DADA2 is a single gene mutation and gene-targeted or comprehensive genomic testing can help confirm the diagnosis. The clinical presentation in patients with DADA2 has many faces at vary widely age including livedo reticularis, fever, lacunar strokes and systemic vasculitis involving all organs, and the most severe manifestations include marrow aplasia, pure red cell aplasia, neutropenia, liver disease, and neurological impairments. The estimated prevalence of DADA2 could be as high as 4:100,000.4 Due to the lack of understanding of the disease or the restriction of detection methods, the incidence rate may be higher than the current prevalence. Overall, patients with DADA2 have been identified globally, with reported ethnicities including Europe, North America, Morocco, Brazil, Japan, Singapore, China, and Middle East, and Europe has the highest incidence rate.3
The highly variable clinical presentation renders early diagnosis difficult. Onset of disease is usually in childhood and mortality is significant with up to 8% of patients succumbing to the disease before the age of 30 years; cause of death includes complications of recurrent stroke or infection.5 Cutaneous manifestations are the most common feature of DADA2 and are found in > 75% of patients and 51% of patients have experienced one or more neurological events. Of all reported patients, 50% have experienced Immunological and hematological manifestations.5 The patient has only cutaneous manifestations when admitting to our unit, which is very easy to cause misdiagnosis. The clinical manifestations of children with the disease are diverse. Most of them consulted their doctor with symptoms such as stroke, fever or anemia. The case is first report of taking cutaneous manifestations as the first symptom to seek medical treatment and finally diagnose. Cutaneous manifestations of DADA2 may show as purpura, livedo, subcutaneous nodules, Raynaud phenomenon, ulcers or non-specific rash. Therefore, it is easy to be misdiagnosed as HSP, livedoid vasculopathy, vasculitis, polyarteritis nodosa, erythema multiforme or skin ulcer without typical manifestations such as fever, stroke and anemia. The patient had only cutaneous manifestations when admitting to our unit, which was misdiagnosed as HSP by the local hospital. and finally diagnosed after further improvement of the examination in our hospital. When she was 5 months old, she was hospitalized in the infection department of our hospital due to fever of unknown origin. Cefepime, meropenem and linezolid were given intravenous anti infection treatment successively, and the effect was poor. After intravenous gamma globulin, the fever disappeared. At that time, it was suspected that there might be genetic metabolic diseases, however, due to the lack of understanding of the disease and the limitation of gene detection technology, gene detection is not perfect.
The majority of patients with DADA2 are compound heterozygous for missense mutations. The most common disease variants are p.Gly47Arg (p.G47R), p.Gly47Ala (p.G47A),p.Arg169Gln (p.R169Q), and p.Tyr453Cys (p.Y453C).1,2 These mutations are found in patients of different ancestries; however, some of them are more common in founder populations and it has not been found in Asians.4, 6-12 Genetic analysis confirmed that our patient had two CECR1 gene mutations (c.1240G>A, p.Val414Met from her mother, it has been reported12; and c.97dupA, p.Thr33AsnfsTer29 from her father, it is a novel CECR1 gene mutations), and the new contacts would form among these residues and influence the protein structure.
There are no guidelines about when and how to treat patients, especially given the broad spectrum of disease and disease severity. In the past, immunosuppressive therapies were used to control the severe systemic inflammation in patients with early-onset or recurrent strokes. Steroids, azathioprine, cyclosporine, tacrolimus, cyclophosphamide and methotrexate have all been used yet with little success.1,2 Other case reports disclosed partially successful therapies with Anti-IL-6, Anti-interleukin-1, sirolimus, colchicine and mycophenolate mofetil. 13-15 For patients with a vasculitic-predominant phenotype, TNF-α inhibition (etanercept, adalimumab, or infliximab) has been shown to be highly efficacious.16-20 Anti TNF-α therapy has strong protective effects against stroke.18,21 Long-term, possibly lifelong, use of TNF-α inhibitors has been proposed because of the risk of relapse with therapy cessation, especially in those with vasculitis and neurological manifestations.18 Patients of small sample studies and case reports who had hematopoietic stem cell transplantation (HSCT) were cured, and all are doing well at a median follow-up of 18 months.22,23 The mainstay of treatment is TNF-inhibition and HSCT may be an option in patients presenting with hematological disease and immunodeficiency not responding to TNF-inhibitors, but details and evidence for their use remain scant. In our report, because the patient only had cutaneous manifestations, we intervened with traditional Chinese medicine for promoting blood circulation and dispersing stasis simply. During the follow-up, the rash gradually subsided, D-dimer and the alanine aminotransferase returned to normal, and there was no stroke, fever and other manifestations. It is suggested that traditional Chinese medicine may alleviate the skin symptoms of DADA2. However, the Neurological manifestations incidence rate of this disease is 51% and the mortality is high. In addition, the head CT enhanced scan and MRA of the child indicates that the morphology of cerebral vessels has changed. Therefore, we are still in continuous follow-up and remind parents to pay attention to children's neurological symptoms.