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Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVKgene. Patients with MKD typically have an early onset in infancy. MKD is characterized by recurrent episodes of high fever, abdominal distress, diffuse joint pain, and skin rashes. In a subset of patients, MKD is also associated with elevated serum immunoglobulin D (IgD) levels (hyperimmunoglobulinemia D syndrome, HIDS). The clinical phenotype of MKD varies widely and depends on the severity of the impaired mevalonate kinase activity. Complete impairment results in the severe metabolic disease, mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentation, including HIDS. The precise molecular mechanisms behind the elevated serum IgD levels and inflammation that occurs in MKD remain unknown. Children who exhibit symptoms of MKD should be tested for mutations in the MKDgene. However, the complexity of MKD often results in delays in its definitive diagnosis and the outcome in adult age is not completely known. Therapeutic options for MKD are based on limited data and include non-steroidal anti-inflammatory drugs, corticosteroids, and biological agents that target specific cytokine pathways. In recent years, some studies have reported promising results for new biological drugs; however, these cases have failed to achieve satisfactory remission. Therefore, further studies are needed to understand the pathogenesis of MKD and identify innovative therapeutic tools for its management.

Fever of unknown origin (FUO) in adults is conventionally defined by the occurrence of body temperatures above 38.3°C (101°F) for a period of 3 weeks without any identified etiology after a period of 1-week hospitalization. The issue of FUO in pediatrics is rather hazy and still represents a challenging diagnostic dilemma. Most of the available data are limited to nationwide cohorts of patients of any age. The major difficulty in establishing a diagnosis is that the characteristic features rendering specific disorders clinically recognizable are absent or subtle, hence only a painstaking questioning on family background may elicit the correct investigative path. No diagnostic algorithms are actually available and clinicians must rely on a very careful step-by-step evaluation of the single patient. The need for invasive diagnostic techniques should be closely taken into consideration when laboratory tests or simple imaging procedures fail to discern the origin of FUO. Fevers with no reasonable explanation and no localizing signs often conceal different common diseases in children, which tend to display an unusual or atypical pattern. The principal causes behind FUO in pediatric age remain infections, followed by collagen vascular diseases and neoplastic disorders, although most children with malignancies present other systemic signs or suggestive laboratory abnormalities. The possibility of autoinflammatory syndromes, drug fever, and factitious fever should also be taken into account.

Cryopyrin-associated periodic syndromes are categorized as a spectrum of three autoinflammatory diseases, namely familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome. All are caused by mutations in the NLRP3gene coding for cryopyrin and result in active interleukin-1 release: their rarity and shared clinical indicators involving skin, joints, central nervous system and eyes often mean that correct diagnosis is delayed. Onset occurs early in childhood, and life-long therapy with interleukin-1 blocking agents usually leads to tangible clinical remission and inflammatory marker normalization in a large number of patients, justifying the need to facilitate early diagnosis and thus avoid irreversible negative consequences for tissues and organs.

Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFVgene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1Agene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFVand TNFRSF1Aand, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFVand TNFRSF1Agenes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<0.001), thoracic pain (OR 3.17, p<0.001), abdominal pain (OR 3.80, p<0.001) and skin rash (OR 1.58, p=0.103). The diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic multivariate model (cut-off equals to 0.24) revealing good sensitivity (0.778) and good specificity (0.718). In conclusion, our score may serve in the diagnostic evaluation of adult patients presenting with recurrent fever episodes suspected of having an autoinflammatory disorder, helping identify the few subjects among them who may be carriers of mutations in MEFVand TNFRSF1Agenes.

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.

To date, the rate of detection of autoinflammatory gene mutations in patients suspected of having an autoinflammatory disorder is very low. However, most of these data refer to pediatric populations. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. Our aim was to develop and validate a set of variables for predicting the risk that a given adult patient presenting with recurrent fever episodes carries mutations in the MEFVor TNFRSF1Agenes, in order to increase the probability of obtaining positive results on genetic testing. One hundred and ten consecutive patients with a clinical history of periodic fever attacks were screened for mutations in the TNFRSF1Aand the MEFVgenes. The mean age at disease onset was 27.85 years. Detailed information about each patient's family history, personal history, and clinical manifestations were retrospectively collected. A diagnostic score was constructed based on univariate and multivariate analysis in a randomly-selected dataset (training set; n=40). The score was validated on an independent set of the remaining patients (validation set; n=70). Age at onset (odds ratio [OR] 0.958, P= 0.050), positive family history of recurrent fever episodes (OR 5.738, P= 0.006), thoracic pain (OR 7.390, P= 0.002), abdominal pain (OR 2.853, P= 0.038) and skin involvement (OR 8.241, P= 0.003) were independently correlated with a positive genetic test result. A diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic model (cut off equal to 0.24) revealing high sensitivity (0.94), high specificity (0.94) and high accuracy (0.94). We have identified variables that appear to be strongly related to the probability of detecting gene mutations in MEF and TNFRSF1Ain adults, thus improving the evaluation of patients with suspected autoinflammatory disorders.

Tumor necrosis factor-α receptor (TNFRl)—associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1Agene. TRAPS is characterized by recurrent attacks of fever typically lasting from 1 to 3 weeks; in addition to fever, common clinical features include mainly periorbital oedema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthritis or arthralgia; serosal membrane inflammation is also possible. The identification of TNFRSF1Amutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. In the past few years, isolated reports and case-series have been published suggesting that inhibition of TNF-α might represent a promising therapeutic approach in TRAPS. We present here our experience with etanercept in the treatment of patients affected with TRAPS, and we also add a review of the literature.

Chronic 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.We 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.This 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.

Objective: To evaluate the feasibility of a sedation protocol based on Lidocaine spray and Intranasal Midazolam (INM) administered by Mucosal Atomizer Device (MAD) in uncooperative children undergoing minor painful procedures or diagnostic investigations.Patients and design: Fourty-six children, aged 6-60 months, underwent INM (0.5 mg/kg) by MAD after delivering a puff of Lidocaine spray (10 mg per puff) before the execution of various procedures, such as peripheral line placements, venipunctures, intramuscular injections, heart ultrasound examinations, computed tomographic scans, auditory tests or dental manipulation. A questionnaire was designed to evaluate the effect of sedation in performing the procedures. Statistical analysis was performed to compare sedation times with age and weight of children tested.Results: The degree of sedation achieved by INM allowed all procedures to be completed without any additional drugs. Premedication with Lidocaine spray prevented any nasal discomfort or pain related to INM. The mean duration of sedation effect was 23.1 minutes. No significant side effects could be recorded in the cohort of children studied. The degree of appreciation for both medical staff and children's parents was good. A significant correlation of effect start and end time was found only with age.Conclusions: This study showed that the association of Lidocaine spray and atomized INM is safe and effective to obtain children's short-term sedation and to easily perform all the procedures.

Background: Sanfilippo syndrome, or mucopolysaccharidosis (MPS) type III, is a rare lysosomal storage disease, resulting from errors in the catabolism of heparan sulphate. Aim: To evaluate bone turnover and bone mineral density (BMD) in MPS type III patients. Design: Clinical and observational study. Methods: We evaluated serum markers of bone formation or resorption, and measured BMD using dual-energy X-ray absorptiometry (DEXA), in three patients with MPS type III. Results: Serum vitamin D were low, and BMDs greatly reduced at lumbar and femoral sites, indicating the possibility of osteoporosis and osteomalacia. Discussion: These skeletal effects probably result from nutritional deficiencies and inability to walk, rather than from the genetic defect itself. Secondary skeletal involvement in patients with MPS type III may represent a considerable cause of morbidity, and requires interventions to reduce the risk of pathological fractures.