Is it X-Linked or autosomal recessive chronic granulomatous disease?

Abstract

Background Neutrophil oxidative burst (NOB) activity as assessed by dihydrorhodamine-123 flow cytometric assay, is used in the diagnosis of chronic granulomatous disease (CGD) and may provide insight into its inheritance pattern. Case report We present a consanguineous family with complete absence of NOB activity in three male siblings. Each affected sibling suffered a severe form of CGD characterised by clinical manifestations within the first year of life, recurrent bacterial and fungal pneumonia, and death in two siblings by the ages of 3 and 4. This complete absence of NOB activity and severe phenotype is atypical for classic autosomal recessive CGD. The unaffected parents and siblings displayed normal NOB activity. In addition, no bimodal peak was detected in the mother, which is atypical for X-linked CGD. Extreme skewing of lyonisation in the maternal X-chromosome was excluded. CGD mutation analysis was performed by GeneDx (Gaithersburg, USA, 2008) on the proband. A novel autosomal recessive p67-phox (NCF2) homozygous deletion mutation [NM_000433.3(NCF2): c.482delA] was identified. Objective and results A targeted bi-directional PCR sequencing analysis was developed in a local molecular laboratory (Pathology Queensland) to help identify this novel mutation in other members of this family. The heterozygous carrier status in both parents and the homozygous mutation in a newborn male sibling were demonstrated by this analysis. Discussion This case report confirms the autosomal recessive mode of inheritance of this novel c.482delA mutation in the p67-phox (NCF2) gene. The mutation is predicted to result in a frame shift and premature stop codon [NP_000424.2(NCF2): p.Lysl61 Argfs*16], potentially explaining the complete absence of NOB activity and severe clinical phenotype in the affected male siblings. Neutrophil oxidative burst (NOB) activity as assessed by dihydrorhodamine-123 flow cytometric assay, is used in the diagnosis of chronic granulomatous disease (CGD) and may provide insight into its inheritance pattern. We present a consanguineous family with complete absence of NOB activity in three male siblings. Each affected sibling suffered a severe form of CGD characterised by clinical manifestations within the first year of life, recurrent bacterial and fungal pneumonia, and death in two siblings by the ages of 3 and 4. This complete absence of NOB activity and severe phenotype is atypical for classic autosomal recessive CGD. The unaffected parents and siblings displayed normal NOB activity. In addition, no bimodal peak was detected in the mother, which is atypical for X-linked CGD. Extreme skewing of lyonisation in the maternal X-chromosome was excluded. CGD mutation analysis was performed by GeneDx (Gaithersburg, USA, 2008) on the proband. A novel autosomal recessive p67-phox (NCF2) homozygous deletion mutation [NM_000433.3(NCF2): c.482delA] was identified. A targeted bi-directional PCR sequencing analysis was developed in a local molecular laboratory (Pathology Queensland) to help identify this novel mutation in other members of this family. The heterozygous carrier status in both parents and the homozygous mutation in a newborn male sibling were demonstrated by this analysis. This case report confirms the autosomal recessive mode of inheritance of this novel c.482delA mutation in the p67-phox (NCF2) gene. The mutation is predicted to result in a frame shift and premature stop codon [NP_000424.2(NCF2): p.Lysl61 Argfs*16], potentially explaining the complete absence of NOB activity and severe clinical phenotype in the affected male siblings.