Achille Stabile

Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome

Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare disorder of unknown aetiology with neonatal onset, characterized by severe arthropathy, persistent skin rash and central nervous system disease. Joint involvement may vary from minimal swelling to destructive arthritis, with inability to stand or walk. The most striking findings of CINCA syndrome are cartilage anomalies with epiphyseal modifications and abnormal ossification, for which a pathogenetic role of tumour necrosis factor‐α (TNF‐α) is postulated. We describe a 4‐year‐old child affected with CINCA syndrome and presenting progressive joint disease, in whom non‐steroidal anti‐inflammatory drugs (NSAID) and systemic corticosteroidal therapy had been ineffective. Etanercept, anti‐TNF‐α therapy, was administered over a 6‐month‐period resulting in a dramatic improvement of the arthropathy. This good response to anti‐cytokine treatment supports our hypothesis that TNF‐α might play an important role in the pathogenesis of CINCA syndrome, which needs to be evaluated and confirmed in further studies.

Hydrocephalus in CINCA syndrome treated with anakinra

IntroductionChronic infantile neurologic, cutaneous, articular (CINCA) syndrome is a rare congenital autoinflammatory disease characterized by neonatal-onset chronic meningitis, hydrocephalus, sensorineural hearing loss, persistent urticarial rash, deforming arthritis, and recurrent fever. This clinical entity is believed to result from dysregulation of cytokine production. No recommended treatment protocol exists so far for CINCA syndrome.Case reportWe report a 7-year-old child affected with CINCA syndrome in whom no therapy had resulted effective. Anakinra, an interleukin-1-receptor antagonist, was administered in a 1-year period with complete inflammatory symptom remission and dramatically ameliorated laboratory tests. This optimal response has been supported by the demonstration of a stabilized hydrocephalus upon magnetic resonance imaging and by an overall improvement of the neurodevelopmental issues.DiscussionThis paper emphasizes and discusses the medical approach with anakinra in CINCA syndrome presenting with hydrocephalus in which a consistent control of the neurological picture can be obtained.

The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age

IntroductionInterleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype.Methods13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation.Resultsseven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab.ConclusionsThe use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.

Factitious disorders and Munchausen syndrome: The tip of the iceberg

This population-based study evaluates the prevalence of factitious disorders, Münchausen syndrome, and Münchausen syndrome by proxy in a clinical setting. All children referred to the Pediatric Unit of the Department of Pediatrics of the Catholic University Medical School (Agostino Gemelli Hospital) in Rome were recruited between November 2007 and March 2010. An experienced interdisciplinary team of medical professionals analyzed all suspected cases. A total of 751 patients were hospitalized. Factitious disorders were diagnosed in 14/751 patients, resulting in a prevalence of 1.8%. Three of 14 (21.4%) patients fulfilled the criteria for Münchausen syndrome. Münchausen syndrome by proxy was identified in four of 751 patients, resulting in a prevalence of 0.53%. The perpetrator was the mother in three of four of these cases. The epidemiological data obtained in this population-based study indicate that the prevalence of factitious disorders, Münchausen syndrome, and Münchausen syndrome by proxy is higher than previously observed. Moreover, early detection was possible thanks to the awareness of an expert interdisciplinary team. We suggest that physicians must consider the possibility of these diagnoses whenever there are discrepancies in a child’s illness presentation.

Prognostic Impact of Atypical Presentation in Pediatric Systemic Lupus Erythematosus: Results from a Multicenter Study

OBJECTIVES The aim of the study is to assess the rate of atypical manifestations at onset in pediatric systemic lupus erythematosus (SLE) and to evaluate their effect on disease outcome. STUDY DESIGN This is a multicenter retrospective cohort study. A manifestation was considered atypical if it was not included in the American College Rheumatology classification criteria for SLE but was reported in literature as associated with SLE. Unfavorable outcome was considered presence of organ damage in the Systemic Lupus International Collaborative Clinics/American College of Rheumatology Damage Index at the last available evaluation. RESULTS One hundred patients were enrolled in the study; 24% presented atypical clinical features at onset. Univariate analysis showed a significant association of worse outcome variables with the presence of atypical manifestations at onset (P = .004), as well as renal involvement (P = .027). A multivariate logistic regression analysis showed that atypical manifestations at onset (P = .018), renal involvement at onset or during follow up (P = .024), and central nervous system disease involvement during follow up (P = .021) were independent predictors of poor prognosis. CONCLUSIONS Our data support a relatively high rate of atypical onset in pediatric SLE. Presence of atypical manifestations at presentation and early kidney disease correlate with poor outcome. Similarly, during follow-up, kidney and central nervous system diseases are associated with worse outcome.

Serum interleukin-18 in children with Henoch-Schonlein purpura: a promising marker of disease activity?

Henoch-Schönlein purpura (HSp) is the most common systemic vasculitis of childhood with typical skin involvement and concurrent signs involving joints, gastrointestinal tract, and kidney. HSp pathogenesis is still far from being completely understood, though a knotty cytokine complex is believed to contribute to its intimate processes. The aim of our evaluation is to establish the relationship between serum levels of interleukin (IL)-18 and disease outcome and establish its feasibility to provide a marker of disease activity or even a prognostic tool in clinical practice. We examined clinical/laboratory variables and serum IL-18 in 17 children hospitalized during a year for HSp, diagnosed by EULAR/PRINTO/PRES criteria; the same patients were re-evaluated after 6 months. All results were compared with 25 age-matched healthy controls. IL-12 and IL-6 were also evaluated in a cohort of the same patients and compared with controls. General and clinical variables (sex, edema of the extremities, gastrointestinal or renal complications, relapses and renal involvement at 6 months) had no relationship with cytokine levels. Serum IL-18 and IL-6 levels were found significantly increased at diagnosis in HSp patients when compared with healthy controls. After 6 months, serum IL-18 and IL-12 levels were significantly decreased in patients, while IL-12 and IL-6 levels were significantly increased compared to healthy controls. Though preliminary and expecting further confirmation on a larger sample, our data support the conclusion that serum IL-18 levels reflect HSp activity.

CEFTRIAXONE-ASSOCIATED GALLBLADDER LITHIASIS IN CHILDREN

Sir: Ceftriaxone, a third-generation cephalosporin, has potent activity against a broad range of Gram-posit ive and Gramnegative bacteria [6]. It has long half-life and is mainly eliminated by the kidney and only partially excreted into bile [6]. Pharmacokinetic profile and clinical activity suggest its use in severe infection in children and adults [2, 9]. Review of recent data indicates that ceftriaxone treatment has been associated with the development of sludge or stones in the gallbladder [ 1, 3-5, 7, 8]. To evaluate this correlation we have performed serial gallbladder sonography in children treated with ceftriaxone. Between January 1993 and November 1993, 41 children (26 males and 15 females; mean age 4.78+/-2.69 years, range 2-12) were eligible for enrollment in our study. These children were admitted to the Department of Paediatrics of the Catholic University of Rome. The study was approved by local Ethics Committee and informed consent was obtained from the parents. All patients were treated with ceftriaxone for serious infections (above all, bronchopulmonary and urinary tract infections). The recommended dose was 50-80 mg/kg in one daily parenteral dose. Biliary sonography was performed during, just after, and at 1 and at 3 months after the end of the treatment. All patients were evaluated. Response to treatment with ceftriaxone was good in the majority of children; in 31 (75.6%) patients the infection resolved completely and in 9 (21.9%) patients improved. Only 1 (2.43%) child showed clinical deterioration. Five patients developed gallbladder lithiasis (multiple hyperechogenic precipitations) 7 days after ceftriaxone treatment. Four patients who acquired gallbladder sonographic abnormalities had maternal family history of cholelithiasis or nephrolithiasis. Subsequent symptoms (tenderness in the right upper quadrant) developed in one patient with disappearance after the end of ceftriaxone treatment. In all patients sonographic abnormalities completely resolved 10 days (4 children) or 30 days (one child) after the end of treatment. Ceftriaxone has been reported to result in so-called pseudolithiasis of the gallbladder in 21.4% of men [3] and 47% of children [7] with subsequent symptoms in a minority of patients. Generally the gallstone spontaneously dissolved at 2-63 days after the end of ceftriaxone therapy. In previous studies the cholecystectomy and the stone analysis showed that ceftriaxone comprised approximately 80% of stones [5]. On the contrary Cometta et al. [1 ] have investigated the incidence of biliary lithiasis 6 and 12 months after treatment with ceftriaxone and have compared it with that in patients treated with amoxycillin/clavulanate. One hundred patients were randomized and 74 were evaluable. Gallbladder lithiasis developed in 1 patient 12 months after the amoxycillin/clavulanate treatment. The gallbladder precipitations that were seen in 2 patients given ceftriaxone during and at the end of treatment resolved spontaneously. The authors have conclude that ceftriaxone treatment does not appear to lead to gallstone formation more often than another antibiotic that is not eliminated through the bile. In our study we have found reversible ceftriaxone-associated biliary lithiasis in 12.2% treated children. These sonographic abnormalities were acquired in all patients with family history of gallbladder lithiasis. The clinical effectiveness and tolerance of ceftriaxone is well recognized and the use of this drug is appropriate in therapy of serious infections in children. However, it may have importance to perform abdominal sonography in all ceftriaxone-treated children, specially in the patients who have abdominal pain during or just after ceftriaxone therapy. We suggest that a change in antibiotic treatment should be considered in all children with family history of gallbladder disease.

Mevalonate kinase genotype in children with recurrent fevers and high serum IgD level

In selected cases, childhood’s recurrent fevers of unknown origin can be referred to systemic autoinflammatory diseases as mevalonate kinase deficiency (MKD), caused by mutations in the mevalonate kinase gene (MVK), previously named “hyper-IgD syndrome” due to its characteristic increase in serum IgD level. There is no clear evidence for studying MVK genotype in these patients. From a cohort of 305 children evaluated for recurrent fevers in our outpatient clinic during the decade 2001–2011, we have retrospectively selected 10 unrelated Italian children displaying febrile episodes, associated with recurrent inflammatory signs (variably involving gastrointestinal tube, joints, lymph nodes, and skin) and persistently increased serum IgD levels. All these patients were examined for MVK genotype: only 2 presented bonafide MVK mutations, 5 showed the same S52N MVK polymorphism, while the remaining 3 had a wild-type MVK sequence. Clinical details of these patients have been reviewed through the critical analysis of their medical charts. Our report underscores the pitfalls of MKD diagnosis based on clinical grounds and IgD levels, emphasizing the uncertain contribution of MVK polymorphisms in the diagnostic assessment of the syndrome.

Mononuclear cell reactivity to food allergens in neonates, children and adults

A model of antigen‐specific T‐cell proliferative responses based on reciprocal patterns of responses to dietary and inhalant allergens has been suggested, the former being frequent in infancy but rare in adults, whereas the latter are preserved and expand between infancy and adulthood. We have evaluated the age‐related variations of mononuclear cell reactivity to food allergens. The cord blood mononuclear cells (CBMC) of 30 neonates without family history of atopy and the peripheral blood mononuclear cells (PBMC) of 20 healthy children and of 40 healthy adults were stimulated in vitro with β‐lactoglobulin (BLG) or ovalbumin (OVA) and the cultures were harvested after 7 days. Neonates, children and adults were compared for the percentages of positive responses and for the magnitude of response. Adult subjects showed significantly lower percentages of positive responses and reduced magnitude of response than those observed in neonates and children either in BLG or in OVA cultures. We have not observed a decrease of food allergen mononuclear cell reactivity between neonates and children for the frequency of positive responses. The magnitude of response of neonates was significantly lower than that of children in BLG cultures. Our results seem to confirm the loss of mononuclear cell reactivity to food allergens in adult age. However, other reports show conflicting data. We suggest that a rigorous standardization of the methodological steps of in vitro mononuclear cell stimulation with allergen is necessary.

A novel MEN1 frameshift germline mutation in two Italian monozygotic twins

Abstract Background: This report describes clinical, biochemical and molecular findings regarding two Italian monozygotic twins carrying a novel multiple endocrine neoplasia type 1 (MEN1) mutation inherited from their mother. Methods: Clinical, biochemical and genetic evaluations of the above-mentioned family members were performed. Results: All three members were heterozygous for a deletion involving the first nucleotide at codon 98 in exon 2 of the MEN1 gene, which results in early termination of the protein. The clinical phenotypes were as follows: one out of the two twins suffered from insulinoma and hyperparathyroidism, while the second one was asymptomatic. Furthermore, the mother suffered from hyperparathyroidism, as well as from hypergastrinemia for several years before the daughter was diagnosed of MEN-1. Conclusions: We describe a family with a new heterozygous mutation (g.292delC) in the MEN1 gene not described previously. The mutation leads to a truncated protein without activity, explaining the clinical picture of this family. Clin Chem Lab Med 2008;46:824–6.