and lower concentrations of IgA (thyroid agenesis, P<10(-6); thyroid ectopy, P<10(-5); dyshormonogenesis, P=0.0002) and IgM (thyroid agenesis, P=0.0002; thyroid ectopy, P<10(-6); dyshormonogenesis, P=0.0017) compared to control group. No difference was observed between patients with transient hypothyroidism and controls. A significant correlation was observed between serum IgA and IgM concentrations and fT4 levels. IgA and IgM deficiency is correlated with the severity of congenital hypothyroidism and may help to evaluate the duration and severity of thyroid hormone deficiency during prenatal life.

Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases. A one year followup study.

OBJECTIVE: To evaluate at baseline and after one year the bone status in children with chronic rheumatic diseases (CRD) using quantitative ultrasound techniques. METHODS: We evaluated bone status in 67 children, 52 female, 15 male, age range 2.80 to 18.10 years; 46 juvenile idiopathic arthritis, 11 juvenile dermatomyositis, and 10 systemic lupus erythematosus. Twenty-seven of 67 patients were taking only nonsteroidal antiinflammatory drugs (NSAID), 11 were given NSAID and methotrexate (MTX), 15 were also receiving steroids (prednisone), and 14 patients were given steroids and alendronate. Broadband ultrasound attenuation (BUA) by bone was determined at the left calcaneus using two 12.5 mm diameter, 1 MHz transducers mounted in hand-held calipers linked to a pediatric contact ultrasound bone analyzer. RESULTS: At baseline in the whole patient group mean BUA values and Z scores were significantly lower than in controls: 41.84 +/- 21.64 vs 61.69 +/- 17.42 dB/MHz (p < 0.001); Z score -0.91 +/- 1.07 vs 0.09 +/- 0.62 in controls (p < 0.001). At one year followup in the patient group BUA values were significantly increased compared to baseline (BUA 46.43 +/- 21.51 dB/MHz; p = 0.002); no significant difference was found in Z score. The 15 children receiving steroids in addition to NSAID and MTX showed a decrease in BUA value at one year (NS), while Z scores were significantly reduced compared to baseline (-1.45 +/- 1.40 vs -1.08 +/- 1.11; p < 0.05). The 14 patients in the group receiving NSAID and MTX who also received alendronate showed significant increases in BUA (56.93 +/- 19.32 vs 44.21 +/- 15.67; p < 0.001) and Z score (-0.87 +/- 1.19 vs -1.56 +/- 0.82; p < 0.002). CONCLUSION: Contact ultrasound bone analysis at the calcaneus is a useful tool in the assessment and monitoring of bone status in children with CRD.

Changed bone status in human immunodeficiency virus type 1 (HIV-1) perinatally infected children is related to low serum free IGF-I.

INTRODUCTION: Adults and children affected by human immunodeficiency virus type-1 (HIV-1) infection show bone demineralization. Little is known about skeletal status using a quantitative high-frequency ultrasound (QUS) technique in these patients. OBJECTIVE: To evaluate the bone quality and assess the role of the IGF system in the bone metabolism and skeletal status of HIV-1 perinatally infected children. PATIENTS AND METHODS: Serum free and total IGF-I, IGFBP-3, serum osteocalcin level, urinary deoxypyridinoline concentration, spontaneous interleukin-6 (IL-6) release and broadband ultrasound attenuation (BUA) were evaluated in 44 prepubertal children who had perinatal HIV-1 infection. The patients were divided into two groups depending on the severity of their clinical condition: group 1 (23 children with no or mild clinical symptoms, mean age 8.0 +/- 2.9 years) and group 2 (21 children with severe clinical symptoms, mean age 8.58 +/- 2.47 years). Fifty-five healthy age- and sex-matched controls were analysed for comparison. RESULTS: Compared with group 1 and the controls, group 2 patients showed a significantly reduced BUA Z-score (P < 0.001), and significantly reduced concentrations of serum osteocalcin (P < 0.001) and urinary deoxypyridinoline (P < 0.001 and P < 0.05, respectively). Group 2 patients also showed significantly reduced serum free IGF-I (P < 0.001) and total IGF-I (P < 0.05) levels compared with the controls, but not with group 1. No statistically significant differences were found between the three groups with regard to IGFBP-3. Group 2 patients showed significantly higher spontaneous IL-6 release than group 1 patients and controls (P < 0.001). BUA Z-scores displayed a significant correlation with free IGF-I in group 2 (r = 0.96; P < 0.001), group 1 (r = 0.56; P = 0.005) and controls (r = 0.50; P < 0.001). CONCLUSION: Our study shows that only patients affected by perinatal HIV-1 infection with severe clinical manifestations present significant changes in bone quality and bone metabolism. Our data also show that impairment of skeletal status is related to reduction in serum total and free IGF-I. Children with perinatal HIV-1 infection, because of a considerable improvement in life expectancy, seem at great risk of not obtaining an optimal bone mass. A possible therapeutic approach should be considered in these children.