Deficiency of Adenosine Deaminase 2 in Adult Siblings: Many Years of a Misdiagnosed Disease With Severe Consequences

Abstract

Objective: Describe the clinical characteristics and histopathology findings in a family with two siblings affected with deficiency of adenosine deaminase 2 (DADA2). Both patients presented in childhood with polyarthritis and developed significant neurological and gastrointestinal features of DADA2 in ear, including variable degrees of immunologic and hematologic manifestations.

Methods: Adenosine Deaminase 2 (ADA2; also known as cat eye syndrome chromosome region, candidate 1 gene; CECR1) exon sequencing and serum ADA2 levels were performed to confirm the diagnosis of DADA2. Comparison of serum adenosine deaminase 2 levels was made to DADA2 patients, carriers, and healthy controls in Patient 2. Autopsy specimens from brain and liver tissues were submitted for analysis.

Results: Both patients were found to carry a previously reported rare intronic missense mutation predicted to affect the transcript splicing (c.973-2A > G; rs139750129) and an unreported missense mutation p.Val458Asp (c.1373T > A; V458D). Both brothers started therapy with a tumor necrosis factor inhibitor following the molecular diagnosis of DADA2 with good response and were eventually tapered off prednisone. However, Patient 1 died 18 months later due to complications of end-stage liver disease. His autopsy showed evidence for nodular hyperplasia of the liver often seen in common variable immunodeficiency (CVID) and numerous small, old infarcts throughout the brain that had not been demonstrated on prior MRI/MRA imaging.

Conclusion: These cases emphasize the importance of recognition of DADA2 in adults, compare CNS imaging modalities to pathologic findings and suggest similarities in liver pathology between DADA2 and CVID. MRI may not be most sensitive method to identify small subcortical infarcts in patients suspected to have DADA2.

Keywords: adenosine deaminase 2; adenosine deaminase 2 deficiency; nodular regenerative hyperplasia; polyarteritis nodosa; stroke; vasculitis.

Figure 1

(A,B) Electropherograms of ADA2 pathogenic mutations identified in the family. (C) Family pedigree, both unaffected parents are carriers of these mutations. WT indicated wild-type or non-mutated ADA2 allele. (D) cDNA sequencing shows that the p.V458D mutation appears heterozygous at the genomic DNA and as a homozygous mutant allele when transcribed in cDNA indicating null expression of the second allele due to the c.973-2A>G mutation.

Figure 2

Serum ADA2 enzyme activity and cDNA sequencing to confirm pathogenic mutations: enzymatic activity (%) was significantly lower in the affected Patient 2 when compared to age-matched controls (n = 5) and heterozygous carriers (n = 11), but similar to other patients with DADA2 (n = 20). Samples were not available for patient.

Figure 3

Infarcted lesion in basal ganglia (A–C). (A) Cavity lesion with residual histiocytes and adjacent dense astrocytosis (4 × 10 magnification). (B) Same lesion at 20 × 10 magnification. (C) KP1 stain highlights histiocytes within cavity (4 × 10 magnification). Hepatic findings (D–F). Nodular regenerative hyperplasia (NRH) shows in (A) (4 × 10) and (B) (20 × 10). Mild sinusoid fibrosis is seen in areas of NRH demonstrated by Trichrome Masson stain (C) (20 × 10).