Clarifying main nutritional aspects and resting energy expenditure in children with Smith-Magenis syndrome.

Our study aims to define resting energy expenditure (REE) and describe the main nutritional patterns in a single-center cohort of children with Smith-Magenis syndrome (SMS). REE was calculated using indirect calorimetry. Patients' metabolic status was assessed by comparing measured REE (mREE) with predictive REE (pREE). Patients also underwent multidisciplinary evaluation, anthropometric measurements and an assessment of average energy intake, using a 3-day food diary, which was reviewed by a specialized dietitian. Twenty-four patients (13 M) were included, the median age was 9 years (IC 95%, 6-14 years), 84% had 17p11.2 deletion, and 16% had RAI1 variants. REE was not reduced in SMS pediatric patients, and the mREE did not differ from the pREE. In patients with RAI1 variants (16%, n = 3/24), obesity was more prevalent than those with 17p11.2 deletion (100% vs 38%). Lower proteins intake and higher total energy intake were reported in obese and overweight patients, compared to healthy weight children. No significant difference was found between males and females in energy or macronutrient intake. CONCLUSIONS: In SMS, the onset of obesity is not explained by REE abnormalities, but dietary factors seem to be crucial. Greater concern should be addressed to patients with RAI1 variants. A better understanding of the molecular mechanisms causing obesity in SMS patients could set the basis for possible future targeted therapies. WHAT IS KNOWN: • More than 90% of SMS patients after the age of 10 are overweight or obese. WHAT IS NEW: • Onset of overweight and obesity in SMS pediatric patients is not explained by abnormal resting energy expenditure. • The development of syndrome-specific dietary guidelines for SMS patients should be of utmost relevance and are highly needed.

Predicting the clinical trajectory of feeding and swallowing abilities in CHARGE syndrome.

To date, the feeding and oral-motor abilities of patients with CHARGE syndrome (CS) have not been longitudinally assessed. This study aims to investigate the level of these abilities at different ages and evaluate how they evolve during growth. We retrospectively analysed oral-motor features of 16 patients with molecularly confirmed CS (age range 4-21 years old; mean 11 years; SD 6 years; median 10 years). Nearly 100% of CS new-borns had weak sucking at birth, and half of them demonstrated poor coordination between breathing and swallowing. Over time, the percentages of children with tube feeding dependence (60% at birth) faced a slow but steady decrease (from 33% at 6 months, 25% at 12 months, to 13% at school age) in tandem with the decreasing risk of aspiration. The ability of eating foods requiring chewing was achieved at school age, after the acquisition of an adequate oral sensory processing. A mature chewing pattern with a variety of food textures was not achieved by more than half of patients, including those requiring artificial enteral nutrition. Most patients started prolonged oral-motor treatments with speech language therapists in early childhood. CONCLUSIONS: Although feeding and swallowing disorders are constant features in CS patients, a slow and gradual development of feeding abilities occurs in most cases. Rehabilitation plays a key role in overcoming structural and functional difficulties and attaining appropriate eating skills. WHAT IS KNOWN: • Feeding problems and swallowing dysfunction have been noted in CHARGE syndrome. • The involvement of multiple factors, including structural problems in the mouth, throat, or esophagus, and neurological impairment, make feeding a complicated task in CHARGE individuals. WHAT IS NEW: • Dysphagia gradually improves in most CHARGE children over time, though with a wide interindividual variability. • The percentages of children with tube feeding dependence decrease over time from 60% at birth to 33% at 6 months and 13% at school age.

Drooling outcome measures in paediatric disability: a systematic review.

Drooling, or sialorrhea, is a common condition in patients with cerebral palsy, rare diseases, and neurodevelopmental disorders. The goal of this review was to identify the different properties of sialorrhea outcome measures in children. Four databases were analysed in search of sialorrhea measurement tools, and the review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. The COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) checklist was used for quality appraisal of the outcome measures. The initial search yielded 891 articles, 430 of which were duplicates. Thus, 461 full-text articles were evaluated. Among these, 21 met the inclusion criteria, reporting 19 different outcome measures that encompassed both quantitative measures and parent/proxy questionnaires.   Conclusions: Among the outcome measures found through this review, the 5-min Drooling Quotient can objectively discriminate sialorrhea frequency in patients with developmental disabilities. The Drooling Impact Scale can be used to evaluate changes after treatment. The modified drooling questionnaire can measure sialorrhea severity and its social acceptability. To date, the tests proposed in this review are the only tools displaying adequate measurement properties. The acquisition of new data about reliability, validity, and responsiveness of these tests will confirm our findings. What is Known: • Although sialorrhea is a recognized problem in children with disabilities, especially those with cerebral palsy (CP), there is a lack of confidence among physicians in measuring sialorrhea. What is New: • Few sialorrhea measures are available for clinicians that may guide decision-making and at the same time have strong evidence to provide confidence in the results. • A combination of both quantitative measures and parent/proxy questionnaires might provide an adequate measurement of sialorrhea in children.

Long-term treatment with anakinra and canakinumab resolves patellar subchondral erosion in neonatal-onset multisystem inflammatory disease.

Not available.

Acute myocarditis as a revealing clue of complete Kawasaki disease.

Not available.

Efficacy of high-dose methylprednisolone pulses in a child with noninfectious persistent pleuropericarditis revealing systemic juvenile idiopathic arthritis.

Not available.

Coexistence of axial spondyloarthritis and thromboangiitis obliterans in a young woman.

A peculiar coexistence of axial spondyloarthritis and ischemia of the feet and the fourth finger of the left hand in a young woman, who was a heavy smoker, is discussed in this report. This picture was considered within the context of thromboangiitis obliterans. Positivity of anti-nuclear antibodies and mild elevation of inflammatory parameters were noted. Computed tomography angiograms of upper and lower limbs showed luminal narrowing and occlusion of the left humeral, left anterior/posterior tibial and right anterior tibial arteries. Daily iloprost perfusions were started, and smoking cessation was strongly recommended. Coldness and rest pain in the distal extremities improved within a few weeks. The possibility that spondyloarthritis might precede the clinical picture of thromboangiitis obliterans should be considered in heavy smokers.

Infections and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that presents a protean spectrum of clinical manifestations, and may affect any organ. The typical course of SLE is insidious, slow, and progressive, with potential exacerbations and remissions, and even dramatically acute and rapidly fatal outcomes. Recently, infections have been shown to be highly associated with the onset and/or exacerbations of SLE, and their possible causative and/or protective role has been largely emphasized in the medical literature. However, the etiopathogenesis of SLE is still obscure and far from being completely elucidated. Among infections, particularly Epstein-Barr virus (EBV), parvovirus B19, retrovirus, and cytomegalovirus (CMV) infections might play a pivotal pathogenetic role. The multifaceted interactions between infections and autoimmunity reveal many possibilities for either causative or protective associations. Indeed, some infections, primarily protozoan infections, might confer protection from autoimmune processes, depending on the unique interaction between the microorganism and host. Further studies are needed in order to demonstrate that infectious agents might, indeed, be causative of SLE, and to address the potential clinical sequelae of infections in the field of autoimmunity.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: an overview.

The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been used to describe a syndrome characterized by various obsessions, compulsions, tics, hyperactivity, motor stereotypies, and paroxysmal movement disorders that are correlated with prior infection by group A beta-hemolytic Streptococcus pyogenes (GABHS) infections. Five clinical criteria can be used to diagnose PANDAS: (1) the presence of obsessive-compulsive disorder (OCD) and/or any other tic disorders; (2) prepuberal onset (between 3 years of age and the start of puberty); (3) abrupt onset and relapsing-remitting symptom course; (4) a distinct association with GABHS infection; and (5) association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity). The exact pathogenesis of PANDAS remains unclear, and several theories that focus on multiple etiologic or contributive factors have emerged. PANDAS appears to be a neurobiological disorder that potentially complicates GABHS infections in genetically susceptible individuals. The current standard of care for PANDAS patients remains symptomatic, and cognitive behavioral therapy, such as exposure and response prevention, combined with family counseling and psychoeducation, should be the first approach for treating PANDAS. This review examines current theories of PANDAS pathogenesis, identifies possible treatments for managing this complex condition, and highlights areas for future research. Moving forward, developing more standardized diagnostic criteria and identifying specific laboratory markers to facilitate PANDAS diagnoses are crucial.

Current advances in the understanding and treatment of mevalonate kinase deficiency.

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVK gene. 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 MKD gene. 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.

A roadmap for fever of unknown origin in children.

Fever of unknown origin (FUO) in adults is conventionally defined by the occurrence of body temperatures above 38.3 degrees C (101 degrees 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.

Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined.

Autoinflammatory disorders are characterized by spontaneous episodes of systemic inflammation deriving from inherited defects of the innate immune system. Childhood is usually the lifetime involved in most inherited autoinflammatory disorders, but a moderate number of patients may experience disease onset during adulthood. Herein we report our experience in the clinical and genetic approach to the diagnosis of autoinflammatory disorders in regard of the first 500 pediatric and adult patients evaluated during the period 2007-2012 in our Center, due to histories of periodically-recurring inflammatory attacks, giving emphasis to the differences observed according to patients'age and to the most relevant data differentiating child and adult-onset autoinflammatory disorders in the medical literature.

High reinfection rate of Helicobacter pylori in young type 1 diabetic patients: a three-year follow-up study.

BACKGROUND: Several studies have demonstrated that Helicobacter pylori (H. pylori) eradication does not affect metabolic control in diabetic patients. The prevalence of H. pylori infection and reinfection rate in adult diabetic patients seems to be higher than in controls. AIM OF THE STUDY: To evaluate the reinfection rate of H. pylori three years after a standard eradicating treatment and the late effect of eradication upon metabolic control in young diabetic patients. METHODS: We enrolled 75 diabetic patients and 99 controls, from previous our studies in which we had evaluated H. pylori infection. In all subjects we re-evaluated the presence of H. pylori by means of 13C-Urea Breath Test, metabolic control and the prevalence of gastrointestinal symptoms. The effect of age, sex and socio-economic factors on H. pylori reinfection were also evaluated. RESULTS: The prevalence of H. pylori infection was higher in diabetic patients (17/69, 24%) than in dyspeptic controls of similar age, gender and socio-economical status after three years of follow-up. The reinfection rate was higher in diabetic patients than in controls. Multivariate analysis confirmed that age and socio-economical status were independently associated with H. pylori reinfection. CONCLUSIONS: Young patients with diabetes present a higher risk of H. pylori gastric reinfection than controls. In addition, age and mean annual income are associated with reinfection.

Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes.

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 NLRP3 gene 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.

Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults.

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 MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. 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 MEFV and TNFRSF1A and, 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 MEFV and TNFRSF1A genes; 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 MEFV and TNFRSF1A genes.

[The laboratory approach in the diagnosis of systemic autoinflammatory diseases]. / L'approccio laboratoristico nella diagnostica delle malattie autoinfiammatorie sistemiche.

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immunity characterized by the recurrence of febrile attacks lasting from few hours to few weeks and multi-district inflammation of different severity involving skin, serosal membranes, joints, gastrointestinal tube and central nervous system. The vast majority of these conditions is caused by mutations in genes involved in the control of inflammation and apoptosis mechanisms. The group includes familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, hereditary pyogenic and granulomatous disorders. Their diagnostic identification derives from the combination of clinical and biohumoral data, though can be sometimes confirmed by genotype analysis.

Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature.

Tumor necrosis factor-alpha receptor (TNFR1)-associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1A gene. 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 TNFRSF1A mutations 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-alpha 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.

Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders.

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 MEFV or TNFRSF1A genes, 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 TNFRSF1A and the MEFV genes. 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 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 TNFRSF1A in adults, thus improving the evaluation of patients with suspected autoinflammatory disorders.

The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration.

Systemic autoinflammatory syndromes are a group of inherited and acquired disorders of the innate immunity characterized by recurrence of seemingly unprovoked febrile attacks of variable duration and multi-district inflammation of different severity. The vast majority of these conditions when observed in pediatrics is caused by mutations in genetic systems involved in the orchestration of inflammation and apoptosis. The group includes hereditary recurrent fevers, idiopathic febrile syndromes, hereditary pyogenic disorders, bone autoinflammatory diseases, immune-mediated granulomatous diseases, complement disorders, hemophagocytic and vasculitic syndromes. Diagnostic identification derives from the combination of genotype studies and clinical/bioumoral data showing the spontaneous activation of cells of the innate immunity in the absence of specific ligands, although diagnosis remains only clinical for idiopathic febrile syndromes such as systemic-onset juvenile idiopathic arthritis and PFAPA syndrome. Meeting the needs of patients with complex chronic diseases as systemic autoinflammatory syndromes requires the provision of collaborative multidisciplinary care and the expertise of a number of health care providers across varied health care settings.