ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters

Abstract

The objective of this paper is to: describe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2 activity, cytokine expression, interferon-stimulated and neutrophil-stimulated gene signatures, and the results of CECR1 sequencing. The first patient presented with intermittent fever, cutaneous vasculitis, myalgia and muscle inflammation on MRI leading to a provisional diagnosis of periarteritis nodosa. Subsequently, two cerebral lacunar lesions were identified following a brain stroke. Clinical features improved on anti-tumour necrosis factor therapy. The first patient's sister demonstrated early-onset, long-lasting anaemia with mild biological inflammation; at the ages of 3 and 5 years, she had presented 2 acute, transient neurological events with lacunar lesions on MRI. CECR1 sequencing identified both sisters to be compound heterozygous for a p.Tyr453Cys mutation and a previously undescribed deletion of exon 7. ADA2 activity was reduced by 50%. Neutrophil-stimulated genes were not overexpressed, but interferon-stimulated genes were. The expression of a panel of other cytokine transcripts was not significantly altered. In conclusion, searching for CECR1 mutation or assessing ADA2 activity should be considered in patients with an atypical presentation of inflammatory disease.

Keywords: Fever Syndromes; Inflammation; Systemic vasculitis.

Figure 1

Imaging of patient 1. (A) Muscle MRI of both legs performed at the age of 5 years: coronal gadolinium-enhanced T1-weighted sequence at different levels, showing patchy inflammatory muscular lesions. (B) Cerebral MRI performed at the age of 7 years. Left: axial gadolinium-enhanced T1-weighted sequence, showing gadolinium-enhanced mesencephalic (up) and peduncular (down) lesions. Right: axial diffusion-weighted sequence showing mesencephalic (up) and peduncular (down) hyperintensities. (C) Cerebral MRI performed 4 months later: axial gadolinium-enhanced T1-weighted sequence showing evolution towards lacunar lesions (up: mesencephalic lesions/down: peduncular lesions). (D) Cerebral MRI performed 3 years later: gadolinium-enhanced T1-weighted sequences showing lacunar lesions located in the internal capsule.

Figure 2

Illustration of the mutation and ADA2 activity. (A) Sanger sequencing analysis illustrating the point c.1358A>G mutation which was identified in both sisters. (B) Reverse quantitative PCR (RQ-PCR, copy number calculated) illustrating the exon 7 deletion in the two sisters and in the father. CECR1-E7a and CECR1-E7b are two distinct amplicons encompassing exon 7 of CECR1 gene, to avoid a possible rare polymorphism in a primer hybridisation site. (C) CECR1 mutations result in a decrease in ADA2 activity in patient plasma. The figure shows the ADA2 activity in the plasma of the two patients tested on two occasions, compared with ADA2 activity in the plasma of four controls (***p<0.001).

Figure 3

IFN and neutrophil gene expression studies. The RQ value for each transcript is equal to the normalised fold change relative to a control. (A) Quantitative reverse transcription PCR of a panel of six IFN-1-stimulated genes in CECR1 mutation-positive sisters on two occasions. IFN score was 4.82 before treatment and 1.86 after treatment in patient 1 and 11.79 and 9.47 before treatment in patient 2. IFN-stimulated genes are variably overexpressed in the two patients. (B) The expression of a panel of neutrophil-stimulated genes was measured in patients 1 and 2 on two occasions. Neutrophil-stimulated gene expression was essentially similar to that in controls. IFN-1, interferon 1; NA, not applicable; RQ value, relative quantification value.