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Background: Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis). Case Presentation: Herein, we describe a 2.5‐year‐old male patient born to consanguineous parents who presented at 8‐month‐old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole‐exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full‐matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti‐thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft‐versus‐host‐disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism. Discussion: HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long‐term survival. Ongoing challenges in various aspects of HSCT remain to be addressed. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Most children with nephrotic syndrome heal without any sequelae. However, rare life‐threatening complications such as thromboembolism may occur in pediatric nephrotic syndrome and should be considered in those with a new‐onset neurologic deficit. The thromboembolism (TE) as a complication of nephrotic syndrome (NS) is rare and serious, and may involve renal, cerebral, pulmonary, or peripheral venous and/or arterial thrombosis. Here, we describe a 4.5‐year‐old male with a history of nephrotic syndrome, who developed hemorrhagic stroke in the territory of middle cerebral artery (MCA). [ABSTRACT FROM AUTHOR]

Background: Defective Cernunnos gene in nonhomologous end‐joining (NHEJ) pathway of the DNA repair is responsible for radiosensitive severe combined immunodeficiency (SCID). Herein, presented a new patient with Cernunnos deficiency and summarized the clinical, immunological, and molecular features of reported patients in the literature. Case: The patient was a 6‐month‐old female born to consanguineous parents. She presented with long‐lasting fever, diarrhea, poor feeding, and restlessness. She had suffered from recurrent fever of unknown origin and multiple episodes of oral candidiasis. In the physical examination, microcephaly, failure to thrive, oral candidiasis, pustular rash on fingers, and perianal ulcers, but no dysmorphic feature were observed. The immunologic workup revealed lymphopenia, neutropenia, normocytic anemia, low T‐ but normal B‐ and natural killer (NK)‐ cells, low immunoglobulin (Ig)G, and normal IgA, IgM, and IgE. The T‐cell receptor excision circle (TREC) was low and the lymphocyte transformation test (LTT) was abnormal to mitogens and antigens. She was diagnosed with T− B+ NK+ SCID and improved by intravenous immunoglobulin along with antimicrobials. A homozygous splice site variant, c.390 + 1G > T, at the intron 3 of the NHEJ1, was identified and the diagnosis of Cernunnos deficiency was established. However, while a candidate for hematopoietic stem cell transplantation, she developed sepsis and died at 11 months of age. Conclusions: Cernunnos deficiency should be considered as a differential diagnosis in patients with microcephaly, growth retardation, recurrent infections, T‐cell defects, and hypogammaglobulinemia. The normal B‐cell level in the index patient is an unexpected finding in Cernunnos deficiency which requires further evaluation. [ABSTRACT FROM AUTHOR]

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a group of genetic disorders characterized by early‐onset lymphoproliferation, autoimmune cytopenias, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. In this study, we conducted a systematic review of patients with ALPS and ALPS‐like syndrome. Methods: The literature search was performed in Web of Science, Scopus, and PubMed databases to find eligible studies. Additionally, the reference list of all included papers was hand‐searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS‐like syndrome. Results: Totally, 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS‐like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS‐like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenias and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS‐like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS‐like patients compared to ALPS. Most (85%) of the ALPS and ALPS‐like cases with determined genetic defects carry mutations in the FAS gene. About one‐third of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3%) received hematopoietic stem cell transplantation with successful engraftment, and all except two patients survived after transplantation. Conclusion: Our results showed that the FAS gene with 85% frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; therefore, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene. [ABSTRACT FROM AUTHOR]

Background: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations. Methods: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. Results: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0‐20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0‐7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity. Conclusions: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next‐generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Asthma and anaphylaxis are two atypical presentations of hyper-IgE syndrome (HIES). Early diagnosis and management of HIES can improve quality of life of patients through minimizing orthodontic problems and other complications related to this disorder. [ABSTRACT FROM AUTHOR]