Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?

AIM: To investigate risk factors of adverse outcome in a cohort of very preterm children treated mainly with nasal continuous positive airway pressure (CPAP) during the neonatal course. METHODS: In Denmark, preterm children are treated with nasal CPAP as a first approach to respiratory support. A national prospective study of all infants with a birthweight below 1000 g or a gestational age below 28 wk born in 1994-1995 was initiated to evaluate this approach. Of the 269 surviving children 164 (61%) were not treated with mechanical ventilation in the neonatal period. A follow-up of the children at 5 y of age was conducted. Data from the neonatal period and the 5-y follow-up were analysed. RESULTS: In multivariate analyses including 250 children, a severely abnormal neonatal brain ultrasound scan was predictive of cerebral palsy (OR = 19.9, CI 95%: 6.1-64.8) and intellectual disability (OR = 6.2, CI 95%: 2.3-16.5). A high Clinical Risk Index for Babies (CRIB) score (OR = 2.4, CI 95%: 1.1-5.5) and chronic lung disease (OR = 2.8, CI 95%: 1.2-6.9) were predictive of intellectual disability. In univariate analyses mechanical ventilation was associated with cerebral palsy (OR=4.3, CI 95%: 1.7-10.8) and intellectual disability (OR = 2.2, CI 95%: 1.2-4.2), but the associations became insignificant in multivariate analyses including chronic lung disease and a severely abnormal ultrasound scan. CONCLUSION: The associations between neonatal risk factors and adverse outcome in our cohort were very similar to those found in other cohorts with another initial treatment of respiratory insufficiency. We found no significant adverse effects of mechanical ventilation beyond what could be explained by associations with chronic lung disease and IVH 3-4/PVL.

Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population.

The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.

Biotinidase deficiency: two cases of very early presentation.

Two infants with early presentation of biotinidase deficiency (age 3 weeks and 2 weeks) are described. On admission, both children had severe neurological symptoms. In the first patient, magnetic resonance imaging (MRI) of the brain showed frontal and temporal atrophy, and in the second patient, CT of the brain showed diffuse periventricular hypodensities, particularly in the frontal region. Oral treatment with biotin (15mg and 10mg per day respectively) made all symptoms disappear within a few weeks. On follow-up 13 and 16 months later, both children were still asymptomatic on this treatment. Their psychomotor development was normal. MRI and CT of the brain had normalized. Later, a moderate hearing loss was detected in the first patient. In biotinidase deficiency, early diagnosis and treatment with oral biotin are essential in order to prevent irreversible damage to the central nervous system and early death from metabolic acidosis. Neonatal screening for biotinidase deficiency would fulfil this goal.

Association between carriage of oral yeasts and malnutrition among Tanzanian infants aged 6-24 months.

OBJECTIVE: To determine if there is an association between carriage of oral yeasts and malnutrition in infants. DESIGN: A case-control study within a cross-sectional study. The dependent variable was carriage of oral yeasts. The exposure variable was malnutrition and confounders to be adjusted for were age, sex, and breast-feeding. SETTING: A maternal and child health clinic in Dar-es-Salaam, Tanzania that offers routine medical check-ups to all expectant mothers and children aged between 0 and 5 years in its catchment areas. SUBJECTS AND METHODS: 972 infants aged 6-24 months participated. Smears from the tongue and cheek mucosa were examined for candidal hyphae and blastospores. Malnutrition was categorized according to Tanzanian standards (weight-for-age) and World Health Organization (WHO) standards (weight-for-height and height-for-age). MAIN OUTCOME MEASURE: Carriage of oral yeasts (hyphae and blastospores). RESULTS: Carriage of oral yeasts was significantly higher in the 227 malnourished compared with the 745 well nourished adjusted for confounders. Odds ratio for presence of hyphae in smears from the severely malnourished (weight-for-age) was 4.5 (90% CI: 2.0-10.0). Odds ratio for presence of hyphae was 2.3 (90% CI: 1.1-4.8) when weight-for-height were used to categorize for malnutrition. CONCLUSION: The study tends to confirm the generally held view that malnutrition may predispose to carriage of oral yeasts and subsequent oral candidiasis.

[Is recurrent abdominal pain in children a symptom of hyperreactivity disorder?]. / Er børns recidiverende mavesmerter udtryk for en hyperreaktivitetslidelse?

Suggestions in the literature about a possible role of hypersensitivity in children with recurrent abdominal pain induced an open controlled investigation in twenty children with recurrent abdominal pain and in twenty healthy children. The purpose was to look for differences in the numbers of hypersensitivity markers in pain and control children. Hypersensitivity markers were defined in four areas: familial disposition to atopic disease, atopic disease in the child's history, atopic disease disclosed at a clinical examination, and elevated levels of blood eosinophils and serum immunoglobulin E antibodies to selected inhalant allergens and food allergens. In no child was abdominal pain provoked by specific food intake. The total number of markers in the pain children was 21, and in the control children 31. In spite of the small material it thus seems unlikely that hypersensitivity plays an influential part in the etiology of children's recurrent abdominal pain.

Monozygotic twins discordant for gastroschisis: case report and review of the literature of twins and familial occurrence of gastroschisis.

We describe a pair of monozygotic (MZ) female twins discordant for gastrochisis. To our knowledge, this is the first such case reported. The zygosity was verified by DNA analysis using highly polymorphic microsatellites. There was no family history of gastroschisis. During pregnancy there was no suspicion of any exposure responsible for the malformation. The number of twin cases described so far does not allow any conclusion as to hereditary factors in the cause of gastroschisis, but the number of families reported with familial gastroschisis suggests that the recurrence risk is higher than previously thought.

Motilin in children with recurrent abdominal pain: a controlled study.

The aim of this study was to compare serum motilin levels in children with and without recurrent abdominal pain, based on the assumption that recurrent abdominal pain in children is a gut motility disorder. In this controlled study, 19 children between 6 and 15 years of age with recurrent non-organic abdominal pain and 20 control children between 6 and 15 years of age without abdominal pain or other functional somatic complaints were evaluated. No statistical significant difference was found in serum motilin levels between children with and without abdominal pain. Median difference between the groups was 11 pmol/l (95% confidence limits of median difference -9 to +33). This investigation could not support the assumption that motilin might be a pathogenic factor in children with recurrent abdominal pain. It is suggested, however, that future research should compare serum motilin levels during and between attacks of pain.

[Identification of Y chromosome material in an XX male by means of fluorescent in situ hybridization]. / Identifikation af Y-kromosommateriale hos en XX male ved hjaelp af fluorescens in situ hybridisering.

This article describes a case of 46,XX male, the most frequent form of sex reversal syndromes in humans. A method of identifying Y chromosome material in these and other patients with structural chromosomal abnormalities involving chromosome Y is given. Chromosomes from a phenotypically normal male child without any congenital malformation, where prenatal diagnosis revealed the female karyotype 46,XX, were analysed using fluorescence in situ hybridisation (FISH). The analysis revealed an X chromosome, containing Y chromosome sequences on the tip of the short arm. The sequences are not normally visible in conventional cytogenetic analyses of XX males. The breakpoint on Y was determined to be in the region of Yp11.2, which is proximal for the putative sex determining gene on Y. The results are consistent with theories of abnormal crossing-over during the paternal meiotic cell division where meiotic recombination can give rise to structural abnormalities, which can then cause sex reversal syndromes. Prenatal diagnosis of structural sex chromosome abnormalities has become available using the FISH method.

Fractional gastrointestinal transit time: intra- and interindividual variation.

The intra- and interindividual variation in the gastrointestinal transit times was measured in 12 healthy adult test subjects using a scintigraphic method with 111In marked single unit tablets. Test conditions were semi-standardized. The variation within the same individual was as large as the variation between different subjects regarding the transit times through both the small and the large intestines. The small intestine transit time was 5 h (median) with an interquartile range of 4-7 h. The median transit time through the large intestine was 23.5 h (interquartile range 19.0-40.5 h). The coefficient of repeatability for the small intestinal and large intestinal transit time was 4 h and 33 h respectively. Our conclusion is that the 111In single unit capsule method can be used for measuring the fractional gastrointestinal transit times, but the intra- and interindividual variations are rather large and similar. From a radiation-hygienic point of view the 111In single unit capsule method is acceptable. The large inter- and intraindividual variation in gastrointestinal transit time might be an important factor in the absorption of certain drugs.

Riboflavin responsive multiple acyl-CoA dehydrogenation deficiency. Assessment of 3 years of riboflavin treatment.

A boy with riboflavin-responsive beta-oxidation deficiency (multiple acyl-CoA dehydrogenation deficiency) was assessed clinically and biochemically after 3 years of continuous riboflavin medication. He was diagnosed at the age of three years after an attack of a Reye's syndrome-like disease. During the 3 years of assessment he has experienced no serious disease; although short episodes of fatigue and loss of appetite have been noted. His mental and physical development has been normal. Biochemically the abnormal excretion of organic acid metabolites, characteristic of the acyl-CoA dehydrogenation deficiency, has been continuously present. Quantitatively there has been a trend to a more simple picture with ethylmalonic acid as the predominant metabolite. However, because of the large within-day variation in the excretion of all the metabolites, changes following diet and riboflavin trials must be interpreted with caution in these patients.

C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects.

The abnormal metabolites-adipic, suberic, and sebacic acids-were detected in large amounts in the urine of a boy during a Reye's syndrome-like crisis. Substantial amounts of 5-OH-caproic acid, caproylglycine, glutaric acid, and 3-OH-butyric acid and moderately elevated amounts of ethylmalonic acid, methylsuccinic acid, 3-OH-isovaleric acid, and isovalerylglycine were also found. These metabolites were consistently present in urine samples collected in the boy's habitual condition after the attack. 1-[14C]-Palmitic acid was oxidized at a normal rate, whereas U-[14C]-Palmitic acid was oxidized at a reduced rate in cultured skin fibroblasts from the patient, thus indicating a defect at the level of medium- and/or short-chain fatty acid oxidation. Riboflavin medication (100 mg three times a day) significantly reduced the excreted amounts of pathologic metabolites, suggesting a flavineadeninedinucleotide-related acyl-CoA dehydrogenation defect as the cause of the disease. Carnitine in plasma was low in the patient (6 mumole/liter, controls 26-74 mumole/liter), suggesting carnitine deficiency as a secondary effect of the acyl-CoA dehydrogenation deficiency. The present patient, who presented with a Reye's syndrome-like attack, suffers from impaired dehydrogenation of acyl-CoA resulting in accumulation of acyl-CoA in the cells. Attacks with similar symptoms are seen in other acyl-CoA dehydrogenation deficiencies, such as glutaric aciduria types I and II, other types of C6-C10-dicarboxylic acidurias and isovaleric acidemia. Reduced flow through the acyl-CoA dehydrogenation steps may therefore be an ethiologic factor in Reye's syndrome. Several of the accumulated acyl-CoA's are toxic and may be responsible for some of the symptoms. The low carnitine level in plasma and the elevated esterified carnitine excretion in the present patient indicate that acyl-CoA accumulation may cause a functional carnitine deficiency by sequestration of carnitine as acyl-carnitines. As the inborn defect, systemic carnitine deficiency may exhibit symptoms like those of Reye's syndrome, it may be speculated whether functional carnitine deficiency in patients with accumulated acyl-CoA is another causal factor in the development of the symptoms during attacks.