Extremely Preterm Born Children at Very High Risk for Developing Autism Spectrum Disorder.

This study aimed to provide a more comprehensive picture of the prevalence of autism spectrum disorder (ASD) in a geographic cohort of extremely preterm born adolescents by using established diagnostic instruments in addition to screening instruments. 53 participants passed a screening procedure with two screening instruments and a diagnostic evaluation with a semi-structured assessment and a parent interview. 28 % of the adolescents had a community based clinical diagnosis of ASD. When research diagnoses were also taken into account, this rate increased to 40 %. Intellectual disability, language impairment and behavioural difficulties are characteristic for these children with ASD. This study is to our knowledge the first to use ASD-specific diagnostic instruments to confirm ASD diagnoses in extremely preterm born children in early adolescence. The study expands findings of previous research and raises the need for follow-up into late childhood and early adolescence.

Extremely high mutation load of the mitochondrial 8993 T>G mutation in a newborn: implications for prognosis and family planning decisions.

UNLABELLED: The propositus presented with hypotonia, respiratory failure, and seizures in the newborn period and was found to have severe hyperlactacidemia and a hypertrophic heart. He carried a de novo pathogenic mutation (m.8993 T>G) in the gene encoding subunit 6 of the mitochondrial ATP synthase (MTATP6). Although the lactate concentration in serum normalized and the proband recovered after a short period at the neonatal intensive care unit, his ultimate motor and cognitive development was poor. Brain MRI at the age of 6 months showed bilaterally signal abnormalities in the caudate nucleus, putamen, thalamus, and mesencephalon. He died at the age of 9 months. The difficulty in genetic counseling in families with a maternal mitochondrial mutation disorder is emphasized. CONCLUSION: Here, we report on a neonate with the m.8993 T>G mutation and emphasize implications of mtDNA disorders on family planning decisions.

Functional polymorphism in gamma-glutamylcarboxylase is a risk factor for severe neonatal hemorrhage.

A neonate who received vitamin K (VK) supplementation then developed severe late-onset bleeding with abnormal prothrombin time and activated partial thromboplastine time. The bleeding was corrected after intravenous VK. Molecular analysis of the gamma-glutamylcarboxylase gene revealed a heterozygous single nucleotide polymorphism, which decreases carboxylase activity and induces VK-dependent coagulation deficiency.

Influence of gestational age on nosologic CP characteristics in a high-risk population.

The aim of this study is to investigate the interrelationship between gestational age (GA) and nosologic characteristics (type, distribution and severity) of cerebral palsy (CP) in a cohort of high-risk infants. One thousand ninety-nine consecutively neonatal intensive care unit-admitted high-risk infants (i.e., all infants with a GA less than 30 weeks and specified infants with GA >or= 30 weeks with a complicated neonatal course and/or brain lesion) were prospectively assessed up to the corrected age of 2 years or more. In 177 (16%) of these infants, CP was diagnosed. Of these infants, 26 were extremely preterm infants (GA 23-27 weeks), 62 very preterm (28-31 weeks), 36 moderately preterm (32-36) and 53 term infants (GA >or= 37 weeks). Spastic CP was significantly more present in the three preterm groups (77%, 90% and 72%, respectively) compared with the term ones (42%). At variance, dyskinetic CP was present in nearly half of the term group (47%) and remarkably less in all three preterm age groups (12%, 7% and 22%, respectively). Ataxic CP (7%) was of rare occurrence in all age groups. Distributive classification showed that bilateral spastic CP gradually dropped from 100% in the extremely preterm group down to 50% in the term infants. Inversely, unilateral spastic CP rises steeply with advancing GA. Severity of CP was significantly associated with birth year period in favour of mild CP. In high-risk neonates, dyskinetic CP increases steeply with increasing GA, whereas spastic CP decreases. Bilateral and unilateral involvements are gradually and oppositely changing with gestational age. It is tempting to explain the maturity-related association by gestational age-specific brain injuries.

Predictability of cerebral palsy and its characteristics through neonatal cranial ultrasound in a high-risk NICU population.

The aim of the study is to evaluate the predictive value of various types of brain injury detected by ultrasound in the neonatal period for the occurrence of cerebral palsy and its characteristics in a large cohort of high-risk infants. Thousand twenty-one consecutively NICU-admitted high-risk infants were assessed up to the corrected age of at least 2 years. Cerebral palsy (CP) was categorised into spastic or non-spastic, bilateral or unilateral and mild, moderate or severe CP. Different types of brain injury were identified by serial cranial ultrasound (US) during the NICU stay: white matter disease (WMD), haemorrhage, cerebral infarction, deep grey matter and parasagittal cerebral injury. There is a significant overall association between different types of brain injury and gestational age. Only 4% of the children with normal US develop CP. In the presence of any abnormal US image, the likeliness to develop CP is at least seven times higher. Within the group of infants with WMD and haemorrhage, the degree of brain involvement has a clear impact on the occurrence of CP. Concerning the characteristics of CP, deep grey matter lesion predict non-spastic CP versus spastic CP (OR = 31, P < 0.001). Cerebral infarction and haemorrhage grade IV are strong predictors of unilateral spastic CP versus bilateral spastic CP (OR = 49 and 24, respectively, P < 0.001). Deep grey matter lesion is a significant predictor for severe versus mild and moderate CP (OR = 6). In conclusion, neonatal cranial US is a useful tool in predicting CP and its characteristics.

Lactic acidosis in a newborn with adrenal calcifications.

A patient is reported who presented in the newborn period with an unusual combination of congenital lactic acidosis and bilateral calcifications in the adrenal medulla, visible on standard abdominal x-ray and ultrasound examination. At birth, the proband was hypotonic and dystrophic. She developed respiratory insufficiency, cardiomegaly, and hepatomegaly and died at the age of 38 d. Examination of postmortem heart muscle revealed multiple areas of myocardial infarction with dystrophic calcifications. In the medulla of the adrenal glands, foci of necrosis and calcifications, and in the liver, multiple zones of necrosis and iron deposition were detected. Biochemical analysis in heart muscle revealed a decreased activity of complex IV of the oxidative phosphorylation (OXPHOS) and in liver a combined deficiency involving the complexes I, III, IV, and V. The findings were suggestive of a defect in biosynthesis of the mitochondrially encoded subunits of the OXPHOS complexes. Extensive analysis of the proband's mitochondrial DNA revealed neither pathogenic deletions and point mutations nor copy number alterations. Relative amounts of mitochondrial transcripts for the ribosomal mitochondrial 12S rRNA (12S) and mitochondrial 16S rRNA (16S) were significantly increased suggesting a compensatory mechanism involving the transcription machinery to low levels of translation. The underlying molecular defect has not been identified yet.

Influence of gestational age on the type of brain injury and neuromotor outcome in high-risk neonates.

This study was an investigation of a possible correlation between either the gestational age (GA) and type of brain injury or between the gestational age and type, distribution and severity of cerebral palsy (CP). Four hundred sixty-one children with a birthweight > or = 1250 g and GA > or = 30 weeks with a complicated neonatal period and/or brain injury on serial cerebral ultrasound were selectively followed at the regional Center for Developmental Disorders. The children were divided into a preterm and term group. There were 40 children with cerebral palsy in the preterm group and 38 children with cerebral palsy in the term group. Various types of brain injury diagnosed by echography were nosologically classified. The type, distribution and severity of cerebral palsy were also registered. The type of brain injury most frequently occurring in the term group was hypoxic-ischemic injury to the basal ganglia (39%), focal ischemia (18%), subcortical hemorrhage (13%) and parasagittal cerebral injury (10%). In the preterm group 39% of the children with cerebral palsy had periventricular leukomalacia, 24% intraventricular hemorrhage and 18% persistent flares. There was a significant correlation between the GA and type of brain injury (P < 0.001; Cramer's V = 0.76) and between the GA and type (P = 0.004; Cramer's V = 0.47) and distribution (P < 0.001; Cramer's V = 0.55) of CP. There was no significant correlation between the GA and severity of CP. The type of brain injury detected by serial ultrasound during the neonatal period, as well as the type and location of CP detected during later childhood, are all GA-dependent in at-risk newborn infants with a birthweight of > or = 1,250 g and GA > or = 30 weeks.

Outcome at 3 years of age in a population-based cohort of extremely preterm infants.

OBJECTIVE: To assess health and neurodevelopmental outcome at 3 years of age in neonatal intensive care unit (NICU)-surviving children who were born at 26 or fewer weeks of gestation in a geographically defined region of Belgium from 1999 through 2000. METHODS: The study included a clinical examination and a standardized neurologic and developmental assessment. Disabilities were defined by international criteria. In 97% (92 of 95) of the children, accurate information on the presence of overall disability could be collected. RESULTS: Thirty-six percent (95% confidence interval [CI] 25-47%) of the formally assessed children (28 of 77) had deficient neuromotor development, with 5% of them showing severe sensory-communicative impairment. Mean (+/-standard deviation) scores on the Mental Developmental Index and Psychomotor Developmental Index were 81.2 (18.8) and 73.2 (17.8), respectively. Seventy percent (95% CI 60-80%) had a mental (Mental Developmental Index) or psychomotor (Psychomotor Developmental Index) impairment or both, assessed to be more than 1 standard deviation below the population mean. Mental and psychomotor outcome did not differ significantly when compared according to either gestational age, gender, or multiple birth (all P>.05). When either minor central dysfunction or cerebral palsy was not taken into account, normal mental development was recorded in 62% of the subjects. The cumulative of poor outcome (ie, disability- or prematurity-related death) among the 95 infants discharged alive was estimated to be 58% (95% CI 48-68%), representing 25 (26%) mildly-to-moderately disabled and 28 (29%) severely disabled toddlers, including two infants whose postdischarge deaths were directly related to prematurity. CONCLUSION: The average developmental outcome is poor in children born as extremely preterm infants. Finding early predictors of adverse outcome is a major challenge.

Novel microdeletions on chromosome 14q32.2 suggest a potential role for non-coding RNAs in Kagami-Ogata syndrome.

In approximately 20% of individuals with Kagami-Ogata syndrome (KOS14, MIM 608149), characterized by a bell-shaped thorax with coat-hanger configuration of the ribs, joint contractures, abdominal wall defects and polyhydramnios during the pregnancy, the syndrome is caused by a maternal deletion of the imprinted gene cluster in chromosome 14q32.2. Most deletions reported so far included one or both of the differentially methylated regions (DMRs) - DLK1/MEG3 IG-DMR and MEG3-DMR. We present two unrelated families with two affected siblings each, presenting with classical KOS14 due to maternally inherited microdeletions. Interestingly, all four patients have lived through to adulthood, even though mortality rates for patients with KOS14 due to a microdeletion are relatively high. In the first family, none of the DMRs is included in the deletion and the methylation status is identical to that of controls. Deletions that do not encompass the DMRs in this region are thus sufficient to elicit the full KOS14 phenotype. In the second family, a partially overlapping deletion including both DMRs and MEG3 was detected. In summary, we show that patients with KOS14 can live into adulthood, that causal deletions do not have to include the DMRs and that consequently a normal methylation pattern does not exclude KOS14.

Enzymatic differentiation of Candida parapsilosis from other Candida spp. in a membrane filtration test.

A previously reported enzyme assay on a membrane filter using 4-methylumbelliferyl (4-MU)-N-acetyl-beta-D-galactosaminide, -phosphate and -pyrophosphate as substrates for the differentiation of four Candida spp. has been extended to Candida parapsilosis. The substrate 4-MU-beta-D-glucoside was hydrolyzed by 28 test strains of this species but to a variable extent by seven other yeasts also. For a full enzymatic differentiation of C. parapsilosis from other medical yeasts, a battery of six reactions was required. Of 71 C. parapsilosis positive clinical samples, 4.2% gave a false negative result due to overgrowth by Candida albicans. The present assay is more rapid than a described spectrofluorometric determination of beta-D-glucosidase in a broth, i.e., 9-11 h versus up to >48 h.

Healthcare-associated bloodstream infections in a neonatal intensive care unit over a 20-year period (1992-2011): trends in incidence, pathogens, and mortality.

OBJECTIVE: To analyze trends in the incidence and pathogen distribution of healthcare-associated bloodstream infections (HABSIs) over a 20-year period (1992-2011). DESIGN: Historical cohort study. SETTING: Thirty-two-bed neonatal intensive care unit (NICU) in a tertiary referral hospital. PATIENTS: Neonates with HABSIs defined according to the criteria of the National Institute of Child Health and Development (NICHD). METHODS: A hospital-based ongoing surveillance program was used to identify HABSI cases in neonates. A distinction between definite or possible HABSI was made according to the NICHD criteria. Incidence, incidence densities (HABSIs per 1,000 hospital-days and HABSIs per 1,000 total parenteral nutrition-days), and case fatality rate were calculated. Logistic regression analysis was used to find time trends. Four periods of 5 years were considered when executing variance analysis. RESULTS: In total, 682 episodes of HABSIs occurred on 9,934 admissions (6.9%). The median total incidence density rate was 3.1 (interquartile range, 2.2-3.9). A significant increasing time trend in incidence density was observed for the period 1995-2011 (P < .003). A significant decrease in the case fatality rate was found in the last 5-year period (P < .001). No neonate died following possible HABSIs, whereas the case fatality rate among neonates with definite HABSIs was 9.7%. Most HABSIs were caused by coagulase-negative staphylococci (n = 414 [60.7%]). A significant increase in Staphylococcus aureus HABSI was observed in the last 10-year period (P < .001). CONCLUSIONS: An increase in incidence density rate occurred, while the case fatality rate dropped. Better perinatal care could be responsible for the latter. A decrease in days before infection and a high incidence of coagulase-negative Staphylococcus HABSIs indicate the need for vigorous application of evidence-based prevention initiatives, in particular for catheter care.

Desmopressin lyophilisate for the treatment of central diabetes insipidus: first experience in very young infants.

INTRODUCTION: In neonates and small infants, early diagnosis of central diabetes insipidus (CDI) and treatment with desmopressin in low doses (avoiding severe hypo- or hypernatremia) are important to prevent associated high morbidity and mortality in this particular age group. CASE PRESENTATION: We described pharmacokinetic and pharmacodynamic results of the use of recently launched oral desmopressin lyophilisate (Minirin Melt®) in two infants with CDI, diagnosed at the age of 12 and 62 days, respectively. We observed that a starting dose of 60 µg of Minirin Melt® in the first case resulted in a pharmacokinetic profile largely exceeding the reference frame observed in children with nocturnal enuresis, while a dose of 15 µg in the second case resulted in acceptable concentrations. After initial dose adjustments, administration of sublingual lyophilisate resulted in rather stable serum sodium concentrations. CONCLUSIONS: Using Minirin Melt® in infants with CDI appears to be effective, easy to use and well tolerated.

Citrulline levels in a paediatric age group: does measurement on dried blood spots have additional value?

BACKGROUND: Citrulline is considered to be a marker of absorptive enterocyte mass. Citrulline levels can be measured in plasma or dried blood spot (DBS) samples. The purpose of this study is to calculate reference intervals for plasma and DBS citrulline concentrations in children and to examine the effect of age and gender. METHODS: In 151 healthy subjects ranging from 1 month to 20 years of age, plasma and DBS citrulline concentration were determined by using Liquid Chromatography-tandem Mass Spectrometry. Citrulline concentrations were examined in relation to age and gender. Reference values were calculated according to the guidelines of the International Federation of Clinical Chemistry and the National Committee on Clinical Laboratory Standards. RESULTS: No significant influence of age and gender could be discerned on plasma or DBS citrulline concentration. In children, the reference intervals for citrulline bounded by the 2.5 and 97.5 percentiles are 13.31-69.05 µmol/L and 23.70-49.04 µmol/L for plasma and DBS samples respectively. CONCLUSIONS: The reference intervals for citrulline levels in healthy children are widely dispersed. Measuring citrulline concentrations in dried blood spots delivers no additional value to plasma measurements for the calculation of reference intervals in children.

Unilateral bloody nipple discharge in a two-month-old male.

Bloody nipple discharge is a rare but distressing finding in neonates and infants. We report on a 2-month-old boy with unilateral bloody nipple discharge. Ultrasound examination revealed dilated mammary ducts. This benign phenomenon is most likely to be caused by mammary ductal ectasia. Invasive investigations or surgery should be avoided in neonates or infants with bloody nipple discharge unless the discharge is unilateral, spontaneous, persistent and accompanied with a palpable mass. Otherwise only serial clinical follow-up is recommended until spontaneous resolution.

Congenital pontocerebellar atrophy and telencephalic defects in three siblings: a new subtype.

We report three siblings, two of whom had a neuropathological study, with a new subtype of congenital ponto-cerebellar atrophy (PCH). In addition to the brain stem and cerebellar anomalies common to all types of this heterogeneous condition, there were unique developmental defects in the telencephalon: absence of the claustrum, diffuse cortical changes particularly in the insula and an extremely small brain. In an attempt to shed some light on the pathogenesis of this developmental disorder, we have analyzed the pattern of brain stem and cerebellar abnormalities in ours and in previously reported patients with PCH, to possibly distinguish primary from secondary effects of the mutant gene upon the cerebellar circuitry, and compared our patients' cerebellar and cerebral defects to those of some other human brain malformations and to mutant mice with both hindbrain and forebrain anomalies. Although this and previous observations of familial congenital PCH with apparent autosomal recessive inheritance spawn the endeavor to compare and classify patients into subgroups, any final classification must await identification and molecular characterization of the causal gene(s).

Maternal vitamin A deficiency and neonatal microphthalmia: complications of biliopancreatic diversion?

Biliopancreatic diversion (BPD) for morbid obesity carries a serious risk of nutritional deficiencies that might impair embryogenesis. Consequently, attention should be given to the potential of risk to the fetus of BPD in women of childbearing age. We present the case of a pregnant woman who had undergone BPD 8 years previously, with documented vitamin A deficiency, who gave birth to a child with bilateral microphthalmia. Infectious and genetic causes of microphthalmia were excluded. A search of the literature revealed that vitamin A deficiency may cause a disruption of ocular development. We conclude that nutritional deficiencies may cause a spectrum of fetal malformations. As the effect of BPD relies on malabsorption, fetal risk should be considered before BPD is offered to morbid obese women of childbearing age.

Evidence for autosomal dominant inheritance in prenatally diagnosed CHAOS.

Congenital high airway obstruction syndrome (CHAOS) is a rare prenatal diagnosis consisting of a typical fetal triad of large hyperechogenic lungs, flattened or inverted diaphragms and ascites. Most cases are sporadic with unknown incidence. Before attempts of fetoscopic fetal salvage or ex utero intrapartum treatment (EXIT) are considered, additional malformations must be carefully excluded as CHAOS may be part of various monogenic conditions or chromosomal disorders. We report an unique family with autosomal dominant inheritance of CHAOS and variable expression in the affected father and two affected children. It is concluded that minor expression in one of the parents may be an important indicator for genetic counseling in CHAOS and management of future pregnancies.

Transplacental passage of a nonionic contrast agent.

UNLABELLED: We report the presence of iopromide in the bowel and urine of a preterm infant, born 10 days after intravenous administration of the nonionic monomer to his mother. Excessive urinary iodine excretion and borderline hyperthyrotropinaemia were observed in the infant. Moreover, crossing of the fetal blood-brain barrier was demonstrated by detection of the angiographic material in CSF and thus direct fetal neurotoxic effects cannot be excluded. CONCLUSION: These widely used contrast media may cross the placenta and accumulate in various fetal tissues in significant amounts causing possible neonatal toxicity. Therefore the perinatal safety of these diagnostic agents should at least be questioned.

Phototherapy-mediated syndrome of inappropriate secretion of antidiuretic hormone in an in utero selective serotonin reuptake inhibitor-exposed newborn infant.

Although selective serotonin reuptake inhibitors (SSRIs) have gained wide acceptance in the off-label treatment of mental disorders in pregnant women, there seems to be an increased risk for serotonergic adverse effects in newborn infants who are exposed to SSRIs during late pregnancy. Hyponatremia as a result of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a relatively common serious side effect of the use of SSRIs in (mostly elderly) adults. Severe hyponatremia as a result of an SIADH is proposed here as part of a neonatal serotonin toxicity syndrome in a newborn infant who was exposed prenatally to an SSRI. The definite reversal to normal serum sodium levels after fluid restriction, the lack of any alternative cause for the SIADH, and the positive temporal relation with a high score on a widely used adverse drug reaction probability scale offer solid support for the hypothesis of a causal relationship between the SIADH and the prenatal sertraline exposure in our neonate. Moreover, accumulative data on the acute enhancement of serotonergic transmission by intense illumination led us to hypothesize that phototherapy used to treat hyperbilirubinemia in the newborn infant could have been the ultimate environmental trigger for this proposed new cause of iatrogenic neonatal SIADH. The speculative role of phototherapy as a physical trigger for this drug-related adverse event should be confirmed in other cases by thorough study of the serotonin metabolism, assay of SSRI levels in cord blood, and serial measurement of plasma levels in exposed neonates. As phototherapy is used frequently in jaundiced neonates and an apparently increasing number of infants are born to mothers who take SSRIs, serotonin toxicity in neonates deserves increased attention.