G Calcagno

Differentiating PFAPA syndrome from monogenic periodic fevers

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

Long-Term Clinical Profile of Children With the Low-Penetrance R92Q Mutation of the TNFRSF1A Gene

Objective To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor–associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). Methods The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). Results The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. Conclusion Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population

Objective To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever. Methods 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients. Results Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of ‘familial Mediterranean fever (FMF)-like symptoms’ decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms’. Conclusions This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.

A preliminary disease severity score for juvenile systemic sclerosis

OBJECTIVE To develop a preliminary disease severity score for juvenile systemic sclerosis (SSc). METHODS We conducted an evidence- and consensus-based study that included the following 5 phases: 1) prospective collection of data regarding the demographic and clinical characteristics of patients with diffuse juvenile SSc who were followed up for at least 4 years or until death; 2) blinded evaluation of the disease course profiles of these patients by experts in juvenile SSc, so that patient profiles with a defined clinical course could be used as the gold standard for the score validation phase; 3) definition of candidate severity indices to be included in potential scores; 4) selection of the pediatric severity score with the best statistical performance, as determined by its ability to classify individual patients as having improvement or worsening of disease compared with baseline values or the previous evaluation; 5) validation of the efficiency of the selected score in patients with a mild, moderate, or severe disease course and comparison with the Medsger severity score for adults with SSc. RESULTS Thirty-five patients classified as having a mild (n = 17), moderate (n = 10), or severe (n = 8) disease course entered the study. The selected pediatric SSc score, defined as the Juvenile Systemic Sclerosis Severity Score (J4S), included indices of 9 organ systems each scored on a scale of 0-4. To weight the importance of the involvement of different organ systems, a coefficient of severity was introduced. Compared with the modified Medsger severity score, the J4S performed significantly better in detecting change in severity, both in patients with a moderate disease course (0.89 versus 0.52) and in patients with a severe disease course (0.82 versus 0.75). CONCLUSION The J4S is a valid instrument to assess disease severity in juvenile SSc.

Arthritis and gum bleeding in two children.

In developed countries, scurvey is quite rare and can be seen in children with severely restricted diets, related to psychiatric or developmental problems. Clinical presentation can include arthralgias/arthritis, myalgias, hemarthrosis, purpura and ecchymosis.

Impact of mevalonate kinase deficiency (MKD) on the quality of life in children and young adults: a national multicentre study

Methods MVK gene was analyzed in 950 consecutive patients with periodic fever. 40 MKD patients were identified. Spontaneous disease course was classified as follows: i) resolution (no episodes in the last 6 months), ii) improvement (reduction of more then 30% of fever episodes) iii) stationary iv) worsening (increase frequency of fever episodes or appearance of new major clinical manifestation).The Child Health Questionnaire (CHQPF 50) was used to assess the health related quality of life (HRQL). An international sample of 3315 healthy children (52.2% female), with a mean (SD) age of 11.2 (3.8) years constituted the healthy control group.

Clinical response to thalidomide and colchicine in two siblings with Behcet’s disease carrying a single mutated MEFV allele

Behcet’s disease (BD), an idiopathic multisystem vasculitis aVecting young adults clustered along the ancient “silk road,” extending from Eastern Asia to Mediterranean countries, characterized by recurrent orogenital ulcerations, variable skin manifestations and severe uveitis, is known to share diVerent clinical features with monogenic autoinXammatory syndromes [1]. The pathogenesis of BD is not known, though it possibly involves a complex interaction of genetic, immunological and environmental clues [2]. In particular, the mutations M694V, V726A and E148Q causing familial Mediterranean fever (FMF), the most frequent autoinXammatory syndrome worldwide, have been reported in patients with BD, rising the hypothesis that they act as susceptibility or modiWer factors [3, 4]. There are conXicting data regarding the simultaneous presence of BD and FMF among diVerent populations, which are, however, related to adulthood. Poor data are available for the pediatric age. We report two siblings, aged 14 and 12 years, full-term born to Egyptian father and Italian mother, who started presenting recurrent fevers without evidence of any infectious focus, respectively, when they were 14and 6-month old: fever episodes recurred every 2–3 months and were associated with cervical lymph node enlargement, oropharyngeal aphthosis and intense abdominal pain. InXammatory parameters were increased in febrile Xares, but negative in the interfebrile periods. Corticosteroid therapy was prescribed to treat fever recurrence in the hypothesis of PFAPA syndrome, but all clinical signs were resistant to anti-inXammatory drugs and various types of mouthwash. The younger child presented also ligamentous hyperlaxity, but no signiWcant joint abnormality, and persistent aphthosis unrelated to fever episodes. Abdominal symptoms, even of severe grade, recurred periodically with vomiting and bloody diarrhea on some occasions. Vomiting and diarrhea were resistant, respectively, to methoclopramide and racecadotril. Bowel walls appeared normal on repeated transabdominal echographies. Blood cell count, c3, c4, creatinkinase, fecal calprotectin and serum immunoglobulins (including IgD) were normal, while fecal occult blood, immunological tests, IgA anti-transglutaminase and IgG anti-Saccharomyces cerevisiae antibodies were negative in both siblings. Endoscopy was not performed due to these negative results. Both children underwent genetic screening for FMF (through the complete gene sequencing), respectively, at 10 and 8 years, which revealed the presence of the only E148Q mutation in the MEFV gene. Genetic analysis for other autoinXammatory syndromes (hyper-IgD syndrome, tumor necrosis factor-receptor associated periodic syndrome and cryopyrinopathy) was negative. The decision to treat these children with colchicine (1 mg/day, subsequently increased to 1.5 and 2 mg/day) was taken to conWrm the diagnostic hypothesis of FMF. Fever episodes D. Rigante (&) Department of Pediatric Sciences, Università Cattolica Sacro Cuore, Largo A. Gemelli, 8, 00168 Rome, Italy e-mail: drigante@gmail.com

Impact of MEFV genotype in Caucasian children with periodic fever

Despite FMF is considered an autosomal recessive disease caused by mutations of MEFV, one third of patients carries one mutation only.

A riddle for paediatricians: Two siblings with recurrent urticaria and fever

Patient 1 is the first son of non-consanguineous parents of Caucasian origin. At 12 weeks of age, after the first vaccination, he developed fever, erythematous rash on the trunk and lower limbs, and diarrhea, which lasted for 5 days, with spontaneous resolution. Since then, he had experienced recurrent and selflimited febrile attacks accompanied by a diffuse pruritic maculopapular rash (Fig. 1), abdominal pain, watery stools, cervical lymphadenopathy, headache with significant elevation in the acute-phase reactants. Attacks occurred every 4–6 weeks, lasting for 4–7 days, and were interrupted by asymptomatic intervals. At the age of 5 years, he was referred to our Unit with ongoing episodes of periodic fever associated with abdominal pain, vomiting and a macular pruritic rash. Extensive investigations revealed erythrocyte sedimentation rate 90 mm/h (Westergreen, normal value (n.v.) < 16 mmh), C-Reactive protein 60 mg/L (n.v. 5 mg/L), white blood cells 15.00 ¥ 10/L with 82% of neutrophils, haemoglobin 10.9 g/dL, platelet count 546 ¥ 10/L, Serum Amyloid A (SAA) 90 mg/L (n.v. 0–10) at the time of fever. Serum immunoglobulins, including immunoglobulin D (IgD) and immunoglobulin A (IgA), were in the normal range for age: IgD 25 IU/mL (n.v. 0–40), IgA 152 mg/dL (n.v. 14–159). Additional investigations were non-contributory. An autoinflammatory syndrome was suspected. DNA analysis of genes associated with TNF receptor associated periodic syndrome (TNFRSF1A), cryopyrin associated periodic syndrome (CIAS1) and familial Mediterranean fever were normal. The patient was confirmed to have hyper-immunoglobulin D syndrome (HIDS) with mutation of the mevalonate kinase (MVK) gene (compound heterozygote I268D, 3137W). Colchicine was commenced, resulting initially in the reduction of the duration of attacks. Whilst on colchicine, the child has not had any further attacks for the last 2 years and SAA has normalised.

A 14-year-old girl with a sudden arm swelling after axillary depilatory wax.

Takayasu’s arteritis is a systemic vasculitis predominantly affecting the aorta and its major branches. We report a 14-year-old girl in whom incidentally a deep upper limb vein thrombosis was found. She was referred to the emergency unit due to swelling and intermittent cyanosis of the right arm following an axillary depilatory wax. High-resolution echo colour Doppler ultrasonography showed a deep vein thrombosis with thickening of the proximal common carotids. A diagnosis of type IIb Takayasu’s arteritis was made. The patient’s history revealed fatigue, myalgia and headache. Immunosuppressive treatment and anticoagulation were introduced with a rapid and sustained improvement.