Research

Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S367-S368. doi: 10.1016/S2152-2650(22)01518-X.

ABSTRACT

CONTEXT: Inherited errors of immunity (IEI) or primary immunodeficiencies are a group of genetic rare diseases predisposing to severe infections, autoimmunity, and malignancies. The overall risk for malignancies in pediatric IEI-patients is estimated to range from 4-25%, of which 60% of cases are of hematological origin.

OBJECTIVE: Evaluation of hematological malignancies in pediatrics IEI.

METHODS: Were included 13 patients 3 of which developed hematological malignancies and were evaluated for demographics, clinical features, and prognosis.

RESULTS: The prevalence of hematological malignancies among our patients was 23% (3/13). The male-to-female ratio was 2:1. The mean age at diagnosis of malignancy was 8.6 years (range 5-14). Non-Hodgkin lymphoma was the malignancy type diagnosed in all the pediatric patients (n=3, of which Wiskott-Aldrich-1, ataxia-telangiectasia-1, common variable immunodeficiency (CVID)-1. However, 2 patients (52.5%) died (1-during first line-chemotherapy, 1-NHL was established postmortem). 1 patient underwent bone marrow transplantation and is currently under supervision.

CONCLUSIONS: In this study, we related an association between hematological malignancies and IEI. Lymphoid malignancies were the most common malignancy, this warns of the need for multidisciplinary monitoring of these patients.

PMID:36164067 | DOI:10.1016/S2152-2650(22)01518-X

Curr Rheumatol Rep. 2022 Sep 27. doi: 10.1007/s11926-022-01086-2. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To provide a comprehensive overview of the spectrum of large and medium vessel vasculitis in adults with primary vasculitides, arthritides, connective tissue, and fibroinflammatory diseases as well as vasculitis mimics, for an efficient differential diagnosis and initial diagnostic approach.

RECENT FINDINGS: Imaging has had a tremendous impact on the diagnosis of medium to large vessel vasculitis, now often replacing histopathologic confirmation and identifying new disease manifestations (e.g., intracranial disease in giant cell arteritis; vascular manifestations of IgG4-related disease). Novel diseases or syndromes involving blood vessels have been described (e.g., VEXAS-Syndrome with polychondritis). The use of the terms “medium” or “large” vessel varies considerably between medical specialties. The differential diagnosis of large and medium vessel vasculitis is becoming increasingly complex as new entities or disease manifestations of known inflammatory rheumatic diseases are regularly identified. A more precise and widely recognized definition of the vessel sizes would make future research more comparable.

PMID:36166150 | DOI:10.1007/s11926-022-01086-2

Front Immunol. 2022 Sep 8;13:975017. doi: 10.3389/fimmu.2022.975017. eCollection 2022.

ABSTRACT

Autosomal dominant mutations in the signal recognition particle (SRP) 54 gene were recently described in patients with severe congenital neutropenia (SCN). SRP54 deficiency cause a chronic and profound neutropenia with maturation arrest at the promyelocyte stage, occurring in the first months of life. Nearly all reported patients with SRP54 mutations had neutropenia without a cyclic pattern and showed a poor or no response to granulocyte colony-stimulating factor (G-CSF) therapy. We report here an 11-year-old female patient with cyclic neutropenia and recurrent heterozygous p.T117del (c.349_351del) in-frame deletion mutation in SRP54, who showed remarkable therapeutic response to G-CSF treatment. The diagnosis of cyclic pattern of neutropenia was established by acceptable standards. ELANE gene mutation was excluded by using various genetic approaches. The patient described here also had dolichocolon which has not been described before in association with SCN.

PMID:36159802 | PMC:PMC9493107 | DOI:10.3389/fimmu.2022.975017

Front Immunol. 2022 Sep 9;13:937108. doi: 10.3389/fimmu.2022.937108. eCollection 2022.

ABSTRACT

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including systemic vasculitis, immunodeficiency, and cytopenia. We report a case of a 16-year-old girl affected by recurrent viral infections [including cytomegalovirus (CMV)-related hepatitis and measles vaccine virus-associated manifestations] and persistent inflammation, which occurred after Parvovirus infection and complicated by secondary hemophagocytic lymphohistiocytosis (HLH). HLH’s first episode presented at 6 years of age and was preceded by persistent fever and arthralgia with evidence of Parvovirus B19 infection. The episode responded to intravenous steroids but relapsed during steroids tapering. High-dose intravenous immunoglobulin (IVIG) helped manage her clinical symptoms and systemic inflammation. The frequency of IVIG administration and the dosage were progressively reduced. At the age of 9, she experienced varicella zoster virus (VZV) reactivation followed by the recurrence of the inflammatory phenotype complicated by HLH with neurological involvement. Again, high-dose steroids and monthly IVIG resulted in a quick response. Targeted next-generation sequencing (NGS) for autoinflammatory diseases and immunodeficiencies revealed the homozygous Leu183Pro ADA2 mutation, which was confirmed by Sanger analysis. ADA2 enzymatic test showed a complete loss of ADA2 activity. For about 3 years, IVIG alone was completely effective in preventing flares of inflammation and neurological manifestations. Anti-TNF treatment was started at the age of 13 for the appearance of recurrent genital ulcers, with a complete response. This case further expands the clinical spectrum of DADA2 and emphasizes the importance of extensive genetic testing in clinical phenotypes characterized by persistent unspecific inflammatory syndromes. The use of high doses of IVIG might represent a possible effective immune modulator, especially in combination with anti-TNF treatment.

PMID:36159847 | PMC:PMC9503826 | DOI:10.3389/fimmu.2022.937108

Noro Psikiyatr Ars. 2022 Aug 15;59(3):248-252. doi: 10.29399/npa.27900. eCollection 2022.

ABSTRACT

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) haploinsufficiency is the defect of one of the checkpoint inhibitory molecules and defined as a primary immunodeficiency characterized by immune dysregulation. A 26-year-old female with a history of autoimmune hemolytic anemia, autoimmune thrombocytopenia, and hypogammaglobulinemia was admitted with an inability to walk, urinary hesitancy, and bowel incontinence. Neurological examination revealed mild weakness, pyramidal, and deep sensorial involvement of the left lower extremity. Brain MRI revealed periventricular, juxtacortical, and cerebellar inflammatory lesions. Thoracic spinal MRI showed a longitudinaly extensive cord lesion. Additionally, thoracal CT showed parenchymal opacities and bilateral hilar lymph nodes. The biopsy from mediastinal lymph nodes and lung parenchyma demonstrated a low-grade lymphoproliferation and grade 1 “Lymphomatoid granulomatosis”. Detailed laboratory analyses indicated the diagnosis of ”common variable immunodeficiency”. Next-generation sequencing with primary immunodeficiency panel revealed a heterozygous mutation in CTLA-4 (c.436G>A(p.G146R)(p.Gly146Arg)). After molecular diagnosis, abatacept therapy was started as a targeted therapeutic approach with subcutaneous immunoglobulin therapy.

PMID:36160072 | PMC:PMC9466633 | DOI:10.29399/npa.27900

J Clin Immunol. 2022 Sep 26. doi: 10.1007/s10875-022-01368-5. Online ahead of print.

ABSTRACT

PURPOSE: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia.

METHODS: Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed.

RESULTS: A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype.

CONCLUSION: Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.

PMID:36155879 | DOI:10.1007/s10875-022-01368-5

Am J Med Genet A. 2022 Sep 25. doi: 10.1002/ajmg.a.62974. Online ahead of print.

ABSTRACT

Children with genetic diseases endure a prolonged and costly “diagnostic odyssey.” The use of whole exome sequencing (WES) and whole genome sequencing (WGS) has improved the diagnosis rate, ending the odyssey. However, the additional costs associated WES/WGS has impeded their adoption in Asian settings. We aim to estimate the expected change to the mean number of diagnostic tests used, and the associated costs from a decision to use WES early in the diagnostic pathways of pediatric phenotypes, as compared to Existing Practice. Retrospective data from a patient cohort recruited under the Singapore Undiagnosed Disease Program from a tertiary hospital in Singapore, for the period October 2004 to September 2020, was analyzed. Four phenotype-specific subgroups were used: multiple congenital anomalies (MCA) without developmental delay; global developmental delay (GDD); neuromuscular disorder (NMD) and primary immunodeficiency disorder (PID). Patients had undergone a traditional diagnostic pathway and received a diagnosis either through clinical exome or WES or WGS. A costs only analysis was performed, by tabulating the outcomes “test quantity” and “test costs” incurred by patients. The outcomes were compared with alternate diagnostic pathways which incorporates the early introduction of WES trio testing. To include uncertainty in cost outcomes, simulation studies were done on uncertain parameters. Cost outcomes are reported in Singapore dollars (S$). The 92 included patients had MCA (n = 48), GDD (n = 29), NMD (n = 10), or PID (n = 5). Patients were aged between 18 days and 26 years, 52.2% were males. The majority were of Chinese ethnicity (81.5%). If patients had access to WES directly, test quantity reduced by 97.38% for MCA, 96.98% for GDD, 96.56% for NMD, and 99.84% for PID. The expected cost savings per patient were $5940 for MCA (US$4433), $5342 for GDD (US$3986), $4622 for NMD (US$3449), and $58,497 for PID (US$43,654). Uncertainty assessment for MCA and GDD patients showed a respective likelihood of 86.9% and 97.4% for cost savings. Adoption of alternate diagnostic pathways with early WES in selected pediatric subgroups are likelt to reduce costs, when compared to Existing Practice. Benefits arising from earlier diagnosis, and the potential cost savings could mitigate the large initial cost of implementing WES in Asian settings.

PMID:36156406 | DOI:10.1002/ajmg.a.62974

Pediatr Int. 2022 Sep 24:e15362. doi: 10.1111/ped.15362. Online ahead of print.

ABSTRACT

BACKGROUND: Subcutaneous immunoglobulin (SCIG) is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (Hizentra®; L-proline-stabilized 20% human SCIG) is approved for agammaglobulinemia or hypogammaglobulinemia due to PID or secondary immunodeficiency (SID); however, its safety and effectiveness had not been assessed in a real-world setting.

METHODS: This multicenter, open label post-marketing surveillance (PMS) study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose.

RESULTS: Among 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n=28, SID n=11). At least one ADR was observed in 27 patients (31.8%; PID n=21, SID n=6); the most common was injection site reactions (n=17, 20.0%). Four patients (PID n=3, SID n=1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n=2; SID n=4), but in only one patient with SID during IgPro20 treatment (1.2%).

CONCLUSIONS: IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID in Japan.

PMID:36151913 | DOI:10.1111/ped.15362

Immunology. 2022 Sep 24. doi: 10.1111/imm.13579. Online ahead of print.

ABSTRACT

In the past few years, the spectrum of monogenic systemic auto-inflammatory diseases (MSAID) has widely expanded beyond the typical recurrent fever. Immuno-hematological features, as cytopenias, hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. The objective of this review was to describe these particular MSAID. MSAID must be suspected in front of immuno-hematological features associated with non-infectious recurrent fever, chronic systemic inflammation, inflammatory cutaneous manifestations, arthritis or inflammatory bowel disease. Genes and cellular mechanisms involved are various but some of them are of special interest. Defects in actine regulation pathway are notably associated with cytopenia and immune deficiency. Because of their frequency, ADA2 deficiency and Vacuoles, E1-Enzyme, X-linked, auto-inflammatory, Somatic (VEXAS) syndrome deserves to be noticed. ADA2 deficiency results in polyarteritis nodosa-like presentation with a wide panel of manifestations including cytopenia(s), lymphoproliferation and immune deficiency. Neutrophilic dermatosis or chondritis associated with macrocytic anemia or myelodysplasia should lead to screen for VEXAS. Of note, most of MSAID are associated with inflammatory anemia. We proposed here a clinical and pragmatic approach of MSAID associated with immuno-hematological features.

PMID:36151885 | DOI:10.1111/imm.13579

Diagnostics (Basel). 2022 Sep 9;12(9):2177. doi: 10.3390/diagnostics12092177.

ABSTRACT

Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as hyper-immunoglobulin E syndromes, Wiskott-Aldrich syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, STAT5B deficiency, Omenn syndrome, atypical complete DiGeorge syndrome; metabolic disorders such as acrodermatitis enteropathy, multiple carboxylase deficiency, prolidase deficiency; and other rare syndromes like severe dermatitis, multiple allergies and metabolic wasting syndrome, Netherton syndrome, and peeling skin syndrome frequently perform with eczema-like lesions. These genodermatosis may be misguided in the context of eczematous phenotype. Misdiagnosis of severe disorders unavoidably affects appropriate treatment and leads to irreversible outcomes for patients, which underlines the importance of molecular diagnosis and genetic analysis. Here we conclude clinical manifestations, molecular mechanism, diagnosis and management of several eczema-related genodermatosis and provide accessible advice to physicians.

PMID:36140582 | DOI:10.3390/diagnostics12092177