Consistent disease manifestations with a staggered time course in two identical twins affected by adenosine deaminase 2 deficiency. DADA2TWINS

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency and hematologic manifestations, with potential progression over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of adenosine deaminase 2 (ADA2) activity in the plasma of both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense mutation on the paternal ADA2 allele, while whole genome sequencing identified an intronic deletion on the maternal allele; both variants were validated by Sanger sequencing. Reduced ADA2 expression was documented in patients’ monocytes by western blot. Lymphocyte subsets were characterized by flow cytometry. The two patients were compound heterozygous for ADA2 gene variants: a documented missense mutation (p.Leu188Pro) and an unreported deletion in intron 6 (IVS6_IVS7del*), predicted to produce a transcript missing exon 7. During childhood, they experienced the onset of the disease with early-onset strokes (Patient 1 at 2 years of age and Patient 2 at 8 years of age), followed over years by other shared DADA2-associated clinical manifestations, including neutropenia, hypogammaglobulinemia, decrease in switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed between the two patients, indeed clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 underwent an urgent and successful hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, evolution of the disease and is currently on anti-TNF therapy. The unique herein presented cases confirm that heterozygous patients with null ADA2 activity deserve to be deeply investigated as possible structural variants on a single allele may occur. Moreover, this report emphasizes the importance of timely recognizing DADA2 at onset to perform an adequate follow-up and timely recognize subtle changes that contribute to disease progression. Finally, the therapeutic management in this case of identical twins raises major concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like allogeneic HSCT as elective procedure. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes at an earlier stage of severity.