The TAND checklist: a useful screening tool in children with tuberous sclerosis and neurofibromatosis type 1.

BACKGROUND: Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4-20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, -to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort. RESULTS: TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist. CONCLUSION: The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.

Perinatal Outcomes of Non-Primary Maternal Cytomegalovirus Infection: A 15-Year Experience.

OBJECTIVE: To evaluate perinatal outcomes in case of non-primary maternal cytomegalovirus (CMV) infection. METHODS: We performed a retrospective cohort study of pregnant women with active CMV infection referred to our unit over a 15-year period (January 2000 to December 2014). Non-primary infection was diagnosed on the basis of the results of confirmatory serological and virological tests (avidity test, immunoblotting, real-time PCR-DNA). The vertical transmission rate and the percentage of symptomatic congenital infection were determined in this group of patients. RESULTS: A total of 205 pregnant women were enrolled. Congenital infection occurred in 7 (3.4%) fetuses/neonates. Symptomatic disease was present at birth in 3 of the 7 congenitally infected neonates (1.5%). Two out of 3 symptomatic newborns presented a pathologic second-trimester ultrasound scan. CONCLUSION: Maternal immunity offers substantial protection against intrauterine transmission of CMV infection, but not against disease once the fetus is infected.

Evolving treatment implementation among HIV-infected pregnant women and their partners: results from a national surveillance study in Italy, 2001-2015.

BACKGROUND: The current global and national indications for antiretroviral treatment (ART, usually triple combination therapy) in adolescent and adults, including pregnant women, recommend early ART before immunologic decline, pre-exposure chemoprophylaxis (PrEP), and treatment of HIV-negative partners in serodiscordant couples. There is limited information on the implementation of these recommendations among pregnant women with HIV and their partners. METHODS: The present analysis was performed in 2016, using data from clinical records of pregnant women with HIV, followed between 2001 and 2015 at hospital or university clinics within a large, nationally representative Italian cohort study. The study period was divided in three intervals of five years each (2001-2005, 2006-2010, 2011-2015), and the analysis evaluated temporal trends in rates of HIV diagnosis in pregnancy, maternal antiretroviral treatment at conception, prevalence of HIV infection among partners of pregnant women with HIV, and proportion of seronegative and seropositive male partners receiving antiretroviral treatment. RESULTS: The analysis included 2755 pregnancies in women with HIV. During the three time intervals considered the rate of HIV diagnosis in pregnancy (overall 23.3%), and the distribution of HIV status among male partners (overall 48.7% HIV-negative, 28.6% HIV-positive and 22.8% unknown) remained substantially unchanged. Significant increases were observed in the proportion of women with HIV diagnosed before pregnancy who were on antiretroviral treatment at conception (from 62.0% in 2001-2005 to 81.3% in 2011-2015, P < 0.001), and in the proportion of HIV-positive partners on antiretroviral treatment (from 73.3% in 2001-2005 to 95.8% in 2011-2015, P = 0.002). Antiretroviral treatment was administered in 99.1% of the pregnancies that did not end early because of miscarriage, termination, or intrauterine death, and in 75.3% of those not ending in a live birth. No implementation of antiretroviral treatment was introduced among male HIV-negative partners. CONCLUSIONS: The results suggest good implementation of antiretroviral treatment among HIV-positive women and their HIV-positive partners, but no implementation, even in recent years, of Pre-Exposure Prophylaxis (PrEP) among uninfected male partners. Further studies should assess the determinants of this occurrence and clarify the attitudes and the potential barriers to PrEP use.

Congenital Cytomegalovirus Infection: Prognostic Value of Maternal DNAemia at Amniocentesis.

BACKGROUND: Human Cytomegalovirus (HCMV) is the most common cause of childhood hearing loss and can lead to neurodevelopmental delay. To date, few studies have examined the correlation between maternal viremia and congenital HCMV infection. The aim of our study was to ascertain if HCMV DNA in the peripheral blood of pregnant women with primary HCMV infection at the time of amniocentesis may have a prognostic value in terms of congenital infection and neonatal symptomatic disease. METHODS: We performed a prospective observational study of pregnant women referred to our maternal-fetal medicine division with suspected HCMV infection. Primary infection was diagnosed based on seroconversion for HCMV and/or HCMV immunoglobulin M-positive and low or moderate HCMV immunoglobulin G avidity. At the time of amniocentesis, maternal blood samples were collected and analyzed by means of real-time polymerase chain reaction to determine the presence of viral DNAemia. Fetuses and newborns were evaluated for the presence of congenital infection and symptomatic disease. RESULTS: A total of 239 pregnant women were enrolled; 32 blood samples (13.4%) were positive, and 207 (86.6%) were negative for HCMV DNA. The overall rate of transmission was 23.4%. Fifteen infected patients (26.8%) were symptomatic. Vertical transmission occurred in 14 women (43.8%) with positive and 42 (20.3%) with negative results for HCMV DNAemia (P = .006; odds ratio, 3.06; 95% confidence interval, 1.41-6.64). Symptomatic infection occurred in 6 (42.9%) infected fetuses or newborns from women with and in 9 (21.4%) from women without viral DNAemia (P = .16). CONCLUSION: Maternal viremia at amniocentesis is associated with a 3-fold greater chance of congenital infection, but it is not correlated with symptomatic disease.

Study of Soluble HLA-G in Congenital Human Cytomegalovirus Infection.

Human leukocyte antigen-G (HLA-G) is a nonclassical HLA class I antigen that is expressed during pregnancy contributing to maternal-fetal tolerance. HLA-G can be expressed as membrane-bound and soluble forms. HLA-G expression increases strongly during viral infections such as congenital human cytomegalovirus (HCMV) infections, with functional consequences in immunoregulation. In this work we investigated the expression of soluble (s)HLA-G and beta-2 microglobulin (component of HLA) molecules in correlation with the risk of transmission and severity of congenital HCMV infection. We analyzed 182 blood samples from 130 pregnant women and 52 nonpregnant women and 56 amniotic fluid samples from women experiencing primary HCMV infection. The median levels of sHLA-G in maternal serum of women with primary HCMV infection were higher in comparison with nonprimary and uninfected pregnant women (p < 0.001). AF from HCMV symptomatic fetuses presented higher sHLA-G levels in comparison with infected asymptomatic fetuses (p < 0.001), presence of HLA-G free-heavy chain, and a concentration gradient from amniotic fluid to maternal blood. No significant statistical difference of beta-2 microglobulin median levels was observed between all different groups. Our results suggest the determination of sHLA-G molecules in both maternal blood and amniotic fluid as a promising biomarker of diagnosis of maternal HCMV primary infection and fetal HCMV disease.

Diagnosis and prognosis of congenital CMV infection: a case report and review of the literature.

Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensori-neural hearing loss and neurodevelopmental sequelae. Despite these alarming facts, the general public healthcare system is often not aware of CMV and not enough is done to prevent congenital CMV infection.We describe the clinical and laboratory monitoring of a case with primary CMV infection occurring before the first trimester of gestation. Specific literature review is included in order to point out major goals achieved in the diagnosis and prognosis of congenital CMV infection and the many questions still unanswered. Serological diagnosis of primary CMV infection was performed based on serum-CMV specific-IgM antibodies, combined with low avidity anti-CMV IgG antibodies. The maternal infection was asymptomatic, as it is for most infections in immunocompetent patients. Therefore, disclosing primary infection depended on specific serological tests during the initial period of pregnancy (before weeks 12-16 of gestation). The invasive (amniocentesis) and non-invasive (ultrasonographic examination) prenatal tests, carried out at 21 weeks gestation, revealed a severe CMV infection in a fetus small for gestational age with ventriculomegaly. The presence of overt ultrasound abnormalities combined with high viral load in the amniotic fluid sampled at the appropriate times was highly suggestive of an unfavourable prognosis. The autopsy performed on the fetus confirmed severe disseminated CMV infection with histological brain damage.

Congenital cytomegalovirus infection and small for gestational age infants.

OBJECTIVE: To evaluate the incidence of infants with birth weight less than the 10(th) centile for small for gestational age (SGA) in primary maternal cytomegalovirus (CMV) infection and to determine whether SGA predicts poor neurodevelopmental outcome. METHODS: A retrospective cohort study, which included singleton live-born infants from pregnancies complicated by primary maternal CMV infection. Infants were classified as uninfected or infected based on viral virus isolation and real-time PCR in urine at birth. SGA neonates rate and long-term sequelae were evaluated. RESULTS: Between 2000 and 2012, 848 women with primary CMV infection were referred to our center with 588 infants assessed at birth. Congenital CMV infection was diagnosed in 119 cases (20%), of which 8 were SGA (6.7%) compared with 27 out of the 469 uninfected infants (5.7%) (p-value = 0.69). Among the 119 infected babies, 14 infants were symptomatic at birth or at postnatal follow-up (12%), of whom two were SGA compared with six out of the 105 asymptomatic neonates (5.7% versus 15%, respectively, p-value = 0.22). CONCLUSION: Congenital CMV infection does not seem to be associated with a higher incidence of SGA, and long-term outcomes do not seem to be affected by isolated impaired fetal growth.