Case report: Single-cell mapping of peripheral blood mononuclear cells from a patient with both Crohn's disease and isolated congenital asplenia.

Crohn's disease (CD), as one of the principal form of inflammatory bowel disease (IBD), is characterized by the chronic and recurring inflammatory conditions in the intestine resulting from the over-activation of intestinal immunity. Hyposplenism is strongly associated with CD, while the effect of human spleen on the differentiation and development of immune cell subsets in CD patients remains unclear. Isolated congenital asplenia (ICA) is an extremely rare condition characterized by the absence of a spleen at birth without any other developmental defects. Here, we describe the first case of a patient with both ICA and CD, and follow the progression of CD from remission to active stage. Using cytometry by time of flight (CyTOF) analysis, we draw the first single-cell mapping of peripheral blood mononuclear cells (PBMC) from this unique patient, tracing back to the innate or adaptive immune cell subsets and cell surface markers affected by the spleen. Based on our analysis, it is speculated that the spleen contributes to maintaining immune homeostasis, alleviating intestinal inflammation and improving prognosis by influencing the differentiation and development of peripheral immune cell subsets and the expression of cell surface markers in patients with CD.

Germline 3p22.1 microdeletion encompassing RPSA gene is an ultra-rare cause of isolated asplenia.

BACKGROUND: Isolated Congenital Asplenia (ICA, OMIM #271400) is a rare, life-threatening abnormality causing immunodeficiency, which is characterized by the absence of a spleen. Diagnosis should be completed in early childhood and antibiotic prophylaxis applied with additional vaccinations. CASE PRESENTATION: We report the case of a six-month old girl with hematologic abnormalities and asplenia documented in imaging, with Howell-Jolly bodies in peripheral blood smear. Targeted Next Generation Sequencing screening did not reveal any pathogenic variant in genes associated with congenital asplenia. Since absence of the spleen was found by imaging, high-resolution copy number variations detection was also performed using genomic Single Nucleotide Polymorphism microarray: a heterozygous 337.2 kb deletion encompassing the RPSA gene was observed, together with SLC25A38, SNORA6, SNORA62 and MOBP genes. Despite haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP, no change in the clinical picture was observed. A search of available CNV databases found that a deletion of the RPSA locus seems to be unique and only duplications were found in this region with the frequency of less than 0.02%. CONCLUSIONS: Copy number variations in RPSA gene locus are ultrarare cause of isolated asplenia. Furthermore, since the patient does not present any concomitant clinical features, it would appear that haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP genes does not affect the phenotype of patients. However, to confirm this thesis a longer follow-up of the patient's development is needed.

Isolated Congenital Asplenia in an Asymptomatic Patient: A Very Rare Diagnosis.

Isolated congenital asplenia is a rare condition that mostly manifests in the early years, usually due to fatal systemic infections. In this paper, however, we present a case of a 36-year-old asymptomatic patient who was referred for suspected hyposplenism, with no history of splenectomy. There were no significant changes on physical examination. Blood analysis revealed leukocytosis and thrombocytosis as well as moderate anisopoikilocytosis and red blood cells with Howell-Jolly bodies. No spleen or other malformations were identified on imaging. Individuals with isolated congenital asplenia have an increased susceptibility to invasive infections and sepsis, with rapid clinical decline and a high mortality rate despite treatment. LEARNING POINTS: Isolated congenital asplenia is underdiagnosed in adults and should be excluded in patients with Howell-Jolly bodies in a peripheral blood smear, leukocytosis or/and thrombocytosis.Febrile episodes may present initially in these patients with mild symptoms; however, rapid progress to septic shock can occur. As a result, a delay in initiating broad-spectrum antibiotics may compromise their survival.Prevention with an individual vaccination plan and patient education is paramount.

Case report of congenital asplenia presenting with Haemophilus influenzae type a (Hia) sepsis: an emerging pediatric infection in Minnesota.

BACKGROUND: In the pre-vaccine era, invasive disease with Haemophilus influenzae, type b (Hib) commonly presented with osteoarticular involvement. Haemophilus influenzae, type a (Hia) sepsis is a rare but emerging problem in recent years. Here, we report a case of sepsis with concomitant osteoarthritis due to Hia that was the presenting infectious disease manifestation of isolated asplenia in a young child. This unique observation adds to our understanding of sepsis and asplenia in children. CASE PRESENTATION: A five-year-old girl developed acute Hia bacteremia and sepsis. The patient developed arthritis shortly after onset of septic shock. Arthrocentesis was culture-negative, but given the difficulty differentiating between septic and reactive arthritis, prolonged antibiotic administration was provided for presumed osteoarticular infection, and the patient had an uneventful recovery. The finding of Howell-Jolly bodies on blood smear at the time of presentation prompted an evaluation that revealed isolated congenital asplenia. Evaluation for known genetic causes of asplenia was unrevealing. Investigation by the Minnesota Department of Health revealed an emergence of Hia infections over the past 5 years, particularly in children with an American Indian background. CONCLUSIONS: Hia is an important pathogen in the differential diagnosis of invasive bacterial infections in children and shares overlap in clinical presentation and pathogenesis with Hib. Invasive Hia disease can be a presenting manifestation of asplenia in children. Hia is an emerging pathogen in American Indian children.

Pneumococcal infection transmission between family members with congenital asplenia: A case report.

BACKGROUND: Asplenia, the lack of a spleen, can be congenital and increases susceptibility to severe infections caused by encapsulated bacteria, such as Streptococcus pneumoniae (S. pneumoniae). We report two cases of severe pneumococcal infection in two asplenic family members living in the same household. CASE SUMMARY: Patient 1, a 38-year-old man with a history of congenital hepatitis B infection and hypospadias, was brought to our emergency department with complaints of cyanosis, cough, and edema of his limbs. He was clinically diagnosed as hyposplenic with overwhelming pneumococcal sepsis. He was admitted to the intensive care unit and was administered antibiotics and catecholaminergic therapy but died 2 h after admission. Patient 2, a 63-year-old woman with a history of type 2 diabetes, was brought to our emergency department one month after admission of Patient 1. She was diagnosed as asplenic with overwhelming pneumococcal sepsis. History-taking revealed that she was the mother of Patient 1 and the two had lived in the same household. She was admitted to the intensive care unit and was rapidly provided antibiotics and catecholaminergic intervention but died one day after admission. CONCLUSION: Pneumococcal bacteremia caused by virulent S. pneumoniae may be transmitted within households. All residents of households where individuals with pneumococcal bacteremia are living should be educated about the risk of transmissibility. Family members of patients with congenital asplenia/hyposplenia, all family members should be examined to assess their splenic function.

Incomplete penetrance for isolated congenital asplenia in humans with mutations in translated and untranslated RPSA exons.

Isolated congenital asplenia (ICA) is the only known human developmental defect exclusively affecting a lymphoid organ. In 2013, we showed that private deleterious mutations in the protein-coding region of RPSA, encoding ribosomal protein SA, caused ICA by haploinsufficiency with complete penetrance. We reported seven heterozygous protein-coding mutations in 8 of the 23 kindreds studied, including 6 of the 8 multiplex kindreds. We have since enrolled 33 new kindreds, 5 of which are multiplex. We describe here 11 new heterozygous ICA-causing RPSA protein-coding mutations, and the first two mutations in the 5'-UTR of this gene, which disrupt mRNA splicing. Overall, 40 of the 73 ICA patients (55%) and 23 of the 56 kindreds (41%) carry mutations located in translated or untranslated exons of RPSA. Eleven of the 43 kindreds affected by sporadic disease (26%) carry RPSA mutations, whereas 12 of the 13 multiplex kindreds (92%) carry RPSA mutations. We also report that 6 of 18 (33%) protein-coding mutations and the two (100%) 5'-UTR mutations display incomplete penetrance. Three mutations were identified in two independent kindreds, due to a hotspot or a founder effect. Finally, RPSA ICA-causing mutations were demonstrated to be de novo in 7 of the 23 probands. Mutations in RPSA exons can affect the translated or untranslated regions and can underlie ICA with complete or incomplete penetrance.

Sporadic isolated congenital asplenia with fulminant pneumococcal meningitis: a case report and updated literature review.

BACKGROUND: Isolated congenital asplenia (ICA) is a rare and life-threatening condition that predisposes patients to severe bacterial infections. Most of the reported cases are familial and the mode of inheritance is usually autosomal dominant. Here, we report a case of sporadic isolated asplenia and review the literature while focusing on sporadic cases. CASE PRESENTATION: We report the case of an 11-month-old female infant who developed fulminant pneumococcal meningitis. The pneumococcal vaccine-unimmunized patient was hospitalized with fever, irritability, and purpura, and was diagnosed as having meningitis, septic shock, and disseminated intravascular coagulation. Streptococcus pneumoniae was isolated from both cerebrospinal fluid and blood. She was successfully treated with prompt antibiotic therapy. During hospitalization, abdominal ultrasonography and computed tomography findings, scintigraphy results, and Howell-Jolly body-containing red blood cells indicated the presence of asplenia without any visceroarterial anomalies. Moreover, the findings of peripheral blood smears and spleen ultrasonographic examinations of her parents were normal. CONCLUSIONS: Majority of sporadic ICA cases were detected only after the onset of overwhelming infection and had a high mortality. In cases of severe invasive pneumococcal disease, a systematic search for Howell-Jolly bodies on blood smears and the presence of asplenia on abdominal imaging are essential for detecting ICA even in the absence of any family history. After the diagnosis of ICA, patient and parent education, vaccinations, antibiotic prophylaxis, and prompt empiric treatment of febrile episode should be provided.