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.

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

“…The spectrum of DADA2 phenotype is evolving as more atypical presentations have been reported recently. [7][8][9][10][11][12][13][15][16][17][18] Table 1 summarizes hematological manifestations that were reported in DADA2. In the present case, ALPS-like disorder was the main presentation with absence of signs of vasculitis, livedo reticularis, or stroke, causing a diagnostic challenge that was only resolved after obtaining exome sequencing result.…”

“…Response ranging from stable disease to complete remission was reported with the use of anti-TNF medications in DADA2. 2,7,[16][17][18] Complete response was also described with the use of thalidomide. 16 Methotrexate, azathioprine, rituximab, MMF, cyclophosphamide, and anti-interleukin1 were not effective.…”

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…In line with this view, Zhu et al showed recently that ADA2 mediates cross talk between M2‐like glioma‐associated macrophages and pericytes via a platelet‐derived growth factor dependent pathway, resulting in neoangiogenesis. At the mRNA level, several studies have demonstrated a type I interferon blood gene expression signature in patients with DADA2 . Even though the hallmark of type I interferonopathies, intracranial calcifications, is not present in DADA2, the identification of a type I interferon signature potentially paves the way for novel treatment strategies.…”

“…A homozygous 770‐kb genomic deletion including IL‐ 17RA and ADA2 was found in two siblings with a severe immunodeficiency . Intragenic deletions of exon 1 and exon 7 have also been reported . Most pathogenic variants are missense substitutions, nonsense, and splice‐site mutations.…”

“…1 In the severe spectrum of the disease are patients presenting with cranial nerve palsy, diplegia, paraplegia, peripheral polyneuropathy due to perineuritis, ataxia, sensorineural hearing loss, mononeuritis multiplex, labyrinthitis, neuromyelitis, encephalopathy and cerebral atrophy. 1,2,73,74,76,79,81,82 At the histology level, the brain lesions correspond to erythrocyte extravasation in brain parenchyma.…”