Sezgin Şahin

Autosomal recessive spastic tetraplegia caused by AP4M1 and AP4B1 gene mutation: expansion of the facial and neuroimaging features.

Adaptor protein complex‐4 (AP4) is a component of intracellular transportation of proteins, which is thought to have a unique role in neurons. Recently, mutations affecting all four subunits of AP4 (AP4M1, AP4E1, AP4S1, and AP4B1) have been found to cause similar autosomal recessive phenotype consisting of tetraplegic cerebral palsy and intellectual disability. The aim of this study was analyzing AP4 genes in three new families with this phenotype, and discussing their clinical findings with an emphasis on neuroimaging and facial features. Using homozygosity mapping followed by whole‐exome sequencing, we identified two novel homozygous mutations in AP4M1 and a homozygous deletion in AP4B1 in three pairs of siblings. Spastic tetraplegia, microcephaly, severe intellectual disability, limited speech, and stereotypic laughter were common findings in our patients. All patients also had similar facial features consisting of coarse and hypotonic face, bitemporal narrowing, bulbous nose with broad nasal ridge, and short philtrum which were not described in patients with AP4M1 and AP4B1 mutations previously. The patients presented here and previously with AP4M1, AP4B1, and AP4E1 mutations shared brain abnormalities including asymmetrical ventriculomegaly, thin splenium of the corpus callosum, and reduced white matter volume. The patients also had hippocampal globoid formation and thin hippocampus. In conclusion, disorders due to mutations in AP4 complex have similar neurological, facial, and cranial imaging findings. Thus, these four genes encoding AP4 subunits should be screened in patients with autosomal recessive spastic tetraplegic cerebral palsy, severe intellectual disability, and stereotypic laughter, especially with the described facial and cranial MRI features.

Comparison of Disease Characteristics, Organ Damage, and Survival in Patients with Juvenile-onset and Adult-onset Systemic Lupus Erythematosus in a Combined Cohort from 2 Tertiary Centers in Turkey

Objective. Age at onset has been shown to affect the clinical course and outcome of systemic lupus erythematosus (SLE). Herein, we aimed to define the differences in clinical characteristics, organ damage, and survival between patients with juvenile-onset (jSLE) and adult-onset SLE (aSLE). Methods. For the study, 719 patients (76.9%) with aSLE and 216 (23.1%) with jSLE were examined. Comparisons between the groups were made for demographic characteristics, clinical features, auto-antibody profiles, damage, and survival rates. Results. These results were significantly more frequent in jSLE: photosensitivity, malar rash, oral ulcers, renal involvement, neuropsychiatric (NP) manifestations, and autoimmune hemolytic anemia (AIHA). Of the autoantibodies, a higher frequency of anti-dsDNA and anticardiolipin IgG and IgM were observed in the jSLE group. A significant proportion of patients with aSLE had anti-Sm positivity and pleuritis. The proportion of patients with jSLE who developed organ damage was comparable to that of patients with aSLE (53% vs 47%) and the mean damage scores were similar in both groups. Renal damage was significantly more frequent in jSLE while musculoskeletal and cardiovascular system damage and diabetes mellitus were more prominent in aSLE. Comparison of survival rates of the 2 groups did not reveal any significant differences. Conclusion. We report a higher frequency in the jSLE group of renal involvement, cutaneous symptoms, oral ulcers, NP manifestations, AIHA, and anti-dsDNA positivity. A significant proportion of patients in the jSLE group had damage, most prominently in the renal domain. Our findings might support different genetic/environmental backgrounds for these 2 subgroups.

Evaluation of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis: single center experience over a one-year period

AIM This study aimed to evaluate the demographic, clinical, laboratory properties of patients with macrophage activation syndrome and treatment outcomes. MATERIAL AND METHODS The data of the patients who were diagnosed with macrophage activation syndrome secondary to systemic juvenile idiopathic arthritis between June 2013-May 2014 were evaluated by screening patient records. RESULTS Ten patients with macrophage activation syndrome were followed up in one year. The mean age at the time of diagnosis was found to be 7.6±4.5 years. The most common clinical finding at presentation (80%) was increased body temperature. Hepatosplenomegaly was found in half of the patients. The most common hematological finding (90%) was anemia. The mean erythrocyte sedimentation rate was found to be 71.8±36.2 mm/h, whereas it was measured to be lower (31.2±25.2 mm/h) at the time of the diagnosis of macrophage activation syndrome. Increased ferritin level was found in all of our patients (the mean ferritin level was found to be 23 957±15 525 ng/mL). Hypertriglyceridemia was found in nine patients (90%). The mean triglyceride level was found to be 397±332 mg/dL. Systemic steroid treatment was administered to all patients. Cyclosporine A was given to eight patients (80%), canakinumab was given to four patients (40%) and anakinra was given to five patients (50%). Plasmapheresis was performed in two patients. Improvement was found in all patients except for one patient. The patient in whom no improvement was observed showed a chronic course. CONCLUSIONS The diagnosis of macrophage activation syndrome should be considered in presence of sudden disturbance in general condition, resistant high fever and systemic inflammation findings in children with active rheumatic disease. Complete recovery can be provided with early and efficient treatment in macrophage activation syndrome which develops secondary to systemic juvenil idiopathic arthritis.

Mucolipidosis type III gamma: Three novel mutation and genotype-phenotype study in eleven patients

Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood. Biallelic mutations in the GNPTG gene, which encode the γ subunit of the N-acetylglucosamine-1-phosphotransferase enzyme, are the underlying cause of MLIII gamma. The aim of this study is to evaluate the longitudinal findings and genotype of eleven patients from eight families with MLIII gamma and to establish a genotype-phenotype correlation. The most frequently observed initial finding was stiffness of finger joints, which detected in patients between 18month-olds and five year-olds. However, in four patients presented here, initial finding was knee pain or waddling gait, which started between six-16years of age. All patients also had variable degrees of stiffness on large joints. The longest follow up period was 16years while the shortest was three years and six months. We observed that the patients who had an early onset disease and severe joint stiffness had also rapidly progressive joint involvement mostly localized in hands, shoulders, and hip. However; the patients with late onset and/or mild joint stiffness experienced slowly progressive symptoms. Most patients dropped in their growth curve in time and the ones who were severely affected reached the final height below the third centile. Seven disease-causing mutations, three of them novel, were detected in GNPTG gene. According to our clinical observations c.493_494insC and c.283_284insC mutations lead to a severe phenotype and c.196C>T, c.347_349del, c.652_655delTACT and c.445delG/c.367A>G mutations seemed to generate a milder phenotype.

Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis is the most common chronic rheumatic disease of unknown aetiology in childhood and predominantly presents with peripheral arthritis. The disease is divided into several subgroups, according to demographic characteristics, clinical features, treatment modalities and disease prognosis. Systemic juvenile idiopathic arthritis, which is one of the most frequent disease subtypes, is characterized by recurrent fever and rash. Oligoarticular juvenile idiopathic arthritis, common among young female patients, is usually accompanied by anti-nuclear antibodie positivity and anterior uveitis. Seropositive polyarticular juvenile idiopathic arthritis, an analogue of adult rheumatoid arthritis, is seen in less than 10% of paediatric patients. Seronegative polyarticular juvenile idiopathic arthritis, an entity more specific for childhood, appears with widespread large- and small-joint involvement. Enthesitis-related arthritis is a separate disease subtype, characterized by enthesitis and asymmetric lower-extremity arthritis. This disease subtype represents the childhood form of adult spondyloarthropathies, with human leukocyte antigen-B27 positivity and uveitis but commonly without axial skeleton involvement. Juvenile psoriatic arthritis is characterized by a psoriatic rash, accompanied by arthritis, nail pitting and dactylitis. Disease complications can vary from growth retardation and osteoporosis secondary to treatment and disease activity, to life-threatening macrophage activation syndrome with multi-organ insufficiency. With the advent of new therapeutics over the past 15 years, there has been a marked improvement in juvenile idiopathic arthritis treatment and long-term outcome, without any sequelae. The treatment of juvenile idiopathic arthritis patients involves teamwork, including an experienced paediatric rheumatologist, an ophthalmologist, an orthopaedist, a paediatric psychiatrist and a physiotherapist. The primary goals of treatment are to eliminate active disease, to normalize joint function, to preserve normal growth and to prevent long-term joint damage. Timely and aggressive treatment is important to provide early disease control. The first-line treatment includes disease-modifying anti-rheumatic drugs (methotrexate, sulphasalazine, leflunomide) in combination with corticosteroids, used in different dosages and routes (oral, intravenous, intra-articular). Intra-articular application of steroids seems to be an effective treatment modality, especially in monoarthritis. Biological agents should be added in the treatment of unresponsive patients. Anti-tumour necrosis factor agents (etanercept, infliximab, adalimumab), anti-interleukin-1 agents (anakinra, canakinumab), anti- interleukin-6 agents (tocilizumab) and T-cell regulatory agents (abatacept) have been shown to be safe and effective in childhood patients. Recent studies reported sustained reduction in joint damage with even complete clinical improvement in paediatric patients, compared to previous data.

Diagnostic approach and current treatment options in childhood vasculitis

All inflammatory changes in the vessel wall are defined as vasculitis. Pediatric vasculitis may present with different clinical findings. Although Henoch-Schönlein purpura which is the most common pediatric vasculitis generally recovers spontaneously, it should be monitorized closely because of the risk of renal failure. Although Kawasaki disease is easy to diagnose with its classical findings, the diagnosis may be delayed in case of incomplete Kawasaki disease. Kawasaki disease should be considered especially in infants in case of prolonged fever even if the criteria are not fully met and intravenous immunoglobulin treatment should be administered without delay in order to prevent development of coronary artery aneurism. Reaction at the site of administration of Bacillus Calmette-Guerin (BCG) vaccine may be observed as commonly as cervical lymphadenopathy in Kawasaki disease and may be used as a valuable finding in suspicious cases. Although anti-neutrophil cytoplasmic antibody-associated vasculitides are rare in children, renal involvement is more common and progression is more severe compared to adults. Hence, efficient and aggressive treatment is required. Takayasus arteritis is observed commonly in young adult women and rarely in adolescent girls. Therefore, a careful physical examination and blood pressure measurement should be performed in addition to a detailed history in daily practice. In children with unexplained neurological findings, cerebral vasculitis should be considered in the absence of other systemic vasculitides and necessary radiological investigations should be performed in this regard. This review will provide an insight into the understanding of pediatric vasculitis, current diagnostic approaches and prognosis by the aid of new studies.

The Assessment of Serum Endocan Levels in Children With Juvenile Idiopathic Arthritis

Objectives This study aims to evaluate the levels of serum endocan in children with juvenile idiopathic arthritis (JIA). Patients and methods Sixty-seven children with JIA (30 males, 37 females; mean age 10.4±4.9 years; range 2 to 18 years) and a sex- and age- matched healthy control group of 39 children (16 males, 23 females; mean age 9.3±4.1 years; range 1 to 17 years) were recruited. Patients with JIA were divided into two groups as the clinically active JIA group (n=27) and inactive JIA group (n=40). Results The median serum endocan level in patients with JIA was significantly higher than in the control group (633.75 ng/L vs. 379.76 ng/L, p<0.01). Comparison between patients with active JIA and inactive JIA was not significant in terms of endocan levels (618.70 ng/L vs. 687.36 ng/L, p=0.34). There was a weak negative correlation between Childhood Health Assessment Questionnaire scores of patients with JIA and serum endocan levels. Conclusion The high level of serum endocan highlighted the endothelial damage in patients with JIA.

Erratum to: Evaluation of cardiac functions in juvenile systemic lupus erythematosus with two-dimensional speckle tracking echocardiography

The aim of this study was to investigate subclinical systolic and diastolic dysfunction in juvenile-onset systemic lupus erythematosus (j-SLE) patients with speckle tracking echocardiography (STE) and the effects of disease activity on left ventricular (LV) regional functions. Thirty-five patients with j-SLE and 30 healthy children (control group) were evaluated between January and August 2015. STE was performed on all patients and controls. Medical records, including diagnosis criteria, age at diagnosis, and duration of disease, were evaluated. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). j-SLE patients had lower ejection fraction than did control subjects but still within normal range. LV end-diastolic and end-systolic dimensions were significantly larger in j-SLE patients (32.43 ± 3.2 vs 28.3 ± 3.1 and 21.1 ± 1.9 vs 18.9.0 ± 2.2, respectively; p = 0.001). There was a significant reduction in longitudinal strain of LV segments in the j-SLE patients compared with controls. J-SLE patients were further divided into subgroups. Group 1 comprised patients having SLEDAI scores >8 at the onset of disease but who improved with therapy during follow-up. Group 2 included j-SLE patients with SLEDAI scores >8 at diagnosis and persistently >4 at the end of follow-up. In the LV mid-inferior and mid-inferolateral segments, STE strain measurements of group 2 were significantly lower than those of group 1 (15.9 ± 6.4 vs 20.0 ± 4.4, 17.9 ± 7.2 vs 23.2 ± 3.8; p = 0.075, p = 0.055, respectively). Simple and non-invasive STE would be helpful in predicting cardiovascular prognosis with new therapeutic medications/interventions or in objectively comparing the effects of immunosuppressive drugs in comparison with preceding STE evaluation.

LACC1 Gene Defects in Familial Form of Juvenile Arthritis

Juvenile idiopathic arthritis [JIA; Mendelian Inheritance in Man (MIM) 604302] is the most common chronic childhood arthritis, characterized by chronic articular findings of unknown origin, with heterogeneity in disease course and systemic involvement1,2. Epidemiologic studies based on different diagnostic criteria showed varying prevalence from 0.07 to 4.01 per 1000 children across populations, an increased risk for European descendants, and different subtype distributions among ethnic groups3,4. JIA is generally known as a complex genetic trait with non-Mendelian inheritance pattern possibly resulting from interactions of multiple genetic loci and environmental factors5. However, several studies have reported causative variants in the Laccase (multicopper oxidoreductase) domain-containing 1 ( LACC1 ; MIM 613409) gene in rare familial forms6,7,8. We present 17 patients (10 males and 7 females) from 7 families (5 with known parental consanguinity), each with 2–4 affected members diagnosed with JIA. This study was approved by the Institutional Review Board of Istanbul Technical University (MBG.22/2014) and carried out in compliance with the Declaration Helsinki. … Address correspondence to Dr. E. Tahir Turanli, Dr. Orhan Ocalgiray Molecular Biology-Biotechnology and Genetics Research Centre, Istanbul Technical University, Ayazaga Campus, 34469 Maslak, Istanbul, Turkey. E-mail: turanlie{at}itu.edu.tr

Juvenile Scleroderma: A Referral Center Experience

Objectives This study aims to evaluate the demographic and clinical features, laboratory data, treatment modalities, and outcomes of juvenile systemic sclerosis (JSS) and juvenile localized scleroderma (JLS) patients at a referral pediatric rheumatology center in Turkey. Patients and methods Medical records of a total of 57 patients, including 29 with JSS (1 male, 28 females; mean age 18.3±3.2 years; range 14 to 27 years) and 28 with JLS (6 males, 22 females; mean age 14.4±4.8 years; range 6 to 23 years), diagnosed betweenJanuary 2006 and Mart 2015 and followed-up for at least six months were evaluated in this retrospective longitudinal study. All medical records were retrospectively analyzed for demographic, clinical, and laboratory findings. Results Mean age at disease onset was 9.9±4.2 years and 7.7±3.9 years for JSS and JLS, respectively. Mean ages at diagnosis and at the time of study were lower in JLS: 9.1±3.5 years vs. 11.7±3.7 years and 14.4±4.8 years vs. 18.3±3.2 years, respectively. Mean disease duration was 7.8±5.2 years and 8.0±4.3 years for JSS and JLS, respectively. Among JSS patients, interstitial lung disease was seen in eight (27%), pulmonary hypertension in three (10%), and arrhythmia in one (3%). One JSS patient (3%) died as a consequence of cardiac sclerosis. Corticosteroids with methotrexate were used in 29 JSS patients (100%) and in 21 JLS patients (75%). Patients with vasculopathy were treated with nifedipine (n=18, 62%) and bosentan (n=12, 41%). Internal organ involvement was treated with high-dose cyclophosphamide (n=10, 34%) or biological agent (n=3, 10%). Conclusion Close monitoring of internal organ involvement is of great importance in preventing disease-related complications in JSS and JLS. Although rare, vital organ involvement has a devastating effect on prognosis. Biological agents represent an option for patients resistant to standard immunosuppressive treatment.