Discovery of a Novel Missense Variant in NLRP3 Causing Atypical Cryopyrin-Associated Periodic Syndromes With Hearing Loss as the Primary Presentation, Responsive to Anti-Interleukin-1 Therapy.

OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS), also known as NLRP3-associated autoinflammatory diseases, are a spectrum of rare autoinflammatory diseases caused by gain-of-function variants in the NLRP3 gene, resulting in inflammasome hyperactivation and dysregulated release of interleukin-1ß (IL-1ß). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) because of cochlear autoinflammation, which may be the sole manifestation in rare cases. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting with autosomal-dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821.3:c.1784G>A p.Ser595Asn). METHODS: We conducted an ex vivo functional assessment of the NLRP3 inflammasome in heterozygous individuals (n = 10) and healthy family members (n = 5). RESULTS: The assay revealed hyperactivation of the inflammasome among heterozygous individuals, supporting the hypothesis that this missense variant is a pathogenic gain-of-function variant. Administration of IL-1 receptor antagonist resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1 to 3 months of treatment. CONCLUSION: Our findings highlight the crucial role of early diagnosis and treatment with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high- and ultrahigh-frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Extreme Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA): a discrete group of patients.

OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA). STUDY DESIGN: The medical records of 365 patients with PFAPA who attended Schneider Children's Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson's chi-squared, and Fisher's exact tests. RESULTS: Forty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7-2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment. CONCLUSION: About half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.

Loss of function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling.

Histiocytoses are inflammatory myeloid neoplasms often driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) cascade genes. H syndrome is an inflammatory genetic disorder caused by germ line loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, through phenotypic, molecular, and functional analysis of primary cells from a cohort of patients with H syndrome, we reveal the molecular pathway leading to histiocytosis and inflammation in this genetic disorder. We show that loss of function of ENT3 activates nucleoside-sensing toll-like receptors (TLR) and downstream MAPK signaling, inducing cytokine secretion and inflammation. Importantly, MEK inhibitor therapy led to resolution of histiocytosis and inflammation in a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, establishing a novel pathway leading to histiocytosis and inflammation.

Adherence to colchicine prophylaxis among patients with familial Mediterranean fever treated with interleukin-1 inhibitors.

OBJECTIVE: Interleukin-1 (IL-1) inhibitors are approved for treating familial Mediterranean fever (FMF) that is resistant to colchicine. However, continued concomitant treatment with colchicine is imperative, as it is the only drug proven to prevent secondary amyloidosis. We aimed to compare the adherence to colchicine between patients with colchicine-resistant FMF (crFMF) who were treated with IL-1 inhibitors and patients with colchicine-sensitive FMF (csFMF) who were treated only with colchicine. METHODS: The databases of Maccabi Health Services, a 2.6-million-member state-mandated health provider in Israel were searched for patients with FMF diagnosis. The medication possession ratio (MPR), calculated from the day of the first colchicine purchase (index date) until the last colchicine purchase was the main outcome measure. Patients with crFMF were matched in a 1:4 ratio to patients with csFMF. RESULTS: The final cohort included 4526 patients. Of them, 108 (2.4%) were with crFMF, and were matched to 432 with csFMF. The total mean MPR in each of the matched groups was similar (78.9 ± 41.4 and 82.5 ± 80.6, respectively, P = 0.5). Statistically significant differences in MPR were not found between the groups according to age or duration of colchicine use. However, adherence to colchicine was insufficient (MPR<80%) among more than 50% of the patients in both groups. CONCLUSION: In contrast to initial concerns, adherence to colchicine was similar between patients with crFMF and csFMF. However, in both groups, adherence to colchicine was poor. Education of both caregivers and patients is essential to increase adherence.

Juvenile idiopathic arthritis patients with positive family history of autoimmune thyroid disease might benefit from serological screening: analysis of the international Pharmachild registry.

BACKGROUND: Little is known about the association between juvenile idiopathic arthritis (JIA) and autoimmune thyroid disease (AITD) and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. The objective of this study is to determine the prevalence and predictors of symptomatic AITD in JIA patients from the international Pharmachild registry. METHODS: Occurrence of AITD was determined from adverse event forms and comorbidity reports. Associated factors and independent predictors for AITD were determined using univariable and multivariable logistic regression analyses. RESULTS: The prevalence of AITD after a median observation period of 5.5 years was 1.1% (96/8965 patients). Patients who developed AITD were more often female (83.3% vs. 68.0%), RF positive (10.0% vs. 4.3%) and ANA positive (55.7% vs. 41.5%) than patients who did not. AITD patients were furthermore older at JIA onset (median 7.8 years vs. 5.3 years) and had more often polyarthritis (40.6% vs. 30.4%) and a family history of AITD (27.5% vs. 4.8%) compared to non-AITD patients. A family history of AITD (OR = 6.8, 95% CI: 4.1 - 11.1), female sex (OR = 2.2, 95% CI: 1.3 - 4.3), ANA positivity (OR = 2.0, 95% CI: 1.3 - 3.2) and older age at JIA onset (OR = 1.1, 95% CI: 1.1 - 1.2) were independent predictors of AITD on multivariable analysis. Based on our data, 16 female ANA positive JIA patients with a family history of AITD would have to be screened during ±5.5 years using standard blood tests to detect one case of AITD. CONCLUSIONS: This is the first study to report independent predictor variables for symptomatic AITD in JIA. Female ANA positive JIA patients with positive family history are at increased risk of developing AITD and thus might benefit from yearly serological screening.

Validation of the psoriasis epidemiology screening tool (PEST) and the new early arthritis for psoriatic patients (EARP) in pediatric population: pilot study.

OBJECTIVE: Juvenile psoriatic arthritis (JPsA) is a severe inflammatory arthritis, which is associated with psoriasis in most cases. While there are few validated screening tools for diagnosis of arthritis for adult patients with psoriasis, those screening tools were never evaluated in children. The aims of this study were to evaluate two screening tools among pediatric patients with psoriasis. METHODS: Thirty-nine patients with the diagnosis of psoriasis completed two screening questionnaires: The Psoriasis Epidemiology Screening Tool (PEST) questionnaire and the new Early Arthritis for Psoriatic Patients (EARP) questionnaire. All patients were evaluated by a rheumatologist for the diagnosis of JPsA, and the accuracy of the two questionnaires was compared. RESULTS: The 4/39 (10.1%) patients diagnosed with JPsA had a PEST questionnaire score of ≥ 3, compared to a median PEST score of the patients without the diagnosis of JPsA of 0 (0-2). Thus, both the sensitivity and specificity of the PEST in diagnosing JPsA were 100%. For the EARP questionnaire, 8/39 patients had a screening questionnaire score of ≥ 3, suggestive of JPsA, four were true positive, and four false positive. Thus, the sensitivity and specificity of EARP in diagnosing JPsA were 100% and 89%, respectively. CONCLUSION: Both the PEST and EARP questionnaires were easy to use and had high sensitivity for the diagnosis of JPsA in the pediatric population with psoriasis. The PEST questionnaire had a higher specificity than the EARP. KEY POINTS: • EARP and PEST are good screening tools for diagnosis of arthritis in pediatric population with psoriasis.

Pyoderma gangrenosum-like ulceration as a presenting feature of pediatric granulomatosis with polyangiitis.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is an anti-neutrophilic cytoplasmic antibody-associated vasculitis affecting small to medium-sized vessels and involves most commonly the kidneys and the respiratory tract. Skin involvement can be seen in up to 50% of children with GPA and is the initial presenting symptom in 7.7%. Pyoderma gangrenosum (PG)-like ulcers are rarely described as a skin manifestation in GPA and very few cases have been reported previously in children. CASE PRESENTATION: We describe 3 new pediatric cases of GPA with PG-like ulcerations. The median age at first symptom was 15 years. Two patients had PG-like ulceration as their initial presentation; additional symptoms eventually led to the diagnosis of GPA 2-24 months later. In 1 case, proteinase 3 (PR3) was negative when first tested, but converted to positive when systemic symptoms emerged; in the other 2 cases PR3 was positive at presentation. All 3 patients had prominent facial lesions. None of the patients responded to treatment with antibiotics or medications commonly used to manage PG, including corticosteroids and cyclosporine. All patients had excellent responses to rituximab. An electronic database literature review was performed and 4 previously reported cases were identified. We assessed the clinical characteristics, serology, and response to treatment of the previously reported and our newly diagnosed cases. CONCLUSION: PG-like ulceration is a rare presentation of pediatric GPA which may precede classic systemic GPA symptoms. The predominance of facial ulcer, granulomatous and neutrophilic inflammation on skin biopsy and lack of response to PG treatments are characteristic of GPA-associated PG-like ulcers. Our review suggests that treatment with rituximab may be needed to improve the skin lesions. Recognizing that PG-like ulcerations can occur in pediatric GPA may result in timely diagnosis, appropriate treatment and improved prognosis.

[NEW ONSET OF VALVULAR HEART DISEASE ALONG WITH ANCIENT PATHOLOGIC FINDING].

INTRODUCTION: Rheumatic fever (RF) is an autoinflammatory disease that is caused by the host response to an infection with group A ß-hemolytic streptococcus. In this case report we describe a 15 years old boy with Down syndrome who had unusual presentation of acute rheumatic fever with a fulminant multisystemic which included heart failure secondary to pancarditis and adult respiratory distress syndrome. The final diagnosis was confirmed after cardiac biopsy that was performed during valve replacement surgery and demonstrated Aschoff bodies - a pathognomonic finding in acute rheumatic fever.

Recurrent Neuroretinitis: A Unique Presentation of Behçet's Disease in a Child.

We describe a case of Behçet's disease (BD) in a young child that presented with recurrent neuroretinitis and developed retinal lesions during follow-up. A 4.5-year-old girl presented with fever of 39.5°C, erythema nodosum in her legs, bilateral knee arthritis, and perineum aphthae. On ocular examination, visual acuity was 20/25 in both eyes. Right eye examination was normal and the left eye (LE) showed mild anterior and intermediate uveitis, normal optic disc, and a macular star appearance. Laboratory workup demonstrated elevated C-reactive protein levels, a normal abdominal ultrasound, and a normal colonoscopy. The patient was diagnosed with BD. One month post initial presentation, the patient presented with visual acuity of finger counting in the LE with significant anterior uveitis, mild intermediate uveitis, and recurrent neuroretinitis. Under treatment of IV methylprednisolone, oral betamethasone, infliximab, and colchicine, a complete systemic remission was noticed, and uveitis became quiescent. On last examination, 4.5 years post first presentation, visual acuity was 20/25 in both eyes and the LE demonstrated a remnant of a juxtafoveal retinal scar. To the best of our knowledge, this is the first case of neuroretinitis presenting as a manifestation of pediatric BD. Ophthalmologists should be aware of these unique manifestations of ocular BD.

Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents.

INTRODUCTION: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology. METHODS: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center. RESULTS: Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial. DISCUSSION: The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available.

Phenotypic Features and Longterm Outcomes of Pediatric Inflammatory Bowel Disease Patients with Arthritis and Arthralgia.

OBJECTIVE: The natural history of pediatric inflammatory bowel disease (IBD) patients with joint involvement has not been clearly described. Thus, we aimed to investigate phenotypic features and clinical outcomes of this distinct association. METHODS: The medical records of patients with pediatric IBD diagnosed from 2000 to 2016 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, surgery, and biologic therapy. RESULTS: Of 301 patients with Crohn disease (median age 14.2 yrs), 37 (12.3%) had arthritis while 44 (14.6%) had arthralgia at diagnosis. Arthritis and arthralgia were more common in women (p = 0.028). Patients with arthritis and arthralgia demonstrated lower rates of perianal disease (2.7% and 4.5% vs 16.9%, p = 0.013), whereas patients with arthritis were more likely to be treated with biologic therapy (HR 2.05, 95% CI 1.27-3.33, p = 0.009). Of 129 patients with ulcerative colitis (UC; median age 13.7 yrs), 3 (2.3%) had arthritis and 16 (12.4%) had arthralgia at diagnosis. Patients with arthralgia were treated more often with corticosteroids (p = 0.03) or immunomodulator therapies (p = 0.003) compared with those without joint involvement. The likelihood to undergo colectomy was significantly higher in patients with arthralgia (HR 2.9, 95% CI 1.1-7.4, p = 0.04). During followup (median 9.0 yrs), 13 patients developed arthritis (3.3%). Arthralgia at diagnosis was a significant predictor for the development of arthritis during followup (HR 9.0, 95% CI 2.86-28.5, p < 0.001). CONCLUSION: Pediatric IBD patients with arthritis have distinct phenotypic features. Arthralgia at diagnosis is a predictor for colectomy in UC and a risk factor for the development of arthritis during followup.

Acute hemorrhagic edema of infancy: the experience of a large tertiary pediatric center in Israel.

BACKGROUND: Acute hemorrhagic edema of infancy (AHEI) is a rare leukocytoclastic vasculitis of the small vessels occurring at a young age and considered as a benign self-limited disease. Due to its low prevalence, there are limited data on the presentation and complications of this disease. METHODS: All computerized files of children who were hospitalized at a tertiary pediatric center due to AHEI over a 10 year period were reviewed. Clinical, laboratory and histopathological data were collected. RESULTS: Twenty-six patients were included in our study, accounting for 0.7 cases per 1000 admissions of children aged 2 years or less. Mean age was 12.9 months. More than two thirds of the children had preceding symptoms compatible with a viral infection. Upon admission, all patients presented with typical findings of a rash and edema. Edema was most profound over the lower extremities (73%). Concomitant viral or bacterial infections were found in six children. Skin biopsy was performed in six patients revealing leukocytoclastic vasculitis. Thirteen children (50%) had systemic involvement including joint involvement (n=9), gastrointestinal hemorrhage (n=4), microscopic hematuria (n=1) and compartment syndrome of the limb (n=1). The latter was diagnosed in a patient with familial Mediterranean fever. CONCLUSIONS: Our largest data series highlighted what is known regarding clinical and histological findings in children with AHEI. However, contrary to what was previously reported, we found a higher rate of systemic involvement. Although AHEI is a rare entity, pediatricians should be familiar with its presentation, management and our reported complications.

Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy.

BACKGROUND: Canakinumab is a human anti-interleukin-1ß (IL-1ß) monoclonal antibody neutralizing IL-1ß-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA). METHODS: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197. RESULTS: Microarray analysis identified 984 probe sets differentially expressed (≥2-fold difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving ≥50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (≥2-fold difference; P < 0.05) on day 3 versus baseline, including IL-1ß, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥1.5-fold decline, P ≤ 0.002). CONCLUSIONS: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

[EOSINOPHILIC FASCIITIS (EF)].

INTRODUCTION: Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by erythema, edema and myalgia with induration and thickening of the skin and soft tissue, especially subcutaneous fascia. Laboratory findings usually show peripheral eosinophilia, and full-thickness wedge biopsy is essential to establish the diagnosis. Corticosteroids are effective and remain the standard therapy for EF, although some patients may improve spontaneously. In this article we report a case of a 17 years old male who has been diagnosed with EF 2 years after bone marrow transplantation and review the clinical manifestations, pathology, diagnosis, differential diagnosis, and treatment of EF.

Cutaneous polyarteritis nodosa successfully treated with topical diflucortolone valerate: a case report & review of the literature.

Cutaneous Polyarteritis Nodosa (cPAN) was first described in 1931. cPAN is considered a rare disease, its true incidence is unknown. The age of onset is diverse. Most studies have shown no significant gender predominance. cPAN presents with distinct skin findings, such as a maculopapular rash, subcutaneous nodules, livedoid vasculitis, panniculitis, ischemic finger lesions, or erythematous patchy rash. Etiology is unclear. It is still believed to be an immune complex-mediated disease, although a possible mechanism recently proposed relates a familial form of the disease to impaired activity of Adenosine Deaminase 2. cPAN may reflect an underlying disease, infection or medical treatment. There is no consensus as to initial treatment, dosage and length of treatment. Patients with constitutional symptoms, visceral involvement, a more severe course of the disease, or high acute phase reactants, were treated mainly with systemic corticosteroids and/or cytotoxic agents for varying durations. However, persistence of cutaneous lesions has been documented. We describe a 14 year old male suffering from persistent cPAN, with no constitutional symptoms or involvement of internal organs. The patient was treated with a local corticosteroid-based ointment during exacerbations, until complete remission. Although reported in only one study, treatment with topical corticosteroid compound may result in significant improvement or complete regression of skin lesions in cPAN patients.

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy syndrome is associated with activation of GM-CSF and burst-like expression of IL-8 in peripheral blood.

INTRODUCTION: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenopathy (PFAPA) is an autoinflammatory syndrome characterized by periodic fever with aphthous stomatitis, cervical lymphadenopathy, myalgia, and abdominal pain. Peripheral blood concentrations of selected cytokines of PFAPA patients during and between febrile episodes were analyzed in a search for PFAPA-specific molecular signature. METHODS: 23 children with PFAPA (age 6.07 ± 2.94 years, range 5-9 years) and three control children with severe oropharyngeal infections (age 6.2 ± 7.95 years, range 1-17 years) participated in the study. Peripheral blood concentrations of IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-γ, GM-CSF, TNF-α were measured using Luminex technology. RESULTS: PFAPA febrile episodes were characterized by detection of GM-CSF - 134.07 ± 315.5 pg/mL; significant (P < 0.001), compared to baseline and controls, elevation of concentrations of IL-8 (3193.7 ± 2508 pg/mL vs. 100.36 ± 119. pg/mL vs. 2.04 ± 4.08 pg/mL, respectively), IL-6 (1355.38 ± 2026.53 pg/mL vs. 28.8 ± 44.2 pg/mL and 27.13 ± 26.42 pg/mL, respectively). IL-1ß was detected only in febrile and afebrile PFAPA patients (922.8 ± 1639 pg/mL vs. 10.98 ± 19.4 pg/ml, P < 0.002, respectively), but not in controls. Peripheral blood concentration of TNFα did not differ significantly between study groups. IL-2, IL-4, IL-5, and IL-10 were negligible in all study subjects. DISCUSSION: PFAPA febrile episodes are characterized by activation of GM-CSF and IL-8 with Th1 skewing. We propose a molecular mechanism governing this phenomenon.

Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Growing pains: myth or reality.

Growing pains are common among children aged 2-12 years and are characterized by recurrent, self-limited, bilateral lower extremity pain, mostly in the afternoon and evening, and even at night, in an otherwise healthy child. The etiology is unknown and prognosis is excellent. It is important to distinguish between this benign condition and other serious rheumatic or malignant diseases.

Neuropsychiatric manifestations in pediatric systemic lupus erythematosus and association with antiphospholipid antibodies.

OBJECTIVE: To determine the prevalence of neuropsychiatric (NP) manifestations in children with systemic lupus erythematosus (SLE) using the 1999 American College of Rheumatology case definitions for NP syndromes in SLE, and their association with antiphospholipid antibodies (aPL). METHODS: We performed a retrospective cohort study of 106 pediatric and adolescent SLE patients at 2 academic medical centers. Clinical and laboratory data were obtained by medical record review. All aPL testing was performed in standard clinical laboratories. RESULTS: Twenty-five patients (23.6%) had NP manifestations, including seizures (9.4%), headaches (4.7%), mood disorders (4.7%), cognitive dysfunction (4.7%), cerebrovascular accident (CVA), psychosis and pseudotumor (2.8% each), aseptic meningitis (0.9%), acute confusional state (0.9%), anxiety (0.9%), and cranial neuropathy (0.9%). NP events were not necessarily accompanied by an SLE flare. aPL were positive in 70% of all SLE patients, including anticardiolipin antibodies (aCL) in 64%, aCL IgG in 56%, aCL IgM in 35%, rapid plasma reagin or Venereal Disease Research Laboratory test in 13%, and lupus anticoagulant (LAC) in 18%. The only significant association between NP manifestations and aPL was for CVA and IgM aCL (p=0.03). LAC was slightly more common among patients with NP events, and the finding of LAC on more than one occasion was significantly associated with developing a NP event (p = 0.01). CONCLUSION: NP manifestations occur in about one-fourth of children with SLE, are an early event in the course of the disease, and are not necessarily accompanied by an SLE flare. Seizures are the most frequent symptom. Although aPL are common, their association with NP events, unlike in adults, is weak, except for CVA, suggesting a different pathogenic mechanism for NP manifestations in pediatric SLE.

Increased prevalence of antithyroid antibodies and subclinical hypothyroidism in children with juvenile idiopathic arthritis.

OBJECTIVE: To estimate the occurrence of antithyroid antibodies (ATA) and hypothyroidism in children with juvenile idiopathic arthritis (JIA) compared to matched healthy controls. METHODS: The occurrence of ATA, including antithyroglobulin (anti-TG) and antithyroid peroxidase (anti-TPO) antibodies, was evaluated by quantitative immunometric ELISA in children with JIA and in a healthy matched control group. Thyroid function was assessed in both groups. RESULTS: The study group included 66 patients with JIA (50 girls, 16 boys) of mean age 11.7 +/- 4.4 years (range 2-23). The control group included 89 children (71 girls, 18 boys) of mean age 10.8 +/- 4.2 years (range 2-18). Mean age at onset of joint disease was 7.3 +/- 3.6 years (range 1-15). Anti-TG antibodies were found in 7 of 62 patients (11.3%) in the JIA group and 2 of 89 controls (2.2%) (p = 0.03); anti-TPO antibodies were found in 5 of 65 patients (7.9%) and one of 89 controls (1.1%) (p = 0.08). All patients with ATA had oligoarticular type JIA (p = 0.01). Mean thyroid stimulating hormone (TSH) levels were higher in the study group than in controls (2.6 +/- 2.3 vs 1.9 +/- 1.0 mIU/l; p = 0.01); levels were above normal range (0.4-4 mIU/l) in 8 study patients (12%) and 3 controls (3.4%) (p = 0.055). Overall, ATA were found in 9 of the 150 study participants, 4 (44%) of whom had TSH levels above 4 mIU/l (p = 0.001). CONCLUSION: Children with JIA have a higher than normal incidence of ATA and subclinical hypothyroidism and should be routinely screened for these variables.