ABSTRACT
PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.
Subject(s)
Biosimilar Pharmaceuticals/therapeutic use , Growth Disorders/drug therapy , Human Growth Hormone/therapeutic use , Product Surveillance, Postmarketing/methods , Child , Female , Follow-Up Studies , Growth Disorders/epidemiology , Humans , Longitudinal Studies , Male , PrognosisABSTRACT
Ectodermal dysplasias are a group of genetic disorders defined by ectodermal derivative impairment (EDI). To test the impact of the Wnt/beta-catenin pathway in the genetic screening of EDI, we performed a molecular gene study of WNT10A in 60 subjects from a population of 133 young Italian patients referred for the impairment of at least one major ectodermal-derived structure and who had a previous negative molecular screen for ectodysplasin signaling pathway genes ED1, EDAR, and EDARADD. Fourteen WNT10A mutations were identified in 33 subjects (24.8%), 11 of which were novel variants. The phenotype was evaluated through a detailed clinical examination of the major and minor ectodermal-derived structures. This study is the first to show that, after ED1, WNT10A is the second molecular candidate for EDI in a large Italian Caucasian population. The study confirmed that Phe228Ile is the most frequent WNT10A variant in Caucasian populations, and that WNT10A mutations are associated with large variability in EDI.
Subject(s)
Ectodermal Dysplasia/diagnosis , Ectodermal Dysplasia/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Wnt Proteins/genetics , Adolescent , Adult , Alleles , Amino Acid Substitution , Child , Child, Preschool , Female , Genetic Association Studies/methods , Humans , Male , Mutation , Phenotype , Young AdultABSTRACT
Ectodermal dysplasias (EDs) are a group of genetic disorders characterized by the abnormal development of the ectodermal-derived structures. X-linked hypohidrotic ectodermal dysplasia, resulting from mutations in ED1 gene, is the most common form. The main purpose of this study was to characterize the phenotype spectrum in 45 males harboring ED1 mutations. The study showed that in addition to the involvement of the major ectodermal tissues, the majority of patients also have alterations of several minor ectodermal-derived structures. Characterizing the clinical spectrum resulting from ED1 gene mutations improves diagnosis and can direct clinical care.
Subject(s)
Ectodermal Dysplasia 1, Anhidrotic/genetics , Ectodermal Dysplasia 1, Anhidrotic/pathology , Ectodysplasins/genetics , Mutation/genetics , Phenotype , Cohort Studies , Ectodermal Dysplasia 1, Anhidrotic/classification , Humans , Italy , MaleABSTRACT
The congenital vomer defect (CVD) is a rare and still partially unknown condition. Only few cases have been reported in the international literature and the large majority of them appeared to be isolated. We report a case of CVD detected in a 7-year-old girl affected by ectodermal dysplasia clefting syndrome caused by a mutation of the TP63 gene.
Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Ectodermal Dysplasia/genetics , Transcription Factors/genetics , Tumor Suppressor Proteins/genetics , Vomer/abnormalities , Abnormalities, Multiple/diagnosis , Child , Cleft Lip/surgery , Cleft Palate/surgery , Female , Heterozygote , Humans , Magnetic Resonance Imaging/methods , Mutation , Nasal Septum/abnormalities , Rare Diseases , SyndromeABSTRACT
Acute respiratory tract infections (ARTIs) are the most frequent illnesses in pediatric age, frequently experienced in children with Down Syndrome (DS) due to the associated immune defects of both specific and non-specific immunity. Pidotimod, a synthetic immunostimulant, was shown to reduce the rates of ARTIs in children with DS, however the mechanisms associated with this effect is currently unknown. We analyzed immune parameters in DS children who received the seasonal 20112012 virosomal-adjuvanted influenza vaccine. Eighteen children aged 3-10 years (mean age 7.1+/-2.6 years) were randomly assigned (1:1 ratio) to receive Pidotimod 400 mg, administered orally once a day for 90 days or placebo. At the recruitment (T0) all children received a single dose of virosomal-adjuvanted influenza vaccine (Flu). Blood samples were collected at T0 and 3 months after the recruitment (T3) in order to evaluate innate and adaptative immune responses pathway. Flu-specific IgG1 and IgG3 levels in plasma samples were determined at pre-vaccination (T0), and 1 (T1) and 3 months (T3) post-vaccination. The use of Pidotimod was associated with the upregulation of a number of genes involved in the activation of innate immune responses and in antimicrobial activity. Interestingly the ratio of Flu-specific IgG1/IgG3 was skewed in pidotimod-treated individuals, suggesting a preferential activation of complement-dependent effector mechanisms. Although preliminary these data suggest that Pidotimod can potentiate the beneficial effect of immunization, possibly resulting in a stronger activity of both innate and adaptive immune responses.
Subject(s)
Down Syndrome/drug therapy , Down Syndrome/immunology , Immunologic Factors/therapeutic use , Pyrrolidonecarboxylic Acid/analogs & derivatives , Thiazolidines/therapeutic use , Adaptive Immunity/drug effects , Adaptive Immunity/genetics , Child , Child, Preschool , Down Syndrome/blood , Female , Gene Expression Regulation/drug effects , Humans , Immunity, Innate/drug effects , Immunity, Innate/genetics , Immunoglobulin G/blood , Immunologic Factors/immunology , Immunologic Factors/pharmacology , Influenza Vaccines/immunology , Male , Pyrrolidonecarboxylic Acid/immunology , Pyrrolidonecarboxylic Acid/pharmacology , Pyrrolidonecarboxylic Acid/therapeutic use , Thiazolidines/immunology , Thiazolidines/pharmacology , Vaccines, Virosome/immunologyABSTRACT
AIMS/HYPOTHESIS: The aim of this study was to assess the prevalence of glucokinase gene mutations in Italian children with MODY and to investigate genotype/phenotype correlations of the mutants. METHODS: Screening for sequence variants in the glucokinase gene was performed by denaturing gradient gel electrophoresis and direct sequencing in 132 children with maturity onset diabetes of the young (MODY) and in 9 children with chronic fasting hyperglycaemia but without laboratory evidence for Type I (insulin-dependent) diabetes mellitus and with normoglycaemic parents ("non-classical" MODY). RESULTS: Altogether 54 mutations were identified in the MODY group (54/132 or 41%) and 3 among the "non-classical" MODY individuals (3/9 or 33%). Paternity testing indicated that the latter mutations have arisen de novo. Mean fasting plasma glucose concentrations of the children with the mutant glucokinase was in the expected impaired fasting glucose range. In contrast, results of the oral glucose tolerance test showed a wide range from normal glucose tolerance (Group 1: 2-h OGTT = 6.7 +/- 1.1 mmol/l; 11 patients) to diabetes (Group 2: 2-h OGTT = 11.5 +/- 0.5 mmol/l; 9 patients), with the remaining in the impaired glucose tolerance range. Disruptive mutations (i.e. nonsense, frameshifts, splice-site) were equally represented in Groups 1 and 2 and were not clearly associated with an impaired first-phase insulin response. Surprisingly, 5 out of 11 children (or 45%) in Group 1 were found to be overweight but no children in Group 2 were overweight. Sensitivity index (SI), calculated by a recently described method, was found to be significantly lower in Group 2 than in Group 1 (SI Group 2 = 0.0013 +/- 0.0009 ml Kg(-1) min(-1)/muU/ml; SI Group 1 = 0.0068 +/- 0.0048, p < 0.0035). CONCLUSION/INTERPRETATION: Mutations in glucokinase are the first cause of MODY among Italian children selected through a low threshold limit of fasting plasma glucose (i. e. > 5.5 mmol). The lack of correlation between the molecular severity of glucokinase mutations, insulin secretion at intravenous glucose tolerance test and differences in glucose tolerance suggests that factors outside the beta cell are also involved in determining post-load glucose concentrations in these subjects. Our results seem to indicate that the differences observed in the 2-h responses at the OGTT among children with MODY 2 could be related to individual differences in insulin sensitivity.
Subject(s)
Blood Glucose/metabolism , Body Mass Index , Diabetes Mellitus, Type 2/genetics , Glucokinase/genetics , Insulin/metabolism , Mutation , Amino Acid Substitution , Child , Conserved Sequence , Diabetes Mellitus/enzymology , Diabetes Mellitus/physiopathology , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/physiopathology , Fasting , Female , Glucose Tolerance Test , Humans , Hyperglycemia/blood , Insulin/blood , Insulin Resistance/genetics , Insulin Secretion , Italy , Male , Mutation, Missense , Obesity , Pedigree , Sensitivity and SpecificityABSTRACT
Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant monogenic form of type 2 diabetes mellitus (DM) representing 5% of youth-onset DM in the Caucasian population. In young adults the disease can be present as either non-insulin dependent or insulin-dependent DM. The diagnosis of this genetic disorder in children and adolescents is rare because of the mild glucose metabolism disorder at this time. We performed a metabolic, autoimmune and genetic study in 40 offspring of young parents affected by insulin-dependent DM (Group A) and in 35 offspring of young parents affected by early-onset non-insulin-dependent DM (Group B). Two children of Group A (5%) were found to be affected by fasting hyperglycemia and carry a GCK gene mutation that in one case was present also in the diabetic father. Eighteen offspring of Group B (51%) were positive for GCK or HNF-1alpha gene mutations present in the affected parents. All but two of these young patients had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Eleven of them were younger than 16 years. We conclude that screening for DM in youth should be extended to MODY in young families with both non-insulin-dependent and insulin-dependent DM. The sensitivity of the metabolic tests will precede the genetic diagnosis.
Subject(s)
DNA-Binding Proteins , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Nuclear Proteins , Adolescent , Blood Glucose/analysis , Child , Child, Preschool , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Fasting/blood , Glucokinase/genetics , Glucose Intolerance/etiology , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Humans , Hyperglycemia , Mutation , Parents , Transcription Factors/geneticsABSTRACT
The differential diagnosis of hyperglycemia in childhood and adolescence has to take into consideration early-onset non-insulin-dependent diabetes, defined as maturity onset diabetes of the young (MODY). To date, mutations in genes of five proteins have been shown to cause MODY: glucokinase (MODY2), hepatic nuclear factor-1 alpha (HNF-1 alpha) (MODY3), hepatic nuclear factor-4 alpha (HNF-4 alpha) (MODY1), insulin promoter factor 1 (IPF-1) (MODY4) and hepatic nuclear factor-1 beta (HNF-1 beta) (MODY5), but other MODY genes still await elucidation. Clinical and metabolic heterogeneity of these subtypes of type 2 diabetes need to be defined, as deficiency of each factor has its own phenotype. Pediatric diabetologists should be aware of the increasing importance of MODY as a possible cause of hyperglycemia in children and adolescents. This will allow for the early diagnosis of these metabolic conditions and for the appropriate follow-up and treatment.
Subject(s)
DNA-Binding Proteins , Diabetes Mellitus, Type 2 , Homeodomain Proteins , Nuclear Proteins , Pediatrics , Adolescent , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Child , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Glucokinase/genetics , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Hepatocyte Nuclear Factor 4 , Humans , Insulin/metabolism , Insulin/pharmacology , Insulin Secretion , Mutation , Phosphoproteins/genetics , Trans-Activators/genetics , Transcription Factors/geneticsABSTRACT
To study the heterogeneity of islet cell antibodies (ICA), recombinant rat and human GAD65 expressed as bacterial fusion proteins were used to inhibit ICA reactivity in sera from recent onset type 1 diabetic children and ICA-positive first degree relatives of diabetic patients. Rat GAD65 was expressed as a fusion protein in the expression vector RSET and inhibited ICA (GAD+ICA) in 26% of 23 recent onset patients, 29% of 14 ICA positive first degree relatives (FDR) who progressed to diabetes (prediabetics) and 50% of 20 FDR who did not progress to diabetes 18 months to 5 years (31 +/- 14 months) after collection of the sample. GAD+ICA were inversely associated with the presence of insulin autoantibodies (IAA) (P = 0.006). GAD antibodies (GAD-Ab) were also detected by immunoprecipitation of in vitro transcribed and translated [35S] methionine-labelled human GAD65. GAD-Ab were present in 83% of recent onset patients, 86% of prediabetics and 95% of the relatives who did not progress to diabetes. The level of GAD-Ab was higher in the presence of GAD+ICA (1.39 +/- 0.57 vs 0.79 +/- 0.6 index units; P = 0.001). ICA levels were higher in GAD-Ab negative than in GAD-Ab positive sera (377 +/- 256 vs 195 +/- 231 JDFU; P = 0.03). Our results confirm that a recombinant GAD65 fusion protein can be used to detect ICA heterogeneity. However, neither inhibition of ICA with recombinant GAD, nor direct detection of GAD-Ab improved the prediction of progression to clinical diabetes in ICA positive FDR.
Subject(s)
Autoantibodies/immunology , Diabetes Mellitus, Type 1/immunology , Glutamate Decarboxylase/immunology , Adolescent , Animals , Child , Disease Progression , Female , Follow-Up Studies , Gene Expression , Glutamate Decarboxylase/genetics , Humans , Male , Precipitin Tests , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunologyABSTRACT
We evaluated the pituitary and gonadal suppression in 40 girls and nine boys treated with depot leuprorelin (3.75 mg sc if body weight > or = 20 kg, 1.87 mg if body weight < 20 kg) every 28 days for central precocious puberty. Gonadal suppression was obtained in most of the children with this dose: 3 months after initiation of the treatment, 85% of children had a peak plasma luteinizing hormone response to gonadotropin-releasing hormone < 3 IU/l and the gonadal axis remained suppressed throughout the duration of the study (up to 24 months). Four patients required higher doses of leuprorelin to achieve suppression. In two girls, a cutaneous reaction to the drug was associated with incomplete suppression and the treatment had to be interrupted. Plasma leuprorelin levels tended to increase from day 3 to day 28 after injection. Residual leuprorelin levels measured 28 days after injection were stable during the first year of the study. We conclude that an initial dose of depot leuprorelin of 3.75 mg sc every 28 days is efficient in most children with central precocious puberty.
Subject(s)
Leuprolide/administration & dosage , Puberty, Precocious/drug therapy , Bone Development/drug effects , Child , Delayed-Action Preparations , Drug Eruptions/etiology , Drug Tolerance , Female , Gonadotropin-Releasing Hormone/pharmacology , Growth/drug effects , Headache/etiology , Humans , Leuprolide/adverse effects , Leuprolide/blood , Luteinizing Hormone/blood , Male , Puberty, Precocious/blood , Puberty, Precocious/pathologyABSTRACT
Metabolic control and psychological parameters in forty insulin-dependent diabetic adolescents were evaluated during a sequential crossover study comparing two insulin regimens: a) 6 months of conventional insulin therapy (CIT) (T0-T1) using twice-daily mixture of short-acting and intermediate-acting insulins (AcHM and MoHM); b) 6 months of intensified insulin therapy (IIT) (T1-T2) using two pre-meal injections of short-acting insulin (AcHM) and one pre-dinner mixture of short-acting plus ultralente-acting insulin (AcHM + UtHM). Twenty patients received the pre-meal short-acting insulin with a pen-injector (group A) and twenty with conventional syringes (group B). All of participant received the pre-dinner insulin mixture with traditional syringes. Fasting blood glucose (BG), fructosamine, HbA1c, anxiety, depression levels and patient daily life adjustment (T1, T2) were investigated. The metabolic parameters showed similar results in both groups. There was no fasting BG variation during IIT, while post-meal (lunch and dinner) BG reduction (p less than 0.01) was observed. HbA1c levels didn't decrease but fructosamine levels significantly decreased at T2 time. Severe hypoglycemia where never observed, while the frequency of slight hypoglycaemic reactions didn't change during the study. The psychological parameters showed no differences at T0 and T1, while the differences became remarkable between the groups at T2 time. Home anxiety slightly decreased in group A and increased in group B (p less than 0.05). In group A an improvement of self-care initiative (self-injections) occurred too. In conclusion this study showed that, in a limited group of insulin-dependent diabetic adolescents, IIT with three daily injections improved fructosamine and post-meal BG levels.(ABSTRACT TRUNCATED AT 250 WORDS)