Silvia Vannelli

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 Turners Syndrome (ISGTS) undertook a nationwide survey, involving the retrospective collection of cross‐sectional data and longitudinal growth profiles of 772 girls with Turners 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.

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 μg/l) revealed an interrupted pituitary stalk and ectopic neurohypophysis or a mass. In patients with less serious isolated growth hormone deficiency (growth hormone > 3 μg/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.

Impaired GH Secretion in Patients with SHOX Deficiency and Efficacy of Recombinant Human GH Therapy

Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height –2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from –1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from –2.41 ± 0.71 to –1.81 ± 0.87; p < 0.001), and IGF-1 values (from –0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = –0.618, p = 0.032), bone age (r = –0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature

Leri–Weill dyschondrosteosis is a pseudoautosomal dominantly‐inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non‐coding cis‐regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non‐coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX‐related disorders, we describe seven patients (five with Leri‐Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non‐coding element regions, identified by multiplex ligation‐dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation‐dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri–Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis‐regulatory DNA elements can result in a SHOX‐related phenotype.

Combined therapy with insulin and growth hormone in 17 patients with type-1 diabetes and growth disorders.

Background/Aim: Combined growth hormone (GH) and insulin therapy is rarely prescribed by pediatric endocrinologists. We investigated the attitude of Italian physicians to prescribing that therapy in the case of short stature and type-1 diabetes (T1DM). Methods: A questionnaire was sent and if a patient was identified, data on growth and diabetes management were collected. Results: Data from 42 centers (84%) were obtained. Of these, 29 centers reported that the use of combined therapy was usually avoided. A total of 17 patients were treated in 13 centers (GH was started before T1DM onset in 9 patients and after the onset of T1DM in 8). Height SDS patterns during GH therapy in the 11 patients affected by GH deficiency ranged from -0.3 to +3.1 SDS. In the 8 diabetic patients in whom GH was added subsequently, mean insulin dose increased during the first 6 months of therapy from 0.7 ± 0.2 to 1.0 ± 0.2 U/kg (p = 0.004). HbA1c was unchanged during the first 6 months of combined therapy. Conclusions: Most Italian physicians do not consider prescribing the combined GH-insulin therapy in diabetic children with growth problems. However, the results of the 17 patients identified would confirm that the combined therapy was feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth in most patients and did not affect diabetes metabolic control.

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 μg/kg iv)+pyridostigmine (120 mg po) + GnRH (100 μg iv) + TRH (400 μg iv) + hCRH (100 μg 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 μg/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 μg/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 μg/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 hy-pothalamo-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.

Evaluation of Tibial Osteopathy Occurrence in Neurofibromatosis Type 1 Italian Patients

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disorder characterized by high penetrance, widely variable expressivity and occurrence of specific skeletal changes such as tibial osteopathy (TO). We collected data on patients referred to the Italian Neurofibromatosis Study Group in order to compare clinical features between 49 NF1 patients with TO, and 98 age‐matched NF1 patients without TO, and to determine whether the presence of TO is associated with a different risk of developing the typical NF1 complications. We assessed both groups for: age at diagnosis of NF1, gender distribution, family history, gender inheritance, presence of scoliosis, sphenoid wing osteopathy, other skeletal abnormalities, macrocrania, hydrocephalus, plexiform neurofibromas, tumors, optic pathway gliomas, T2H (high‐signal intensity areas on T2 weighted brain MRI), epilepsy, headache, mental retardation, cardiovascular malformations, and Noonan phenotype. Patients of both groups were subdivided by gender and re‐evaluated for these items. Statistical comparison was carried out between the two groups of patients for each feature. We collected data on type of treatment and on the clinical conditions of NF1‐TO patients after follow‐up. Patients age at NF1 diagnosis was significantly younger in NF1‐TO subjects compared with NF1 subjects without TO, and the incidence of T2H was significantly reduced in NF1‐TO males compared with NF1 males without TO. The presence of TO does not imply that there is an increased risk of developing typical complications of NF1 (e.g., optic pathway glioma, plexiform neurofibroma, etc.), however, it does allow us to make an earlier diagnosis of NF1.