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- Background: The human signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor and one of seven members of the STAT family. Autosomal dominant (AD) STAT1 gain-of-function (GOF), characterized by enhanced phosphorylation of the tyrosine-701 residue and STAT1 activation, is commonly associated with chronic mucocutaneous candidiasis (CMCC), immunodeficiency, aneurysms, malignancies, and autoimmune phenomena.The best management strategies for patients with STAT1 GOF remain unclear. Typically, the standard care includes supportive treatments such as antimicrobial prophylaxis, either alone or combined with immunoglobulin replacement therapy. Biological therapies such as JAK inhibitors have been shown to alleviate symptoms of infection and autoimmune disorders in patients with STAT1 GOF mutations. However, there is a lack of long-term outcome data for JAK inhibition. Hematopoietic stem cell transplantation (HSCT) is an alternative treatment option for a subset who experience a persistent disease course despite conventional therapy. However, the effectiveness of HSCT for this condition is not yet well established.Methods: Our patient’s medical records were analyzed retrospectively, including her medical history.Results: We present the outcome of HSCT performed on a 27-year-old female with STAT1 GOF, conducted as a treatment for acute myeloid leukemia (AML).Conclusion: HSCT may serve as an alternative and potentially curative treatment for certain STAT1 GOF patients with progressive, life-threatening conditions that do not respond to conventional therapies. Additional research is needed to improve the management of these patients.Statement of Novelty: We present a novel case study of HSCT as a treatment for AML in a 27-year-old patient with STAT1 GOF, highlighting the potential for curative outcomes in progressive, life-threatening conditions unresponsive to conventional therapies. This case contributes to the limited body of evidence supporting the efficacy and challenges of HSCT in STAT1 GOF patients.
- Background: Due to widespread vaccination efforts worldwide, the mortality rates linked to COVID-19 have been decreasing. Nevertheless, there persists a notable level of morbidity, marked by increased occurrences of post-COVID-19 conditions. This includes the development of new autoimmune and inflammatory diseases in individuals who have recovered from COVID-19. A more severe progression of COVID-19 has been correlated with an increased probability of newly diagnosed autoimmune disease, and among individuals with pre-existing autoimmune conditions, COVID-19 increased the risk of developing another autoimmune disease.Methods: Our patients’ medical records were analyzed retrospectively, including their medical history.Results: We present two cases of primary immunodeficiency patients. One of them experienced the onset of new autoimmune symptoms, while the other had a worsening of her autoimmune condition following COVID-19 infection.Conclusion: Recognizing the potential connection between COVID-19 and autoimmune conditions is crucial for identifying symptoms promptly in primary immunodeficiency patients and ensuring timely treatment. Further research is required to comprehensively grasp the relationship between COVID-19 and the development of autoimmunity in this particular patient group.Statement of novelty: In this paper, we present a novel exploration into the emergence of autoimmune manifestations in primary immunodeficiency patients subsequent to COVID-19 infection, through an analysis of two distinct case reports.
- OPEN ACCESSDefects in interleukin (IL)-10 cytokine and receptors are associated with severe immune dysregulation, with affected patients presenting mainly with very early onset inflammatory bowel disease (VEO-IBD), arthritis, and skin manifestations such as dermatitis and folliculitis. We have created a database of published mutations in the genes encoding for IL-10, IL-10 receptor A (IL-10RA), and IL-10 receptor B (IL-10RB). All published mutations were reviewed and clinical as well as laboratory phenotypes recorded. Many variants in these genes are reported to be associated with IBD, as well as other diseases and pathologies. However, in this review we have focused on mutations considered harmful to the gene product and which lead to the classic presentation of VEO-IBD. This database can assist clinicians in the diagnosis of patients with specific features of immunodeficiency. A yearly update of new mutations and phenotypes will be performed.Statement of novelty: The presented database and short review is the first extensive collection of reported mutations and the clinical features of Very Early Onset IBD due to IL10 related genes.
- OPEN ACCESSBackground: Hoyeraal–Hreidarsson syndrome (HHS), the severe clinical variant of X-linked dyskeratosis congenita, is caused by germline mutations in telomere associated genes. HHS usually manifests within the first years of life and is characterized by progressive bone marrow failure, immunodeficiency, neurological features including microcephaly and developmental delay, as well as intrauterine growth retardation. The typical mucocutaneous manifestations are nail dysplasia, lacy skin pigmentation, and oral leukoplakia. Importantly, gastrointestinal involvement is reported in most patients with HHS, and may be the presenting feature. Given the spectrum of gastrointestinal diseases with a similar presentation, recognizing the unique gastrointestinal histopathology of HHS may facilitate earlier diagnosis and treatment.Methods: This case series highlights the gastrointestinal pathology findings of 2 patients with HHS caused by DKC1 gene mutations.Results: Gastrointestinal biopsies reveal loss of mucosal glands, regenerative glandular alterations and increased colonic epithelial cell apoptosis. Immunostaining of biopsies for cleaved caspase 3, a marker of cellular apoptosis, demonstrates abnormal nonapical and random locations of enterocyte exit which was further exacerbated by enteritis.Conclusion: Gastrointestinal involvement is usually the presenting feature of patients with HHS. This case series highlights the important role on gastrointestinal histopathology in facilitating a diagnosis of HHS.Statement of novelty: Detailed gastrointestinal biopsy images associated with HHS involving DKC1 mutations.
- OPEN ACCESSIntroduction: Cartilage–hair hypoplasia (CHH) is a rare skeletal dysplasia that presents with various degrees of immunodeficiency, short stature, and a susceptibility to malignancies. Individuals with CHH can present with severe combined immunodeficiency or combined immunodeficiency and are at risk for severe and unusual infections irrespective of their laboratory findings. In addition, individuals with CHH can present with variable skeletal abnormalities, mainly involving the metaphysis of long bones. CHH is a rare disease and familiarity with the variable features is crucial for diagnosis.Methods: We report the clinical, radiological, and genetic findings for 5 patients with proven diagnoses of CHH.Results: In this study we describe a cohort of patients with CHH and present their clinical findings and progressions. In addition, we present the radiological images and the immunological investigations that were done in these patients. Although all the patients in our cohort had poor cellular immunity, they had a variable clinical course. Three out of 5 patients received a bone marrow transplant (BMT) and 2 out of 5 died at an early age (1 after BMT). Those who had poor humoral function had a worse prognosis compared with those with good humoral function. The skeletal findings were characteristic for CHH.Conclusion: CHH is a disease with a variable presentation. Clinicians should be aware of the characteristic skeletal and immunological findings to identify the disease as early as possible.Statement of novelty: We present novel clinical and radiological findings in patients with variable RMRP gene mutations.
- OPEN ACCESS
- Mark R. Stein,
- Richard L. Wasserman,
- James Moy,
- William Lumry,
- Eyal Grunebaum,
- Agnes Nemet,
- Chaim M. Roifman, and
- Gordon Sussman
Background: IVIG-SN is a modern intravenous immunoglobulin with multiple pathogen elimination steps. This clinical trial in patients with primary immunodeficiency (PID) was designed to evaluate the safety, efficacy, and tolerability of this product in adults and children.Methods: Forty-four patients with PID were treated with IVIG-SN for 12 months. IgG trough levels and pharmacokinetics of IVIG-SN were evaluated as well as efficacy and safety according to standard FDA guidelines.Results: Overall, a total of 572 IVIG-SN infusions were administered according to either a 21- or a 28-day schedule. IgG trough levels during the treatment period ranged from 823.00 to 902.77 mg/dL, respectively, and half-life in serum of the administered IgG was 43.45 ± 30.25 days. There were no deaths and no adverse events leading to withdrawal from the study. Of all infusions administered, only 137 (24%) were temporally associated with an adverse event (AE). The upper bound for the 95% CI for the frequency of infusions temporally associated with an AE was 29.2%. Drug-related AEs were predominantly mild, and there were no acute serious bacterial infections during the study. Efficacy was also demonstrated by low rates of missed work, school, or daycare days (mean 2.6 days); unscheduled visits to physicians (mean 1.7); and therapeutic antibiotic use (mean 15 days).Conclusion: IVIG-SN is effective in preventing infections and is safe and well tolerated.Statement of novelty: This efficacy and toxicity trial was conducted using a new IVIG preparation. - OPEN ACCESSChronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the subunits of nicotinamide adenine dinucleotide phosphate oxidase complex, required for proper phagocyte killing of bacteria and fungi. Most of the cases are X-linked, but autosomal recessive cases have also been identified. Patients suffer from recurrent, life-threatening infections and granulomatous inflammation of the skin, lymph nodes, lungs, liver, spleen, brain, and bones. CGD can be cured by hematopoietic stem cell transplantation. Imaging studies such as radiography, ultrasound, computed tomography, and magnetic resonance imaging play a key role in identifying the changes driven by both infection and dysregulated inflammation. These studies are critical for guiding management of this disorder. We present the most illustrative images from 7 patients with CGD.Statement of novelty: Imaging studies are highly useful for diagnosis, treatment, and follow-up of patients with CGD. We present images from children with CGD that manifested their disease in different organs and tissues, illustrating the typical location of infections and dysregulated inflammation in these types of patients.
- OPEN ACCESSBackground: Hyper IgE syndrome (HIES) is a primary immunodeficiency with sporadic, autosomal dominant (STAT3 mutation) and autosomal recessive (DOCK8 and TYK2 mutations) inheritance patterns. HIES is characterized by recurrent Staphylococcus infections including lung infections, skin and visceral abcesses, pulmonary pneumatoceles, mucocutaneous candidiasis, and eczematous rash with associated elevated IgE. Patients with STAT3 mutations have additional features including connective tissue, skeletal, dental, and vascular abnormalities.Methods: This case series highlights the clinical presentation, radiographic findings, and immunologic investigations of 4 siblings with HIES caused by STAT3 mutation.Results: Our patients presented with infections including Staphylococcus aureus visceral abscesses, skin lesions, pneumonia with associated pneumatocele, and minimal signs of inflammation such as fever. Additional characteristic features included eczematous rash, scoliosis, fractures, and delayed shedding of primary teeth. Immune investigations were essentially unremarkable apart from elevated IgE and eosinophil counts. Detailed imaging identified infectious processes and associated noninfectious features of STAT3 mutations.Conclusion: Patients presenting with recurrent Staphylococcal cutaneous and visceral infections, pneumatoceles, candidiasis, and eczematous rash with associated elevated IgE should be investigated for STAT3 mutations. This case series highlights the important role of radiographic imaging to identify infectious processes as well as noninfectious associated features in patients with STAT3 mutations.Statement of novelty: Detailed images of morbidity associated with a STAT3 deficiency.
