Nebulized budesonide after hospitalization for recurrent bronchial obstruction in children younger than 18 months.

A multi-center, double-blind, randomized dose-response study was performed to assess the effect of 3 months of treatment with two different doses of inhaled nebulized budesonide in children with acute recurrent bronchial obstruction (BO) causing hospitalization. Steroid-naive children younger than 18 months were included when admitted to hospital because of BO for at least the second time, and were followed-up monthly for 15 months. Forty-five of 49 subjects (43 boys, 2 girls) (mean age 9.3 months upon inclusion) completed the study. Twenty-four patients (20 boys, 4 girls) received nebulized budesonide 0.5 mg twice daily for 1 month followed by 0.25 mg daily for the next 2 months, whereas 25 children received 0.1 mg twice daily throughout the 3-month treatment period. Outcome (number of BO episodes, time to first BO after start of treatment, and use of rescue medication), as well as height/length and weight, were assessed at the start of treatment and monthly for the following 3 months, as well as for 12 months after cessation of treatment (15 months in total). There was an overall tendency towards better symptom control (fewer episodes of acute BO during treatment and follow-up, fewer hospital visits because of acute BO, lower clinical score during follow-up, and less use of rescue medication during follow-up) in the high-dose treatment group vs. the low-dose treatment group. However, the differences did not reach statistical significance for any of the outcomes. The only significant difference in effect between the groups was fewer children in the high-dose group treated openly with nebulized budesonide during follow-up. Length/height and weight gain did not differ significantly between the two treatment groups throughout the study. There was no significant dose-dependent beneficial effect of 3 months of treatment with nebulized budesonide in infants and toddlers with at least two hospitalizations for acute bronchial obstruction.

Coinheritance of two alpha-spectrin gene defects in a recessive spherocytosis family.

We studied a recessive hereditary spherocytosis (HS) family from Norway in which all four children had haemolytic spherocytosis while spectrin (Sp) deficiency was detected in the proband. Molecular analysis demonstrated that all affected children had inherited the low expression alpha-Sp allele LEPRA (Low Expressed PRAgue) from the father. Haplotyping with a polymorphic dinucleotide repeat for the alpha-Sp gene (alphaVNTR) located in the 3' untranslated region of mRNA showed that all recessive children had inherited the same maternal alpha-spectrin allele. The paternal Sp-alphaLEPRA allele was found in cis of the polymorphic alpha-Sp Bughill allele (alphaBH) characterized by the A970D point mutation in the Sp alpha-chain. This mutation was identified on two-dimensional electrophoresis of Sp tryptic digests as an acidic shift of the alphaII tryptic domains (spots alphaIIa). Analyses of the relative expression of the paternal alpha-Sp Bughill polymorphism in the proband showed that the product of the maternal alpha-Sp gene is almost completely absent from the mature erythrocyte membrane. Comparative analysis between alphaVNTR PCR-amplified from genomic DNA and from cDNA showed that the maternal low expression alpha-Sp allele is associated with a decreased amount of mRNA. Results from molecular and biochemical studies showed that all the affected children of this family are compound heterozygous for two different low expression alpha-Sp alleles: an uncharacterized defective alpha-Sp allele on the maternal side and an alphaLEPRA allele tagged by the alphaIIa polymorphism on the paternal side.

[Adults treated as children for acute lymphocytic leukemia--methotrexate, late effects and quality of life]. / Voksne behandlet for akutt lymfatisk leukemi som barn--metotreksat, seneffekter og livskvalitet.

From 1975 to 1980, 153 Norwegian children were diagnosed with acute lymphocytic leukaemia. In 1995, all 98 survivors were studied and compared to matched family controls. 132 children were treated with the national protocol. Of these, 93 (70.5%) were survivors at the time of the study. The remaining five survivors were treated with different treatment schemes. The national protocol included methotrexate infusions combined with intrathecal methotrexate as prophylactics against neuroleukaemia, instead of the irradiation. Neither doxorubicin nor cyclophosphamide were included. In this study, a questionnaire was used that covered demographic data, quality of life, and medical information the response rates were 96% (94 persons) for survivors and 92% (90 persons) for family controls. Information was also obtained for the remaining four survivors. No significant differences were found between survivors and controls with regard to quality of life and demographics, with one exception, Somatisation on the GHQ-28. Hospital records of all patients were checked for possible late effects. One case of serious sequela (hemiparesis during therapy) was found, probably related to methotrexate therapy. Seven other serious, possible sequelae were recorded, but probably not related to methotrexate. There were no cases of secondary malignant neoplasm.

Long-term survival and quality of life in patients treated with a national all protocol 15-20 years earlier: IDM/HDM and late effects?

In a follow-up matched control study the 93 (70.5%) survivors of 132 children treated with a national protocol for acute lymphoblastic leukemia (ALL) and 5 survivors of the other 21 cases of ALL in childhood diagnosed in the same period were evaluated. Thus it was also a population-based study. The national treatment protocol was used in the period 1975-1980. Methotrexate (MTX) infusions combined with intrathecal MTX were used as prophylaxis against neuroleukemia instead of irradiation. Neither doxorubicin (Adriamycin) nor cyclophosphamide was used in the protocol. A questionnaire covering demographic data, number of offspring, learning problems, level of athletic performance, education, and work status as well as medical information was used. Forms were received from 94 (96%) of the 98 adult surviving cases and corresponding controls in the family. Interviews were performed in the remaining four cases (4%). There were no statistical differences between the two groups with respect to physical and mental health and quality of life. Hospital records of all patients were also checked for possible late effects. There was no definite case of secondary malignant neoplasm; however, there was one case of prolactinoma and only one case of serious sequelae (hemiparesis during therapy), probably due to intrathecal and intravenous MTX.

Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome.

We describe nine children with a similar pattern of features including macrocephaly and cutis marmorata telangiectatica congenita. All were large at birth and had a distinctive capillary haemangioma involving the philtrum and upper lip. The seven who survived all developed hydrocephalus and had developmental delay. Six developed body asymmetry and three had internal arteriovenous malformations. Syndactyly of the second and third toes and/or the third and fourth fingers or toes was commonly seen. All of the cases were sporadic. This condition is easily recognizable and should be considered in the differential diagnosis of patients presenting with overgrowth and macrocephaly.

Impact of pollution and place of residence on atopic diseases among schoolchildren in Telemark County, Norway.

For estimation of the prevalence, degree of severity, and association with outdoor pollution, a questionnaire on asthma and other atopic diseases was distributed to the parents of 4666 7-13-year-olds, comprising all the children in 36 schools in Telemark County, Norway, including 37% of the schoolchildren in the county. The response rate was 94%. In a validity study employing clinical evaluations, the questionnaire-based diagnosis of asthma was found to have a sensitivity of 0.96 and a specificity of 0.88. The lifetime prevalence of asthma in Telemark was 9% (boys 11.3%, girls 6.6%; p < 0.001). There was no significant difference in the lifetime prevalence of asthma by pollution zone; 8.3% in heavily, 9.3% in moderately, and 9.2% in minimally polluted zones. The asthma prevalence was significantly higher (14.2%; p < 0.05) among boys in the coastal area of the county than in the mountainous area (8.9%). Both of these areas were in the minimal pollution zone. Of asthma cases, 67% were categorized as mild, 29% as moderate, and 4% as severe. The lifetime prevalence was 17.8% (boys 21.3%, girls 14.2%; p < 0.001) for allergic rhinitis, 13.2% (boys 11.4%, girls 15.2%; p < 0.001) for atopic eczema, and 29.6% (boys 31.7%, girls 27.4%; p < 0.01) for overall atopic disease (asthma, allergic rhinitis, eczema). These findings are not compatible with the hypothesis that outdoor pollution is associated with the lifetime prevalence of asthma in school-age children. The results also show that less than 0.5% of schoolchildren suffer from severe asthma.

[Meningococcal project Telemark. Experiences after 5 years with contact tracing and eradication of the pathogenic bacteria in near contacts of the patients with meningococcal disease]. / Meningokokkprosjekt Telemark. Erfaringer etter fem år med smitteoppsporing og sanering av den sykdomsfremkallende bakterien hos naerkontakter av pasienter med meningokokksykdom.

Since 1987 we have analysed throat samples from 1,086 healthy contacts of 32 patients with meningococcal disease. The disease-causing strain was found in contacts of 17 out of the 32 patients. 161 (18%) of the contacts carried meningococci, and 30 (3%) of them were carriers of the disease-causing strain as determined by DNA fingerprinting. The carrier strain was eradicated in 29 of these 30 contacts by treatment with rifampicin. No secondary case of meningococcal disease was observed. During the four-year period 1984-87, there were 39 confirmed cases of meningococcal disease, including 12 verified and four suspected secondary cases of meningococcal disease. Therefore identification and eradication of the disease-causing strain seems to prevent secondary cases. A change in the Norwegian recommendations for preventing secondary cases of meningococcal disease should be discussed.

Prader-Willi syndrome in a brother and sister without cytogenetic or detectable molecular genetic abnormality at chromosome 15q11q13.

We report on a 12-year-old boy and his 7-year-old sister with the Prader-Willi syndrome. They both had severe initial hypotonia with feeding problems and later developed an increasing appetite. Both sibs have almond-shaped eyes, triangular mouth, hypogonadism, retarded growth, and mental retardation. An older brother suffered from severe hypotonia and died at 7 days of age. The children have normal chromosomes by high-resolution technique and have inherited the same chromosomes 15 short arm polymorphisms from their parents. The family was informative for one of four DNA markers specific for the 15q11q13 region. No deletion was found using this marker. The parents were healthy and unrelated. Autosomal recessive inheritance or a paternally inherited submicroscopic deletion are possible explanations for the sib occurrence in this family.

VACTERL or MURCS association in a girl with neurenteric cyst and identical thoracic malformations in the father: a case of gonosomal mosaicism?

We report on a female infant with lethal congenital malformations including extreme hydrocephalus due to aqueductal stenosis, vertebral segmentation anomalies, fused costae, anal atresia, renal dysplasia, and bicornuate uterus with a double blind vagina. The VACTERL and the MURCS associations are possible diagnoses. Her father had a neurenteric cyst in infancy. He has identical vertebral and costal malformations as his daughter but is otherwise healthy. The possibility of dominant inheritance with gonosomal mosaicism in the father is discussed.

Preventing secondary cases of meningococcal disease by identifying and eradicating disease-causing strains in close contacts of patients.

In Norway, the use of chemoprophylaxis after cases of meningococcal disease is not recommended. Instead, household members less than 15 years are treated with penicillin for 7 days. Failures of this treatment have been reported. We therefore used DNA fingerprinting to identify the disease-causing strain in healthy contacts combined with selective rifampicin prophylaxis to these carriers to prevent secondary cases. During a 2-year period (1987-89) there were 13 cases of meningococcal disease in the County of Telemark (165000 inhabitants). 65 (14.7%) out of 441 contacts to these 13 patients harbored meningococci in their throat; 16 (3.6%) carried the disease-causing strain. Only 1 carrier fulfilled the criteria for being treated with penicillin; 8 were adults and the remaining 7 were not household members. No secondary cases of meningococcal disease occurred during the study period or the following 12 months. During the 4-year period (1984-87) preceding the study period there were 39 cases of meningococcal disease in Telemark; 7 of them were index cases for 12 bacteriologically verified and 4 clinically suspected secondary cases of meningococcal disease. We conclude that selective prophylaxis with rifampicin seems to be more efficient that penicillin treatment of household members less than 15 to prevent secondary cases of meningococcal disease.

Hereditary tyrosinemia of chronic course without rickets and renal tubular dysfunction.

Three patients with hereditary tyrosinemia type 1, two brothers and one girl, studied at the age of 5, 12 and 15 years, respectively, had neither generalized hyperaminoaciduria, glucosuria nor clinical symptoms of rickets. Untreated the elder brother had only slightly elevated plasma tyrosine level (141 mumol/l, normal less than 80), and low excretion of p-hydroxyphenyllactate. He presented with pronounced thrombocytopenia (3 X 10(9)/l). At 13 years of age he contracted hepatocellular carcinoma. The younger brother presented with serum tyrosine of 318 mumol/l and thrombocyte count 48 X 10(9)/l. Succinylacetone in urine was elevated in both, 30 and 79 mumol/mmol creatinine, respectively. The female patient was investigated for hepatomegaly in infancy, atypical tyrosinemia being considered, but afterwards developed normally without diet or any other treatment until she contracted hepatoma at the age of 15 years. Her plasma tyrosine level was 600-700 mumol/l, and she excreted large amounts of p-hydroxyphenyllactate. Succinylacetone in urine was low but elevated (8 mumol/mmol creatinine). The fumarylacetoacetase activity in fibroblasts from the brothers and in lymphocytes from the girl was less than 5% and 10% of control levels, respectively. In conclusion, the chronic form of hereditary tyrosinemia may occur without evidence of renal tubular dysfunction.

[Examination of the environment in meningococcal disease. Identification and clearing of the virulent microorganism from the environment of patients with meningococcal disease]. / Miljøundersøkelse ved meningokokksykdom. Oppsporing og sanering av den sykdomsfremkallende mikrobe i miljøet til pasienter med meningokokksykdom.

During the period from January 1987 to June 1988 DNA fingerprinting was used to identify carriers of the disease-causing strain of Neisseria meningitidis among the patients contacts. A total of 432 persons were screened during nine episodes. The overall carrier-rate was 16.2%, and the causative strain was found in 3.4% of the contacts. Eleven carriers were successfully treated with rifampicin, whereas two of three carriers treated with penicillin remained carriers. We conclude that DNA fingerprinting is a valuable tool for rapid identification of carriers of the causative organism in order to eradicate the epidemic strain of N. meningitidis.

Cytogenetic screening of a new-born population.

Chromosomes were analysed using banding techniques in 1830 consecutively born infants. The prevalence of chromosomal aberrations was 19.67 per 1000, which is higher than figures found in previous cytogenetic surveys using conventional staining (8.34 and 5.75 per 1000 in a Danish and a combined survey, respectively). The use of banding techniques may explain the higher rate of detection of chromosomal variants in the present study. This is illustrated by the findings of 7.10 autosomal inversions per 1000 compared to 0.13 in a combined survey, and Y chromosome inversions of 3.14 compared to 0.26 per 1000. A prevalence of 2.73 balanced reciprocal translocations per 1000 was found, involving chromosomes 1, 2, 3, 9, 11, 13, 16 and 22, which all belong to a group of ten chromosomes with the highest number of spontaneous breaks in the study of Aymé et al. (1976). Fourteen infants were found to have chromosomal mosaicism, and three of them were defined as real mosaics. With the increasing concern about the effect of environmental toxicants, it is of interest to keep a record of aberrant cells in presumably karyotypically normal newborns for possible use in future epidemiological surveys.

Familial hypomagnesemia--a follow-up examination of three patients after 9 to 12 years of treatment.

Three children with familial hypomagnesemia from infancy were treated perorally with magnesium for 9 to 12 years. Their somatic and intellectual development have since been normal. Without therapy, the serum magnesium fell from subnormal (about 0.5 mmoles/liter) to very low values (0.2 to 0.3 mmoles/liter) within 1 to 4 wk. We observed a secondary fall in serum calcium and potassium and an increase in sodium and phosphate although serum concentrations of PTH, calcitonin, and 25-OH-vitamin D in the blood remained normal. Balance studies confirmed the presence of a defect in the intestinal absorption of magnesium and excluded a defective renal tubular transport system. The subjects continued to require daily magnesium supplements to avoid serious symptoms. Optimal dosage was found to be in the range 0.5 to 0.75 mmoles/kg . day; doses above this caused diarrhoea and a fall in the serum and urine levels of magnesium. Pathophysiologic mechanisms involved in the electrolyte changes that occurred secondarily to the hypomagnesemia are discussed.

Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome.

A male boy is described, who suffered from an intractable diarrhoea and several infections and who died in a severe marasmic state at the age of 8 months. Immunological studies revealed a block in the normal differentiation of B cells to Ig-producing plasma cells. After the age of 5 months, however, this block disappeared, leading to a dramatic increase in circulating Ig, most pronounced in the IgM class. In the intestine, plasma cells could only be detected after the age of 5 months, and then with a marked preponderance of IgM cells. Our results thus indicate a reversible block in the normal maturation of B cells in our patient. An older brother may have had a similar disease, suggesting a possible genetic basis for the disorder.

Mumps meningitis: prolonged pleocytosis and occurrence of mumps virus-specific oligoclonal IgG in the cerebrospinal fluid.

A pleocytosis of the CSF occurred in all of 10 children with mumps meningitis and persisted for weeks and months in some patients. Oligoclonal IgG proteins were detected in the cerebrospinal fluid (CSF) during the 2nd week after onset of meningitis or later in 4 out of 10 patients, and could be detected as late as 11 and 12 months after meningitis in 2 patients. Evidence is presented that the oligoclonal IgG represents mumps virus-specific antibody synthesized locally in the brain. Oligoclonal virus antibodies were demonstrated also in serum samples. The persistence for weeks and moths of pleocytosis and oligoclonal IgG virus antibody in the CSF may imply that a virus infection in some cases persists in the brain in spite of apparently complete clinical recovery.