MEFV c.2230G>T p.(Ala744Ser) rs61732874 previously misclassified as pathogenic variant due to lack of a population specific database.

BACKGROUND: Familial Mediterranean fever is a hereditary inflammatory disorder caused by variants in MEFV. c.2230G>T p.(Ala744Ser) rs61732874 is considered to be an established pathogenic variant in MEFV, but in this study we provide a complete evaluation that suggests this variant is likely benign. METHODS: Using an in-house exome database from 924 individuals, we extracted all individuals harboring this variant for clinical, laboratory, and familial evaluation. RESULTS: We identified the variant in 58 individuals from 39 families. The allele frequency of this variant in our database is 4.2%. None of the identified individuals match the diagnosis of Familial Mediterranean Fever. Using the American College of Medical Genetics and Genomics guidelines for variant classification, this variant is classified as likely benign and not pathogenic. CONCLUSION: Conflicting evidence about variants creates challenges for testing laboratories and impacts patient care. Sharing information drawn mainly from underrepresented populations and clinical phenotyping are important tools for precise curation of genetic variants.

Shock: an unusual presentation of Kawasaki disease.

UNLABELLED: Kawasaki disease (KD) is a common acute systemic vasculitis of childhood. Although KD has wide spectrum of clinical features, shock is not one of its common presentation form. We describe a 5-month-old female infant with severe shock syndrome requiring fluid resuscitation, inotropic support, and PICU admission. She was diagnosed retrospectively to have KD complicated by coronary artery aneurysms in spite of receiving early course of IV immunoglobulin. CONCLUSION: Diagnosis of KD could be missed in the pediatric intensive care unit because of its atypical presentation and the wide array of associated clinical symptoms. Subsequently, intensivists and emergency room physicians should maintain a high index of suspicion not to miss it or diagnose it at an advanced stage of the illness.

Distal acroosteolysis, poikiloderma and joint stiffness: a novel laminopathy?

LMNA encodes lamin A and lamin C, two major components of the nuclear lamina, and its pathogenic variants lead to a dozen distinct clinical entities collectively known as laminopathies. Most LMNA-related laminopathies are autosomal dominant but four are autosomal recessive; furthermore, some of the dominant variants have been associated with distinct phenotypes when inherited recessively, further complicating the ability to correlate genotype with phenotype. We report a consanguineous family in which the index presented with an apparently unique constellation of poikiloderma, joint motion restriction and distal acroosteolysis but lacks features of muscle weakness, lipodystrophy, or cardiac or craniofacial involvement. Molecular analysis revealed the presence of a novel homozygous LMNA missense variant (NM_170707.3:c.1774G>A; p.(Gly592Arg)) within an area of autozygome that is not shared by his unaffected siblings. The proposed causal link is further supported by in silico analysis of this variant. Our case suggests an expansion of LMNA allelic disorders to include distal acroosteolysis, poikiloderma and joint stiffness (DAPJ).

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

OBJECTIVE: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. METHODS: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. RESULTS: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. CONCLUSION: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis.