Neonatal liver failure and haemophagocytic lymphohistiocytosis caused by a new perforin mutation.

UNLABELLED: Acute liver failure is a rare heterogeneous syndrome in neonates. We report of a newborn with haemophagocytic lymphohistiocytosis presenting as acute liver failure. Pancytopenia and multi-organ failure occurred later in the course. He carried two mutations of the perforin gene (PRF-1), one of which not previously described, causing a complete loss of perforin expression and natural killer cell function. CONCLUSION: Perforin expression and function should be promptly assessed in neonatal/infantile acute liver failure, as haemophagocytic lymphohistiocytosis requires specific treatment and represents a contra-indication to liver transplant.

RFT1-CDG: deafness as a novel feature of congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis of glycans and in the attachment of glycans to lipids and proteins. Actually, some 42 CDG are known including defects in protein N-glycosylation, in protein O-glycosylation, in lipid glycosylation, and in multiple and other glycosylation pathways. Most CDG are multisystem diseases and a large number of signs and symptoms have already been reported in CDG. An exception to this is deafness. This symptom has not been observed as a consistent feature in CDG. In 2008, a novel defect was identified in protein N-glycosylation, namely in RFT1. This is a defect in the assembly of N-glycans. RFT1 is involved in the transfer of Man(5)GlcNAc(2)-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum. According to the novel nomenclature (non-italicized gene symbol followed by -CDG) this defect is named RFT1-CDG. Recently, three other patients with RFT1-CDG have been reported and here we report two novel patients. Remarkably, all six patients with RFT1-CDG show sensorineural deafness as part of a severe neurological syndrome. We conclude that RFT1-CDG is the first 'deafness-CDG'. CDG should be included in the work-up of congenital, particularly syndromic, hearing loss.

Cannula tip intravascular migration in an infant.

In infants, the tip of a cannula is sometimes used as introducer during peripherally inserted central catheters placement. We report a rare complication of this procedure, characterized by intravascular migration of the cannula tip during peripheral insertion of a central venous catheter. We review this unlikely complication and treatment options.

Birth weight discordancy in twins: new definition and standard.

OBJECTIVE: The aim of this study was to improve the definition of birth weight discordancy based on its distribution in the population after a correction in the unlike sex pairs. STUDY DESIGN: The analysis was conducted on 849 Italian twin pairs. Male's birth weight in the unlike sex pairs was corrected by the physiological birth weight difference estimated on 21.595 Italian twins data. Birth weight discordancy was computed as a percentage of the larger twin's birth weight and it was compared by sex pairs and by gestational ages (Kruskal-Wallis test). Kolmogorov-Smirnov test was used to fit a normal distribution to the square-root transformed birth weight discordancy. RESULTS: The estimated physiological birth weight difference between males and females was 4.39%, without any difference among gestational ages. The 90th centile of birth weight discordancy was 23.9% and the 95th centile was 29.2%. CONCLUSIONS: Ninetieth and 95th centiles of the fitted distribution are proposed as cut-off values for the definition of mild and severe birth weight discordancy.

Clinical approach to the analysis of causes of death in the first two years of life of very-low-birthweight infants in a multicentre setting.

Mortality in the first 2 years of 634 very-low-birthweight infants admitted to eight neonatal intensive care units in Italy, and the factors associated with the net probability of death from each cause, were studied by means of the Cox proportional hazard model. A clinical classification of the causes of death was used. Overall mortality was 33.7% (intercentre range 12.6-52.9%). The highest cause-specific mortality rates were observed for respiratory problems, intra-ventricular haemorrhage (IVH) and infections (14.5%, 6.3% and 5.7% respectively). The leading causes of death were respiratory problems and IVH in the first week of life, infections from the second week up to the end of the first month, and bronchopulmonary dysplasia (BPD) afterwards. Birthweight < 1000 g, gestational age < 30 weeks, absence of spontaneous respiratory activity, unknown body temperature and pH < 7.20 at admission were associated with death from respiratory problems and IVH. Male sex, birthweight < 1000 g and unknown body temperature at admission were associated with death from BPD. Mortality from infections was higher in one centre; no other differences emerged among the eight NICUs. The classification of the causes of death employed and the use of the net probabilities of death appear as practical and useful instruments to study the relationship between specific aspects of medical care and mortality, and to investigate the reasons for differences in performance between neonatal units.

What proportion of multiple births are due to ovulation induction? A register-based study in Italy.

OBJECTIVES: This study evaluated the increase in risk of multiple births associated with ovulation induction and calculated the proportion of multiple births attributable to this treatment. METHODS: Cases were 350 multiple births and controls were 737 single births enrolled from April 1993 to March 1994 in the Mercurio Project, an investigation of reproductive outcomes in Italy. RESULTS: Ovulation induction was used in 45 case births (12.9%) and 24 control births (3.3%); the adjusted odds ratio was 4.1 (95% confidence interval [CI] = 2.4, 6.9). The odds ratio for triplet or higher order births was 72.2 (95% CI = 25.7, 202.8). When unlike-sexed multiple births were considered, the odds ratio increased for twin births, but not for triplet or higher births. The highest odds ratios were found when ovulation induction was used with assisted reproduction. The proportion of multiple births attributable to ovulation induction was 9.7% overall, 5.4% for twin births, and 69.8% for triplet or higher births. CONCLUSIONS: Ovulation induction increases the risk of multiple births and has been responsible for the rise in the rate of triplet or higher order births in Italy in the last decade. Its indiscriminate and improper use should be avoided.

Is maternal asthma a risk factor for low birth weight? Results of an epidemiologic survey.

The association between history of asthma in the mother and low birth weight (< 2,500 g) was studied in 2,929 primary schoolchildren, randomly selected from three areas of the Lazio Region, Italy, and enrolled in a cross-sectional survey to assess their health status in relation to environmental factors. A history of asthma in the mother was associated with a higher prevalence of low birth weight, with a crude OR of 2.95 (95% CI 1.10-6.72). After stratification for other variables, an association was still present only for males (OR 4.13; 95% CI 1.01-12.53), when mothers had smoked in pregnancy (OR 8.02; 95% CI 1.63-32.28) and were resident in an industrial town (OR 10.21; 95% CI 2.69-32.27). An OR of 6.43 was also found when mothers belonged to low social class, but the 95% CI included the unity. These results suggest that a history of asthma in the mother is a risk factor for low birth weight, but only when other adverse factors are concurrently present.

Ultrasonography in pregnancy and fetal abnormalities: screening or diagnostic test? IPIMC 1986-1990 register data. Indagine Policentrica Italiana sulle Malformazioni Congenite.

The aim of the present study was to assess the sensitivity of ultrasound diagnosis used as a screening test in detecting major congenital anomalies in the prenatal period in a large nation-based multicentre setting. Data from the IPIMC register were collected in the period 1986-1990. One hundred and thirty-five hospitals, located in 17 out of the 20 regions in Italy, participated in the register. Study cases were 3479 infants with major congenital anomalies diagnosed at birth or in the first week of life. Subjects with chromosomal anomalies or multiple defects were excluded. The sensitivity of ultrasound prenatal diagnosis was 49.5 per cent for central nervous system anomalies, 3.8 per cent for congenital heart diseases, 17.1 per cent for gastrointestinal tract defects, 46.6 per cent for abdominal wall defects, 74.8 per cent for urinary tract anomalies, and 22.9 per cent for skeletal abnormalities. The detection rate for diaphragmatic hernia was 24.2 per cent. Overall, only 18 per cent of the defects diagnosed in utero were detected before 24 weeks' gestation. The sensitivity of prenatal diagnosis was 30.1 and 19.0 per cent in the northern, central, and southern regions, respectively. In light of its low sensitivity, ultrasonography as a screening test in the general population should be abandoned, although some improvement in its performance should be expected following adequate training of the ultrasound staff and the use of good technical equipment.

Favism in a female newborn infant whose mother ingested fava beans before delivery.

We describe a case of favism in a female newborn infant with glucose-6-phosphate dehydrogenase (G6PD) deficiency whose mother had ingested fava beans 5 days before delivery. At birth there were clinical and hematologic signs of hemolytic anemia, hemoglobinuria, and no blood group immunization. Study of the G6PD activity and 2-deoxy-glucose-6-phosphate utilization rate revealed that the infant and the mother were heterozygous for G6PD deficiency.

Epidemiology and genetics of microtia-anotia: a registry based study on over one million births.

The epidemiology and genetics of microtia-anotia (M-A) were studied using data collected from the Italian Multicentre Birth Defects Registry (IPIMC) from 1983 to 1992. Among 1,173, 794 births, we identified 172 with M-A, a rate of 1.46/10,000; 38 infants (22.1%) had anotia. Of the 172 infants, 114 (66.2%) had an isolated defect, 48 (27.9%) were multiformed infants (MMI) with M-A, and 10 (5.8%) had a well defined syndrome. The frequency of bilateral defects among non-syndromic cases was 12% compared to 50% of syndromic cases (p = 0.007). Among the MMI only holoprosencephaly was preferentially associated with M-A (four cases observed upsilon 0.7 expected, p = 0.005). No significant variations were identified in the prevalence of non-syndromic cases by geographical area (range 0.62-2.37/10,000 births) or by five month time periods (range 0.21-2.58/10,000 births), nor was there evidence of time trends. When M-A cases were compared to controls, we found that mothers with parity 1 had a higher risk of giving birth to an MMI with M-A, and that mothers with chronic maternal insulin dependent diabetes were at significantly higher risk for having a child with M-A. MMI with M-A had higher rates of prematurity, low birth weight, reduced intrauterine growth, and neonatal mortality than infants with isolated M-A and controls. Babies with isolated M-A had, on average, a lower birth weight than controls; the difference was higher for females. The analysis of pedigrees and familial cases suggests an autosomal dominant trait with variable expression and incomplete penetrance in a proportion of cases, or a multifactorial aetiology. Three cases had consanguineous parents, but the absence of M-A among previous sibs does not support autosomal recessive inheritance.

Social and geographical inequalities in prenatal care in Italy.

The purpose of this study was to find out possible differences in prenatal diagnosis (PD) by amniocentesis or chorionic villus sampling and ultrasound examination before 16 weeks' gestation (early ultrasound examination, EUE), according to area of residence and level of education of the mothers. Data come from a multicentre study in Italy involving 43 maternity hospitals (Mercurio project) and were collected through structured interviews a few days after delivery. Study subjects were 1541 mothers of single non-malformed infants born between April 1992 and March 1994. Overall, the incidence of PD and EUE was 5.8 and 80 per cent, respectively. After adjustment for maternal age and other possible confounders, the odds ratios for PD were 2.19 (95 per cent confidence interval (CI) = 1.26-3.81) when women residing in the northern regions were compared with those residing in the southern regions, and 2.06 (95 per cent CI = 1.12-3.79) and 4.08 (95 per cent CI = 1.97-8.42) when women with medium and high levels of education were compared with those with low level. For EUE, the odds ratios were 1.77 (95 per cent CI = 1.32-2.36) and 2.88 (95 per cent CI = 1.56-5.29) when comparing women with medium and high levels of education with those with low level. No relationship was found between area of residence and EUE. These geographical and social inequalities in prenatal care in Italy should be taken into account for the organization, delivery, and evaluation of pregnancy services in the coming years.

Increased bilirubin production, ceruloplasmin concentrations and hyperbilirubinaemia in full-term newborn infants.

Ceruloplasmin possesses antioxidant activity in vitro, but such a property has not been substantiated in vivo so far. However, it has been suggested that the lack of factors protective against oxidative haemolysis might have a role in neonatal hyperbilirubinaemia. Ceruloplasmin and alphafetoprotein concentrations were measured in cord blood in 78 unselected full-term singleton newborn infants without G6PD deficiency and haemolytic disease of the newborn; in the same infants, the carboxyhaemoglobin level was assessed on the fourth day of life and taken as an index of bilirubin production. The relationship between these variables and maximum bilirubin level in the first 4 days was studied by multiple regression analysis. High carboxyhaemoglobin levels and low ceruloplasmin concentrations, but not alphafetoprotein resulted, associated with hyperbilirubinaemia (P < 0.001). No relationship was found between carboxyhaemoglobin and ceruloplasmin levels. These results exclude an important role for ceruloplasmin in protecting against possible oxidative haemolysis in full-term newborn infants. Ceruloplasmin levels in cord blood are most probably related to hepatic metabolism and are better predictors of hyperbilirubinaemia than alphafetoprotein concentrations.

Italian multicentre study on very low-birth-weight babies. Neonatal mortality and two-year outcome.

The Italian multicentre study on very low-birth-weight babies is the first collaborative project in Italy on the health status of newborns weighing 500-1499 g at birth: 634 such babies were admitted in 1987-88 to eight Italian NICUs; 424 infants survived and were followed until two years of age, corrected for prematurity. Logistic regression analysis of pre-admission risk factors of in-hospital mortality identified eight statistically significant variables: birth weight, gestational age, sex, antepartum steroids, 1-min Apgar score and, on admission to the NICU, body temperature, pH and absence of spontaneous respiration. Using the equation derived from the logistic model, a theoretical mortality rate was calculated for each centre, predicted on the basis of the local incidence of preadmission risk factors. In no case was the predicted mortality significantly different from the observed one. At two years of age, 8 children were blind and 48 had motor disability. Of these, 46 had cerebral palsy: based on a functional evaluation score 14 had severe (degree 4), 20 intermediate (degree 3) and 12 mild cerebral palsy (degree 2). Among 25 variables entered in a logistic regression as risk factors for cerebral palsy, only periventricular leukomalacia and acidosis were significantly associated with the outcome.

'Idiopathic' jaundice in Sardinian full-term newborn infants: a multivariate study.

'Idiopathic' hyperbilirubinaemia in the first 4 days of life was studied in 431 unselected healthy full-term (gestational age > or = 37 weeks) singleton Sardinian infants with birthweight > or = 2500 g. All infants were free from malformations or any disease requiring treatment other than jaundice, they were ABO and Rh compatible with their mothers and were not G6PD deficient. The serum bilirubin level was > 11.9 mg/dl (204 mumol/l) and > 14.9 mg/dl (256 mumol/l) in 37.1% and 15.3% of the study subjects. The vast majority of the infants (94%) were breast fed; no difference in the incidence of jaundice was found between breast-fed and bottle-fed infants. A logistic regression analysis indicated that high alpha-fetoprotein concentrations in cord blood, history of neonatal jaundice in previous full-term siblings, delayed first meconium passage and weight loss were associated with jaundice, defined as a serum bilirubin level > 11.9 mg/dl. These results suggest that the high rate of neonatal hyperbilirubinaemia in Sardinia is mostly related to constitutional and possibly hereditary factors.

Survival of children with Down syndrome in Italy.

A cohort of 917 Down syndrome (DS) children born in Italy between 1978 and 1984 was studied for survival through the age of 8 years. The highest mortality occurred in the first month of life (7.9%); survival was about 80% at 1 year, 78% at 2 years, and 76% at 5 years, with small decreases thereafter. At the univariate analysis, survival was lower for subjects with congenital heart disease (CHD), birth weight less than 2,500 g, parity of 3 or plus, maternal age greater than or equal to 35 years, and for those born in Southern Italy compared with Northern Italy. No differences in survival were observed by sex and by socioeconomic status. The Cox proportional hazard model was used to evaluate the effect of each variable adjusted for all the others present in the model. Presence of CHD (odds ratio = 3.27; 95% confidence interval (C.I.) 2.31-4.63), birth in the South (odds ratio = 2.69; 95% C.I. 1.91-3.79), and low birth weight (odds ratio = 1.87; 95% C.I. 1.29-2.72) were independently associated with survival. None of the other variables emerged as a statistically significant prognostic factor. Various hypotheses were considered to interpret the unexpected effect of place of birth on survival. Quality of medical care provided in the South of Italy is the most likely determinant of the high mortality observed among children with DS born in that area of Italy. Such differences in survival within the same country could occur in other developed nations as well.