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Fulltext Chronic granulomatous disease--a report in two Malay families

Mohd Noh L, Noah RM, Wu LL, Nasuruddin BA, Junaidah E, Ooi CP, et al.

Singapore Med J, 1994 Oct;35(5):505-8.
PMID: 7701372

Chronic granulomatous disease (CGD) is a very rare disease whose defect lies in an abnormal intracellular killing resulting in recurrent abscesses, lymphadenitis and granuloma formation. We describe 2 Malay male infants with CGD whom we believe to be the first report of this disorder in Malays. Both children presented with recurrent abscesses, pneumoniae and hepatosplenomegaly; lymphadenopathy was also present in one of the patients. The organisms isolated were catalase positive bacteria. Both neutrophil chemiluminescence (against fungal and bacterial antigens, phorbol myristate acetate) and intracellular killing assays were severely depressed. Recognition of CGD is important as great strides have been made in the treatment of this disease which include gamma interferon therapy besides the conventional prophylactic antibacterial therapy.

Matched MeSH terms: Granulomatous Disease, Chronic/diagnosis*; Granulomatous Disease, Chronic/drug therapy; Granulomatous Disease, Chronic/immunology
Fulltext Revealing Chronic Granulomatous Disease in a Patient With Williams-Beuren Syndrome Using Whole Exome Sequencing

Ripen AM, Chiow MY, Rama Rao PR, Mohamad SB

Front Immunol, 2021;12:778133.
PMID: 34804071 DOI: 10.3389/fimmu.2021.778133

Blended phenotypes exhibited by a patient may present a challenge to the establishment of diagnosis. In this study, we report a seven-year-old Murut girl with unusual features of Williams-Beuren syndrome (WBS), including recurrent infections and skin abscesses. Considering the possibility of a second genetic disorder, a mutation screening for genes associated with inborn errors of immunity (IEI) was conducted using whole exome sequencing (WES). Analysis of copy number variations (CNVs) from the exome data revealed a 1.53Mb heterozygous deletion on chromosome 7q11.23, corresponding to the known WBS. We also identified a biallelic loss of NCF1, which indicated autosomal recessive chronic granulomatous disease (CGD). Dihydrorhodamine (DHR) flow cytometric assay demonstrated abnormally low neutrophil oxidative burst activity. Coamplification of NCF1 and its pseudogenes identified a GT-deletion (ΔGT) at the start of exon 2 in NCF1 (NM_000265.7: c.75_76delGT: p.Tyr26Hisfs*26). Estimation of NCF1-to-NCF1 pseudogenes ratio using ΔGT and 20-bp gene scans affirmed nil copies of NCF1 in the patient. While the father had a normal ratio of 2:4, the mother had a ratio of 1:5, implicating the carrier of ΔGT-containing NCF1. Discovery of a 7q11.23 deletion involving one NCF1 allele and a ΔGT in the second NCF1 allele explained the coexistence of WBS and CGD in our patient. This study highlights the capability of WES to establish a molecular diagnosis for a case with blended phenotypes, enabling the provision of appropriate prophylactic treatment.

Matched MeSH terms: Granulomatous Disease, Chronic/diagnosis; Granulomatous Disease, Chronic/genetics*; Granulomatous Disease, Chronic/immunology; Granulomatous Disease, Chronic/therapy
Fulltext Recurrent Chromobacterium violaceum infection in a patient with chronic granulomatous disease

Sureisen M, Choon SK, Tai CC

Med J Malaysia, 2008 Oct;63(4):346-7.
PMID: 19385503 MyJurnal

We report a rare case of recurrent infection of Chromobacterium violaceum in an immunocompromised patient. Despite the high mortality rate associated with this infection as reported in the literature, this patient survived three episodes of recurrent infection. We believe that with high clinical suspicion, prompt treatment and appropriate antimicrobial agents, it is possible for clinicians to treat this infection effectively and reduce the mortality rate.

Matched MeSH terms: Granulomatous Disease, Chronic/complications*
Fulltext Defining p47-phox deficient Chronic Granulomatous Disease in a Malay family

Gill HK, Kumar HC, Dhaliwal JS, Zabidi F, Sendut IH, Noah RM, et al.

Asian Pac J Allergy Immunol, 2012 Dec;30(4):313-20.
PMID: 23393912

BACKGROUND: The most common autosomal form of Chronic Granulomatous Disease, p47-phox deficient CGD, generally features a GT (deltaGT) deletion in the GTGT sequence at the start of exon 2 on the NCF-1 gene. This consistency is due to the coexistence of and the recombination between 2 homologous pseudogenes (psi s) and NCF-1. The GTGT: deltaGT ratio mirrors the NCF-I: NCF-1 psi ratio and is 2:4 in normal individuals.
OBJECTIVE: To determine the molecular basis of the Autosomal-CGD in a family with 2 children, a male and female, affected by the disease. The female patient suffered recurrent infection, retinitis pigmentosa and discoid lupus.
METHODS: Chemiluminescence (CL) was used to study the respiratory burst, while genetic analysis was done by RT-PCR, PCR, deltaGT and the 20bp gene scans.
RESULTS: The CL response of the patient was profoundly low. The patient's p47-phox band was absent in the RT-PCR for NADPH-oxidase component mRNAs. The deltaGT scan showed that the patient's GTGT: deltaGT ratio was 0:6, the parents' and the younger brother's was 1:5 and the younger sister's was 2:4. Examination of other NCF-1/ NCF-1 psi s differences showed that the father had a compound deltaGT allele ie. deltaGT-20bp, inherited by the patient, and that both parents had compound GTGT alleles with a single 30bp segment in intron 1.
CONCLUSIONS: The patient was a classic, homozygous deltaGT p47-phox deficient CGD with one allele harbouring a compound deltaGT-20bp gene. The deltaGT and 20bp gene scans offer a relatively simple and efficient means of defining a p47-phox deficient CGD patient.
Key words: Chronic Granulomatous Disease, Primary Immunodeficiency, NCF-1, p47-phox, NADPH-oxidas

Matched MeSH terms: Granulomatous Disease, Chronic/enzymology; Granulomatous Disease, Chronic/genetics*; Granulomatous Disease, Chronic/pathology
Detection of polymorphonuclear leukocyte dysfunctioin via chemilumi-nescence assay in children with recurrent bacterial infections

Noah, R.M., Yusuff, Z., Jais, M.R., Noh, L.M.

Malaysian Journal of Child Health, 1997;9(2):170-173.
MyJurnal

Chemiluminescence assay was used to assess the respiratory burst activities of polymorpho-nuclear leukocytes from paediatric patients reported to manifest with several episodes of recurrent bacterial infections. From this group of patients evaluated, only 10 cases of severe recurrent bacterial abscess exhibited more than 80% depression in the phagocytic chemilumi-nescence responses. The assay, being a sensitive method, was able to provide further useful laboratory investigation in diagnosing 4 patients with chronic granulomatous disease.

Matched MeSH terms: Granulomatous Disease, Chronic
Fulltext X-linked chronic granulomatous disease in a male child with an X-CGD carrier, Klinefelter brother

Gill HK, Kumar HC, Cheng CK, Ming CC, Nallusamy R, Yusoff NM, et al.

Asian Pac J Allergy Immunol, 2013 Jun;31(2):167-72.
PMID: 23859418 DOI: 10.12932/AP0274.31.2.2013

BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency (PID) caused by a dysfunctional respiratory burst enzyme NADPH-oxidase. The concurrence of Klinefelter’s Syndrome (KS) and CGD would be extremely rare.
OBJECTIVE: We describe the study of a family where the youngest male child had X-linked CGD (X-CGD) while his older brother was both an X-CGD carrier and a Klinefelter.
METHODS: Flow cytometry was used to study respiratory burst and gp91-phox expression, while genetic investigation was done by RT-PCR, PCR and X-chromosome short tandem repeat (X-STR) analysis.
RESULTS: The Dihydrorhodamine (DHR) assay showed the patient’s neutrophils failed to produce a respiratory burst, while both the mother and an older brother showed a bimodal response. gp91-phox expression was absent in the patient’s neutrophils, and bimodal in the mother’s and brother’s neutrophils. The patient’s cDNA showed a C>T change at nucleotide 676 of the CYBB gene. The same change was seen in the patient’s gDNA, while the brother and mother were heterozygous, with C and T, in this position. The c.676C>T is a nonsense mutation that leads to premature termination of the gp91-phox protein. The brother karyotyped as 47, XXY and X chromosome analysis showed that he had inherited both his mother’s X chromosomes.
CONCLUSIONS: This study showed that the patient had gp91-phox deficient CGD while his older brother was a CGD carrier and a Klinefelter, who had inherited both his mother’s X chromosomes. This is the first report of such a concurrence in an individual, and argues for family members to be included in PID studies.
Key words: Chronic granulomatous disease, CYBB, gp91-phox, Klinefelter’s syndrome NADPHoxidase

Matched MeSH terms: Granulomatous Disease, Chronic/enzymology; Granulomatous Disease, Chronic/genetics*
Fulltext Managing a Complicated Acute Otomastoiditis at Day Four of Life

Lim R, Zulkifli S, Hailani I, Hashim ND

Cureus, 2021 Jan 25;13(1):e12905.
PMID: 33654590 DOI: 10.7759/cureus.12905

Acute mastoiditis in a newborn complicated by the presence of facial nerve palsy is an alarming finding requiring rapid assessment and further investigation. Such an early presentation should point the clinician towards an underlying systemic pathology or congenital anatomical abnormality. Facial nerve involvement indicates severe infection and possible dehiscence of the facial canal. Although more frequent in children, it is rare in neonates. We would like to share our experience in managing the youngest known presentation of otomastoiditis at four days of life. The patient presented with otorrhea and facial paralysis and progressed to meningitis. He was finally diagnosed with chronic granulomatous disease.

Matched MeSH terms: Granulomatous Disease, Chronic
Chronic granulomatous disease

Zarina Thasneem Zainudeen, Ilie Fadzilah Hashim, Intan Juliana Abd Hamid

Malaysian Journal of Paediatrics and Child Health, 2019;25(2):1-2.
MyJurnal

Chronic granulomatous disease (CGD) is defined as an inherited phagocyte disorder causing defective superoxide generation and intracellular killing. Reduced or missing burst activity of nicotinamide dinucleotide phosphate (NADPH) oxide complex is observed in this inborn defect that usually manifests itself during the first two years of life. It can be inherited either by X-linked inheritance or autosomal recessive inheritance. Most patients with CGD develop failure to thrive, severe bacterial adenitis, abscesses, osteomyelitis or hyperinflammaory manifestations. (Copied from article).

Matched MeSH terms: Granulomatous Disease, Chronic
Fulltext Clinical and demographic pattern of chronic granulomatous disease (CGD) from a multicenter perspective: Malaysia's experience over 26 years

Noh LM, Latiff AHA, Ismail IH, Noah RM, Wahab AA, Hamid IJA, et al.

Allergy Asthma Clin Immunol, 2021 May 17;17(1):50.
PMID: 34001231 DOI: 10.1186/s13223-021-00551-4

BACKGROUND: A retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia.
METHODS: Data from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed.
RESULTS: Twenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia.
CONCLUSION: This study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

Matched MeSH terms: Granulomatous Disease, Chronic