Three different clinical presentations, what do they have in common?

We present three different patients with the same diagnosis but different clinical presentations. Our first patient presents with transient erythroblastopenia of childhood, anemia, lymphopenia and hypogammaglobulinemia in the first years of life. He develops later neurologic symptoms: ataxia and subarachnoidal bleeding. Moreover, he also suffers from colitis and ileitis. He has been treated with an allogenic stem cell transplantation. Skin examination reveals:a minimal livedo racemosa on the extremities, erythema of the palms and oedema of the face. The second patient suffers from recurrent fever, abdominal pain and recurrent urinary infections. She also has aminimal IgG2 deficiency. On clinical examination she presents Infiltrated papules on arms and legs and livedo racemosa which shows a sweet-like image on pathology. The last patientpresented with dermatological symptoms and high CRP: painful red-blue nodules on the legs and livedo that developed later. Biopsy showed a polyarteritis nodosa image with vasculitis of small and medium vessels.

How to link those three cases?

Genetic research revealed deficiency of ADA2 (Adenosine deaminase 2) in those three patients. It is an autosomal recessive disease first described in 2014, resulting from a loss of function mutation in ADA2 gene.  The role of ADA2 protein is not fully known and understood but it is important in the proliferation and differentiation of macrophages as well as for endothelial integrity.  This deficiency leads to three main different manifestations: vascular-inflammatory, hematological and immunological, giving different clinical pictures. A vasculopathy of small and medium sized arteries is the major clinical feature, involving central nervous system, gastrointestinal, liver, renal, and the skin. Cutaneous manifestations are the most common feature of DADA2 and can be seen mainly as livedo racemosa and subcutaneous nodules but purpura, urticaria, maculopapular rash and ulcerations have also been described. Hematological manifestations present as cytopenia or medullar aplasia. Finally, immunological manifestations as hypogammaglobiulinemia or common variable immunodeficiency are also part of the spectrum. Concerning treatment, immunosupressive drugs are not so effective, coricosteroids can control the disease at higherdosage but patients become dependent of it. The best option seems to be anti-TNF agents which control inflammation and preserve vascular integrity. Anticoagulants are not recommended as hemorrhagic stroke is a potential complication. According to the clinical presentation and severity other treatments may be necessary: immunoglobulins in case of immunodeficiency and sometimes hematopoietic cell transplantation.


DADA 2 is a recently described entity with a very variable clinical presentation spectrum. The reason of this phenotypical variability remains unexplained and further research is still needed in that field. It is important to think of ADA2 deficiency when confronted with a patient with dermatological signs such as unexplained livedo with recurrent fever and especially periarteritis nodosa in small children.

Dr Spanoudi-Kitrimi Ifigenia, Dr Morren Marieanne (KUL)