Search

Objective To evaluate the epidemiology of infectious meningitis in children in a Lyme borreliosis (LB) endemic area, and to study how clinical and laboratory characteristics may distinguish between different types of childhood meningitis. Design Retrospective, population based study. Setting A paediatric department serving all children (62 000) in a costal LB endemic region of southwestern Norway. Patients All children with cerebrospinal fluid pleocytosis aged 3 months to 14 years. Main outcome measures Epidemiological, clinical and laboratory characteristics of different types of childhood meningitis. Results Infectious meningitis was diagnosed in 211 children (annual incidence 38/100 000). Lyme meningitis (LM) was identified in 142 children (67%), non-Lyme aseptic meningitis in 46 children (22%) and bacterial meningitis in 23 children (11%). Age, month of admission and clinical and laboratory characteristics differed between the groups. An aetiological agent was found in 89% of children. The positive predictive value for having LM if the child had facial nerve palsy or head and/or neck stiffness (meningism) as the only symptom was 97% for both variables. Symptoms of cerebral involvement or signs of systemic inflammation were rare in children with LM compared to children non-Lyme aseptic meningitis. Conclusion LM was diagnosed in two-thirds of children with infectious meningitis in this LB endemic area. Distinct clinical characteristics distinguished the majority of children with LM from children with non-Lyme aseptic meningitis and bacterial meningitis. [ABSTRACT FROM AUTHOR]

Background: Continuous positive airway pressure (CPAP) is commonly used to relieve respiratory distress in infants with bronchiolitis, but has mostly been studied in an intensive care setting. Our prime aim was to evaluate the feasibility of CPAP for infants with bronchiolitis in a general paediatric ward, and secondary to assess capillary PCO2 (cPCO2) levels before and during treatment., Methods: From May 1(st) 2008 to April 30(th) 2012, infants with bronchiolitis at Stavanger University Hospital were treated with CPAP in a general paediatric ward, but could be referred to an intensive care unit (ICU) when needed, according to in-house guidelines. Levels of cPCO2 were prospectively registered before the start of CPAP and at approximately 4, 12, 24 and 48 hours of treatment as long as CPAP was given. We had a continuous updating program for the nurses and physicians caring for the infants with CPAP. The study was population based., Results: 672 infants (3.4%) were hospitalized with bronchiolitis. CPAP was initiated in 53 infants (0.3%; 7.9% of infants with bronchiolitis), and was well tolerated in all but three infants. 46 infants were included in the study, the majority of these (n = 33) were treated in the general ward only. These infants had lower cPCO2 before treatment (8.0; 7.7, 8.6)(median; quartiles) than those treated at the ICU (n = 13) (9.3;8.5, 9.9) (p < 0.001). The level of cPCO2 was significantly reduced after 4 h in both groups; 1.1 kPa (paediatric ward) (p < 0.001) and 1.3 kPa (ICU) (p = 0.002). Two infants on the ICU did not respond to CPAP (increasing cPCO2 and severe apnoe) and were given mechanical ventilation, otherwise no side effects were observed in either group treated with CPAP., Conclusion: Treatment with CPAP for infants with bronchiolitis may be feasible in a general paediatric ward, providing sufficient staffing and training, and the possibility of referral to an ICU when needed.

Background: The development of allergic sensitization and allergic disease may be related to factors during intrauterine life, but the role of maternal preeclampsia is not known.We studied if maternal preeclampsia is associated with long-term allergic sensitization, allergic rhinoconjunctivitis, atopic dermatitis, asthma and with altered lung function in late childhood., Methods: 617 children participated in a 1:2 matched and controlled historical cohort study; 230 born after preeclamptic pregnancies and 387 born after normotensive pregnancies. Specific IgE in serum and lung function were measured at the age of 12.8 years and questionnaires on maternal and adolescent data were completed at the ages of 10.8 years (girls) and 11.8 years (boys), and at 12.8 years (both genders). The association between birth after preeclampsia and the main outcome measures allergic sensitization, allergic rhinoconjunctivitis, atopic dermatitis, asthma and lung function in late childhood were analysed with multiple regression analyses, including possible confounders., Results: Severe maternal preeclampsia was associated with high level allergic sensitization (sum of specific IgE in serum ≥ 3.9 kU/l; the 25 percentile for all children being sensitized); odds ratio (OR): 3.79; 95% confidence interval (CI): (1.54, 9.32); p = 0.015 and with allergic rhinoconjunctivitis in offspring; OR: 2.22, 95% CI: (1.19, 4.14), p = 0.047. Preeclampsia was not associated with atopic dermatitis, asthma or altered lung function in late childhood., Conclusion: Maternal preeclampsia was associated with allergic sensitization and allergic rhinoconjunctivitis in offspring in late childhood, but not with other atopic diseases.

Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.

Background: The Periodic Fever, Aphthous stomatitis, Pharyngitis and cervical Adenitis syndrome (PFAPA) is the most common periodic fever syndrome in childhood. Clinically, PFAPA may resemble autoinflammatory diseases, but the etiology is not fully understood., Methods: We measured inflammatory proteins in plasma and hematologic parameters in children with PFAPA during and between febrile episodes, and in a control group with suspected bacterial pneumonia. In children with PFAPA, a first blood sample was taken within 24 hours of a febrile episode and a second sample between episodes. In children with pneumonia, the first sample was taken shortly after admission and a second sample after full recovery., Results: A total of 22 children with PFAPA and 14 children with pneumonia were included. In children with PFAPA, levels of interleukin (IL) 6, CXCL10 and CCL4 were significantly increased during febrile episodes. The levels of IL-6 and CXCL10 were higher in children with PFAPA during febrile episodes than in children with pneumonia. The levels of CXCL10 remained higher in children with PFAPA between febrile episodes compared to children with pneumonia after recovery. Children with PFAPA had a relative eosinopenia and lymphocytopenia with reduced numbers of both CD4+ and CD8+ T cells during febrile episodes. This pattern was not observed in the children with pneumonia., Conclusions: The results indicate an innate immune response as the initial step in PFAPA, and a subsequent adaptive response with activation and redistribution of T cells. Moreover, an activation of the innate immune system involving CXCL10 may persist between febrile episodes. CXCL10 may be a possibly clinical marker in children with PFAPA.

Aims: To evaluate levels of C-reactive protein (CRP) during febrile episodes in children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA)., Methods: All CRP values during typical episodes of fever in children diagnosed with PFAPA during a 3 years period were retrospectively registered., Results: In 16 children with PFAPA, a total of 87 CRP values were registered during 38 episodes of fever. The mean of the maximum CRP during each episode was 185 mg/L (SD: 69.4, range: 45-322). Values of CRP were elevated throughout the whole period of fever, with higher values on days 2-4 compared to day 1., Conclusion: Levels of CRP are substantially increased during febrile episodes in children with PFAPA. High levels of CRP may suggest a role for immunological mechanisms in PFAPA, and may raise the suspicion of PFAPA when measured in children with periodic fever of unknown origin.

Aim: Respiratory syncytial virus (RSV) is a prominent cause of airway morbidity in children under 1 y of age. It is assumed that host factors influence the severity of disease presentation, and thus the need for hospitalization. The variation of IGHG genes from chromosome 14q32 are linked to serum IgG subclass levels but also to the variations in IgG responses to pneumococcal, meningococcal and Haemophilus influenzae antigens. The aim of this investigation was to clarify whether IGHG genes are involved in the development of severe RSV lower respiratory tract infection (LRTI)., Methods: The alternative expressions of IGHG3(b) and (g), IGHG1(f) and (a), and IGHG2(n) and (-n) genes were studied in a cohort of 49 previously healthy children hospitalized for RSV LRTI. The gene frequencies were compared to a population of healthy individuals., Results: The homozygous IGHG2(-n/-n) genotypes dominated in hospitalized children with severe RSV infection: 55.1%, compared with 34.2% in the healthy population (OR 2.3; p = 0.004). The IGHG2 genotypes containing (n/n) and (n/-n) were significantly decreased. The IGHG(bf-n) alleles were significantly increased (OR 1.7; p = 0.025) and the IGHG(bfn) alleles significantly decreased (OR 0.5; p = 0.005)., Conclusion: The IGHG(bf-n) allele and homozygous IGHG2(-n/-n) genotypes are associated with the development of severe RSV LRTI.

Aim: The prevalence of childhood asthma is increasing, and it is important to monitor factors related to hospital admissions in order to understand the different aspects of the disease. The aim of this study was to investigate admissions for childhood asthma to Rogaland Central Hospital, Norway, in order to elucidate time trends related to rates of admissions and treatment modalities., Methods: A population-based study was conducted in which data extracted from the medical records, including number of admissions, length of hospitalization, medication and symptom scores, were recorded for children aged 1 to 14 y admitted to hospital for asthma during four periods, of two years each, from 1984/1985 to 1999/2000., Results: For all the children there was an increase in annual admission rates for asthma from 1984/1985 to 1989/1990 and stabilization thereafter, but there were substantial differences between age groups. For children of 1 or 2 y of age the annual admission rate increased from 43/10000 in the first period to 104/10000 in the last period (p < 0.001), with an increase in both primary admissions and re-admissions. For children aged 3 and 4 y, the admission rates increased from the first to the second period, and then declined to an annual admission rate of 40/10000 in 1999/2000. For older children, the admission rate was low and stable. There was a gradual increase in the use of inhaled corticosteroids both prior to admission and at discharge, and the percentage of children receiving systemic corticosteroids at admission increased from 19% to 45% (p < 0.001). The average hospital in-days decreased from 3.4 to 1.9 (p < 0.001)., Conclusion: A disturbingly high and increasing rate of both primary admissions and re-admissions for asthma has been observed in children aged 1 and 2 y, which seemed to be unaffected by changes in treatment modalities during the period. The decrease in admissions for children aged 3 and 4 y may have been influenced by the increased use of inhaled corticosteroids.

Unlabelled: Early identification of wheezing children with an increased risk of recurrent wheezing or subsequent asthma is important. The aim of the study was to determine the role of markers of eosinophil activation, along with other parameters, in the prediction of recurrent wheezing and allergic sensitization in children with early and severe wheezing. We examined 105 children without atopic dermatitis, hospitalized for wheezing during the first year of life. At a 20-mo follow-up, 101 of the children were assessed for the occurrence of recurrent wheezing (at least 3 episodes, including 1 in the previous 6 mo) and allergic sensitization (positive skin-prick test). By univariate analysis, levels of eosinophil counts at the time of hospitalization (p = 0.005, OR = 18.9), age in months (p < 0.0001, OR = 1.5), respiratory syncytial virus (RSV)-negative disease (p < 0.0001, OR = 8.8), parental atopy (p = 0.006, OR = 3.3) and male sex (0.02, OR = 2.7) were all predictive factors for recurrent wheezing at follow-up. With all parameters included in a multiple regression analysis, RSV-negative disease was not a predictive factor for recurrent wheezing. A simple model including eosinophil counts > or = 0.1 x 10(9)/L and age had a predictive accuracy of 79%, with only a 6% chance of a child being wrongly predicted as symptomatic. Urinary protein X (U-EPX) was not a predictive factor for recurrent wheezing. When included in a multiple logistic regression analysis, a level of U-EPX > or = 100 microg/mmol creatinine was the only parameter with a positive predictive value for allergic sensitization (p = 0.007, OR = 18.9), whereas age, parental allergy or parental asthma were not., Conclusion: Children with severe wheezing during the first year of life and subsequent recurrent wheezing are characterized by a normal or high eosinophil count in response to viral infections.

It has been suggested that urinary eosinophil protein X (U-EPX) can be used to monitor bronchial inflammation in childhood asthma. However, the influence of atopy and airway infections is not well elucidated. To determine the clinical value of measuring U-EPX in children with asthma and to evaluate the influence of atopy and airway infections, U-EPX was measured in 170 children with asthma (mean age 69 months, range 12-179 months), in 79 children with lower or upper respiratory tract infections (mean age 41 months, range 1-165 months), and in 64 controls. U-EPX was elevated in children with acute asthma (median 132 microg/mmol of creatinine, quartiles 77-195 microg/mmol of creatinine, n = 51, p <0.001) and chronic asthma (median 93 microg/mmol of creatinine; quartiles 46-149 microg/mmol of creatinine, n = 119, p <0.01) compared with controls (median 54 microg/mmol of creatinine, quartiles 40-89 microg/mmol of creatinine, n = 39). Atopic children had higher levels of U-EPX than non-atopics with acute asthma (median 155 microg/mmol of creatinine, quartiles 113-253 microg/mmol of creatinine, n = 27, vs. median 102 microg/mmol of creatinine, quartiles 56-168 microg/mmol of creatinine, n = 24, p <0.05), as well as with chronic asthma (median 110 microg/mmol of creatinine, quartiles 65-162 microg/mmol of creatinine, n = 63, vs. median 60 microg/mmol of creatinine, quartiles 39-123 microg/mmol of creatinine, n = 56, p <0.01). In chronic asthma, children without atopy had levels of U-EPX similar to values of controls; levels were similar in symptomatic and asymptomatic patients, and not influenced by treatment with inhaled corticosteroids. Moreover, U-EPX levels were higher in children with pneumonia (median 207 microg/mmol of creatinine, quartiles 111-280 microg/mmol of creatinine, n = 35, p <0.001), laryngitis (median 109 microg/mmol of creatinine, quartiles 65-161 microg/mmol of creatinine, n = 24, p <0.01), and rhinitis (median 172 microg/mmol of creatinine, quartiles 123-254 microg/mmol of creatinine, n = 19, p <0.001) than in controls (median 62 microg/mmol of creatinine, quartiles 41-93 microg/mmol of creatinine, n = 64). There was significant overlap among all groups of children with disease, as well as between children with disease and controls. Hence, U-EPX may reflect differences in eosinophil involvement and activation between children with atopic and non-atopic asthma, but the individual spread within groups and the influence of airway infections limits the clinical value of U-EPX in childhood asthma.

Atopic disease, including atopic dermatitis (AD), is associated with a T-helper 2 (Th2)-dependent immune response. The cytokine receptor CD30 appears to be preferentially expressed on, and its soluble form (sCD30) released by, Th2 cells. Therefore, sCD30 may be a potential marker for atopic disorders. The aim of this study was to test the hypothesis that the sCD30 level in cord blood could be used to predict the development of atopy or AD in early childhood. In a case-control study, levels of sCD30, as well as soluble low-affinity immunoglobulin E (IgE) receptor (sCD23), interleukin-4 (IL-4) and IgE, were measured in cord blood in 35 children who subsequently developed allergic sensitization and AD before the age of three, and the results were compared to those of 35 matched children without a history of atopy. There was no difference in cord blood levels of sCD30 between controls (32.5 U/ml; 19.7-80.1) and children with subsequent atopy and AD (32.2 U/ml; 22-75.9) (median; quartiles). The concentration of sCD30 showed no relation to the levels of total IgE, sCD23 or IL-4. Levels of sCD23 were similar in children with subsequent atopy (60.2 U/ml; 44.5-76.8) and controls (55.2 U/ml; 38.3-72.5), whereas IL-4 was detectable in 10 of the atopic children and in only two of the controls (p <0.05). In conclusion, cord blood levels of sCD30 or sCD23 do not seem to be related to the subsequent development of atopy or AD at the age of three.

Background: Parameters of eosinophil inflammation have been suggested as markers of disease activity in atopic dermatitis (AD), but the value of urinary eosinophil protein X (U-EPX) in children with AD, as well as the influence of allergic sensitization, is not known., Methods: We measured U-EPX in 59 atopic and 29 nonatopic children with mild (n = 32), moderate (n = 34), and severe (n = 22) AD, as well as in 64 controls., Results: U-EPX was increased in children with AD (110; 67-164 microg/mmol creatinine, median; quartiles) compared to controls (62; 41-95, P<0.001). Children with mild (97; 63-164, P < 0.01), moderate (108; 67-157, P < 0.01), and severe disease (152; 99-202, P < 0.001) had levels of U-EPX higher than controls. U-EPX was significantly higher in children with severe AD than in mild and moderate disease (P < 0.05 for both). Children with AD and a positive skin prick test (120; 81-176) had higher levels of U-EPX than children with a negative skin prick test (87; 56-155, P<0.05)., Conclusions: U-EPX is significantly increased in children with AD and may reflect disease activity. U-EPX may also reflect differences in eosinophil activation between those sensitized and those not sensitized to common allergens.

Background: Bacterial tracheitis is an uncommon, but serious cause of acute respiratory distress in children. The incidence is not known., Material and Methods: The medical records of four children with bacterial tracheitis treated in our hospital are presented, and the literature reviewed to describe symptoms, diagnosis and treatment. A questionnaire was sent to all pediatric departments in Norway to assess the incidence of bacterial tracheitis and epiglotitis during the 1994-98 period., Results: The yearly incidence of bacterial tracheitis was estimated to 4 per 1,000,000 for children aged 0-15, and 8 per 1,000,000 for children aged 0-5. The incidence of epiglotitis was 1.0 per 1,000,000 for children 0-15 years., Interpretation: Bacterial tracheitis is now more common than epiglotitis, and the diagnosis has to be considered in children presenting with acute illness and upper airway respiratory distress. The disease is characterised by marked purulent exudate and formation of pseudomembranes in the trachea. Staphylococcus aureus and Haemophilus influenzae type b are the predominant causes of bacterial tracheitis. Most patients require endotracheal intubation, with the highest frequency in the youngest children. Reported complications include cardiopulmonary arrest, toxic shock syndrome and pulmonary oedema. Appropriate treatment with antibiotics is essential.

To examine their possible predictive value for the development of asthma, the serum concentration of eosinophil cationic protein (ECP) and the total eosinophil count were measured at admission in 25 children aged 1-17 months hospitalized for their first episode of bronchiolitis. After an average of three years the parents of 23 index patients answered a questionnaire to determine development of asthma. Eight children were defined as having asthma at follow-up based on at least three episodes of wheezing. The remaining 15 children had experienced only one or two episodes of wheezing, and all of these children had been wheeze free for the last year. The serum concentrations of ECP were similar in children who subsequently developed asthma (8.0 microg/l; 3.6 to 14.2 (median; quartiles)) and in those who did not (12 microg/l; 4.5 to 16.8). Moreover, the total eosinophil counts were similar in asthmatic (0.10 x 10(9)/l; 0.04 to 0.20) and non-asthmatic patients (0.09 x 10(9)/l; 0.02 to 0.13). In conclusion, our study suggest that neither the serum concentration of ECP nor the total eosinophil count can predict the development of asthma when measured in children admitted for their first episode of bronchiolitis, but larger studies need to be carried out to confirm these results.

The object of the study was to assess the levels of circulating forms of the cellular adhesion molecules ICAM-1, VCAM-1, E-selectin, L-selectin and P-selectin in young children with asthma and acute bronchiolitis. Thirty-nine children aged 12 to 84 months with mild or moderate asthma were studied at admission for acute asthma (n = 15) or in a stable phase (n = 24). Ten of the children with acute asthma were seen again after one month. Twenty-two children aged 1 to 17 months with acute bronchiolitis and nine non-atopic controls were also included in the study. In children with acute asthma, the mean concentration of circulating soluble ICAM-1 (sICAM-1) was increased compared to children with stable asthma (mean 442 micrograms/l versus 363 micrograms/l; p < 0.001) and to controls (363 micrograms/l; p < 0.05). The levels of sICAM-1 remained high at follow up. In children with stable asthma, the mean serum concentration of soluble L-selectin (sL-selectin) (2080 micrograms) was significantly higher than in the controls (1664 micrograms/l; p < 0.05). The levels of circulating cellular adhesion molecules were similar in atopic and non-atopic asthmatics. Children with acute bronchiolitis had increased serum levels of soluble VCAM-1 (sVCAM-1) (1637 micrograms/l versus 1019 micrograms/l in the controls; p < 0.01) and sL-selectin (2041 micrograms/l versus 1664 micrograms/l in the controls; p < 0.05). There was no difference between the levels of circulating cellular adhesion molecules in children with respiratory syncytial virus (RSV) positive and RSV negative bronchiolitis. Soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) in serum were not significantly increased in any of the groups studied. In conclusion, our data suggest differential patterns of circulating cellular adhesion molecules in young children with acute asthma, stable asthma, and acute bronchiolitis, which may reflect differences in the underlying inflammatory processes in these obstructive pulmonary diseases.

Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.

Discitis in children is usually a self-limiting and non-infectious inflammation in the intervertebral disc. The symptoms are diffuse and vary from patient to patient; most often back pain, walking difficulties, crying and irritability. Radiology is often negative initially, and there may be a long delay from onset of symptoms to diagnosis. Magnetic resonance imaging may help in making an early diagnosis. Treatment is controversial; most authors recommend antibiotics only in special cases. It is important to be aware of the condition in order to avoid unnecessary investigations and treatment. We describe two patients, to illustrate the etiology, symptoms and treatment.

The aim of our study was to evaluate the clinical applicability of serum eosinophil cationic protein (ECP), interleukin-5 (IL-5) and total eosinophil counts in childhood asthma and bronchiolitis. These parameters were measured in 44 children aged 12-84 months with moderate and mild asthma during symptomatic and asymptomatic phases of disease. Fifteen of the patients were included at the time of admission to hospital due to an acute asthmatic attack, and ten of these were also examined one month after discharge. None of the patients were treated with glucocorticoids or cromoglycate at any time during the study. Serum ECP was significantly increased in the children with acute asthma compared to children with stable moderate asthma, stable mild asthma, as well as to controls. There was no difference between the groups with stable asthma or between stable asthma and controls, and there was large overlap between all groups of asthmatics and controls. Detectable levels of circulating IL-5 were demonstrated in eight of 15 children with acute asthma, with significantly higher levels in atopic children, whereas all samples from children with stable asthma and controls were negative. The results suggest that even though serum ECP and IL-5 increases during acute asthmatic attacks, these parameters cannot alone be used to discriminate between different groups of young children with stable asthma, nor between asthmatics and healthy controls. In addition, the same parameters of eosinophil inflammation were examined in serum samples from 25 children aged 1-17 months undergoing their first episode of acute bronchiolitis. Children with acute respiratory syncytial virus (RSV) bronchiolitis had significantly higher levels of serum ECP than those with RSV negative disease, whereas the total eosinophil counts were significantly decreased in all patients with acute bronchiolitis. Serum IL-5 was only detected in two children with acute bronchiolitis. The results suggest that the inflammation in RSV bronchiolitis differs from that induced by other viruses.

We followed 68 children with recurrent abdominal pain in a prospective study including a standard investigation programme and abdominal ultrasound. We found an organic disease which explained the pain in eight patients (12%). Most children with recurrent abdominal pain can be dealt with by a general practitioner. In our opinion, further investigation, including abdominal ultrasound should only be carried out in the event of specific suspicion of organic disease. At follow-up 16-34 months later, 55 children (85%) had improved or were free of pain. We discuss the differential diagnoses and propose a plan of investigation for these children.