Early neurodevelopmental outcomes in children with asymptomatic congenital CMV infection.

BACKGROUND: Approximately 85-90% of congenital cytomegalovirus infections (cCMV) are asymptomatic. Few studies have investigated early and long-term neurodevelopmental outcomes in children with asymptomatic cCMV (acCMV), and the data is contradictory. In the present study, we did investigate the effect of cCMV asymptomatic infection on neurological outcomes and in cognitive, language and motor development at 6 months of age. METHODS: Fifty-six children with cCMV asymptomatic infection were followed for 6 months, as part of a long-term surveillance program, examining their neurological and developmental outcomes. Neurological examination and Bayley-III Scales were performed. RESULTS: Clinical evaluation revealed that early neurological outcomes were essentially normal, with minor neurological deficits (i.e., tone abnormalities) in a subgroup of patients. Bayley-III scores were substantially in the normal range, with 14% showing a score less than 85 (-1SD) in the Motor Scale. Children's neurological and neurodevelopmental outcomes at 6 months of age did not differ according to the trimester of infection. CONCLUSIONS: Some infants with cCMV asymptomatic infection may present minor neurological abnormalities in early stages of life. It seems useful to monitor this population for early and late neurodevelopmental sequelae.

Neurodevelopmental outcome in one-year-old children born preterm: differences between low birth weight and very low birth weight.

BACKGROUND: In preterm infants, low birth weight represents one of the major risk factors for health and developmental issues. In Italy, most of the studies are focused on extremely preterm or Very and Extremely Low Birth Weight (VLBW, ELBW) children, whereas little data are available on the neurodevelopmental outcome of Low Birth Weight (LBW) children. We aimed to study the developmental profile of a group of preterm children at 12 months of corrected age, comparing cognitive, language and motor performances between LBW and VLBW. METHODS: We assessed 108 children born preterm (53 LBW and 55 VLBW) at 12 months of corrected age (M= 12.9 months; SD = .95) with Bayley-III. We compared the mean scores between and within groups and the rates of mild and severe delay using the Italian norms. RESULTS: LBW children performed better than VLBW peers, particularly in the cognitive and gross motor areas. No differences between groups were found in relation to language subscales. The rate of mild and severe delay is elevated in both groups, resulting significantly higher in the VLBW group only in the motor area. CONCLUSIONS: These results strongly suggest the need of a multidisciplinary follow-up to monitor the development of premature newborns, including those with birth weights above 1500 g. The early identification of cognitive, language and motor problems is essential to promote children's well-being and intervention prior to school entry.

Congenital hypothyroidism due to ectopic sublingual thyroid gland in Prader-Willi Syndrome: a case report.

BACKGROUND: Thyroid gland disorders are variably associated with Prader-Willi syndrome (PWS). Many of the clinical features in newborns with PWS are similar to those found in congenital hypothyroidism (CH). CASE PRESENTATION: We report a case of a girl with CH and PWS. At the age of 9 months CH caused by an ectopic sublingual thyroid was diagnosed, and hormone replacement therapy was started. In spite of this treatment a decrease in growth velocity, weight excess and delayed development were observed. At the age of 9 years PWS was suspected on the basis of phenotype and genetic tests confirmed a maternal uniparental disomy of chromosome 15. This is the second reported case of hypothyroidism due to an ectopic sublingual thyroid gland in PWS suggesting that, although rare, an association between CH and PWS may exist. In our case diagnosis of PWS was delayed because mental retardation, hypotonia, obesity and short stature were initially attributed to hypothyroidism. CONCLUSIONS: In this context PWS should be considered in obese children with CH who do not improve adequately with l-thyroxine therapy. Also, thyroid function in all PWS children should be assessed regularly in order to avoid delayed diagnosis of hypothyroidism.

Prevalence of maternal preconception risk factors: an Italian multicenter survey.

OBJECTIVES: Adequate preconception maternal health care is essential to reduce the risk of unwanted pregnancy outcomes and complications. Still, many women are exposed to a number of unhealthy risk factors both before and early in pregnancy. This study aimed to estimate the prevalence of a number of important preconception risk factors using data from a recent multicenter study in Italy. METHODS: The study was based on cross-sectional data from seven maternity clinics located in six different regions in Italy during the period January - June, 2012. Data on maternal preconception risk factors and characteristics were collected from 1,892 women who delivered healthy children and 320 women who were pregnant in the first trimester. RESULTS: About 97% of the women (n =2,212) were exposed to one or more preconception risk factors. The overall prevalence of the most essential maternal risk factors was as follows: 41% had a age ≥35 years, 36% mistimed or did not intend their pregnancy, 58% did not request a preconception health visit to their doctor, 76% did not use folic acid supplements before pregnancy, 26% smoked at the last menstrual period, 19% had a body mass index ≥25 kg/m2 before pregnancy, and 10% suffered from pregestational chronic diseases. The prevalence of certain variables varied between the maternity clinics. CONCLUSIONS: Many Italian women are exposed to a number of preconception risk factors that have been associated with adverse pregnancy complications and outcomes. More effective intervention programs to improve preconception health in Italian women are strongly needed.

Focal congenital hyperinsulinism managed by medical treatment: a diagnostic algorithm based on molecular genetic screening.

OBJECTIVE: Congenital hyperinsulinism (CHI) requires rapid diagnosis and treatment to avoid irreversible neurological sequelae due to hypoglycaemia. Aetiological diagnosis is instrumental in directing the appropriate therapy. Current diagnostic algorithms provide a complete set of diagnostic tools including (i) biochemical assays, (ii) genetic facility and (iii) state-of-the-art imaging. They consider the response to a therapeutic diazoxide trial an early, crucial step before proceeding (or not) to specific genetic testing and eventually imaging, aimed at distinguishing diffuse vs focal CHI. However, interpretation of the diazoxide test is not trivial and can vary between research groups, which may lead to inappropriate decisions. Objective of this report is proposing a new algorithm in which early genetic screening, rather than diazoxide trial, dictates subsequent clinical decisions. PATIENTS, METHODS AND RESULTS: Two CHI patients weaned from parenteral glucose infusion and glucagon after starting diazoxide. No hypoglycaemia was registered during a 72-h continuous glucose monitoring (CGMS), or hypoglycaemic episodes were present for no longer than 3% of 72-h. Normoglycaemia was obtained by low-medium dose diazoxide combined with frequent carbohydrate feeds for several years. We identified monoallelic, paternally inherited mutations in KATP channel genes, and (18) F-DOPA PET-CT revealed a focal lesion that was surgically resected, resulting in complete remission of hypoglycaemia. CONCLUSIONS: Although rare, some patients with focal lesions may be responsive to diazoxide. As a consequence, we propose an algorithm that is not based on a 'formal' diazoxide response but on genetic testing, in which patients carrying paternally inherited ABCC8 or KCNJ11 mutations should always be subjected to (18) F-DOPA PET-CT.

Residual ß-cell mass influences growth of prepubertal children with type 1 diabetes.

BACKGROUND: The growth deceleration observed in children with type 1 diabetes (T1D) has been related to poor glycemic control. It is unclear whether growth impairment persists despite the optimization of therapy. We analyzed the effects of intensive insulin treatment on prepubertal growth. METHODS: One hundred and four T1D children were evaluated from T1D diagnosis up to puberty onset. Height, weight, insulin requirement and glycated hemoglobin (HbA1c) were recorded at 3- to 6-month intervals. Residual ß-cell mass was estimated by fasting C-peptide at T1D onset. RESULTS: Age at T1D onset was 5.91 ± 1.9 years. Follow-up duration was 4.84 ± 1.58 years. Height velocity standard deviation score (SDS) was -0.14 ± 1.84. Height SDS changed from 0.52 ± 1.04 at T1D onset, to 0.36 ± 1.10 at the end of follow-up (p = 0.04). BMI SDS increased from -0.04 ± 1.48 to 0.32 ± 1.03 (p = 0.01). Multivariate analysis showed that height velocity was directly affected by C-peptide (p = 0.03) and insulin requirement (p = 0.004) and inversely related to HbA1c (p = 0.006). BMI gain was negatively influenced by HbA1c (p = 0.01) and positively related to T1D duration (p = 0.01). CONCLUSION: Despite insulin intensive therapy, T1D still negatively affects growth. Residual ß-cell mass has a direct positive impact on growth, independently from the quality of glycemic control.

Congenital hyperinsulinism: clinical and molecular analysis of a large Italian cohort.

Congenital hyperinsulinism (CHI) is a genetic disorder characterized by profound hypoglycemia related to an inappropriate insulin secretion. It is a heterogeneous disease classified into two major subgroups: "channelopathies" due to defects in ATP-sensitive potassium channel, encoded by ABCC8 and KCNJ11 genes, and "metabolopathies" caused by mutation of several genes (GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) and involved in different metabolic pathways. To elucidate the genetic etiology of CHI in the Italian population, we conducted an extensive sequencing analysis of the CHI-related genes in a large cohort of 36 patients: Twenty-nine suffering from classic hyperinsulinism (HI) and seven from hyperinsulinism-hyperammonemia (HI/HA). Seventeen mutations have been found in fifteen HI patients and five mutations in five HI/HA patients. Our data confirm the major role of ATP-sensitive potassium channel in the pathogenesis of Italian cases (~70%) while the remaining percentage should be attributed to other. A better knowledge of molecular basis of CHI would lead to improve strategies for genetic screening and prenatal diagnosis. Moreover, genetic analysis might also help to distinguish the two histopathological forms of CHI, which would lead to a clear improvement in the treatment and in genetic counseling.

Creatine metabolism in urea cycle defects.

Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 µmol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.