Manish Butte

Endocr Metab Immune Disord Drug Targets. 2022 Aug 22. doi: 10.2174/1871530322666220822141722. Online ahead of print.

ABSTRACT

BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1.

CASE PRESENTATION: An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies. He was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported.

CONCLUSION: We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.

PMID:35996251 | DOI:10.2174/1871530322666220822141722

Front Immunol. 2022 Aug 5;13:937872. doi: 10.3389/fimmu.2022.937872. eCollection 2022.

ABSTRACT

Common variable immunodeficiency (CVID) represents the largest group of primary immunodeficiencies that may manifest with infections, inflammation, autoimmunity, and cancer, mainly B-cell non-Hodgkin’s lymphoma (NHL). Indeed, NHL may result from chronic or recurrent infections and has, therefore, been recognized as a clinical phenotype of CVID, although rare. The more one delves into the mechanisms involved in CVID and cancer, the stronger the idea that both pathologies can be a reflection of the same primer events observed from different angles. The potential effects of germline variants on specific somatic modifications in malignancies suggest that it might be possible to anticipate critical events during tumor development. In the same way, a somatic alteration in NHL could be conditioning a similar response at the transcriptional level in the shared signaling pathways with genetic germline alterations in CVID. We aimed to explore the genomic substrate shared between these entities to better characterize the CVID phenotype immunodeficiency in NHL. By means of an in-silico approach, we interrogated the large, publicly available datasets contained in cBioPortal for the presence of genes associated with genetic pathogenic variants in a panel of 50 genes recurrently altered in CVID and previously described as causative or disease-modifying. We found that 323 (25%) of the 1,309 NHL samples available for analysis harbored variants of the CVID spectrum, with the most recurrent alteration presented in NHL occurring in PIK3CD (6%) and STAT3 (4%). Pathway analysis of common gene alterations showed enrichment in inflammatory, immune surveillance, and defective DNA repair mechanisms similar to those affected in CVID, with PIK3R1 appearing as a central node in the protein interaction network. The co-occurrence of gene alterations was a frequent phenomenon. This study represents an attempt to identify common genomic grounds between CVID and NHL. Further prospective studies are required to better know the role of genetic variants associated with CVID and their reflection on the somatic pathogenic variants responsible for cancer, as well as to characterize the CVID-like phenotype in NHL, with the potential to influence early CVID detection and therapeutic management.

PMID:35990641 | PMC:PMC9390007 | DOI:10.3389/fimmu.2022.937872

Mult Scler Relat Disord. 2022 Aug 1;67:104086. doi: 10.1016/j.msard.2022.104086. Online ahead of print.

ABSTRACT

BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies characterized by impaired immunoglobulin production and dysregulated immune response. Neurological manifestations have been described in a few patients, and little is known about its clinic and therapeutic approach. Thus, this work aimed to review the literature on it and to help differentiate CVID from its mimics, especially sarcoidosis.

METHODS: We described a case report and included a literature review of inflammatory neurological involvement in CVID.

RESULTS: A 32-year-old female patient with a medical history of recurrent bacterial infections, temporal focal epilepsy and granulomatous lung disease under study, and cervix squamous cell carcinoma, was initially admitted to the emergency department due to intracranial hypertension. After excluding infectious and neoplastic etiologies, the most likely hypothesis was that granulomatous pulmonary, cerebral, and leptomeningeal inflammatory involvement were associated with sarcoidosis. Two years later, a diagnosis of CVID was made, and the patient was secondarily diagnosed with Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) and related inflammatory brain disease – both complications of CVID. After starting targeted treatment with immunoglobulin replacement and pulse glucocorticoids followed by a chronic taper, the patient became stable. However, three consecutive failures in immunoglobulin intake during the COVID-19 pandemic led to disease recurrence with relapse of neurological manifestations.

CONCLUSION: This case illustrates the complex multiple organ manifestations of CVID. When granulomatous conditions arise in these patients, a rare lung disease arising in the context of CVID, the GLILD disease with multisystem involvement, should be taken into consideration. Early treatment with combined steroids and immunotherapy seems to be effective in controlling CVID’s neurological manifestations.

PMID:35985210 | DOI:10.1016/j.msard.2022.104086

Front Immunol. 2022 Aug 2;13:928529. doi: 10.3389/fimmu.2022.928529. eCollection 2022.

ABSTRACT

GATA-binding protein 2 (GATA2) is a transcription factor responsible for the regulation of blood cell proliferation, differentiation, and maintenance in hematopoietic stem cells. Here, we describe successful bone marrow transplantation in a carrier of a novel GATA2 pathogenic variant who was diagnosed with immunodeficiency a few years after completion of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. At the age of 4 years, the patient was diagnosed with and treated for BCP-ALL. Antileukemic therapy was complicated by pulmonary cryptococcosis. Two years after completion of the maintenance therapy, the child was consulted by an immunologist because of recurrent respiratory tract infections and an episode of sepsis. Flow cytometry revealed deep monocytopenia, lymphopenia, absence of B lymphocytes, considerably reduced NK cells, poor thymic T lymphocyte production, minor defects in T cell maturation, and absence of TCRγδ+ T cells. The presence of the likely pathogenic, heterozygous missense variant within exon 5 of GATA2 (NM_032638.5: c.1047T>G, Cys349Trp) was identified in the proband and confirmed in the father of the patient, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor due to myelodysplastic syndrome with excess blasts at the age of 22 years. An allogeneic hematopoietic stem cell transplantation with a reduced toxicity conditioning protocol was performed using a matched sibling donor. Pre-transplant conditioning included fludarabine (5 × 30 mg/m2), treosulfan (3 × 14 g/m2), and thiotepa (10 mg/kg). Complete donor chimerism was achieved on post-transplant day 17. During the 12 months of the posttransplant observation period, she remained free from symptoms of acute or chronic graft-versus-host disease, and immunosuppressive treatment was therefore stopped. This is the second reported case of BCP-ALL in a patient with GATA2 deficiency, and the first successfully treated with a reduced-toxicity conditioning HSCT protocol. The co-occurrence of lymphoid malignancies and primary immunodeficiencies points to the role of genetic counseling and family screening for possible cancer predisposition syndromes prior to the selection of related HSCT donors.

PMID:35983050 | PMC:PMC9378963 | DOI:10.3389/fimmu.2022.928529

J Clin Immunol. 2022 Aug 18. doi: 10.1007/s10875-022-01342-1. Online ahead of print.

ABSTRACT

OBJECTIVE: Granuloma etiology includes infections, vasculitis, chemicals, malignancies, lymphoproliferative disorders, and immunological diseases. We hypothesized that patients with granuloma have an underlying primary immunodeficiency disease (PIDD).

PATIENTS AND METHODS: We retrospectively enrolled 82 patients with immunological evaluation among 294 biopsy-proven granuloma patients (0- to 20-year-old). At the same time frame, we followed up with 1910 patients in the same age group.

RESULTS: Out of 82 patients, male/female ratio was 45/37. Median age at symptom onset was 5 years (28 days-17.4 years), age of granuloma at diagnosis was 8.6 years (36 days-19.4 years). Common symptoms at disease onset were fever (23.2%), lymphadenopathy (19.6%), abdominal pain (12.2%), and cough (12.2%). Granuloma was frequent in lymph nodes (26.8%), skin (19.5%), lung (13.4%), and bone (11%). Common infectious agents isolated were Mycobacterium spp. (23.2%) and EBV (4.9%). We document PIDD in 76.8% (63/82) of patients. 49.4% (40/81) of immunologically evaluated granuloma patients had hypogammaglobulinemia. Granuloma rate in pediatric PIDD was 3.3%(63/1910). Patients with multiple granulomas (n = 16) had a PIDD diagnosis. Lung involvement was three times more in PIDD. Brain involvement was only seen in PIDD. Fibroadipose tissue and liver involvement were more frequent in patients without documented PIDD and patients whose evaluation was not completed. The mortality rate in PIDD with granuloma was 15.9%, whereas there was no mortality in patients without PIDD.

CONCLUSION: As documented here, even in a university hospital, the immunologic evaluation ratio is about one-third. We showed high PIDD frequency in children with granuloma, and higher mortality in PIDD with granuloma. Thus, an immunologic evaluation performed meticulously by immunologists is a must for accurate diagnosis and decision of individualized therapeutic options.

PMID:35980494 | DOI:10.1007/s10875-022-01342-1

Innov Surg Sci. 2022 Jun 27;7(1):23-29. doi: 10.1515/iss-2021-0041. eCollection 2022 Mar 1.

ABSTRACT

BACKGROUND: Minimally invasive methods in pilonidal sinus disease (PSD) surgery are becoming standard. Although long-term results are available for some techniques, long-term outcome data of patients after pit picking is lacking. We aimed at investigating perioperative and long-term outcomes of patients undergoing pit picking, Limberg flap or primary open surgery to treat PSD.

METHODS: In a single-centre observational study, we evaluated the outcomes of 327 consecutive patients undergoing PSD surgery between 2011 and 2020.

RESULTS: PSD had recurred in 22% of Limberg flap patients and 62% of pit picking patients at 5 years (p=0.0078; log rank test). Previous pilonidal surgeries, smoking, body mass index, immunodeficiency, and diabetes did not significantly influence the long-term recurrence rate. Primary open treatment was performed for 72% of female patients presenting with primary disease.

CONCLUSIONS: Due to its especially dismal long-term results, pit picking should be abandoned, and Limberg flap should be promoted instead, even for primary disease and in females.

PMID:35974777 | PMC:PMC9352183 | DOI:10.1515/iss-2021-0041

Clin Immunol. 2022 Aug 13:109097. doi: 10.1016/j.clim.2022.109097. Online ahead of print.

ABSTRACT

A better understanding of COVID-19 in people with primary immunodeficiency (PI), rare inherited defects in the immune system, is important for protecting this population, especially as population-wide approaches to mitigation change. COVID-19 outcomes in the PI population could have broader public health implications because some people with PI might be more likely to have extended illnesses, which could lead to increased transmission and emergence of variants. We performed a systematic review on COVID-19-associated morbidity and mortality in people with PI. Of the 1114 articles identified through the literature search, we included 68 articles in the review after removing 1046 articles because they were duplicates, did not involve COVID-19, did not involve PI, were not in English, were commentaries, or could not be accessed. The 68 articles included outcomes for 459 people with PI and COVID-19. Using data from these 459 people, we calculated a case fatality rate of 9%, hospitalization rate of 49%, and oxygen supplementation rate of 29%. Studies have indicated that a number of people with PI showed at least some immune response to COVID-19 vaccination, with responses varying by type of PI and other factors, although vaccine effectiveness against hospitalization was lower in the PI population than in the general population. In addition to being up-to-date on vaccinations, current strategies for optimizing protection for people with PI can include pre-exposure prophylaxis for those eligible and use of therapeutics. Overall, people with PI, when infected, tested positive and showed symptoms for similar lengths of time as the general population. However, a number of people with x-linked agammaglobulinemia (XLA) or other B-cell pathway defects were reported to have prolonged infections, measured by time from first positive SARS-CoV-2 test to first negative test. As prolonged infections might increase the likelihood of genetic variants emerging, SARS-CoV2 isolates from people with PI and extended illness would be good candidates to prioritize for whole genome sequencing.

PMID:35973637 | DOI:10.1016/j.clim.2022.109097

Clin Exp Immunol. 2022 Aug 16:uxac080. doi: 10.1093/cei/uxac080. Online ahead of print.

NO ABSTRACT

PMID:35972956 | DOI:10.1093/cei/uxac080

Am J Med Genet A. 2022 Aug 16. doi: 10.1002/ajmg.a.62956. Online ahead of print.

ABSTRACT

Sphingosine Lyase Insufficiency Syndrome (SPLIS) or SGPL1 Deficiency is a newly described entity that is characterized by steroid-resistant nephrotic syndrome, primary adrenal insufficiency, lymphopenia, ichthyosis, and/or endocrine and neurologic abnormalities. The earliest identification of SGPL1 pathogenic variants in association with this syndrome was reported in 2017. Since then, at least 36 patients have been reported with this pediatric syndrome. Here, we report a new patient with SPLIS who had a prenatal finding of adrenal calcifications, congenital nephrotic syndrome, and abnormal newborn screening concerning for Severe Combined Immunodeficiency. We conclude that SPLIS is a clinically recognizable condition with prenatal onset. This case should increase awareness of SPLIS in the differential diagnosis for adrenal calcifications. We present a case on the severe end of the clinical spectrum of SPLIS, and a review of the literature.

PMID:35972040 | DOI:10.1002/ajmg.a.62956

Qatar Med J. 2022 Apr 7;2022(2):6. doi: 10.5339/qmj.2022.fqac.6. eCollection 2022.

ABSTRACT

Chronic granulomatous disease (CGD) is a known Primary immunodeficiency disease that results in recurrent, life-threatening bacterial, fungal infections and granuloma formation which requires lifelong antibacterial and antifungal prophylaxis. Sulphamethoxazole-trimethoprim (TMP-SMX/Septrin) is the prophylactic antibacterial drug of choice.¹ Adverse drug reactions, including Fixed Drug Eruption (FDE) to TMP-SMX in CGD patients, are challenging as it may result in serious complications and difficulties in management. A seventeen-year-old Qatari female diagnosed with CGD was maintained on prophylactic TMP-SMX and itraconazole since childhood. She developed bullous skin lesions involving the face, neck, and trunk sparing the limbs. The skin lesion was confirmed to be FDE by skin biopsy. TMP-SMX was discontinued as it was suspected to be the causative agent. Atovaquone 1500 mg and clarithromycin 250 mg daily were started as an alternative, but the patient could not tolerate them. TMP-SMX slow graded challenge and desensitization were performed; however, the patient developed similar lesions in the previous affected areas on day 3 of desensitization, which responded well to discontinuation of TMP-SMX along with administration of steroid. FDE to TMP-SMX as the causative agent was confirmed. An MDT meeting was conducted to evaluate other available options for treatment. Also, the case was discussed with international immunology colleagues. The recommendation was to go for bone marrow transplantation to treat the primary disease. Six years post transplants, the patient is doing well and is not on any medications apart from the hormonal replacement therapy patch. CGD predisposes to several gram-positive, gram-negative bacterial (Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species) and fungal infections.² TMP-SMX is an ideal antibiotic as it is relatively cheap with good coverage and orally available. In the medical literature, desensitization can be tried in FDE, especially if there is no alternative for the needed drug. FDE signs should be observed when administered TMP-SMX.

PMID:35968520 | PMC:PMC9340568 | DOI:10.5339/qmj.2022.fqac.6