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Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods.

ABSTRACT: Deficiency of complement factor I is a rare immunodeficiency that typically presents with increased susceptibility to encapsulated bacterial infections. However, non-infectious presentations including rheumatological, dermatological and neurological disease are increasingly recognized and require a high-index of suspicion to reach a timely diagnosis. Herein, we present two contrasting cases of complement factor I deficiency: one presenting in childhood with invasive pneumococcal disease, diagnosed using conventional immunoassays and genetics and the second presenting in adolescence with recurrent sterile neuroinflammation, diagnosed via a genomic approach. Our report and review of the literature highlight the wide spectrum of clinical presentations associated with CFI deficiency and the power of genomic medicine to inform rare disease diagnoses.

SUBMITTER: Shields AM

PROVIDER: S-EPMC6568211 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods.

Shields Adrian M AM Pagnamenta Alistair T AT Pollard Andrew J AJ Taylor Jenny C JC Allroggen Holger H Patel Smita Y SY

Frontiers in immunology 20190607

Deficiency of complement factor I is a rare immunodeficiency that typically presents with increased susceptibility to encapsulated bacterial infections. However, non-infectious presentations including rheumatological, dermatological and neurological disease are increasingly recognized and require a high-index of suspicion to reach a timely diagnosis. Herein, we present two contrasting cases of complement factor I deficiency: one presenting in childhood with invasive pneumococcal disease, diagnos ...[more]

PMID: 31231365

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Project description:Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered.A case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases.Each deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26% reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM. To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled. G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], P = 0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], P = 0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], P = 0.056). Sex-stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes.In a part of Africa where multiple alleles contribute to expression of G6PD deficiency trait, these findings clarify and extend previous work done in populations where a single variant predominates, and taken together suggest a causal role for G6PD deficiency trait itself with respect to severe malaria, with opposing effects seen on two major clinical subphenotypes.

Project description:BackgroundMicrobiological criteria for diagnosing nontuberculous mycobacterial pulmonary disease (NTM-PD) include positive culture results from at least two separately expectorated sputum specimens or one bronchial washing or lavage. However, the clinical similarities and differences between patients diagnosed by these two methods remain unclear. We compared clinical features and prognoses of patients with NTM-PD diagnosed from both specimen types.MethodsWe analysed data from patients who participated in the Seoul National University Hospital NTM-PD cohort ( ClinicalTrials.gov identifier: NCT01616745). Baseline demographics, symptoms, radiographic findings, disease progression, and treatment responses were summarized and compared between patients diagnosed from sputum specimens and patients diagnosed from bronchoscopic specimens.ResultsThree hundred forty-seven patients were included in the analyses. Of these, 279 (80.4%) were diagnosed from two separately expectorated sputum specimens, and 68 (19.6%) were diagnosed from bronchoscopic specimens. Patients diagnosed from sputum specimens had more frequent and severe cough, sputum, postnasal drip, and high St. George's Respiratory Questionnaire scores. However, the extent and severity of the radiographic lesions, disease progression, and treatment responses were similar for both groups. Further analysis based on the following three groups (sputum culture positive, sputum culture negative/bronchoscopy, and scanty sputum/bronchoscopy groups) suggested that the scanty sputum/bronchoscopy group appeared to have the worst prognosis in terms of both time to progression and time to culture conversion.ConclusionsAlthough some symptoms and quality of life were worse in patients with NTM-PD diagnosed from sputum specimens, their prognoses were similar to those of patients diagnosed by bronchoscopic specimen. We recommend bronchoscopic sampling for patients in whom NTM-PD is suspected clinically or radiographically, especially those who have no or scanty sputum.

Dataset Information

Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods.

Publications

Classical and Non-classical Presentations of Complement Factor I Deficiency: Two Contrasting Cases Diagnosed via Genetic and Genomic Methods.

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