Parent-of-origin in individuals with familial neurofibromatosis type 1 and optic pathway gliomas.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant cancer syndromes worldwide. Individuals with NF1 have a wide variety of clinical features including a strongly increased risk for pediatric brain tumors. The etiology of pediatric brain tumor development in NF1 is largely unknown. Recent studies have highlighted the contribution of parent-of-origin effects to tumorigenesis in sporadic cancers and cancer predisposition syndromes; however, there is limited data on this effect for cancers arising in NF1. To increase our understanding of brain tumor development in NF1, we conducted a multi-center retrospective chart review of 240 individuals with familial NF1 who were diagnosed with a pediatric brain tumor (optic pathway glioma; OPG) to determine whether a parent-of-origin effect exists overall or by the patient's sex. Overall, 50 % of individuals with familial NF1 and an OPG inherited the NF1 gene from their mother. Similarly, by sex, both males and females were as likely to inherit the NF1 gene from their mother as from their father, with 52 % and 48 % of females and males with OPGs inheriting the NF1 gene from their mother. In conclusion, in contrast to findings from other studies of sporadic cancers and cancer predisposition syndromes, our results indicate no parent-of-origin effect overall or by patient sex for OPGs in NF1.

Late-onset optic pathway tumors in children with neurofibromatosis 1.

Identification of new optic pathway tumors (OPTs) and progression of pre-existing OPTs in children with neurofibromatosis 1 (NF1) have been reported infrequently after age 6. The authors present eight children with NF1 (mean age 12.2 years) seen in three NF1 centers who had either late-onset (four of eight) or late-progressive (seven of eight) OPT. Continued monitoring of individuals with NF1 into adulthood for the development of OPTs and for progression of known OPTs is warranted.

Children with first-time simple febrile seizures are at low risk of serious bacterial illness.

OBJECTIVE: To describe the rates of serious bacterial illness (SBI) in children presenting to emergency departments (EDs) with first-time uncomplicated febrile seizures. METHODS: The ED visits from seven Chicago metropolitan area hospitals (two tertiary pediatric EDs, five community general EDs) for all pediatric patients seen between July 1995 and December 1997 with a discharge diagnosis including the term "seizure" were retrospectively identified. Records of patients who met criteria for simple, first-time febrile seizure were reviewed (age 6-60 months; temperature > or =38.0 degrees C; single, generalized, tonic-clonic seizure <20 minutes; absence of known central nervous system disease). Rates of bacteremia, urinary tract infection, bacterial meningitis, and pneumonia were determined. RESULTS: Four hundred fifty-five children were identified who had first-time simple febrile seizures. The study participants had a mean age of 21 months and a mean temperature of 39.6 degrees C, and 64% were male. Seventy-three percent were seen in a community hospital setting. Blood cultures were obtained for 315 children (69%). Four children (1.3% [95% CI = 0.1% to 2.5%]) were bacteremic, all with Streptococcus pneumoniae; the rate of bacteremia did not differ in the subset at highest risk for bacteremia (6-36 months, temperature >39 degrees C). No demographic or laboratory data distinguished the bacteremic children from those with negative blood cultures. One hundred seventy-one children (38%) had urine cultures obtained; 5.9% [95% CI = 2.4% to 9.4%] of the cultures grew >100,000 colony-forming units/mL of a single pathogenic organism. One hundred thirty-five children (30%) had cerebrospinal fluid cultures performed. None of these cultures grew a bacterial pathogen [95% CI = 0% to 2.2%]. Two hundred eight children (45.7%) had chest x-rays performed; 12.5% [95% CI = 10.2% to 14.8%] (n = 26) of the x-rays were read as consistent with pneumonia by the radiologist at the treating institution. None of the blood cultures performed on children with abnormal radiographs were positive (cultures drawn on 23 of 26 patients, 88%). Stool cultures were performed on 14 children (3.1%); two cultures (14.3% [95% CI = 0% to 32.6%]) grew a bacterial pathogen, both Shigella. CONCLUSIONS: Rates of SBI in this multi-institution population of children with first-time simple febrile seizures were low and are consistent with those published in the literature for febrile children without seizures.

Setting-based practice variation in the management of simple febrile seizure.

OBJECTIVE: To identify provider-based differences in the ED assessment and management of children presenting with uncomplicated, first-time febrile seizures. METHODS: Multicenter, retrospective cohort study of seven EDs in-the Chicago area: two tertiary academic pediatric EDs (PEDs) and five community-based general EDs (GEDs). The visits of all patients with a discharge diagnosis including the term "seizure" were identified from a 30-month period. Records of patients who met criteria for simple, first-time febrile seizure were reviewed (age 6-60 months; temperature > or =38.0 degrees C; single, generalized, tonic-clonic seizure <20 minutes; "alert" or "arousable" on presentation; absence of known neurologic disease). RESULTS: Four hundred fifty-five records were included: 330 and 125 patients presenting to GEDs and PEDs, respectively. The two groups did not differ in mean age, vital signs, reported duration of seizure, or prior antibiotic use. Lumbar puncture (LP) was performed more often in the GED group (33% vs 22%). No patients were found to have bacterial meningitis. The patients in the GED group were more likely to receive parenteral antibiotics in the ED (56% vs 22%) and to be admitted or transferred (18% vs 4%). In a logistic regression model incorporating age, temperature, seizure duration, seizure in the ED, prior antibiotic use, primary care, and insurance status, the GED patients remained more likely to have an LP (OR 1.5), receive parenteral antibiotics (OR 2.5), and be admitted or transferred (OR 2.5). CONCLUSIONS: There were significant setting-based differences in the evaluation and management of children with simple febrile seizures presenting to GEDs and PEDs.

Intracranial gliomas in neurofibromatosis type 1.

Optic pathway gliomas and brainstem gliomas are the predominant intracranial neoplasms associated with neurofibromatosis type 1 (NF1). Before the past 15 years, studies of optic pathway gliomas in NF1 were hampered by the inaccurate diagnosis of NF1, the unavailability of noninvasive neuroimaging techniques, and the frequent rendering of what would now be considered unnecessary, overly aggressive therapy. When studied systematically, these tumors behave in a much more benign fashion than their counterparts in children who do not have NF1. While they may cause symptoms in as many of 50% of cases, progression to the point where specific intervention is deemed necessary is unusual. Consequently, screening neuroimaging of asymptomatic patients is unwarranted. Because optic pathway tumors universally arise in children younger than 7 years of age, all such children should undergo yearly ophthalmologic evaluations and annual assessments of growth to monitor for signs of precocious puberty. Am. J. Med. Genet. (Semin. Med. Genet.) 89:38-44, 1999.

Carboplatin therapy for optic pathway tumors in children with neurofibromatosis type-1.

Symptomatic optic pathway tumors (OPT) occur in 7% of children with neurofibromatosis type-1 (NF-1). Although tumor progression following diagnosis is unusual in such children, specific therapy may be necessary for patients with either severe or progressive disease. We reviewed the records of 9 children (6 girls, 3 boys) with NF-1 associated OPT who were treated with the second generation platinum compound carboplatin. Carboplatin was given at a dose of 560 mg/mm2 every 4 weeks for a mean of 15 cycles. The mean age at presentation of the OPT was 3.4 years. Eight children had abnormal ophthalmologic examinations at the time of diagnosis. Only 4 patients had documented evidence of progressive disease prior to the institution of therapy. No patient had evidence of progressive disease following therapy. Four patients had radiologic evidence of tumor shrinkage and 2 patients had definite improvement in vision. There was only minimal toxicity. In conclusion, carboplatin is a safe and effective treatment for OPT in children with NF-1. However, as disease stabilization of NF-1 associated OPT often occurs following clinical presentation, the clinician should document tumor progression or visual deterioration prior to the institution of therapy.

Dexamethasone in bronchiolitis: a randomised controlled trial.

BACKGROUND: Although corticosteroids are commonly prescribed in the treatment of bronchiolitis, there is no evidence on the efficacy of these drugs in this disorder. We designed a randomised, double-blind, prospective study to assess the efficacy of dexamethasone in infants with bronchiolitis who require hospital management. METHODS: Infants younger than 12 months who had been admitted to hospital for an initial episode of wheezing, were randomly allocated intramuscular dexamethasone (1 mg/kg daily) or placebo, every 24 h for three doses. We excluded infants who were younger than 4 weeks, who required admission to the intensive care unit, or who had a history of congenital heart disease, mechanical ventilation, or supplemental oxygen use. We assessed infants on admission and every 12 h thereafter--vital signs were taken, severity of accessory muscle use and wheezing were measured by a clinical severity score, and pulse oximetry in room air was done. Our primary endpoints were the time to resolution of symptoms--defined as the number of assessments needed to reach oxygen saturation of more than 95% while receiving no supplemental oxygen, an accessory muscle score of 0, a wheeze score of 0 or 1, and resumption of normal feeding--and duration of oxygen therapy. Follow-up assessments were made 10-14 days after discharge by telephone. We used a proportional-hazards model for our survival analysis. FINDINGS: 197 infants presented with bronchiolitis that required inpatient management. 75 were not enrolled (31 no consent, 28 no approach made, 16 transferred elsewhere). Of the 122 enrolled, four were excluded (clinical deterioration, diagnosis of cystic fibrosis, previous intubation, did not receive all study treatment). There were no differences between the dexamethasone (n = 65) and placebo-treated infants in demographic factors, exposure to tobacco smoke, duration of illness, presence of respiratory syncytial virus (RSV) antigen, respiratory rate, or severity score. More dexamethasone-treated patients had an initial oxygen saturation of 95% or less (51 [79%] dexamethasone vs 31 [59%] placebo, p = 0.02). There were no differences in duration of oxygen therapy (p = 0.74) or time to resolution of symptoms (p = 0.22). Stratification for presence of RSV antigen or family history of atopy did not affect the results. INTERPRETATION: Our findings do not support the use of dexamethasone in the treatment of bronchiolitis in infants.

Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history.

OBJECTIVE: To distinguish the clinical manifestations and natural history of optic pathway tumors (OPT) associated with neurofibromatosis type 1 (NF-1 OPT) from that of OPT not associated with NF-1 (non-NF-1 OPT). METHODS: Two groups of children with OPT were compared: (1) 17 children with NF-1 OPT who were followed prospectively, and (2) 19 children with non-NF-1 OPT who were identified retrospectively by a review of medical records. RESULTS: Precocious puberty was a common initial sign in the children with NF-1 OPT (5/17), and was not found in any patients without NF-1. In contrast, children with non-NF-1 OPT had symptoms attributable to increased intracranial pressure (12/19 and nystagmus (5/19); these symptoms were not found in any patient with NF-1. Decreased visual acuity at the time of diagnosis was common in both groups. There was no significant difference between the children with NF-1 OPT and those with non-NF-1 OPT as to age at diagnosis or sex distribution. Optic nerve involvement was more common in NF-1 (p < 0.001). Both isolated and bilateral optic nerve tumors were found exclusively in children with NF-1, whereas chiasmal (p = 0.016) and optic tract involvement (p = 0.001) were more common in those with non-NF-1 OPT. Radiographic evidence of hydrocephalus was found in none of the children with NF-1 OPT compared with 79% of the non-NF-1 OPT group. Progressive disease was seen in 12% of patients with NF-1 OPT compared with 63% of those with non-NF-1 OPT. CONCLUSIONS: Differences exist between NF-1 OPT and non-NF-1 OPT both at the time of diagnosis and during follow-up. Optic pathway tumors caused by NF-1 and non-NF-1 OPT have different biologic properties that distinguish both their initial clinical manifestations and their natural history.

Precocious puberty in children with neurofibromatosis type 1.

We undertook a comprehensive study of children with neurofibromatosis type 1 (NF-1) cared for in a large multidisciplinary clinic to determine the prevalence of precocious puberty and its relationship to optic pathway tumors (OPTs). Precocious puberty was diagnosed in 7 of 219 children with NF-1 (5 boys and 2 girls) examined between Jan. 1, 1985, and April 20, 1993. All seven children had OPTs involving the optic chiasm; they represented 39% of children with NF-1 and chiasmal tumors (95% confidence interval, 17% to 64%). Eleven prepubertal children (aged 2 to 10 years) with NF-1 and OPTs, and age- and sex-matched NF-1 control subjects without OPTs, underwent luteinizing hormone-releasing hormone (LH-RH) stimulation tests. Two boys with OPTs had pubertal luteinizing hormone (LH) responses, and testosterone levels > 10 ng/dl. Basal LH levels were also elevated in these two boys when tested with a very sensitive immunochemiluminometric assay. None of the children without an OPT had either a pubertal response to LH-RH or an elevated basal LH level. We conclude that precocious puberty in children with NF-1 is found exclusively in those who have OPTs involving the optic chiasm; it is a common complication in those children. With the use of a highly sensitive LH assay, biochemical evidence of hypothalamic-pituitary-gonadal axis activation may be demonstrated, even without provocative testing.

Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study.

To assess the natural history of optic pathway tumors (OPT) in children with neurofibromatosis type 1 (NF-1), from January 1985 through May 1993 we performed a prospective, longitudinal study of OPT in an unselected population of children with NF-1. Of 227 children with NF-1 seen in a specialty clinic, 176 (77%) underwent neuroimaging. Children in whom tumors were identified were followed closely by both repeated neuroimaging and ophthalmologic examinations to detect tumor growth or visual deterioration. Thirty-three children (19%) were found to have OPT at a median age of 4.2 years. The median age of children who had ophthalmologic complaints was significantly lower than that of children who had no such complaints (1.9 vs 5.3 years; p < 0.001). Although eight tumors were discovered because of ophthalmologic complaints or evidence of precocious puberty, 25 children (76%) were free of symptoms at the time of diagnosis. Twenty-one children (64%) had normal ophthalmologic findings at diagnosis; six children, all with chiasmal tumors, had previously unrecognized decreased visual acuity. Only three children (9%) had evidence of either tumor growth or deteriorating vision after diagnosis; the median duration of neuroimaging follow-up was 2.4 years (range, 0.2 to 7.2 years) and of ophthalmologic examinations 3.4 years (range, 0.2 to 8.1 years). All symptomatic OPT were diagnosed before 6 years of age. We conclude that OPT rarely progress during the next few years in children with NF-1 once the OPT have been discovered. The utility of screening neuroimaging for OPT in symptom-free children with NF-1 appears very limited.

Autosomal dominant multiple café-au-lait spots and neurofibromatosis-1: evidence of non-linkage.

Multiple café-au-lait spots have been observed in successive generations of several families without any other manifestations of neurofibromatosis (NF) or any other systemic disorder. The café-au-lait spots in these families segregate as an autosomal dominant trait. The relationship (if any) between the gene for this trait and the NF-1 gene has previously been unknown. We describe a family with five individuals spanning four generations with dominantly inherited café-au-lait spots, without any other stigmata of NF-1. Linkage analysis with probes proximal, distal, and within the NF-1 gene indicate that the trait in this family is not linked to NF-1. We propose that this condition be called Familial Café-Au-Lait Spots (FCAL) to distinguish it from the neurofibromatosis syndromes.

Carboplatin-induced regression of an optic pathway tumor in a child with neurofibromatosis.

Optic pathway tumors are common in children with neurofibromatosis-1 (NF-1). The optimal management of these tumors is unknown, particularly when the optic chiasm and other brain structures are involved. We report the dramatic response to carboplatin in a 10-year-old girl with NF-1 and a progressive optic pathway tumor. Tumor shrinkage was accompanied by striking improvement in visual fields, return of color discrimination, and marked improvement in visual acuity. No significant toxicity was observed. One year following completion of chemotherapy the glioma remains as small or smaller than it was at the conclusion of therapy, and there has been no deterioration of vision. Carboplatin is a promising agent for the treatment of optic pathway tumors in children with NF-1.

Adenovirus infection and childhood intussusception.

OBJECTIVE: To investigate the possible relationship between enteric adenovirus types 40 and 41 and intestinal intussusception in children. DESIGN: Prospective, case-control patient study. PATIENTS: Sixty-three consecutive children suspected clinically of having intestinal intussusception were enrolled in this study. Of these, 25 children (mean age, 1.4 years; range, 3 months to 5 years) had barium enema examination-proved intussusception. Age-matched normal controls (24) and controls with diarrhea (21) were obtained within 1 month of the index case. MEASUREMENTS AND RESULTS: Stools were tested for the presence of nonenteric adenovirus and enteric adenovirus using a monoclonal antibody-based enzyme immunoassay. Five (20%) of 25 children with intussusception had nonenteric adenovirus in their stools compared with one (4%) of 24 normal controls, none (0%) of 21 of the controls with diarrhea, and none (0%) of 37 patients suspected of having intussusception who had negative results on barium enema examination. However, no stool samples were positive for enteric adenovirus. CONCLUSIONS: Nonenteric adenovirus infection and intestinal intussusception may be associated. However, because enteric adenovirus was not found in any of the groups studied, no conclusions can be made regarding their possible influence on the risk for developing intussusception.

Citrobacter freundii septic arthritis.

Septic arthritis in an 8 month old infant due to Citrobacter freundii was treated successfully with a third generation cephalosporin. Infections due to Citrobacter are uncommon in this age group and are almost unknown as a cause of septic arthritis.