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.
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.