Adenosine deaminase 2 deficiency in a Chinese patient: Report of one novel mutation and literature review

Through a case of deficiency of adenosine deaminase 2 (DADA2) to improve domestic clinicians' understanding of the disease, and to review the literature, promote dermatologists for clinical secondary primary lesion diagnosis.


| DISCUSS ION
Adenosine deaminase (ADA) is an amino acid hydrolase, with the ADA2 gene located at 22q11.1, previously known as the CECR1 gene. 2 The multifunctional protein, closely related to purine metabolism and immune function, participates in the process of purine nucleotide metabolism.It mainly acts to catalyze the deamination of adenosine and deoxyadenosine, thus participating in the catabolism of adenosine.It is an essential enzyme for the proliferation and differentiation of lymphocytes and monocyte macrophages.Therefore, when this enzyme is lacking, deoxyadenosine triphosphate (dATP) exceeds 50-100 times that of normal people.This is a toxic metabolite, which can inhibit lymphocyte proliferation, lead to immunodeficiency disease, and plays an important role in the development of the immune system and the regulation of immune cell function. 3

| Deficiency of adenosine deaminase 2 (DADA2)
The homozygous or compound deficiency of adenosine deaminase 2 (ADA2), causing a series of clinical symptoms, the pathogenesis is not clear. 4DADA2 was first reported in 2014, and there are currently about 200 DADA2 cases worldwide, and the DADA2 prevalence may be up to 4∶100 000, as estimated based on the allele mutation frequency of deleterious ADA2 mutation genes. 3Rare in foreign countries, in China can be described as rare disease, more than childhood, before 10 years old, 5 This case is the seventh child reported in China.Therefore, it is very important to improve the understanding of the disease and promote clinicians to make early diagnosis of the disease, and early treatment can alleviate or even avoid the occurrence of serious complications such as the central system in children.
Adenosine deaminase 2 deficiency is highlighted by childhood-onset stroke, immunodeficiency, and bone marrow failure.that four family members were homozygous for pathogenic mutations, but none showed symptoms, 7 It indicates that the clinical and onset age of DADA2 are very different, and the age of onset, onset probability and severity of symptoms of patients with the same pathogenic genotype can also vary, thus increasing the difficulty of early identification and diagnosis. 5The CNS presentation is also a signature change in DADA2, with ischemic stroke being the most common occurrence, and can occur repeatedly.The incidence of hemorrhagic stroke is second only to ischemic stroke.Six out of the 7 children (86%) reported in China, cerebral MRI showed evidence of cerebral vasculitis, among which cerebral infarction accounted for 43% and cerebral hemorrhage accounted for 14%.

Systemic inflammatory manifestations, and common systemic
inflammation in DADA2 patients has recurrent intermittent fever, skeletal muscle events, hypertension, and hepatosplenomegaly.
Hypersensitivity C-reactive protein, erythrocyte sedimentation rate, and transaminase are often elevated in acute-phase patients.
All the 7 children in our study had recurrent fever, C reactive protein and blood sedimentation rate increased in the acute phase, 1 (14%) had liver enlargement on physical examination, 2 (28%) had spleen enlargement, and 2 (28%) had muscle and joint pain.

| Immune dysfunction
The common immune deficiency in DADA2 patients is mainly low gammaglobulinemia, which makes the patients more prone to infection with different viruses.In 7 children, IgM, IgG and IgA were reduced to varying degrees, and two cases (28%) were infected with EB virus infection.In this case, the children were also infected with rubella and cytomegalovirus infection.

| Blood system abnormalities
Five of the seven children had significant anemia symptoms and indicators, and three children had significant platelet increases.

| Asymptomatic phenotype
Genetic screening of DADA2 proband cases has identified asymptomatic people, many in adults, and asymptomatic people often have ADA2 gene defects and low ADA2 protein levels. 7

| Diagnosis
DADA2 clinical features appear highly heterogeneous, So the early diagnosis is more difficult, And there are no clear diagnostic criteria, Standard DADA 2 clinical testing at this stage includes enzymatic detection combined with sequence analysis of the ADA2 coding region, But for children with high suspicion of monogenic disease, One negative genetic result (especially the panel) is not sufficient to deny the diagnosis, If necessary, multiple, multiple sequencing units or expanded range sequencing; In the absence of a high suspicion of a certain single-gene genetic disorder, Whole-exon sequencing may be superior to the panel, Whole-exon sequencing showed an inferior depth of coverage to the panel, Thus there may be genetic mutations that are not covered by, And, for the genetic reports, Especially with the interpretation of the results of the panel, And should be interpreted within their gene list. 8But ADA2 pathogenic variation may not be detected by conventional sequencing and genetic testing, so clear molecular diagnosis is for all family members diagnosis and subsequent treatment becomes important, follow-up we will suggest that children further perfect ADA2 enzymatic detection combined with quantitative RT-PCR detection means to verify the lack of allele, so as to further clarify the pathogenicity of gene mutations. 9sed on the extensive literature review of the genotype and phenotype of DADA 2, pathogenic variants of ADA2 are found throughout the coding region, affecting all domains of ADA2, and exon 7 is found to be a mutation hotspot.Just as our child had a missense mutation in exon 7. Most DADA 2 are compound heterozygous for missense mutations, the most common are p.G47R, p.R169Q, G47R, P251L, Y435C, etc. p. Y435C is more reported, and carriers often show hematological lesions such as fever, reticulata, cerebral infarction, reduction of whole blood cells and low gamma globulin.If pure and mutated, it only shows fever and panniculitis, no nerve and blood involvement. 10Others are mutation-negative patients with clinical and enzymatic phenotypes consistent with DADA2, who may have as yet undescribed variants in intronic regions and non-coding regulatory elements. 7Most of the pathogenic variants in ADA2 were either new or found at low allele frequencies (1:1000) in population databases.Other variants exhibit significantly higher allele frequencies in specific populations, such as p.g yl47arg in the Georgian Jewish population or p.g yl169gln in the Northern European population.The DADA 2 phenotype showed variability to a significant degree, and in some patients showed reduced penetrance. 7,11Even patients homozygous for the same founder pathogenic variant or patients with the same biallelic heterozygous pathogenic variant may vary in age, frequency, and severity of symptoms.At present, there is no clinical standard treatment for the treatment of DADA2, and anti-TNFα, anti-IL-6 and other anti-cytokine monoclonal antibodies, combined with hormones and other immunosuppressants, are generally preferred. 15,16Early and continuous application of TNFαreceptor antagonists can mitigate or even avoid neurological damage. 15Sira Nanthapisal's 7 experiment confirmed that nine out of 10 patients were eventually treated with TNFα receptor antagonist, combined with prednisolone and/or alternative disease to improve antirheumatic drugs (DMARDs), adalimumab, high-dose corticosteroids and 5 mg aspirin per kilogram (daily after excluding cerebral hemorrhage) treatment caused a complete remission of his neurological symptoms, inflammatory markers returned to normal within 7 days.Before diagnosis, it may be misdiagnosed as connective tissue disease, vascular inflammatory disease, such as buceset disease, 8 Inflammatory myopathy, and Kawasaki disease et al, 17 because there is repeated fever, clinical characteristics are highly heterogeneous, difficult to early diagnosis.Often early mistaken for other diseases give human immunoglobulin, glucocorticoids, nonsteroidal anti-inflammatory drugs, immunosuppressive agent treatment, but the effect is limited, although some drugs can control recurrent fever and inflammation, but cannot block the progress of the disease, continuous inflammation will increase the risk of complications, such as high-dose hormone shock treatment effect is ok, but reduce and stop after relapse, can even have serious complications such as stroke and intussusception.HSCT is currently the most effective treatment for DADA2 in clinical practice, which can rapidly reconstruct hematopoiesis and immunity, and improve the systemic inflammatory symptoms. 18However, there is a strict requirement that it must be determined that the related donor does not carry the pathogenic CECR1 gene mutation and has no ADA2 deletion.Consider an unrelated donor without a suitable relative.HSCT can cure angiological features, immunodeficiency and vascular lesions and be difficult to relapse, especially suitable for DADA2 patients with hematological and immune dysfunction. 19Among the 7 patients in China, 2 patients were finally treated with HSCT, with stable condition and free follow-up survival; 3 patients were treated with thalidomide combined with hormone, with stable condition and no recurrence, and regular review.Two patients including the reported present child treated with a TNFα receptor antagonist had no recurrent fever, skin lesion regression, and stable condition at the current follow-up.It is worth proposing that, although 4 out of the 7 children had increased LI-6, and had also been treated clinically with tocilizumab.But the right thalamic infarction in children with DADA 2 after tozumab as reported by Liu et al, 11 Sira Nanthapisal after tocilizumab, as reported by et al. 7 One patient also had a recurrent stroke 2 months after starting tocilizumab and 6 months to adalimumab.Tocilizumab can control recurrent fever and inflammation, 4 But the progression of the disease cannot be blocked, nor can it be cured, the disease is often repeated, and cannot reverse hematology and immunity. 17ere is still no proven correlation of genotype and phenotype, and although there are no common treatment guidelines, anti-TNFαdrugs have proven to be very effective in controlling fever episodes and vascular lesions and in preventing stroke.Non-responsive patients may be candidates for hematopoietic stem cell transplantation (HSCT). 1 Especially those with immune deficiency, cytoreduction, and bone marrow failure phenotype, but the recent reports of B and T lymphocyte abnormal DADA 2 poor response to TNFαdrugs, and immunosuppressive agents may increase the risk of infection, thus suggesting the possibility of genotype and phenotype correlation, but further research and development. 9,20,21There is no doubt that HSCT is a permanent cure. 22,23For the time being, our children only found repeated systemic inflammatory reactions, skin manifestations and increased intraocular pressure, no recurrent central system lesions and immune and blood lesions, so it is suitable for the treatment of anti-TNFαdrugs, and the condition is stable and confirm this view.

livedo reticularis (LR) is also known as dendritic green spot,
ring green spot, dendritic dermatitis, multiple reticuloplebus, reticular pigmented derma.It is a disease with characteristic reticulated or dendritic blue and purple spots on the skin, and it is aggravated by cold. 24Unna believes that the color of reticuloplaque is due to spasm of arterioles in the anastomotic area, increased blood viscosity and thrombosis, capillary and capillary expansion, and endovascular blood stagnation, resulting in the accumulation of deoxy blood in the veins.
According to the etiology of clinical types (1) The physiological reticular green spots (physiological livedo reticularis), also known as marbled skin (cutis marmorata) skin, skin damage is green pur- Idiopathic reticulography (idiopathiclivedo retieularis with systemic involvement) with systemic damage has vasospastic reticulography, the most common cause of reticulosum, including autoimmune connective tissue disease, common in patients with Raynaud phenomenon.Vascular wall disease can also cause reticulogreen plaques, such as vasculitis, skin type, or systemic perinodular arteritis.5.

Secondary reticulogreen plaque (secondary livedo reticularis) This
disease is secondary to some underlying diseases and taking some drugs, and the rash is mostly patchy, with an asymmetric grape green plaque pattern. 2 reticulobus is a characteristic skin manifestation of DADA2, and 5 out of 7 domestic children showed manifestations, Sira Nanthapisal. 6He proposed that the incidence of reticuloplaque in DADA2 patients can be as high as 73.3%, and even confirmed in his experiments that the only clinical feature of some asymptomatic patients is mild reticuloid changes.Therefore, dermatological clinicians need to learn to identify and rule out the occurrence of DADA2 when they encounter refractory erythema tuberosity and reticulum plaques.
Reticticulspot spot mostly secondary and idiopathic, Xu Sijia et al, 25 Tang Yajuan 26 Two cases of secondary LR were previously reported, with both patients taking amamantane-induced LR, and the rash completely disappeared after 20 days of drug withdrawal.Chen Lin, 27 Shen Hongyuan 28 Two cases of white atrophy combined with idiopathic reticulum spot have been reported, Yao Jiachun 29 Three cases of skin allergic vasculitis complicated with network green plaque, with promoting blood circulation and removing blood stasis were reported 30 Have reported a case of systemic lupus erythematosus in web and higher anti-cardiac lipid antibodies, the results found that habitual abortion, CNS lesions, nephropathy, vasculitis and lupus suppressor significantly associated with the emergence of anticardiac lipid antibodies, the authors think that may be an important system involvement of late signs of a skin, and anticardiac lipid antibodies may have pathogenesis significance.After Li Hongjun 31 A case of SLE with LR as the first symptom was also reported; Feng Xinzhong 32 Three cases of LR with cerebrovascular accident were reported, with rash appeared several years before the cerebrovascular accident.Xu Yi white 33 Three cases of LR with cerebrovascular disease were also reported, and all the patients developed neurological symptoms such as expressive aphasia, hemiparalysis and partial sensory disorder to varying degrees, and the rash was preferred or concurrent.Among the seven cases reported in China, six cases are associated with central nervous system lesions.Considering that this disease and cerebrovascular accidents are caused by vascular abnormalities, the cardiovascular and cerebrovascular conditions should be screened, and patients are advised to prevent it as soon as possible.And obtained the idiopathic LR, Liu Ping, 34 Yu Ji Ang, 35 Bai Juan et al, 36 It has been reported that this type is more common in young women, the lesion parts are both lower limbs, most patients have no other medical history, the rash symptoms often worsen in winter or cold, in summer or warm symptoms reduced symptoms characteristics; long standing and running symptoms will also worsen, rest can be relieved 37 reticuloplaque can be secondary to a variety of diseases, and central nervous system lesions, in addition to may be a serious complication of DADA2, but also may be caused by cerebrovascular abnormalities, clinicians need to exclude serious lesions such as DADA2 and Sneddon syndrome as soon as possible, and give patients symptomatic treatment as soon as possible.

AUTH O R CO NTR I B UTI O N S
Duan Yan provided the cases and ideas.Bai Yuxuan collected the case data and the follow-up and independently wrote the article.
Duan Yan reviewed and gave advice.

ACK N O WLE D G E M ENTS
I would like to thank my tutor Duan Yan for her help in my article, and also thank my little patient for cooperating with us to discuss difficult cases.Finally, I would like to thank the Journal of Cosmetic Dermatology for publishing my article, which can make further progress in the diagnosis and treatment of complicated diseases.

CO N FLI C T O F I NTE R E S T S TATE M E NT
All authors have no potential financial and non-potential financial conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C S S TATEM ENT
The acquisition of all the information, including the shooting of the pictures, is obtained with the consent of the patient, and all the content is provided on the basis of protecting the patient's privacy right.
And the first author have obtained the informed written consent from the patient to include these images.
Normal health status: general.Past history: children in April 2020 because of "fever, rash" in Inner Mongolia Medical University affiliated hospital hospitalization for 1 week, in May 2020 in the Inner Mongolia autonomous region of traditional Chinese medicine hospital diagnosis "erythema nodules", for topical medication, poor effect, successively in our dermatology, pediatrics, community clinics, intermittent oral hormones (prednisone), Chinese medicine treatment (irregular), nearly a half years rash repeatedly, sunlight and strenuous activity can aggravate.History of drug allergy: no; personal history: fetal period: maternal pregnancy health; delivery history: cesarean section, the second child; feeding history: breastfeeding, complementary food addition: irregular.Developmental history: no abnormalities in development.Vaccination history according to the regulations, vaccinated with "BCG, polio sugar pill, DPT vaccine, measles vaccine, encephalitis vaccine, meningitis vaccine" and other vaccines; family history: parental health, family illness: denied family genetic history and infectious disease contact history.Physical examination: General record: T38.2°C P 129 times/min (rule), R 23 times/min (rule), BP 91/62 mmHg, weight 18 kg.General situation: clear mind, depressed spirit, moderate nutrition, development is not abnormal.Skin mucosa: visible and scattered red spotted rash in both lower limbs, does not highlight the surface of the skin, between the rash skin is normal, no itching feeling.Lymph nodes: enlarged lymph nodes can be reached under the right mandibular side, about 1 × 0.5 cm in size, tough and smooth in quality, with a clear boundary, OK mobility, and no tenderness.Eupharynx: congestion; tonsils: congestion, enlarged I° enlargement, no purulent secretions.Chest, heart, abdominal and neurological physical examination showed no obvious abnormalities; auxiliary examination: 2021/12/1 blood routine (Affiliated Hospital of Inner Mongolia Medical University) white blood cells 9.46 × 10 ~ 9/L, Absolute neutrophil value of 4.45 × 10 ~ 9/L, The absolute value of lymphocytes was 3.64 × 109/L, The absolute value of eosinophils was 0.02 × 10 ~ 9/L, An absolute value of basophils of 0.03 × 10 ~ 9/L, The absolute value of monocytes was 0.82 × 10 ~ 9/L, BC 4.40 × 10 ~ 12/L, hemoglobin at 110 g/L, The mean erythroid volume of 77f1, Width of RBC distribution (SD)35.60fl, small board 370 × 10 ~ 9/L, The platelet distribution width was 9.60f11, C reactive protein 8.67 mg/L was reviewed in our hospital, From December 4 to 242 021, Leukocyte cells (11.2,7.12,10.27,12.39,10.17,15.89)× 1 0 ~ 9/L, Absolute values of neutrophils (7.89,4.51,5.3,8.51,3.99,9.02)× 10 ~ 9/L, The absolute values of the lymphocytes, Absolute values of the basophils were all normal, The absolute value of eosinophils was 0.01 × 10 ~ 9/L, Erythrocytes (4. mm/h, The three examinations of anti-nuclear antibodies were all: granular type (1:80); The EB virus nuclear antigen antibody, IgG143U/mL, EB virus capsid antigen antibody IgG130U/ mL, Anti-cyclic citrulline polypeptide antibody <7.0 U/mL, Hepatitis B surface antibodies (HBsAb)91.890IU/L, The glomerular basement membrane antibodies, myeloperoxidase antibodies, protease-3 antibodies, and anti-neutrophil cytoplasmic antibodies were all normal, Pituitary prolactin 27.59 ng/mL, Sex hormone-binding globulin 79.42 nmol/L, Sugar water experiment, HAM's hemolysis experiment, erythrocyte fragility experiment, anti-human globulin direct test were all negative; Brucellosis, tuberculosis bacterium negative; Rubella virus IgG antibody was measured by 8.23 AU/ mL, and 3.14 AU/mL by cytomegalovirus IgG antibody.Ultrasound prompt: spleen light and large, electrocardiogram, liver, pancreas and spleen color ultrasound returned normal.After admission, the patient received grade I care; bath and application for cooling; cefotaxime sodium, VitC, cyclophosphoadenosine intravenous infusion, changed to cefoperazone sodium sulbactam on December 20, and the remaining treatment remained unchanged.Improve the relevant examination, please consult with multiple departments, clear diagnosis.After more than 20 days of treatment, the child's symptoms did not ease.The family asked for further treatment in Beijing, and he was discharged.Continuing follow-up, the first author learned that the child was treated in Beijing Children's Hospital affiliated to Capital Medical University, and improved skull magnetic resonance imaging (MRI) examination indicated: left choroidal cleft cyst; left eye P: 22 mmHg.Combined with the medical history of the child, considering that the original disease may be an autoimmune deficiency disease, a genetic test was performed to show the CECR1 mutation site (c.1075G > T p.E359*,c.139G> C p. G47R) was a compound heterozygous mutation, diagnosed with DADA2 and treated with adalimumab (20 mg Q2W subcutaneous injection), prednisone acetate tablet (12.5 mg QD), alfaralcitol soft capsule (0.25 ug QD), calcium carbonate D3 particles (3 g QD), with stable condition, systemic skin lesions subsided 1 week after the first adalimumab use, and no recurrence of systemic inflammatory response during follow-up.He is now in stable condition (Figures 1-8).
Vascular lesion is similar to nodule polyarteritis in clinical practice, reticulate blue spot and skin vasculitis are the most common skin manifestations of DADA2, skin vasculitis is subcutaneous nodules, skin purpura, ulcers, necrosis, etc. 2 Domestic reported 7 cases (57%) have typical erythema skin changes, so these children are often diagnosed with polyarteritis (PAN), 5 cases (71%) have network changes, 2 cases (28%) have finger gangrene changes, and the two cases of F I G U R E 1 Flexion of both upper limbs.F I G U R E 2 Extension of both upper limbs.F I G U R E 3 Flexion of both upper limbs.F I G U R E 4 Extension of bilateral thigh.children have increased LI-6/LI-8 and platelets, later appeared ischemic stroke (all located in the right thalamus), and all accord with heterozygous mutation, but for DADA2 gene phenotype and clinical manifestations need further clinical research.Studies have reported

F I G U R E 5
Flexion of bilateral thigh.F I G U R E 6 Bilateral lower legs.F I G U R E 7 Double dorsum of foot.F I G U R E 8 Bilateral malleolus.
[11][12][13] Sira Nanthapisal et al.8 collected 15 DADA 2 patients for study showed that one third of the patients without clinical symptoms, known as presymptomatic DADA-2, but these patients and other subjects have decreased serum ADA2 enzyme function, the corresponding CECR1 mRNA is the expression is decreased, which is of great significance for diagnosis and prognosis, through follow-up, the 5 patients have the first symptoms in adulthood (18-59 years old), therefore, with the follow-up time, some asymptomatic cases may have DADA-2 symptoms.Sira Nanthapisal et al. proposed risk screening by CECR 1 gene sequencing and serum ADA2 enzyme activity and screening indicators for CECR 1:1.Direct siblings with DADA 2; 2. familial history of vasculitis; 3. patients with polyarteritis nodosa (PAN).Especially for clinically refractory PAN dermatology clinicians must pay attention to other clinical features and actively investigate the occurrence of DADA 2. In Sira Nanthapisal experiment, Sanger sequencing of 9 patients with clinically diagnosed PAN but clinically suspected DADA 2; 5/9 of these patients found CECR 1 mutations.In conclusion, understanding the clinical characteristics and genetic characteristics of DADA 2 can help clinicians to master the characteristics of the disease, and early identify children with early stroke and vasculitis. 14Our child collected 2 mL of venous blood from the child and their parents with the informed consent of the guardian, The whole blood genome was extracted, For the high-throughput sequencing technology detection, Performed medical whole-exon gene capture, The lllumina sequencing platform for line-based highthroughput sequencing, Validation of the high-throughput sequencing results by Sanger sequencing, Later, according to the American Society of Medical Genetics and Genomics (ACMG) guidelines and guidelines, By genetic mode, age of onset, population frequency, hazard prediction and filtering, Reference to the Human Genome 38 (hg38/GRCh38) database, Select loci associated with phenotype and higher likelihood of pathogenic,The final SNV and InDel test results showed the compound heterozygous mutation site at position chr 22:171075 G > T (p.E 345-17 188 345) and the compound heterozygous mutation site at c.139G > C (p. G47R) at position chr 22:17209539-17 209 539, Combined with repeated systemic inflammation-fever, And the left central nervous system lesions such as choroidal fissure cyst and reticuloid skin manifestations, Thus confirming the diagnosis of DADA 2, Literature of c.1075G > T (p.E359), For a new variant, The father also had a heterozygous mutation.The c.139G > C (p. G47R) compound heterozygous mutation caused a missense mutation in exon 2, and the mother had a heterozygous mutation.P.G47R mutant is common in Georgian Jewish, Turkey, Iraq population, the mutation in the Georgian Jews carry rate of 10%, 6 mainly for childhood onset skin polyarteritis, skin and viscera is serious, according to the American society of medical genetics and genomics (ACMG) guidelines, the two mutation sites are pathogenic variation.

3. 4 |
Treatment Regarding adenosine deaminase 2 deficiency (DADA 2), It is similar to PAN (polyarteritis nodosa) small to medium size vasculitis, But are non-similar monogenic forms of systemic vasculitis, It is a biallelic mutation, So for the diagnosis of DADA 2, from the initial detection of plasma ADA2 enzyme activity, Alternative therapies for the corresponding enzymes; To the present sequencing of genes with biallelic mutations in ADA2, Corresponding to stem cell gene therapy (SCGT) and stem cell transplantation (HSCT), Of course, the preferred clinical treatment is still a TNFαantagonist, Because ADA2 is the highest level of purine nucleotide metabolism enzyme expressed in immature lymphocytes, Predisposing trigger a significant decrease in thymocytes and circulating T and B cells, Thus triggering a systemic inflammatory response, Especially in the central system, Repeated inflammatory responses may cause irreversible damage, Therefore, the early diagnosis and early intervention of diseases is the best means to improve the prognosis. 1 ple spots, similar to marble, spots are diffuse, mild, asymptomatic, often located in the lower limbs, is a transient physiological response to cold, visible in 50% of normal children and some adults.If the combination of various systemic diseases can cause weakness, or can cause vascular blood stasis (such as paralysis) can make the symptoms more obvious, some neonatal diseases can also aggravate this disease.This disease can be accompanied by chilblain, acrocyanosis, and cyanosis.(2) Congenital reticulosus (congenital livedo) is also known as congenital telangiecilator marbling oily skin (marmorata telangiectatica congenita).(3) Obtained idiopathic reticulate green spot (acquired idiopathic livedo reticularis) of unknown etiology, Mainly occurs in young and middle-aged women, The condition is often mild and harmless, Can combine the physiological reticulate green spot, Rashes often occur in the 30 to 40, Start to onset after cold, It was a short time, Subsequent persistence followed, Skin has tingling and numbness, Disease sustainability or progressive development, In more severe cases, Although ulcers can occur suddenly in the summer months, But often in winter, The ulcer was located around the calf and ankle and on the back of the foot, The ulcer morphology was irregular, diameter 1-5 mm, Different shades vary, With ecchymosis, hemorrhagic papules, blood blisters, and subcutaneous nodules, The ulcer healed slowly, After healing can leave white atrophic move mark.Between 20% and 25% of migraine patients have reticuloplebus, and this subtype is more frequent, which can be used as a clinical marker of their increased risk of attack.4.