Publications by authors named "Marco Yamazaki-Nakashimada"

76 Publications

Perineal Erythema in Kawasaki Disease and MIS-C.

Indian J Pediatr 2021 Mar 13. Epub 2021 Mar 13.

Clinical Immunology Department, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Insurgentes Cuicuilco, Coyoacán, 04530, Mexico City, CP, Mexico.

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http://dx.doi.org/10.1007/s12098-021-03717-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954681PMC
March 2021

Diagnostic and therapeutic caveats in Griscelli syndrome.

Scand J Immunol 2021 Mar 3:e13034. Epub 2021 Mar 3.

Dermatology Department, Instituto Nacional de Pediatria, Mexico City, Mexico.

Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.
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http://dx.doi.org/10.1111/sji.13034DOI Listing
March 2021

[Kawasaki disease in infants under one year of age. A challenge for the diagnosis and treatment of patients. Experience in a hospital center in Mexico].

Rev Chilena Infectol 2020 Nov;37(5):584-590

Instituto Nacional de Pediatría, Ciudad de México, México.

Background: Frequency of Kawasaki disease (KD) in infants is low in almost all countries. These patients are at higher risk of developing cardiac complications.

Aim: To evaluate the clinical features, treatment used and cardiac outcome in infants under one year of age attending for KD in a third level pediatric hospital in Mexico City, Mexico.

Methods: A cross-sectional study was conducted in our hospital from August 1995 to August 2019. We analyzed the clinical features, laboratory results, treatment used and cardiac outcomes in infants younger than one year of age and compared them with older patients.

Results: We included 687 patients, 152 were younger than one year of age (22.1%). There was a delayed diagnosis in younger patients with an increased frequency of incomplete clinical presentations. Coronary artery abnormalities were most common in younger infants who also had an increased frequency of giant coronary artery aneurysms. Two patients in the younger group died in the acute phase of KD of myocardial infarction.

Conclusions: Diagnosis of KD in infants younger than 1 year of age is a clinical challenge with an increased rate of incomplete clinical presentations and also an increased risk of development of severe cardiac complications.
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http://dx.doi.org/10.4067/S0716-10182020000500584DOI Listing
November 2020

Multiresistant Kawasaki Disease Complicated With Facial Nerve Palsy, Bilateral Giant Coronary Artery Aneurysms, and Stenosis of the Right Coronary Artery in an Infant.

J Clin Rheumatol 2020 Dec 8. Epub 2020 Dec 8.

Pediatric Cardiology Department Hospital General de Occidente, Jalisco, Mexico Pediatric Infectious Disease Department Hospital General de Occidente, Jalisco, Mexico Cardiology Department Instituto Nacional de Pediatría, Mexico City, Mexico Immuno-Allergy Department Instituto Nacional de Pediatría, Mexico City, Mexico Cardiology Department Instituto Nacional de Pediatría Mexico, City, Mexico

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http://dx.doi.org/10.1097/RHU.0000000000001586DOI Listing
December 2020

Kawasaki disease mimickers.

Pediatr Int 2020 Nov 29. Epub 2020 Nov 29.

Clinical Immunology Department, Instituto Nacional de Pediatría, Mexico City.

Background: Kawasaki disease (KD) is an acute systemic vasculitis that predominantly affects patients younger than five years. In the absence of an available affordable diagnostic test, detailed clinical history and physical examination are still fundamental to make a diagnosis.

Methods: We present five representative cases with KD-like presentation; Systemic onset juvenile idiopathic arthritis, Mycoplasma-induced rash and mucositis, Staphylococcal scalded skin syndrome, BCGosis and the recently described Multisystemic inflammatory syndrome in children (MIS-C) associated with SARS-CoV2.

Results: Rash, fever and laboratory markers of inflammation can be present in several childhood diseases that may mimic KD.

Conclusion: The term Kawasaki syndrome instead of Kawasaki disease may be more appropriate. Physicians should consider alternate diagnosis that may mimic KD, particularly consider MIS-C during the present pandemic since an aggressive diagnostic and therapeutic approach is needed.
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http://dx.doi.org/10.1111/ped.14561DOI Listing
November 2020

Kawasaki Disease Presenting with Hoarseness: A Multinational Study of the REKAMLATINA Network.

Pediatr Int 2020 Oct 25. Epub 2020 Oct 25.

Department of Pediatrics, University of California San Diego & Rady Children's Hospital, San Diego, CA, USA.

Background: Recently, hoarseness affecting the supraglottic structure has been reported in Kawasaki Disease. The objective of this study was to characterize the frequency of hoarseness in acute KD patients in Latin America.

Methods: We used prospective data from the multinational REKAMLATINA Network (Red de Enfermedad de Kawasaki en America Latina) a total of 865 patients from 20 countries were enrolled during the 3-year study period. Data on hoarseness was available in 858 (99.2%) patients. The clinical and laboratory characteristics between hoarse and non-hoarse KD were compared.

Results: Hoarseness was documented in 100 (11.6%) patients. Hoarse patients were younger compared to KD without hoarseness (median age 18 vs. 26 months; p=0.002) and presented with a lower hemoglobin (10.7g/dL vs 11.3g/dL; p= 0.040) and hematocrit levels (32% vs 33%, p=0.048) .

Conclusions: Hoarseness was found to be prevalent as a presenting sign of acute KD in younger children. Anemia may indicate the presence of active inflammation.
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http://dx.doi.org/10.1111/ped.14521DOI Listing
October 2020

Adenoviral-induced rash and mucositis: Expanding the spectrum of reactive infectious mucocutaneous eruption.

Pediatr Dermatol 2021 Jan 16;38(1):306-308. Epub 2020 Oct 16.

Clinical Immunology Department, National Institute of Pediatrics, México City, Mexico.

Mucocutaneous eruptions associated with respiratory pathogens, specifically Mycoplasma pneumoniae (MP), has recently been described as a MIRM (MP-induced rash and mucositis). The term reactive infectious mucocutaneous eruption (RIME) has been proposed, since non-MP pathogens may also cause a similar rash and mucositis. We report two cases with clinical manifestations suggestive of MIRM/RIME, both with documented adenovirus infection.
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http://dx.doi.org/10.1111/pde.14419DOI Listing
January 2021

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Garvan Institute of Medical Research, Darlinghurst, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, Australia. Electronic address:

Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Multisystem inflammatory syndrome associated with COVID19 in children and adolescents: calling for diagnosis.

Rev Chilena Infectol 2020 Jun;37(3):199-201

Servicio de Inmunología Clínica, Instituto Nacional de Pediatría, Ciudad de México, México.

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http://dx.doi.org/10.4067/s0716-10182020000300199DOI Listing
June 2020

Kawasaki Disease in Infants in the First 3 Months of Age in a Mexican Population: A Cautionary Tale.

Front Pediatr 2020 21;8:397. Epub 2020 Jul 21.

Department of Immunology, National Institute of Pediatrics, Mexico City, Mexico.

Kawasaki disease (KD) is an acute febrile illness that largely affects young children before 5 years of age. Younger children with KD are reported to have a higher prevalence of coronary artery abnormalities. Little is known about infants in the first 3 months of age diagnosed with KD. A retrospective study was conducted at the National Institute of Pediatrics in Mexico City from 1995 to 2019. Clinical features, laboratory results and cardiac outcomes were recorded. Infants in the first 3 months of age were compared with older patients. Wilcoxon-Mann-Whitney analysis was performed for continuous variables and Fisher's exact test for categorical variables. Six hundred and eighty-eight cases of KD were included in this study. Fourteen cases were diagnosed in the first three months of age. Heart failure and KD shock-syndrome was found in five cases (35.7%). Giant coronary artery aneurysms were found in six cases in the younger group (42.9%). Diagnosis of KD in children younger than 3 months of age is rare. In most cases, an incomplete presentation contributed to a delay diagnosis, treatment, and complications. Younger patients with KD have an increased risk of presenting cardiac complications, including giant coronary artery aneurysms, shock, and death.
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http://dx.doi.org/10.3389/fped.2020.00397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385248PMC
July 2020

A Teenager With Rash and Fever: Juvenile Systemic Lupus Erythematosus or Kawasaki Disease?

Front Pediatr 2020 7;8:149. Epub 2020 Apr 7.

Department of Clinical Immunology, Instituto Nacional de Pediatría, Mexico City, Mexico.

Kawasaki disease (KD) is an acute vasculitis of small and medium vessels; whereas systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Their presentation is varied and not always straightforward, leading to misdiagnosis. There have been case reports of lupus onset mimicking KD and KD presenting as lupus-like. Coexistence of both diseases is also possible. We present three adolescents, one with fever, rash, arthritis, nephritis, lymphopenia, and coronary aneurysms, a second patient with rash, fever, aseptic meningitis, and seizures, and a third patient with fever, rash, and pleural effusion. The first patient was finally diagnosed with SLE and KD, the second patient initially diagnosed as KD but eventually SLE and the third patient was diagnosed at onset as lupus but finally diagnosed as KD. The first patient was treated with IVIG, corticosteroids, aspirin, coumadin and mycophenolate mofetil. The second patient was treated with IVIG, corticosteroids and methotrexate and the third patient with IVIG, aspirin and corticosteroids. Both diseases may mimic each other's clinical presentation. KD in adolescence presents with atypical signs, incomplete presentation, and develop coronary complications more commonly. An adolescent with fever and rash should include KD and SLE in the differential diagnosis.
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http://dx.doi.org/10.3389/fped.2020.00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154070PMC
April 2020

[Autoimmune lymphoproliferative syndrome. Update and review].

Rev Alerg Mex 2019 Oct-Dec;66(4):456-473

Clínica Casa Blanca, Unidad de Investigación en Inmunología Clínica y Alergia, Aguascalientes, Aguascalientes, México.

The autoimmune lymphoproliferative syndrome (ALPS) is an inborn immunity error, which is the result of a heterogeneous group of mutations in the genes that regulate the apoptosis phenomenon. It typically appears in the first years of life. The most common clinical signs are lymphoid expansion with lymphadenopathy, splenomegaly, and hepatomegaly; immune disease with different types of cytopenia, including thrombocytopenia, hemolytic anemia, and lymphoma. The lab abnormalities that facilitate the diagnosis of ALPS include the presence of double negative alpha/beta T cells, high interleukin levels, vitamin B12 in the blood, and FAS-mediated defective apoptosis in the in vitro assay. The treatment of ALPS is focused on three aspects: The treatment of the manifestations of the disease, the prevention/treatment of complications, and the curative treatment (hematopoietic progenitor cell transplantation [HPCT]). The use of immunosuppressive therapy is suggested only for severe complications of lymphoproliferation or concomitant autoimmune manifestations. Splenectomy is not recommended for autoimmune manifestations in patients with ALPS. HPCT is reserved for selected patients. The survival rate to 50 years is estimated at 85% for patients with FAS deficiency.
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http://dx.doi.org/10.29262/ram.v66i4.646DOI Listing
September 2020

Use of Infliximab in the Treatment of Macrophage Activation Syndrome Complicating Kawasaki Disease.

J Pediatr Hematol Oncol 2021 Apr;43(3):e448-e451

Pediatric Department, Medica Sur Hospital.

Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology. KD can be complicated with macrophage activation syndrome. The optimal treatment for this KD complication has not been established, and a variety of treatments have been used. Infliximab, a chimeric monoclonal antibody that binds tumor necrosis factor, has proved to be efficacious in IV gammaglobulin resistant KD. We present 2 cases of KD complicated with macrophage activation syndrome, including 1 patient with DiGeorge syndrome successfully treated with a combined treatment of IV gammaglobulin, corticosteroids, cyclosporine, and infliximab.
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http://dx.doi.org/10.1097/MPH.0000000000001756DOI Listing
April 2021

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

J Clin Immunol 2020 04 10;40(3):475-493. Epub 2020 Feb 10.

Imagine Institute, Paris University, Paris, France.

Purpose: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019.

Methods: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds.

Results: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations.

Conclusions: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
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http://dx.doi.org/10.1007/s10875-020-00750-5DOI Listing
April 2020

BCG: a vaccine with multiple faces.

Hum Vaccin Immunother 2020 08 29;16(8):1841-1850. Epub 2020 Jan 29.

Department of Pediatrics, Louisiana State University Health Sciences Center, Louisiana Primary Immunodeficiency Network , New Orleans, LA, USA.

BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.
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http://dx.doi.org/10.1080/21645515.2019.1706930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482865PMC
August 2020

Skewed X-inactivation in a Female Carrier with X-linked Chronic Granulomatous Disease.

Iran J Allergy Asthma Immunol 2019 Aug 17;18(4):447-451. Epub 2019 Aug 17.

Immunodeficiencies Research Unit, National Institute of Pediatrics, Mexico City, Mexico.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.
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http://dx.doi.org/10.18502/ijaai.v18i4.1425DOI Listing
August 2019

Latin American consensus on the supportive management of patients with severe combined immunodeficiency.

J Allergy Clin Immunol 2019 10 13;144(4):897-905. Epub 2019 Aug 13.

Fundación Mexicana para Niñas y Niños con Inmunodeficiencias Primarias (FUMENI), Mexico City, Mexico.

Severe combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 "agreed" and 38 "nonagreed" statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.
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http://dx.doi.org/10.1016/j.jaci.2019.08.002DOI Listing
October 2019

Kawasaki disease and immunodeficiencies in children: case reports and literature review.

Rheumatol Int 2019 Oct 16;39(10):1829-1838. Epub 2019 Jul 16.

Clinical Immunology Department, Instituto Nacional de Pediatría, Insurgentes Sur 3700-C, Col. Insurgentes Cuicuilco, 04530, Mexico City, Mexico.

Kawasaki disease (KD) has features that appear supporting an infectious cause with a secondary deranged inflammatory/autoimmune response. The association of KD in adults with human immunodeficiency virus infection and the presence of KD in patients with immunodeficiency disorders support the infectious theory. We present four KD patients associated with immunodeficiencies: one with X-linked agammaglobulinemia, one with HIV infection, and two with leukemia; one of these patients also had Down syndrome. We did a literature search to find out all reported cases of immunodeficiency with KD in children. In immunodeficiency disorders, the inability of the immune system to eradicate the pathogens coupled to an exaggerated inflammatory response, especially in chronic granulomatous disease, may lead to the development of KD. The study of patients with immunodeficiencies complicated with KD may shed light into the etiopathogenesis of the disease.
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http://dx.doi.org/10.1007/s00296-019-04382-wDOI Listing
October 2019

Erythema Multiforme: Think Kawasaki Disease.

J Clin Rheumatol 2020 Sep;26(6):e181-e182

Department of Clinical Immunology, Instituto Nacional de Pediatría, Mexico City, Mexico.

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http://dx.doi.org/10.1097/RHU.0000000000001055DOI Listing
September 2020

Orange-brown chromonychia: A valid sign in Kawasaki disease in children of different ethnicities.

Int J Rheum Dis 2019 06 1;22(6):1160-1161. Epub 2019 May 1.

Department of Pediatrics, Yachiyo Medical Center, Tokyo Women´s Medical University, Yachiyo, Chiba, Japan.

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http://dx.doi.org/10.1111/1756-185X.13587DOI Listing
June 2019

Failing to Make Ends Meet: The Broad Clinical Spectrum of DNA Ligase IV Deficiency. Case Series and Review of the Literature.

Front Pediatr 2018 21;6:426. Epub 2019 Jan 21.

Immunodeficiencies Research Unit at the National Institute of Pediatrics (INP), Mexico City, Mexico.

DNA repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. DNA Ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity, and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo- and radiotherapy; or, they could be asymptomatic. We describe the clinical, laboratory, and genetic features of five Mexican patients with LIG4 deficiency, together with a review of 36 other patients available in PubMed Medline. Four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent CD4+ lymphopenia. Most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low B-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. Dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia, and gastrointestinal bleeding have been reported as well. Most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. Stem-cell transplantation after reduced intensity conditioning regimes may be curative.
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http://dx.doi.org/10.3389/fped.2018.00426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348249PMC
January 2019

IgG levels in Kawasaki disease and its association with clinical outcomes.

Clin Rheumatol 2019 Mar 20;38(3):749-754. Epub 2018 Oct 20.

Department of Pediatrics, Yachiyo Medical Center, Tokyo Women's Medical University, Yachiyo, Chiba, Japan.

Previous studies have suggested an association of IgG levels (before and after IVIG infusion) with clinical outcomes in Kawasaki disease. A retrospective analysis was performed that included 418 patients with KD admitted to Tokyo Women's Medical University Yachiyo Medical Center to evaluate pre- and post-IVIG IgG levels and its relation to outcomes. All patients received an initial IVIG infusion and aspirin; IgG levels were measured in 350 patients before IVIG (pre-IVIG IgG levels) and in 373 patients 48 h after starting IVIG infusion (post-IVIG IgG levels). Media and standard deviation of the pre- and post-IVIG IgG levels were reported and classified according to age. Also, IgG z-scores were calculated according to normal values of IgG by age. The number of cases and corresponding percentage of non-responders were reported by age and total patients. The association of pre-IVIG, post-IVIG IgG levels and post-IVIG IgG level/pre-IVIG IgG level ratio with no-response was evaluated by simple logistic regression model based on the IgG z-score, and regression coefficient, X value, p, and R of Nagelkerke were reported. Pre-IVIG and post-IVIG IgG levels presented an association with non-responders with statistical significance. This association was more evident between post-IVIG IgG levels and non-responders. Regarding coronary alterations, it was not possible to perform an adequate statistical analysis due the small number of patients. Pre- and post-IVIG infusion IgG levels could be an important biomarker in KD as well as in other inflammatory conditions. Higher IgG levels could be associated with a more effective immunomodulatory action and associated with better clinical outcomes.
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http://dx.doi.org/10.1007/s10067-018-4339-0DOI Listing
March 2019

A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency.

J Clin Immunol 2018 07 11;38(5):617-627. Epub 2018 Jul 11.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Necker Hospital for Sick Children, Paris, France.

Purpose: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs.

Methods: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS).

Results: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%).

Conclusion: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
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http://dx.doi.org/10.1007/s10875-018-0527-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329663PMC
July 2018

Kawasaki disease shock syndrome: Unique and severe subtype of Kawasaki disease.

Pediatr Int 2018 Sep;60(9):781-790

Clinical Immunology Department, National Institute of Pediatrics, Médica Sur Hospital, Mexico City, Mexico.

Background: Kawasaki disease shock syndrome (KDSS) is an uncommon presentation of Kawasaki disease (KD). KDSS has been associated with more severe markers of inflammation, coronary abnormalities and i.v. immunoglobulin (IVIG) resistance.

Methods: A retrospective, descriptive study of children with KDSS in two hospitals was performed. Relevant articles about KD and shock were collected, and demographic data, clinical presentation, laboratory variables, echocardiogram findings, treatment and special features were analyzed when available. Twelve patients diagnosed with KDSS were retrospectively reviewed from two centers in Mexico, along with 91 additional cases from the literature.

Results: Seventy-two patients presented with complete KD (69.9%), and 30.1% (31/103) had unusual KD manifestations. The most frequent diagnosis at the time of admission was toxic shock syndrome (TSS; n = 20). Sixteen of the 20 had coronary artery abnormalities. Overall, abnormalities in the coronary arteries were documented in 65% of the patients. The mortality rate was 6.8%.

Conclusion: The presence of coronary aneurysms was significantly and positively correlated with male gender, IVIG resistance, inotrope treatment, cardiac failure, abdominal pain and neurological symptoms. IVIG-resistant patients had higher neutrophil : lymphocyte ratio. Abdominal symptoms, hypoalbuminemia and elevated C-reactive protein were present in almost all of the patients. Multisystem involvement with atypical presentation in KDSS is frequent. An important differential diagnosis is TSS. Mechanical ventilation, gastrointestinal and neurological symptoms were associated with IVIG resistance and the presence of coronary aneurysms. The first line of treatment includes IVIG and pulse corticosteroids; in severe cases, infliximab, anakinra, cyclosporine or plasmapheresis are alternative treatment options.
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http://dx.doi.org/10.1111/ped.13614DOI Listing
September 2018

[Cardiac manifestations in the acute phase of Kawasaki disease in a third level children's hospital in Mexico City].

Arch Cardiol Mex 2018 12 9;88(5):441-446. Epub 2018 Apr 9.

Servicio de Inmunología, Instituto Nacional de Pediatría, SSA, Ciudad de México, México.

Objectives: To describe the cardiac manifestations in the acute phase of patients with Kawasaki disease treated in a third level Children's hospital in Mexico City, Mexico.

Methods: A cross-sectional study was conducted in patients with a diagnosis of Kawasaki disease treated in this hospital from August 1995 to December 2016. Information included patient demographics, clinical features, treatment used, electrocardiographic findings, extra-coronary echocardiographic findings, and the development of coronary artery aneurysms in the acute phase of the disease.

Results: The study included 508 cases of Kawasaki disease, with a mean age at diagnosis of 37.64±35.56 months (range from 2 to 200 months). Almost two-thirds (65.4%) of the patients were male, with a male/female ratio of 1.88:1. Complete Kawasaki disease was diagnosed in 79.2% of cases. Almost all cases (92.4%) received intravenous immunoglobulin. Twenty-eight patients (5.5%) developed arrhythmias, ST changes developed in 29 patients (5.6%), and 5 patients presented with ischaemic changes. In the initial echocardiographic evaluation, 51 patients (9.9%) were diagnosed with myocarditis, 72 patients (14.0%) with pericarditis and 77 cases (15.0%) developed pericardial effusion. Coronary artery anomalies were detected in 169 cases (32.9%). 32 cases were diagnosed as giant coronary aneurysms. Four patients died from cardiac complications in the acute phase of the disease.

Conclusions: There has been an increase in the diagnosis of Kawasaki disease in Mexico. They presented with more cardiac complications than reported in literature. An increased knowledge of Kawasaki disease is required in Mexico in order to establish the cardiac outcomes of this group of patients.
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http://dx.doi.org/10.1016/j.acmx.2018.03.005DOI Listing
December 2018

Delayed diagnosis in X-linked agammaglobulinemia and its relationship to the occurrence of mutations in BTK non-kinase domains.

Expert Rev Clin Immunol 2018 01 11;14(1):83-93. Epub 2017 Dec 11.

a Unidad de Investigación en Inmunodeficiencias , Instituto Nacional de Pediatría, SSA , Ciudad de México , Mexico.

Background: X-linked agammaglobulinemia (XLA) is characterized by the absence of immunoglobulin and B cells. Patients suffer from recurrent bacterial infections from early childhood, and require lifelong immunoglobulin replacement therapy. Mutations in BTK (Bruton's Tyrosine Kinase) are associated with this phenotype. Some patients that present XLA do not show typical clinical symptoms, resulting in delayed diagnosis due to the lack of a severe phenotype. This study presents a report of five XLA patients from four different families and attempts to determine a relationship between delayed diagnosis and the occurrence of BTK mutations.

Methods: Samples from patients with antibody deficiency were analyzed to determine BTK expression, immunophenotyping and mutation analysis. Clinical and laboratory data was analyzed and presented for each patient.

Results: Most patients presented here showed atypical clinical and laboratory data for XLA, including normal IgM, IgG, or IgA levels. Most patients expressed detectable BTK protein. Sequencing of BTK showed that these patients harbored missense mutations in the pleckstrin homology and Src-homology-2 domains. When it was compared to public databases, BTK sequencing exhibited a new change, along with three other previously reported changes.

Conclusions: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.
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http://dx.doi.org/10.1080/1744666X.2018.1413349DOI Listing
January 2018

[Neurological manifestations in atypical Kawasaki disease].

Rev Alerg Mex 2017 Jul-Sep;64(3):376-380

Instituto Nacional de Pediatría, Departamento Inmunología, Ciudad de México, México.

Background: Kawasaki disease (KD) is a type of systemic vasculitis of unknown etiology. Atypical Kawasaki disease is defined as that where there are signs and symptoms not corresponding to the classical criteria for this nosological entity. Children with atypical Kawasaki disease may present with acute abdominal symptoms, meningeal irritation, pneumonia or renal failure.

Clinical Cases: We describe 4 children with ages ranging from 2 to 12 years who had atypical Kawasaki disease, with neurological and gastrointestinal symptoms as part of the systemic presentation of the disease. Treatment consisted of immunoglobulin and corticosteroids with good evolution.

Conclusions: KD is a systemic vasculitis that can involve many territories. Atypical manifestations can mislead the clinician and delay diagnosis. Pediatricians and sub-specialists should be aware of these neurological manifestations in order to provide adequate and opportune treatment.
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http://dx.doi.org/10.29262/ram.v64i3.231DOI Listing
July 2019