IntroductionWhile Systemic Lupus Erythematosus (SLE) typically presents with a multifactorial etiology, rare monogenic forms exist, usually diagnosed during childhood with a severe clinical course. This study aims to identify monogenic causes of SLE within the pediatric population of Northern Israel and to suggest criteria for genetic evaluation in patients with childhood-onset SLE.MethodsClinical and genetic data were collected from a single tertiary pediatric medical center in Israel, between 2010 and 2021. Patients diagnosed with SLE before the age of 18 years were enrolled in the study. Monogenic SLE was suspected in patients with any of the following criteria: (1) family history of SLE, (2) consanguinity, (3) early onset of symptoms (under 10 years), (4), atypical clinical course, (5) male gender, (6) syndromic features. Genetic evaluations were performed for these patients.ResultsSeventy-five patients were diagnosed with SLE, of whom 18 (24%) met the criteria for suspected monogenic SLE. Genetic evaluations were conducted for 13 out of the 18 patients (72%) leading to a diagnosis of a monogenic form of SLE in 6 of the 13 patients (46%), and total of 8% from the entire cohort. Four patients were diagnosed with prolidase deficiency, one patient with Aicardi-Goutières syndrome (AGS) and one patient with Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) syndrome. Additionally, candidate variants in C4B and ITPR3 genes were detected in an additional pedigree.ConclusionsMonogenic SLE was identified in 46% of the children within this selected cohort. A genetic diagnosis can yield direct clinical implications and enhance our understanding of the mechanisms involved in the more common sporadic forms of SLE.

This chapter explores the intricate interplay between immune regulation and craniofacial development, emphasizing the critical role of the immune system in both normal and pathological conditions. The process of craniofacial development, from the formation of pharyngeal arches and facial prominences to palate formation, is outlined, highlighting the susceptibility of these structures to maternal immune disruptions.Key immune interactions at the maternal-fetal interface are discussed, focusing on immune tolerance mechanisms that safeguard the fetus from maternal immune rejection. Dysregulation of this immune balance, whether through maternal infections, inflammation, or nutritional deficiencies, can lead to significant craniofacial defects such as cleft lip and palate. The chapter delves into the teratogenic effects of infections, such as Campylobacter rectus, rubella, and cytomegalovirus (CMV), which disrupt gene expression and interfere with crucial developmental pathways.The chapter further examines immune-mediated craniofacial disorders, including spondyloenchondrodysplasia (SPENCD), cherubism, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), Langerhans Cell Histiocytosis (LCH), and juvenile idiopathic arthritis (JIA), explaining how immune dysfunction leads to abnormal bone remodeling and developmental anomalies. Finally, the chapter addresses preventive strategies, emphasizing the importance of maternal health optimization, adequate nutritional support, and early management of infections to mitigate the impact of immune dysregulation on craniofacial development. This comprehensive exploration provides a foundation for understanding the critical role of the immune system in oral and craniofacial development within the broader context of oral immunity.

Spondyloenchondrodysplasia (SPENCD) is a rare genetic disorder characterized with skeletal dysplasia, immune dysregulation, and neurological impairment. Patients diagnosed with SPENCD at a single pediatric hematology center were included in the study. The patients' clinical characteristics, symptoms at presentation, imaging and laboratory results, and genetic analysis results were collected retrospectively from their files. This study evaluated nine patients diagnosed with SPENCD, eight of whom had autoimmune manifestations at presentation. Common findings included autoimmune hemolytic anemia, hypothyroidism, and elevated transaminase levels. All patients exhibited short stature and skeletal abnormalities. Neurological symptoms were present in six patients, with intracranial calcifications detected in five. Recurrent bacterial and viral infections, including respiratory tract infections, were prevalent. The NM_001611.5 (ACP5): c.772_790del p.(Ser258TrpfsTer39) frameshift variant was identified in all patients. Two patients died during follow-up. The study highlights the clinical characteristics and challenges associated with SPENCD. The findings underscore the need for comprehensive management strategies to address the multifaceted complications associated with SPENCD. • Spondyloenchondrodysplasia (SPENCD) is classified as a type-1 interferonopathy resulting from homozygous mutations in the ACP5 gene, which leads to a deficiency in tartrate-resistant acid phosphatase. • The clinical features associated with this condition encompass skeletal dysplasia, spastic paraparesis, short stature, thrombocytopenia, hemolytic anemia, and systemic lupus erythematosus like autoimmune manifestations. Additionally, patients may experience intracranial calcifications and recurrent infections. • SPENCD exhibits similarities with other type I interferonopathies, including increased levels of type I interferon and specific neurological symptoms; however, it also displays distinct characteristics such as intellectual disability and behaviors associated with autism spectrum disorder. • Despite the rare occurence of the condition and the small number of patients reported here the findings underscore the complexity of managing this condition, particularly in the context of consanguinity and the associated risks of severe complications and mortality.