Francesca Severi

Central diabetes insipidus in children and young adults

BACKGROUND Central diabetes insipidus is rare in children and young adults, and up to 50 percent of cases are idiopathic. The clinical presentation and the long-term course of this disorder are largely undefined. METHODS We studied all 79 patients with central diabetes insipidus who were seen at four pediatric endocrinology units between 1970 and 1996. There were 37 male and 42 female patients whose median age at diagnosis was 7.0 years (range, 0.1 to 24.8). All patients underwent magnetic resonance imaging (MRI) and periodic studies of anterior pituitary function. The median duration of follow-up was 7.6 years (range, 1.6 to 26.2). RESULTS The causes of the central diabetes insipidus were Langerhans-cell histiocytosis in 12 patients, an intracranial tumor in 18 patients, a skull fracture in 2 patients, and autoimmune polyendocrinopathy in 1 patient; 5 patients had familial disease. The cause was considered to be idiopathic in 41 patients (52 percent). In 74 patients (94 percent) the posterior pituitary was not hyperintense on the first MRI scan obtained, and 29 patients (37 percent) had thickening of the pituitary stalk. Eighteen patients had changes in the thickness of the pituitary stalk over time, ranging from normalization (six patients) or a decrease in thickness (one patient) to further thickening (seven patients) or thickening of a previously normal stalk (four patients). Anterior pituitary hormone deficiencies, primarily growth hormone deficiency, were documented in 48 patients (61 percent) a median of 0.6 year (range, 0.1 to 18.0) after the onset of central diabetes insipidus. CONCLUSIONS Most children and young adults with acquired central diabetes insipidus have abnormal findings on MRI scans of the head, which may change over time, and at least half have anterior pituitary hormone deficiencies during follow-up.

Final height in Turner syndrome patients treated with growth hormone.

Growth hormone (GH), alone or in combination with anabolic steroids, seems to improve the growth rate in Turner syndrome, but to exert a less striking effect on the final height (FH). Reports on the FH usually lack a control group, and the GH effect is determined using the gain in centimeters over projected height. Out of a cohort of 32 Turner syndrome girls under recombinant human GH (rhGH) therapy (0.5 IU/kg/week during the 1st year and 1 IU/kg/week subsequently), 18 (treated for 3-6 years) attained FH. The mean chronological age at the first examination was 9.6 +/- (SD) 2.1 years and at the start of GH therapy 13.0 +/- 2.0 (range 8.8-17.2) years. Eighteen untreated subjects matched for chronological age and karyotype served as control group. The FH as SDS according to Lyon and to unpublished Italian Turner syndrome girl standards was not significantly different as compared with pretreatment. In comparison with Italian cross-sectional Turner syndrome standards (FH 142.5 +/- 7.0 cm), the FH of the control group was quite similar (142.2 +/- 4.9 cm), whereas the rhGH-treated group showed a FH of 147.6 +/- 7.3 cm with a mean increment of about 5 cm. The height gain during therapy (as delta height in SDS either according to Lyon or to Italian SDS standards) was compared for each girl with that of a matched girl of the control group during a comparable observation period. A significantly different delta height was observed in the treated versus control groups: 0.3 +/- 1.1 vs. -1.0 +/- 0.8 according to Lyon (p < 0.001) and 0.8 +/- 0.7 vs -0.3 +/- 0.5 according to Italian standards (p < 0.001). If we compared the FH with the projected height according to Lyon standards, the height gain (as delta height in cm) was significantly higher than in the untreated subjects (-1.1 +/- 4.8 vs. -6.2 +/- 3.9 cm; p < 0.05). It seems worthwhile to undertake GH treatment in Turner syndrome girls who represent a very short stature population, even though the response is less significant than in classic GH deficiency and shows a striking variability, probably due to a sort of peripheral resistance.

Dynamic MRI in the congenital agenesis of the neural pituitary stalk syndrome: the role of the vascular pituitary stalk in predicting residual anterior pituitary function

OBJECTIVE Magnetic resonance imaging (MRI) without contrast medium is unable to give detailed information on the hypothalamic‐pituitary structures. MRI using gadopentetate dimeglumine (Gd‐DTPA), and dynamic MRI, were performed in patients with hypopituitarism previously diagnosed as having anterior pituitary hypoplasia, ectopic posterior pituitary and unidentified pituitary stalk (1) to determine whether Gd‐DTPA improves the delineation of hypothalamic‐pituitary structures; (2) to verify whether, if so, such improvement can be correlated with residual pituitary function in patients subjected to long‐term follow‐up; and (3) to identify the hypothalamic‐pituitary vascular network in such cases.

Hypopituitarism and Stalk Agenesis: A Congenital Syndrome Worsened by Breech Delivery?

Thirty-seven patients with idiopathic hypopituitarism, of whom 12 had multiple pituitary hormone deficiencies (MPHD) and 25 isolated growth hormone deficiency (IGHD), were evaluated by magnetic resonance imaging (MRI). Twenty-two of the 37 showed congenital anterior pituitary hypoplasia, stalk agenesis and ectopic posterior pituitary gland at the infundibular recess (group A), while the remaining 15 presented isolated anterior pituitary hypoplasia (group B). Perinatal histories obtained from all patients demonstrated that 18/22 children of group A (81.81%) had histories of adverse perinatal events, with breech presentation in 15 (68.18%). Twelve of 12 children of group A born by breech delivery developed MPHD; 3 born by cesarean section for breech presentation had only IGHD. Patients of group B had also a high incidence of perinatal insults (12/15, 80%), but breech delivery was markedly less frequent (13.33 vs. 68.18% of group A) and responsible for only IGHD. Group B had also higher percentages of maternal spontaneous abortion and low birth weight. Our study suggests that several factors may play a role in the development of growth hormone deficiency. Some patients had severe perinatal insults apparently leading to hypopituitarism. We were able to define by MRI a group of patients with congenital abnormalities, such as anterior pituitary hypoplasia, stalk agenesis and posterior pituitary ectopia, among whom breech presentation was very common. In this group, breech delivery was always followed by MPHD while cesarean or normal delivery in such patients was followed by IGHD only.

Hypothalamic-pituitary dwarfism: Comparison between MR imaging and CT findings

Magnetic Resonance (MR) imaging was carried out on 33 patients with idiopathic growth hormone deficiency, in 22 of whom CT scan had been carried-out previously. Twenty-one patients presented some complications at birth. Both MR and CT were positive in the evaluation of the sella. MR imaging exhibited a higher degree of accuracy than CT in the evaluation of pituitary gland, pituitary stalk and brain anomalies.On the basis of pituitary morphology demonstrated by MR imaging, and perinatal histories, a classification is proposed which divides our patients into three group: A) a first group of 13 patients presenting severe hypoplasia of the anterior pituitary lobe, hypoplasia of the stalk and ectopia of posterior lobe. The underlying cause of these anatomic defects might be developmental in origin, and date from early intrauterine life, probably worsened at birth. B) a second group of 10 patients presenting severe hypoplasia of the anterior pituitary lobe. A perinatal event and birth trauma might be responsible for pituitary damage. C) a third group of 10 patients with no morphological abnormalities of the pituitary gland. A derangement of the neuroendocrine mechanism which control the growth hormone secretion might account for these patients.

Comparison of clinical-radiological and molecular findings in hypochondroplasia

Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature. A mutation (N540K) in the fibroblast growth factor receptor 3 (FGFR3) gene was described in some patients with this condition. The aims of the study were to identify the frequency of the FGFR3 gene mutation, to define the salient clinical and radiological abnormalities of the affected subjects, and to verify the contribution of molecular findings to the clinical and radiological definition of hypochondroplasia. Based on the most common radiological criteria, we selected 18 patients with a phenotype compatible with hypochondroplasia. Height, sitting height, and cranial circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis, and left hand were also obtained. The presence of the N540K mutation was verified by restriction enzyme digestions. Half of our patients carried the N540K mutation. Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly. The association of the unchanged/narrow interpedicular distance with the fibula longer than the tibia was more common in patients with gene mutation. Although we did not find a firm correlation between genotype and phenotype, in our study the N540K mutation was most often associated with disproportionate short stature, macrocephaly, and with radiological findings of unchanged/narrow interpedicular distance and fibula longer than tibia.

Autoimmunity, HLA, Gm AND Km Polymorphisms in Turner's Syndrome

Considering the high frequency of autoimmune disorders in Turners syndrome and the close relationship between autoimmunity, HLA and immunoglobulin constant region gene polymorphisms, we studied 46 patients with Turners syndrome, by determination of autoantibodies, HLA histoglobulins and Gm and Km allotypes. OSA and in particular PCA resulted significantly more frequent in patients than in the controls. A higher frequency of HLA-A31, B38 antigens and of blanks at HLA-A locus was found in Turners subjects than in the controls. A31 was significantly more frequent in autoantibody positive patients while B38 was more frequent in autoantibody negative Turners subjects than in the controls. DR4 antigen was present only in autoantibody negative patients. Gm 3; 23; 5* phenotype was significantly less frequent, while Gm 3;..; 5* phenotype was more frequent in patients than in controls. Our data confirm the higher incidence of autoimmunity disorders in Turners syndrome than in normal subjects. Particular HLA and immunoglobulin types seem to mark this condition. The increase in the blank frequency at A locus could be explained by the presence of a rare antigen at HLA-A locus or a particularly elevated homozygous condition in these subjects.

Serum liver enzymes in Turner syndrome.

Abstract Increased serum concentrations of liver enzymes are sometimes observed, in the absence of clinical symptoms of liver disease, in patients with Turner syndrome. The purpose of this study was to evaluate, in our Turner patients, serum liver enzyme levels and to find a cause for their increase. In 70 Turner patients, serum AST, ALT, GGT levels were evaluated every 6 months during a period of 0.8–21.9 years. In patients in whom increased values of liver enzymes were found, serological markers for infectious hepatitis, serum hepatitis C virus RNA and virus genotype, IgG and IgA antibodies to gliadin and endomysium, coeruloplasmin, copper, α1-antitrypsin, total proteins and electrophoresis, IgG, IgA, IgM, fibrinogen, prothrombin, alkaline phosphatase, creatine kinase and total and direct bilirubin were also determined. Antinuclear, anti-smooth muscle and anti-liver-kidney microsome antibodies together with antithyroglobulin and anti-thyroid peroxidase antibodies were determined in all patients and in 166 age-matched female controls. In 22 patients, increased liver enzymes were observed, not related to karyotype. Follow-up showed that the hepatic disorder did not worsen with the time. Serological markers of hepatitis C virus were positive in three patients. When the serum liver enzyme increase was first observed in the other 19 patients with high enzyme levels (group A), 14 patients had never been submitted to hormonal treatment, 4 were on oestrogen/gestagen treatment and 1 was being treated with both growth hormone and oestrogen. Coeliac disease, α1-antitrypsin deficiency and Wilson disease were ruled out by appropriate investigations. In 8/19 group A patients, antinuclear and/or anti-smooth muscle antibodies were present versus 6/48 of patients with normal liver enzymes (group B). Thyroid antibodies were found in 8/19 patients in group A and in 13/48 in group B. Weight excess SDS was significantly higher in Turner girls with liver enzyme increase. Ultrasonography, performed in 17 patients of group A, showed mild hepatomegaly in 4 and increased echogenicity with fatty infiltration in 6. Conclusion Hepatic abnormalities in Turner syndrome are not progressive. Oestrogen should not be considered the main cause of increased liver enzymes in Turner syndrome since most of our patients with this finding had not been previously treated with oestrogens. An auto-immune pathogenesis might be considered in some cases, whereas the association with weight excess seems the most frequent cause of liver disorder in Turner syndrome.

Auto-immunity in children with diabetes mellitus and in their relatives.

Islet cell antibodies (ICA-IgG and complement-fixing-ICA), parietal cell antibodies (PCA), intestinal epithelial cell antibodies (IECA), thyroglobulin (TgA) and thyroid microsomal antibodies (MsA), antinuclear (ANA) and reticulin antibodics (RA), were studied in 55 insulin-dependent diabetic patients (30 males and 25 females), aged 2–19 years with diabetes from a few days up to 14 years. In 58% of the diabetics one or more autoantibodies were found: ICA-IgG (31%), CF-ICA (16%), PCA (34%), TgA (9%), MsA (9%), ANA (13%), RA (2%). Autoantibodies were significantly more frequent in females (76%) than in males (43%) (P<0.025). ICA-IgG, CF-ICA, PCA, ANA were significantly more frequent in patients than in controls. The frequency of ICA-IgG and CF-ICA was significantly higher during the first 3 years of disease than afterwards (P<0.001); a similar pattern was observed for PCA, TgA, MsA. Of the 87 parents and 30 siblings screened for ICA-IgG, CF-ICA, PCA, IECA, TgA, MsA, ANA and RA, 42 (44%) had one or more autoantibodies, which were more frequent in females than in males. Seven relatives (6%) were ICA-IgG positive (four mothers, two fathers and one brother), and only one mother, ICA-IgG negative, was CF-ICA positive. Other autoantibodies were also more frequent in parents than in controls. Autoantibody-positive relatives have been asymptomatic up to now.

Management of puberty in constitutional delay of growth and puberty.

Abstract Constitutional delay of growth and puberty (CDGP) is the most common presenting form of short stature, but no single test can infallibly discriminate CDGP and isolated hypogonado- trophic hypogonadism. Management of puberty in CDGP aims to optimise not only growth - maintaining body proportions and improving peak bone mass without impairing growth potential - but also well-being; for example, the distress boys often suffer because of their lack of growth and pubertal progression can affect their school performance and social relationships. Typical sex steroid treatments to induce puberty in boys with CDGP include testosterone (T) enanthate, T undecanoate, mixed T esters, T transdermal patches, and oxandrolone p.o. Compared with other regimens, short-course low-dose depot T i.m. is an effective, practical, safe, well tolerated, and inexpensive regimen. Some unresolved problems in management include optimal timing and dose of sex steroid treatment, the role of GH in CDGP, and the management of CDGP in girls.