Variable Presentation of the CYBB Mutation in One Family, Approach to Management, and a Review of the Literature

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Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder marked by abnormal phagocytic function. CGD affects primarily neutrophils and manifests as an early predisposition to severe life-threatening infections. Additionally, patients with CGD are predisposed to unique autoimmune manifestations. While generally spared from infectious complications, heterozygous carriers of the abnormal genes implicated in CGD pathogenesis can still present with autoimmune disorders. A mutation in the CYBB gene is the only X-linked variant of this disease. This article describes a family with the CYBB mutation, its heterogenous presentation, and reviews the literature discussing disease management.

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Most cited references 30

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Chronic granulomatous disease. Report on a national registry of 368 patients.

J A Winkelstein, M C Marino, R Johnston … (2000)

A registry of United States residents with chronic granulomatous disease (CGD) was established in 1993 in order to estimate the minimum incidence of this uncommon primary immunodeficiency disease and characterize its epidemiologic and clinical features. To date, 368 patients have been registered; 259 have the X-linked recessive form of CGD, 81 have 1 of the autosomal recessive forms, and in 28 the mode of inheritance is unknown. The minimum estimate of birth rate is between 1/200,000 and 1/250,000 live births for the period 1980-1989. Pneumonia was the most prevalent infection (79% of patients; Aspergillus most prevalent cause), followed by suppurative adenitis (53% of patients; Staphylococcus most prevalent cause), subcutaneous abscess (42% of patients; Staphylococcus most prevalent cause), liver abscess (27% of patients; Staphylococcus most prevalent cause), osteomyelitis (25% of patients; Serratia most prevalent cause), and sepsis (18% of patients; Salmonella most prevalent cause). Fifteen percent of patients had gastric outlet obstruction, 10% urinary tract obstruction, and 17% colitis/enteritis. Ten percent of X-linked recessive kindreds and 3% of autosomal recessive kindreds had family members with lupus. Eighteen percent of patients either were deceased when registered or died after being registered. The most common causes of death were pneumonia and/or sepsis due to Aspergillus (23 patients) or Burkholderia cepacia (12 patients). Patients with the X-linked recessive form of the disease appear to have a more serious clinical phenotype than patients with the autosomal recessive forms of the disease, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age versus 7.81 years of age, respectively), have a significantly higher prevalence of perirectal abscess (17% versus 7%), suppurative adenitis (59% versus 32%), bacteremia/fungemia (21% versus 10%), gastric obstruction (19% versus 5%), and urinary tract obstruction (11% versus 3%), and a higher mortality (21.2% versus 8.6%).

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Beatriz Marciano, Christine Spalding, Alan Fitzgerald … (2015)

Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades.

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IL-1 receptor blockade restores autophagy and reduces inflammation in chronic granulomatous disease in mice and in humans.

Jakob Begun, Mark Gresnigt, Georgios Chamilos … (2014)

Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidase-deficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade.

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Author and article information

Contributors

Tatyana Gavrilova:

ORCID: https://orcid.org/0000-0001-8428-5944

Journal

Journal ID (nlm-ta): Case Rep Med

Journal ID (iso-abbrev): Case Rep Med

Journal ID (publisher-id): CRIM

Title: Case Reports in Medicine

Publisher: Hindawi

ISSN (Print): 1687-9627

ISSN (Electronic): 1687-9635

Publication date Collection: 2020

Publication date (Electronic): 6 February 2020

Volume: 2020

Electronic Location Identifier: 2546190

Affiliations

¹Division of Allergy and Immunology, Montefiore Medical Center, Albert Einstein College of Medicine, 1525 Blondell Avenue, Bronx, NY 10461, USA

²Department of Dermatology, Montefiore Medical Center, Albert Einstein College of Medicine, 3415 Bainbridge Avenue, Bronx, NY 10467, USA

Author notes

Academic Editor: Timothy J. Craig

Author information

Tatyana Gavrilova https://orcid.org/0000-0001-8428-5944

Article

DOI: 10.1155/2020/2546190

PMC ID: 7026706

SO-VID: 93261034-ddbf-446a-8f65-7338b0fec2aa

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 19 November 2019

Date accepted : 3 January 2020

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