Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.

Familial Incontinentia pigmenti (IP) is a rare X-linked dominant condition. The affected cases have characteristic skin lesions, hair, eye, teeth and nail abnormalities and may also have neurological problems. The diagnosis has traditionally been made on clinical grounds. Segregation analysis has suggested that it is lethal in males. Only one liveborn male has been reported who died at one day of age. Female cases of IP survive because of the moderating effects of Lyonization. This child was the affected son of a female with IP. He had a novel phenotype consistent with hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) but with additional features: he had major problems with hematological disturbances, failure to thrive due to malabsorption, recurrent infections, generalized osteosclerosis and lymphedema of his lower limbs. He also demonstrated some typical features of IP with a generalized reticular skin hyperpigmentation, sparse hair and delayed eruption of teeth. The gene for NEMO (NF-kappa B Essential Modulator) has recently been shown to be mutated in cases of IP. Furthermore, most (80%) of patients possess a recurrent genomic rearrangement that deletes part of the gene resulting in an inactive NEMO protein. In the male case described here, a NEMO stop codon mutation has been identified that has arisen de novo in his affected mother. This mutation is likely to have a less severe effect on NEMO activity and may explain why this child survived for two years and 7 months.

Plasma amino acid profiles in preterm infants receiving Vamin 9 glucose or Vamin infant.

Amino acid profiles were measured in 29 low-birth-weight infants receiving either Vamin 9 glucose (n = 18, group A) or Vamin Infant (n = 11, group B) as the amino acid source in parenteral nutrition; intake was otherwise identical. Infants were sampled when receiving 430 mgN/kg per day (3.2 g/kg per day amino acids) and 90 non-protein kcal/kg per day. There was no difference between groups in birth weight, gestational or postnatal age. The percentage N retention was similar in both (68 and 60%, groups A and B respectively). Phenylalanine and tyrosine levels were higher in those who received Vamin 9 glucose but 55% of infants given Vamin Infant had tyrosine levels below the lower limit of the target range. Cysteine levels were low in both groups. Further modification of the amino acid composition of parenteral solutions for the newborn is necessary. If sufficient non-protein energy can be provided the risk of abnormally high amino acid levels is reduced.

Paediatric eosinophilic oesophagitis presenting to the otolaryngologist.

INTRODUCTION: The prevalence of eosinophilic oesophagitis is increasing. A Pubmed search for 'eosinophilic oesophagitis' and 'eosinophilic esophagitis' yielded 345 publications since 1976. Only seven were in otolaryngology journals.1-7 Patients typically present with dysphagia, vomiting, dyspepsia or food impaction and are therefore usually referred to a paediatric gastroenterologist; otolaryngologists are not usually involved in management. A missed diagnosis may result in oesophageal stricture. METHODS: Two patients, aged two and four years, were referred to the paediatric otolaryngology department with intermittent upper oesophageal food impaction. A paediatric gastroenterologist was involved in the investigation. Histological examination of oesophageal biopsies demonstrated changes consistent with eosinophilic oesophagitis. RESULTS: Both patients were expediently diagnosed, investigated and managed. CONCLUSION: A diagnosis of eosinophilic oesophagitis must be considered in patients presenting with food bolus impaction. Early involvement of a paediatric gastroenterology team in the diagnosis is recommended in children presenting with oesophageal symptoms, in order to avoid delayed diagnosis.

Malrotation volvulus in a neonate: a novel surgical approach.

A newborn presented with bilious vomiting secondary to a malrotation and presumed perinatal-onset volvulus. Laparotomy was performed at 20 h of age at which the volvulus was derotated. Nevertheless the small but not the large bowel appeared to be completely ischaemic and non-viable. A second-look laparotomy was performed 24 h later with no significant improvement. In a new approach to the problem, nothing further was done and the child was left alone on parenteral nutrition and naso-gastric aspiration for 11 weeks. Further exploration showed that 40 cm of small bowel had survived intact and restorative surgery was carried out. Parenteral nutrition was discontinued after 9 months and the child, now aged 3.5 years, is thriving.

Changes in protein turnover after the introduction of parenteral nutrition in premature infants: comparison of breast milk and egg protein-based amino acid solutions.

Rates of protein turnover were measured in 20 infants receiving either Vamin Infant (group A) or Vamin 9 glucose (group B) as the amino acid source in total parenteral nutrition. A constant infusion of L-[1-13C]leucine was used to measure whole body leucine flux, and leucine oxidation rates were derived from measurements of total urinary nitrogen excretion. Infants were first studied when receiving only i.v. glucose and again on each of the next 4 d as total parenteral nutrition was gradually increased to a maximum of 430 mg nitrogen/kg/d and 90 nonprotein kcal/kg/d. Net protein gain and protein synthesis and breakdown rates increased progressively for all infants taken together over the study period as i.v. nutrition was increasing (p less than 0.001). There were no differences between groups in the changes in net protein gain and rates of protein synthesis and breakdown throughout the study period. Nitrogen retention on d 5 for the two groups was similar (60 +/- 16% and 67 +/- 11% in groups A and B, respectively). In a subgroup of infants, measurements were repeated on d 8, when the intake had been constant for 3 d. Protein retention was the same as on d 5, but both synthesis and breakdown were increased. It is concluded that rates of protein turnover increase significantly in response to increasing i.v. nutrition and that this elevation was not influenced by the composition of the amino acid mixture given.

Protein turnover rates in sick, premature neonates during the first few days of life.

Rates of protein turnover were measured in 19 infants during the first few days of life while they were receiving i.v. glucose. The technique consisted of a continuous i.v. infusion of L-[1-13C]leucine to measure whole body leucine flux and determination of total urinary nitrogen excretion to assess leucine oxidation rates. Subsequent to each of the studies, the decision to start total parenteral nutrition (TPN) was made by the clinician concerned, with the result that seven infants did not start TPN and 12 did. There were significantly greater urinary nitrogen excretion (p less than 0.001) and lower rates of whole body protein synthesis (p = 0.024) and breakdown (p = 0.015) in those who did start TPN compared with those who did not. The marked difference in nitrogen excretion between the two groups suggests that this could be a useful determinant for deciding which neonate should start TPN.

Enteropathy and renal involvement in an infant with evidence of widespread autoimmune disturbance.

An 8-month-old infant presented with a 1 month history of protracted diarrhea, vomiting, and weight loss. Small intestinal biopsy showed a flat mucosa and there was no clinical improvement with gluten, cow's milk protein, and disaccharidase-free diet. Serial testing for autoantibodies revealed persistent autoantibodies to gut epithelial cells and to renal brush borders; on two occasions, atypical liver-kidney microsomal antibodies were detected. Treatment with steroids produced clinical improvement but the patient finally succumbed with a combination of gut and renal dysfunction. The widespread nature of the antibodies, with clinical involvement of gut, liver, and kidney, suggest an underlying autoimmune mechanism for the pathogenesis of the condition. Serial autoantibody measurements may provide a means to monitor the disease progress and may be a guide to treatment.

Homozygosity for a null allele of the insulin receptor gene in a patient with leprechaunism.

Mutations in the insulin receptor gene can cause genetic syndromes associated with extreme insulin resistance. We have investigated a patient with leprechaunism (leprechaun/Qatar-1) born of a consanguineous marriage. Postnatally, the proband had episodes of severe hypoglycemia and hyperinsulinernia, with blood glucose levels ranging from 0.9 to 9.9 mmol/L. The C peptide concentration with 1880 nmol/L, and the total insulin concentration was 1409 mU/L. The patient died outside the hospital at the age of four months. All 22 exons of the patient's insulin receptor gene were screened for mutations using denaturing gradient gel electrophoresis. Thereafter, the nucleotide sequences of selected exons were determined directly. The patient was homozygous for a mutation in exon 13; thirteen base pairs were deleted and replaced by a 5 b.p. sequence. This mutation shifts the reading frame and introduces a premature chain termination codon downstream in exon 13. Thus, the mutant allele is predicted to be a null allele that encodes a truncated receptor lacking both transmembrane and tyrosine kinase domains.

Neonatal hypothyroidism: comparison of radioisotope and ultrasound imaging in 54 cases.

Fifty-four neonates with congenital hypothyroidism identified by the North East and North West Thames Regional hypothyroid screening programme between January 1985 and December 1987 were investigated with radioisotope (Tc99m) and ultrasound scans of the thyroid before treatment with 1-thyroxine was commenced. Compared with the radioisotope scans, ultrasound identified normally sited thyroid tissue in only 7 out of 10 cases, and ectopic thyroid tissue in only 5 out of 26 cases. Three out of 18 cases with no isotope uptake in the neck appeared to have normally sited tissue on ultrasound scan. We conclude that in our hands ultrasound of the neck is of only limited value in the assessment of young infants with congenital hypothyroidism.

Prevalence of antibody to human T-lymphotropic virus type III in AIDS and AIDS-risk patients in Britain.

2000 persons in the UK were examined serologically for antibodies to human T-lymphotropic virus type III (HTLV-III). Sera reacting in a membrane immunofluorescence assay (IFA) to HTLV-III were also positive when tested against cells infected with lymphadenopathy virus (LAV-1), and cross-adsorption tests indicated that these retroviruses are probably identical. A competitive radioimmunoassay (RIA), which was wholly concordant with IFA, was used to screen the sera. 30/31 patients with the acquired immunodeficiency syndrome (AIDS) were seropositive, as were 89% patients with persistent generalised lymphadenopathy (PGL), 17% symptomless homosexual men, 34% haemophiliacs receiving pooled clotting factors, and 1.5% intravenous drug abusers. None of more than 1000 unselected blood donors was seropositive. These data confirm the close association between HTLV-III and AIDS and PGL and show that infection with HTLV-III is also prevalent in the populations in whom these syndromes are most likely to develop. However, it would be unwise to presume that AIDS will necessarily develop in seropositive subjects.

Linkage analysis of candidate regions for coeliac disease genes.

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.