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Intravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy.Observational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT.A total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group.In ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use.

Background. Pediatric Mastocytosis is a rare and heterogeneous disease, characterized by accumulation of mast cells in the skin (Cutaneous Mastocytosis) and/or, less frequently, in other organs, mainly liver, spleen, bone marrow, lymph nodes and gastrointestinal tract (Systemic Mastocytosis). Patients affected by Systemic Mastocytosis complaint symptoms caused by the massive release of mast cell mediators: itching, flushing, abdominal pain, generalized weakness, fatigue and neuropsychiatric disorders. Moreover, children with Systemic Mastocytosis are at greater risk of anaphylactic/anaphylactoid reactions, often poorly controlled by the conventional therapy with antihistamines, mast cells stabilizers and steroids. As a result, children affected by Systemic Mastocytosis have a poor quality of life and suffer the consequence of prolonged steroidal treatment. Case presentation. A child with Systemic Mastocytosis and severe symptoms, refractory to symptomatic and steroidal therapy, has been successfully treated with Omalizumab, an anti-IgE monoclonal antibody usually employed in allergic patients with severe asthma and orticaria. The onset of clinical benefit of omalizumab therapy was extraordinarily rapid but proved to be strictly dependent on drug administration. The child has become completely and steadily asymptomatic. No other anaphylactic episodes have been reported. Steroid treatment could be definitively withdrawn and all the other medications were reduced. Omalizumab was well tolerated and no side effects have been observed. Conclusions. In our experience Omalizumab is an effective treatment for children affected by Systemic Mastocytosis not responding to conventional medical treatments. The main strengths of this therapy are its rapid and extraordinary efficacy to control the severe mast cells mediator-related symptoms, the good safety profile and its steroid-sparing effect. However, more extensive and controlled studies in pediatric patients affected by Systemic Mastocytosis are needed to substantiate these promising findings.

Toxocarosis is the consequence of human infection by Toxocara spp. larvae and is one of the most common ascarioses, not only in developing countries, but also in the European region, where its prevalence reaches 14%. Due to their particular behavior, children are at higher risk of this parasitic infection, whose clinical features depend on the localization of the Toxocara larvae. Neurotoxocariasis is very uncommon in children and may take different forms depending on the underlying physiopathologic process: immune reaction against the parasite antigens, vasculitis, treatment complications, or, very rarely, brain localization of Toxocara spp. larvae. The association between neurotoxocariasis and the onset of childhood epilepsy has been postulated but is still debated. Moreover, a Toxocara spp. abscess causing epileptic seizures in children has been rarely described, especially in western countries. Hereby we present a 9-year-old patient with a new diagnosis of epilepsy definitely secondary to brain abscess due to the localization of Toxocara canis larvae. Diagnosis was confirmed by neuroimaging and serological test. The successful treatment with albendazole and steroids was documented with a close and long-term clinical and neuroradiological follow-up. Our experience confirms that every case of cryptogenetic epilepsy in children deserves a neuroimaging study and, in case of cystic images, Toxocara serology is mandatory to avoid further unnecessary invasive diagnostic investigations and to set the specific drug therapy.

Coronavirus disease 2019 (COVID-19) affects people of any age with high mortality and morbidity in adults older than 65 years. Reports on pediatric cases highlighted those children generally develop milder symptoms than adults or are asymptomatic. We aimed to assess the epidemiological and clinical data of children and adolescents with SARS-CoV-2 infection to improve pediatric COVID-19.We retrospectively analyzed clinical and epidemiological features of patients with SARS-CoV-2 infection hospitalized at the Pediatric Hospital of Pavia, Italy, between February 1, 2020, to April 30, 2021.71 patients aged 0-16 years were included; 33 (46%) females and 38 (54 %) males. Thirty-three (46%) patients had comorbidities, such as obesity and hematological diseases. Thirty-one children (44%) were exposed to COVID-19-positive household members. Nine (12.7 %) patients were asymptomatic, whereas 57 (80.3%) had a mild-moderate disease. Only five (7%) showed a severe or critical disease, and two patients required ICU admission. The most frequent symptoms were fever (76%), loss of appetite (26%), gastrointestinal symptoms (19%), and cough (19%). Chest X-ray was performed in 42 patients showing lung abnormalities in more than half of symptomatic patients. The most common laboratory features were lymphopenia and eosinopenia associated with high levels of inflammation markers.This study confirmed that COVID-19 has a mild course in children compared to adults. Most of the enrolled children were asymptomatic or had a mild-moderate disease. Patients with comorbidities were more prone to develop clinical complications.

Background There is mounting evidence on the existence of a Pediatric Inflammatory Multisystem Syndrome-temporally associated to SARS-CoV-2 infection (PIMS-TS), sharing similarities with Kawasaki Disease (KD). The main outcome of the study were to better characterize the clinical features and the treatment response of PIMS-TS and to explore its relationship with KD determining whether KD and PIMS are two distinct entities. Methods The Rheumatology Study Group of the Italian Pediatric Society launched a survey to enroll patients diagnosed with KD (Kawasaki Disease Group – KDG) or KD-like (Kawacovid Group - KCG) disease between February 1st 2020, and May 31st 2020. Demographic, clinical, laboratory data, treatment information, and patients’ outcome were collected in an online anonymized database (RedCAP®). Relationship between clinical presentation and SARS-CoV-2 infection was also taken into account. Moreover, clinical characteristics of KDG during SARS-CoV-2 epidemic (KDG-CoV2) were compared to Kawasaki Disease patients (KDG-Historical) seen in three different Italian tertiary pediatric hospitals (Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste; AOU Meyer, Florence; IRCCS Istituto Giannina Gaslini, Genoa) from January 1st 2000 to December 31st 2019. Chi square test or exact Fisher test and non-parametric Wilcoxon Mann-Whitney test were used to study differences between two groups. Results One-hundred-forty-nine cases were enrolled, (96 KDG and 53 KCG). KCG children were significantly older and presented more frequently from gastrointestinal and respiratory involvement. Cardiac involvement was more common in KCG, with 60,4% of patients with myocarditis. 37,8% of patients among KCG presented hypotension/non-cardiogenic shock. Coronary artery abnormalities (CAA) were more common in the KDG. The risk of ICU admission were higher in KCG. Lymphopenia, higher CRP levels, elevated ferritin and troponin-T characterized KCG. KDG received more frequently immunoglobulins (IVIG) and acetylsalicylic acid (ASA) (81,3% vs 66%; p = 0.04 and 71,9% vs 43,4%; p = 0.001 respectively) as KCG more often received glucocorticoids (56,6% vs 14,6%; p Conclusion Our study suggests that SARS-CoV-2 infection might determine two distinct inflammatory diseases in children: KD and PIMS-TS. Older age at onset and clinical peculiarities like the occurrence of myocarditis characterize this multi-inflammatory syndrome. Our patients had an optimal response to treatments and a good outcome, with few complications and no deaths.

Erythema multiforme (EM) is an immune-mediated reaction first described by von Hebra1 in 1860, presenting typically as acrofacial target lesions. The rash may be confined to the skin (EM minor), or it may involve ocular, oral, or genital mucosa with systemic symptoms (EM major). In most cases, only 1 outbreak of EM occurs in a lifetime; however, very rarely, repeated episodes of EM may occur, known as recurrent EM.2 Few cases of pediatric recurrent EM have been reported, with the etiology being identified in less than half of these cases.3 We report a pediatric case of recurrent EM resistant to conventional treatments in which a peculiar human leukocyte antigen (HLA) haplotype has been identified.

Italy is one of the most exposed countries worldwide to COVID-19, and Lombardy is the most affected region in Italy. In this context, Fondazione IRCCS Policlinico San Matteo in Pavia, one of the largest University hospitals in the region, has been involved in the management of the outbreak since its inception. Immediately after the communication of the first Italian COVID-19+ patient, the Pediatric Unit has been completely reorganized to face the approaching outbreak. The optimization of the Pediatric Unit resources for COVID-19 emergency is reported as an example to safely preserve health activity during the pandemic.(www.actabiomedica.it)

Complete interferon-γ receptor 1 deficiency is a monogenic primary immunodeficiency caused by IFNGR1 germline defects, with autosomal dominant or recessive inheritance, which results in invasive mycobacterial diseases with varying degrees of severity. Most of the autosomal recessive IFNGR1 mutations are homozygous loss-of-function single-nucleotide variants, whereas large genomic deletions and compound heterozygosity have been very rarely reported. Herein we describe the clinical presentation, diagnosis, and successful treatment with hematopoietic stem cell transplantation of a child with disseminated Mycobacterium avium infection due to compound heterozygosity for a subpolymorphic copy number variation and a novel splice-site variant.

Background Cutaneous leishmaniasis has an incidence of 0.7-1.2 million cases per year and represents a growing concern in the outpatient dermatologic practice in Europe because of imported cases due to increased travel to risk areas and to immigration phenomena. When dealing with children, the treatment can be challenging because of side effects and pain of classic antimonial therapy leading to poor rates of course completion and requirement of sedation for several children. Methods We retrospectively studied three cases of cutaneous leishmaniasis in pediatric patients, between the ages of 3 and 6 years of age, treated with oral fluconazole. We examined the efficacy, the tolerability, the safety profile and the cosmetic result of fluconazole at a dose of 6 mg/kg/daily for 6 weeks. Results The patients had a complete resolution of their lesions with minimal scarring. No adverse effect was reported. The leishmaniasis species identified were L. major or L. tropica. Conclusion Considering sides effects and the parents' and the clinician's concern for systemic treatment in the pediatric population, fluconazole represents a valid, safe and easily manageable option for Old World cutaneous leishmaniasis in pediatric outpatients caused by L. major or L. tropica.

The competitive binding between CpG-ODN (single-stranded DNA from pathogens) and HLA-B and HLA-A ligands for the inhibitory Killer Immunoglobulin-like Receptors (KIR)3DL1/2 may lead to possible hypo-sensing of pathogens and ineffective clearance. We observed an overabundance of HLA ligands for inhibitory KIR with three domains in KD subjects.

Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis (CM). Although TMEP has been traditionally thought to be restricted to the skin, a recent retrospective multicentric study established a diagnosis with systemic involvement of mastocytosis in 47% patients affected by TMEP and aggressive systemic mastocytosis in 9%. To evaluate systemic involvement in patients affected by TMEP. We conducted a retrospective monocentric study among patients affected by TMEP visited in our dermatology clinic. Data regarding gender, age at diagnosis, duration of the disease before diagnosis, topography, clinical features, presence of extra-cutaneous symptoms, serum tryptase levels, and histopathological and bone marrow biopsy features were analysed. Among 119 patients classified with mastocytosis, eight patients (six males, two females) with TMEP and one female patient affected by mastocytosis in the skin, a TMEP variant, were retrospectively studied. The mean diagnostic delay was two years (range: 8-26 months). In two patients (25%), bone marrow involvement was identified and osteoporosis and hepatosplenomegaly were also found. The two patients with systemic involvement exhibited a statistically significant increase in serum tryptase levels (p 0.05). The detection of KIT gene mutation in skin specimens revealed a somatic mutation, KITD816 V, only in these two patients. TMEP is a rare form of CM, often neglected. A correct and early diagnosis of TMEP is important to rule out systemic involvement of the disease. Detection of serum tryptase levels may be a useful, rapid, and non-invasive marker of systemic involvement.

Background Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. Objective To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. Methods We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. Results Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naive CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naive ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. Conclusions Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

BACKGROUND In mastocytosis, the skin is almost invariably involved, and cutaneous symptoms deeply affect patients' quality of life. METHODS A retrospective observational analysis of patients affected by cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM) treated with phototherapy/photochemotherapy (PUVA or NB-UVB) has been conducted. For each patient, total numbers of PUVA or NB-UVB exposures, the cumulative UV dose (J/cm2 ), serum tryptase profile, and pruritus, before and after treatment, according to the visual analogue scale (VAS) were considered. Skin lesions of each patient were assessed, before and after treatment, according to a cutaneous scale score. RESULTS Twenty patients affected by CM and ISM were studied; in particular, 10 patients received NB-UVB therapy, and other 10 patients received PUVA. A statistically significant mean reduction of pruritus in both groups (P < 0.01) was observed. The number of treatments necessary to obtain symptom relief was significantly lower in the PUVA group, but the mean exposure dose was significantly higher, if compared to the NB-UVB group. Serum tryptase levels showed a downward trend. The cutaneous score improved in both groups. LIMITATIONS This study was a retrospective study with a small sample size and without a control group. CONCLUSION This work provides evidence that both NB-UVB and PUVA represent a safe and useful second-line therapy of the cutaneous symptoms in mastocytosis.

Acute/subacute haematogenous osteomyelitis (AHOM/SAHOM) are potentially devastating diseases. Updated information about the epidemiology, management and outcome of AHOM/SAHOM is needed to minimize the risk of complications and sequelae. METHODS: A multicenter study was performed to evaluate retrospectively the management and outcome of AHOM/SAHOM in Italy. Data from children aged >1 month, and hospitalized between 2010 and 2016, in 19 pediatric centers, were analyzed. RESULTS: 300 children with AHOM and 98 with SAHOM were included. Median age was 6.0 years (IQR: 2.0-11.0). No clinical difference was observed with the exception of fever at onset (63.0% vs. 42.9%; P < 0.0001), and a more common spinal involvement in SAHOM (6.7% vs 20.4%; P < 0.001). Fifty-Eight Staphylococcus aureus strains were isolated; 5 (8.6%) were MRSA. No Kingella kingae infection was documented. No different risk for complication/sequela was observed between AHOM and SAHOM (38.3% vs. 34.7%; OR:0.85; 95%CI: 0.53-1.38; P = 0.518). Duration and type of antibiotic therapy were not associated with risk of complication/sequelae. CONCLUSION: AHOM and SAHOM displayed some differences, however occurrence and risk factors for complications and sequelae are similar, and the same empiric treatment might be recommended.

The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists’ contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations. Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient’s condition, and disease severity or complications.

Aim: We collected ‘real-life’ data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. Methods: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. Results: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. Conclusion: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.

We report definitive diagnosis and effective treatment with oral cholic acid in one Italian male child affected by 3β- hydroxy-Δ5-C27-steroid dehydrogenase (3β- HSD) deficiency. He presented with failure to thrive, hepatomegaly and multiple cystic images in kidneys, no biochemical evidence of cholestasis. Large amounts of bile acid metabolites was detected in urine by fast atom bombardment ionization mass spectrometry (FAB-MS). HSDH3B7 gene analysis identified one mutation in intron 4, at nucleotide 432, G&gt, A substitution that has never been reported before.The replacement therapy with oral cholic acid started early after the diagnosis and is still ongoing. Three years later hepatomegaly is no longer evident, liver function is normal and the child is growing regularly. In our experience, clinical features of 3β-HSD deficiency can be very poor and even cholestasis can lack at diagnosis. Early replacement therapy with cholic acid is safe and leads to clinical and biochemical control of the disease.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Type 2 autoimmune hepatitis (AIH-2) is a rare disease presenting in early childhood. The immunopathogenetic mechanisms are poorly characterized, although a defect of regulatory T cells (Treg) has been shown. There is virtually no information on innate immune responses and natural killer (NK) cells in particular. We have performed an extended immunophenotypic and functional analysis of NK cells in children with AIH-2. We show that NK cell frequency is reduced in this setting and that the balance between NK activating and inhibitory receptors is skewed toward activation. More importantly, NK cells display an altered cytokine pattern characterized by increased IFNγ and reduced IL2 production which could contribute to impaired Treg function. Exposure of mononuclear cells to IL2 resulted in normalization of NK IFNγ production. Thus, our findings support treatment of AIH-2 with low-dose IL2, which would result in normalization of NK cell function and expansion of the Treg cell subset.

Acute meningitis is an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space that still causes morbidity and mortality. Among the sequelae of meningitis, endocrine complications have been reported in patients recovering from acute central infectious diseases. Although the results of the studies are conflicting, the most common pituitary hormone deficiency during the acute phase or at 1-year follow-up evaluation is growth hormone deficiency, which results in growth impairment in children and a dysregulation of body composition and lipid metabolism throughout life. The mechanisms involved in growth failure secondary to meningitis are unknown. Therefore, endocrinological evaluation, including clinical, auxological, and hormonal assessments, should be performed during the acute phase of the infection and during recovery.

Background Abnormalities of chromosome 22q11, including deletions and translocations, have been described in association with different birth defects and malformations occurring in many combinations and degrees of severity. Case presentation We describe the case of an 8 month-old infant with no dysmorphic signs who showed progressive postnatal growth failure and no chronic systemic diseases. We found a 22q11.2 microdeletion, inherited from the mother, suggesting the diagnosis of DiGeorge syndrome. The patient had an isolated growth hormone (GH) deficiency and a significant increase in linear growth during the first and the second year of GH therapy, and a recovery of weight was shown. Conclusions Sometimes, in infants with growth failure a genetic analysis is strongly suggested, since chromosomal abnormalities may be present.

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries.

Background The risk of cardiomyopathy following exposure to anthracycline in asymptomatic long-term survivors of childhood cancer is still hard to predict and precisely quantify. To identify the impact of different cumulative doses, even within a non-high dose range, and the echocardiographic parameters suitable for evaluating cardiac function, we studied diastolic and systolic echocardiographic parameters in a cohort of patients followed in a single center. Procedure A total of 117 subjects were studied at a median time of 7 years after treatment completion. A complete M-mode, two-dimensional and Doppler echocardiographic study was obtained at rest in all patients according to the standard recommendations of the American Society of Echocardiography. Results Ninety-nine patients (85%) had completely normal cardiac function, while 18 had abnormal echocardiographic findings: 12 had one abnormal value, 5 had two, and 1 had three abnormal values. All the changes were in left ventricular dimensions, wall thickness or indices of systolic function; no alterations in left ventricular diastolic function parameters were found. None of the echocardiographic parameters correlated significantly with the cumulative dose of anthracyclines administered either at univariate analysis or after adjusting for sex, body surface area or considered risk factors. Conclusions Subjects exposed to a median cumulative dose of 214 mg/m2 had no echographic abnormalities a median of 7 years later. We did not find any correlation between cumulative anthracycline dose and the echocardiographic parameters tested. We now offer echocardiographic follow-up to patients with mildly reduced fractional shortening and/or ejection fraction to rule out late onset dysfunction. Med. Pediatr. Oncol. 36:593–600, 2001. © 2001 Wiley-Liss, Inc.

Background Long-term survivors of childhood cancer treated with anthracyclines may have subclinical cardiac dysfunction undetectable at a baseline evaluation. Dobutamine stress echocardiography has been proposed as a more sensitive screening test, but results of previous studies were influenced by selection criteria, infusion protocols, and side effects. Methods We applied a modified dobutamine stress test (from 5 to 10 to 15 μg/kg, infused over a 5-minute period) and evaluated the influence on stress test results of reported risk factors for late cardiac toxicity (female sex, younger age at treatment, higher dose of anthracycline, and longer duration of follow-up). Seventy-one patients (46 male, mean age 15 ± 5 years) treated with anthracyclines (median dose 240 mg/m2) 1 to 16.5 years before and 20 controls (patients’ siblings: 12 male, mean age 19 ± 4 years) were studied. Results No major side effects were recorded. One patient was unable to perform the test because of anxiety. Limiting side effects were infrequent (3%) and occurred at a dobutamine dose of ≥10 μg/kg, when significant changes of hemodynamic and echocardiographic parameters were detectable in all cases. Rest systolic and mean blood pressure and left ventricular fractional shortening were significantly lower in patients than in controls (P

Study objectives To evaluate lung function in patients cured from childhood acute lymphoblastic leukemia (ALL) with chemotherapy alone or plus bone marrow transplantation (BMT). Pulmonary toxicity is a well-recognized side effect of many ALL treatments. Design Cross-sectional study conducted at least 3 years after cessation of therapy. Setting Outpatient pneumology department of the University Hospital. Patients Forty-four subjects (age range at observation, 6 to 23 years): 21 treated only with intensive Berlin-Frankfurt-Munster (BFM)-type chemotherapy for newly diagnosed ALL (group A), and 23 treated with chemotherapy plus BMT (group B). Measurements A detailed history of smoking habit, respiratory symptoms, and diseases was recorded directly from the patients with the aid of their parents. A complete physical examination and lung function testing (lung volumes and diffusion capacity for carbon monoxide [Dlco]) were performed in all subjects. Results No patient reported acute or chronic respiratory symptoms or diseases. In group A patients, lung function was in the normal range, except for three subjects in whom there was an isolated impairment of Dlco. In group B patients, lung function was markedly impaired, with more than half the patients having an abnormal Dlco. A statistically significant difference was found between the two groups for FVC (p = 0.022) and Dlco (p = 0.004). Conclusions Intensive, BFM-type frontline chemotherapy is not associated with late pulmonary dysfunction; however, retreatment including BMT can frequently injure the lung. Thus, in patients who undergo BMT and whose life expectancy is long, careful monitoring of lung function and counseling about avoiding additional lung risk factors is recommended.

Summary Kawasaki disease (KD) is an acute, multisystemic, febrile vasculitis of unknown aetiology, which affects young children mainly under 5 years of age. The clinical variability has until now prevented to decrypt KD aetiological factors. Recently, the importance of genetics and the pivotal role of the immune system have emerged. To investigate in this direction, genomic DNA from 74 Caucasian KD cases and 440 healthy controls has been analysed to characterize functional polymorphisms of relevant HLA class III genes: AGER -429 and -374, TNF -857, -308 and -238, HSPA1A +190, HSPA1B +1267 and HSPA1L +2437. Allele, genotype and haplotype frequencies were therefore compared with the chi-squared test and Fisher’s exact test. Our data showed significant deviations between patients with Kawasaki disease and controls concerning the TNF -308 polymorphism genotype (GG: P = 0.0449) and allele (G,A: P = 0.0433) and -238 polymorphism genotype frequencies (AA: P = 0.0351). Moreover, we found differences concerning the HSPA1A +190 polymorphism (GC: P = 0.0317) and the HSPA1L +2437 polymorphism (TT: P = 0.0072; TC: P = 0.0250; T: P = 0.0037; C: P = 0.0037). The calculation of TNF -238 and HSPA1L haplotype frequencies also pointed out a statistically significant decrease in patients of CG haplotype (P = 0.0001), which could have a role in protecting from the inflammatory processes that characterize the disease progression. The results obtained point to a possible involvement of the entire HLA class III region in KD susceptibility.

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an autosomal-dominant disease caused by mutations of the type I tumor necrosis factor receptor (TNFRI) gene (TNFRSF1A) (1,2). The TNFRSF1A mutations reported in TRAPS patients include missense substitutions, mainly affecting the highly conserved cysteine residues of the extracellular cysteine-rich domains involved in disulfide bond formation and in the folding of the extracellular portion of TNFRI (3,4). These genetic variants (also defined as structural mutations) have a high penetrance, and the corresponding phenotype is characterized by a severe disease course. Patients display long-lasting fever episodes (duration of 1–3 weeks) associated with rash, arthralgia, myalgia, and abdominal pain. Progression toward a more chronic disease course and renal amyloidosis is a possible long-term complication in adulthood (5). Patients may require prolonged treatment with steroids and use of second-line drugs (3–5). Among Caucasian populations, the R92Q mutation is the most frequently observed variant of the TNFRSF1A gene in children with periodic fever (6,7). R92Q is a missense and low-penetrance mutation with no relevant impact on the structure and function of the mutated protein and is usually associated with a milder disease course, characterized by episodes of fever lasting only a few days, lower intensity of disease-associated symptoms, and a much lower prevalence of amyloidosis (3,4). Notably, according to different studies, the allele frequency of the R92Q variant in the general population ranges from 1.2% to 4% (3,4,6,8). Apart from the description of very few anecdotal cases of renal amyloidosis in adults (9), no information is available on the long-term clinical profile of patients affected with TRAPS who are carriers of the R92Q mutation. Indeed, only 10–20% of children with a clinical picture consistent with a periodic fever turn out to be carriers of at least one mutation of the genes known to be associated with monogenic periodic fevers such as familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS (10). The clinical spectrum of the large group of mutation-negative children with periodic fever is extremely variable. In the pediatric population, the most common cause of periodic fever is a clinical entity characterized by recurrent episodes of fever, known under the acronym PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis syndrome) (6,11,12). The genetic basis of this syndrome is not yet documented, and usually spontaneous resolution of the fever episodes will occur a few years after symptom onset. In the present study, we chose to analyze mutation-negative patients who fulfilled the PFAPA criteria, in order to have a more homogeneous disease control group. The aim of the present study was to analyze the long-term clinical course in children with periodic fever carrying the R92Q mutation, as compared with that in TRAPS patients carrying structural mutations of TNFRSF1A and patients with periodic fever of unknown origin fulfilling the criteria for PFAPA.

OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

We present a case of infantile bullous pemphigoid (BP) triggered by primary infection with varicella zoster virus and we analyze the correlation between autoantibody levels and disease activity. With this report we suggest that serum autoantibody titers may not necessarily mirror the clinical course of the disease or represent a helpful tool in guiding therapeutic decisions in infantile BP.

Patients with agammaglobulinemia may excrete enteroviruses, including vaccine-derived poliovirus, for prolonged periods of time. This poses a risk to the patients but it also may pose a risk to the population after eradication of poliovirus and the cessation of routine vaccination. To assess this risk, a pilot study was performed to identify potential poliovirus long-term excretors in a cohort of 38 patients with a definite/presumptive diagnosis of X-linked agammaglobulinemia (XLA). Stool samples were analyzed to detect any polio or other enteroviruses replicating in the gut and neutralizing antibodies against polioviruses were measured in the sera. No viruses were isolated from the stool samples and most sera had neutralizing antibody levels against all three poliovirus serotypes considered by the WHO to be protective in immunocompetent individuals. This suggests that long-term excretion of enteroviruses in patients with agammaglobulinemia is relatively uncommon.

We report on a new patient with deletion of 22q11 associated with hemophagocytic lymphohistiocytosis and a fatal outcome. She had minor facial anomalies and cardiac malformation corresponding to those described in del (22q11) syndrome, normal T and B cell function and NK activity; bone marrow aspiration showed active erythrophagocytosis. Our case in addition to two other children reported previously suggest that such a rare association between lymphocyte-macrophage activation and deletion of 22q11 may be more frequent than previously recognized.

BACKGROUND: The purpose of this study was to determine the prevalence of GB virus type C (GBV-C) infection in subjects treated for childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS: One hundred forty patients (82 males) aged 4 to 27 years (median, 11) diagnosed with ALL between 1976 and 1993, were prospectively followed for a median of 5 years (range, 0.1–17) after completion of therapy. Stored sera were tested for antibody to hepatitis C virus (HCV), HCV RNA, antibody to GBV-C E2 (anti-E2), and GBV-C RNA. RESULTS: Thirty-eight patients (27%) were exposed to GBV-C: 30 were positive for GBV-C RNA (mostly type 2) and 8 were positive for anti-E2. Anti-E2 and GBV-C RNA were mutually exclusive: 61 patients (43%) were positive for HCV RNA, 16 (11%) were coinfected with GBV-C and HCV. Alanine aminotransferase (ALT) levels were increased (>35 mU/mL) in 32 (23%) of 137:3 of 20 who were positive for GBV-C and negative for HCV, 7 of 15 who were positive for GBV-C and HCV, 15 of 44 who were negative for GBV-C and positive for HCV, and 7 of 58 who were negative for GBV-C and HCV (p

Children treated for Langerhans cell histiocytosis (LCH) are at risk for short and long term endocrine sequelae, but biological predictors of specific deficits are not well defined. We evaluated the frequency and progression of LCH-related endocrine deficits during long term follow-up and assessed the ability of dynamic endocrine testing to identify patients at risk for late anterior or posterior pituitary hormone dysfunction. The 17 patients (5 males and 12 females) were followed a median of 10 yr after diagnosis of single system (n = 6) or multisystem (n = 11) disease. Study evaluations, performed a median of 4.1 yr after the diagnosis, comprised pituitary hormone responses to the appropriate challenge, 7-h water deprivation test, 3% hypertonic saline infusion, and magnetic resonance imaging (MRI). The six patients with GH deficiency at the time of evaluation had a significantly lower GH response to GHRH than the other patients [median peak, 7.3 vs. 21.5 micrograms/L (P = 0.03); median area under the curve, 4.7 vs. 13.5 micrograms/L (P = 0.03)]; levels in the latter group did not differ significantly from those in 20 age- and sex-matched controls with constitutional or familial short stature. Two patients who had GH responses to GHRH of 20.6 and 23 ng/mL at 2.8 and 9.5 yr of age developed GH deficiency at 6.5 and 11.2 yr of age, respectively. The TSH response to TRH was less than 10 mU/L in three patients, two of whom later developed central hypothyroidism. ACTH and cortisol responses to CRF, and PRL responses to TRH were normal in all cases, and LH and FSH responses to GnRH were compatible with pubertal stage. Abnormalities in arginine vasopressin responses to water deprivation or hypertonic saline infusion were seen only in four patients who had preexisting diabetes insipidus (DI); one patient who later developed DI had normal findings. On standard MRI, posterior pituitary hyperintensity was absent only in the patients with DI. Pituitary stalk thickening was seen in seven patients, including three who did not have DI and had normal arginine vasopressin responses. Delayed posterior and anterior enhancement on dynamic MRI was present in two patients, both of whom later developed central hypothyroidism. Patients with single system disease had a lower 5-yr probability of LCH reactivation (41% vs. 83% for those with multisystem disease; P = 0.21) and a significantly lower risk of endocrine dysfunction (P = 0.007). In this series, dynamic evaluation of pituitary function was not a useful predictor of late endocrine sequelae, with the possible exception of the progressively decreasing TSH response to TRH. Similarly, a standard MRI was not predictive, although dynamic imaging may be informative regarding evolving pituitary hormone deficiency.

Background: Pulmonary sequelae have been reported in patients treated for Hodgkin's disease (HD). Few data are available about patients treated for childhood HD followed over several years. Patients and methods: In a cross-sectional study carried out for 76 months (median time) after treatment completion, we evaluated the lung function abnormalities and respiratory symptoms in 27 patients (16 males and II females) with HD diagnosed betweeen 1983 and 1994 (median age at diagnosis II years, range 2-16 years). They had been treated with chemotherapy and radiotherapy according to current protocol AIEOP-MH 83 (n = 14) or AIEOP-MH 89 (n = 13). At the time of the study, 26 patients were in first complete remission and one in second remission. Of the 27 patients, 19 had had mediastinal irradiation at a dose of 20 Gy (n = 5) or 20.8-44 Gy (n = 14). Forced vital capacity (FVC), functional residual capacity (FRC), forced expiratory volume in one second (FEV 1 ), FEV 1 / FVC ratio, and maximal expiratory flow at 25% of FVC were registered; diffusion capacity for carbon monoxide (D L CO) was determined. Data were expressed as standard deviation (SD) score. Four patterns of respiratory function abnormalities were defined: restrictive, obstructive, isolated bronchiolar impairment, isolated diffusing impairment. Results: Twelve patients (44%) were asymptomatic and showed completely normal pulmonary function tests. Three patients reported dyspnea on exertion, and one of them also cough and phlegm: out of these symptomatic subjects, only I had functional abnormality (isolated D L CO impairment). A restrictive pattern was found in 5 patients (18%), including 2 who also had a pathological D L CO SD score. Eight additional patients (30%) had isolated diffusing impairment. Oxygen saturation was normal in all patients. Forty-seven percent of patients with normal D L CO had had lower dose irradiation (20 Gy) compared to 10% of patients with impaired D L CO (P = 0.054). Similarly, patients with normal D L CO had had significantly less chemotherapy as compared to patients with abnormal D L CO (P = 0.003). Occurrence of lung abnormalities was not significantly associated with sex, age at treatment, mediastinal irradiation, and time elapsed from treatment completion. Conclusion: Adolescents and young adults treated for childhood HD are at risk for lung function abnormalities, significantly more frequent in patients who received more intense treatment, as mediastinal irradiation at a higher dose (> 20 Gy) and more chemotherapy blocks. Long-term follow-up should be offered to these patients because of their possible limited potential for pulmonary function and possible lesser resistance to adverse agents such as smoke, pollution, infections, and aging.

Second malignant neoplasms (SMN) in individuals who survived childhood cancer have been reported with increasing frequency during the last decades. The overall probability of developing second malignancy for children treated for cancer was estimated at about 2–5% at 25 years. In children, the tumors most often associated with the development of SMN are retinoblastoma and Hodgkin's disease. We report two cases of unusual second tumors in two patients cured of lymphoid malignancy: one boy cured of acute lymphoblastic leukemia developed mediastinal ganglioneuroma nine years later and one girl had gastric carcinoma seven years after Hodgkin's disease. Both developed a tumor in nonirradiated areas. Gastric carcinoma and ganglioneuroma are not reported as recurrent SMN in survivors after childhood cancer, with one single case of gastric carcinoma and one of ganglioneuroblastoma having been reported as second tumor in survivors after childhood cancer. © 1995 Wi1ey-Liss Inc.

Choroid plexus carcinoma (CPC) is a rare tumor with usually severe prognosis, whose optimal treatment has not yet been established. The exact role of complete surgical resection, chemotherapy, and radiotherapy has been debated but not clarified. We report one girl with CPC diagnosed at age 3 months and apparently cured with minimal surgical resection, chemotherapy, and delayed irradiation. At the age of 8 years, she is well, with minor psychomotor retardation and growth hormone deficiency as the only sequelae. © 1994 Wiley-Liss, Inc.