Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. METHODS: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. RESULTS: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. CONCLUSIONS: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

[Leucocyte adhesion deficiency: detection of the first cases in Paraguay]. / Deficiencia de adhesión leucocitaria: detección de los primeros casos en Paraguay.

OBJECTIVE: To implement the diagnostic technique for LAD by evaluating the expression of CD18 and CD15 in healthy patients and in a group with clinical suspicion. METHODS: Observational, descriptive, and cross-secctional study, carried out in pediatric patients attended in the Instituto de Investigaciones en Ciencias de la Salud, and patients from public hospitals with clinical suspicion of LAD were studied. The molecules CD18 and CD15 in peripheral blood leukocytes was evaluated by flow cytometry, establishing a normal range in healthy patients. The presence of LAD was established by decreased expression of CD18 or CD15. RESULTS: Sixty pediatric patients were evaluated: 20 apparently healthy and 40 with clinical suspicion of leukocyte adhesion deficiency; 12 of 20 healthy patients were male (median age: 14 years) and 27 of 40 with suspected disease were female (median age: 2 years). Persistent leukocytosis and respiratory tract (32%) infections predominated. The expression range of CD18 and CD15 in healthy patients was 95%-100%, and in patients with clinical suspicion it was 0%-100%. One patient with 0% of CD18 (LAD-1) and one patient with 0% of CD15 (LAD-2) were detecte. CONCLUSIONS: The implementation of a new diagnostic technique allowed to establish a normal range of CD18 and CD15 by flow cytometry, and it was possible to detect the first two cases of LAD in Paraguay.

OBJECTIVO: Implementar la técnica diagnóstica para deficiencia de adhesión leucocitaria mediante la evaluación de la expresión de CD18 y CD15 en pacientes sanos y con sospecha clínica de la enfermedad. MÉTODOS: Estudio observacional, descriptivo y transversal, llevado a cabo en pacientes pediátricos sanos que acudieron al Instituto de Investigaciones en Ciencias de la Salud y pacientes de hospitales públicos con sospecha clínica de deficiencia de adhesión leucocitaria. Se evaluaron las moléculas CD18 y CD15 en leucocitos periféricos por citometría de flujo, con la intención de estadarizar un rango normal en pacientes sanos. Se estableció el diagnóstico de deficiencia de adhesión lecuocitaria, según la expresión disminuida de CD18 o CD15. RESULTADOS: Se evaluaron 60 pacientes pediátricos: 20 aparentemente sanos y 40 con sospecha clínica de deficiencia de adhesión leucocitaria; 12 de 20 pacientes sanos fueron varones (mediana de edad: 14 años) y 27 de 40 con sospecha de la enfermedad fueron mujeres (mediana de edad: 2 años). Predominaron la leucocitosis persistente y las infecciones respiratorias (32%). La expresión de CD18 y CD15 en pacientes sanos fue del 95-100% y en pacientes con sospecha de deficiencia de adhesión leucocitaria de 0-100%. Se identificó una paciente con 0% de expresión de CD18 (LAD-1) y otro con 0% de CD15 (LAD-2). CONCLUSIONES: La evaluación de las moléculas CD18 y CD15 permitió detectar los primeros casos de deficiencia de adhesión leucocitaria en Paraguay, que sirve de precedente y pone a punto la técnica para el diagnóstico de la enfermedad a nivel local.

Carrier frequency of autosomal recessive disorders (BC, BLAD, FXID and CVM) in Holstein cows in Jalisco, Mexico

The hereditary autosomal recessive disorders bovine citrullinemia (BC), bovine leukocyte adhesion deficiency (BLAD), factor XI deficiency (FXID), and complex vertebral malformation (CVM) have affected dairy cattle breeding significantly around the world. This study examined the carrier frequency of BC, BLAD, FXID, and CVM autosomal recessive disorders in Bos taurus Holstein cows bred in the Altos Norte region of the state of Jalisco, Mexico. We extracted DNA from 408 random samples of peripheral blood, and then used polymerase chain reaction (PCR) to identify insertion mutations for FXID, and PCR with restriction fragment length polymorphism (PCR-RFLP) for CVM, BC and BLAD. We visualized the PCR products using agarose gel electrophoresis stained with GelRed®. We found that 100% of wild-type (N/N) allele homozygous animals for genes CD18, ASS, and FXI were free of the mutations for BLAD, BC and FXID respectively. For gene SLC35A3 we estimated total carrier frequency of 10.3% and allele frequency of 5%.(AU)

Carrier frequency of autosomal recessive disorders (BC, BLAD, FXID and CVM) in Holstein cows in Jalisco, Mexico

The hereditary autosomal recessive disorders bovine citrullinemia (BC), bovine leukocyte adhesion deficiency (BLAD), factor XI deficiency (FXID), and complex vertebral malformation (CVM) have affected dairy cattle breeding significantly around the world. This study examined the carrier frequency of BC, BLAD, FXID, and CVM autosomal recessive disorders in Bos taurus Holstein cows bred in the Altos Norte region of the state of Jalisco, Mexico. We extracted DNA from 408 random samples of peripheral blood, and then used polymerase chain reaction (PCR) to identify insertion mutations for FXID, and PCR with restriction fragment length polymorphism (PCR-RFLP) for CVM, BC and BLAD. We visualized the PCR products using agarose gel electrophoresis stained with GelRed®. We found that 100% of wild-type (N/N) allele homozygous animals for genes CD18, ASS, and FXI were free of the mutations for BLAD, BC and FXID respectively. For gene SLC35A3 we estimated total carrier frequency of 10.3% and allele frequency of 5%.(AU)

Deficiencia de adhesión leucocitaria en un neonato: caso clínico / Leukocyte adhesion deficiency in a neonate: clinical case

Los síndromes de deficiencia de adhesión leucocitaria (leukocyte adhesion deficiency [LAD por sus siglas en inglés]) engloban un conjunto de patologías causadas por defectos en el reconocimiento, la adhesión y la migración de los leucocitos mieloides hacia los lugares de invasión microbiana, lo que provoca la falta de defensa innata del huésped frente a bacterias, hongos u otros microrganismos. Se identifica en lactantes por antecedentes como la demora en la caída del cordón umbilical cuando los niños empiezan a tener complicaciones infecciosas. No es común identificar LAD en niños recién nacidos, posiblemente la presencia de la fistula ano rectal y el tratamiento quirúrgico aceleran la presentación clínica en el paciente facilitando así su diagnóstico. Por ser una enfermedad autosómica recesiva y teniendo el importante antecedente de los fallecimientos en sus dos hermanos anteriores a mayor edad. Poder contar con mecanismos de diagnóstico efectivos facilitan el llegar a una conclusión pronta, mejor manejo en general mejorando las expectativas de vida de los pacientes con este tipo de alteraciones hematológicas.

The syndromes of leukocyte adhesion deficiency (LAD) encompass a group of pathologies caused by defects in the recognition, adhesion and migration of myeloid leukocytes to microbial invasion sites. Causes the lack of innate host defense against bacteria, fungi or other microorganisms. It is identified in infants due to antecedents such as the delay in the fall of the umbilical cord when children begin to have infectious complications. It is not common to identify HDL in newborn children, possibly the presence of anus rectal fistula and surgical treatment accelerate the clinical presentation in the patient, thus facilitating its diagnosis. For being an autosomal recessive disease and having the important antecedent of the deaths in his two older brothers at older age. Being able to count on effective diagnostic mechanisms makes it easier to arrive at a quick conclusion better management in general, improving the life expectancy of patients with this type of hematological alterations.

Leucocyte adhesion deficiency type 1 with developmental delay secondary to CMV infection and filiation questions.

Leucocyte adhesion deficiency (LAD) is a group of rare autosomal recessive (<1:1 000 000 births) inherited disorders characterised by immune deficiency and peripheral neutrophilia. Three types of LAD syndrome have been distinguished. LAD type 1 (LAD-I) is the most common. It results from a mutation in the integrin ß 2 (ITGB2) gene that codes the ITGB subunit (CD18 antigen). Since 1970, it has been reported in more than 300 children worldwide. It is characterised by delayed separation of the umbilical cord, recurrent bacterial and fungal infections, defective wound healing, blood neutrophilia and a high mortality rate at an early age. We report the second fatal case of an infant with LAD-I diagnosed in Chile, with developmental delay associated with a congenital cytomegalovirus infection. CD18/CD11 expression was normal. Genetic analysis of CD18 revealed a homozygous mutation in ITGB2, viz.c.1835G>T; p.C612F, and led us to suspect a biological parent other than the legal father and, therefore, an unwanted social situation.

Successful adjunctive immunoglobulin treatment in patients affected by leukocyte adhesion deficiency type 1 (LAD-1).

Two patients with a severe leukocyte adhesion deficiency type 1 (LAD-1) phenotype were analyzed by flow cytometry and functional assays to demonstrate the improper adhesive and phagocytic responses of their leukocytes. A single homozygous defect that involves a missense mutation (c.817G>A) that encodes for a G273R substitution in CD18 was identified in both patients. The adhesion and phagocytosis assays demonstrated the inability of patients' leukocytes to perform these functions. Expression of the LFA-1 (CD11a/CD18) on the co-transfected HEK 293 cells with the mutated form of CD18 was not detected. Finally, both patients have been treated with immunoglobulin as an adjunctive therapy with positive results. We propose that intravenous immunoglobulin treatment is safe and efficacious in LAD-1 patients before hematopoietic stem cell transplantation and helpful in controlling severe infections. Subcutaneous immunoglobulin appeared to help wound healing in refractory ulcers in these patients.

Incidence of bovine leukocyte adhesion deficiency, complex vertebral malformation, and deficiency of uridine-5-monophosphate synthase carriers in Brazilian Girolando cattle.

Among the various hereditary diseases that have been widely studied in dairy cattle, bovine leukocyte adhesion deficiency (BLAD), deficiency of uridine-5-monophosphate synthase (DUMPS), and complex vertebral malformation (CVM) are noteworthy because of their high impact on overall herd productivity as a consequence of increased calf mortality. The aim of this study was to verify the frequency of carriers of BLAD, CVM, and DUMPS mutant alleles in cows and bulls from the National Girolando Progeny Test carried out in Brazil by using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR assays. A total of 777 animals were genotyped for BLAD, 783 for CVM, and 122 for DUMPS. The frequencies of carriers for BLAD and CVM were 0.77 and 1.53%, respectively, whereas no carriers of DUMPS were observed.

Leukocyte adhesion deficiency syndrome: report on the first case in Chile and South America.

CONTEXT: Adhesion molecule deficiency type 1 is a rare disease that should be suspected in any patient whose umbilical cord presents delay in falling off, and who presents recurrent severe infections. Early diagnostic suspicion and early treatment improve the prognosis. CASE REPORT: The case of a four-month-old boy with recurrent hospitalizations because of severe bronchopneumonia and several episodes of acute otitis media with non-purulent drainage of mucus and positive bacterial cultures is presented. His medical history included neonatal sepsis and delayed umbilical cord detachment. Laboratory studies showed marked leukocytosis with predominance of neutrophils and decreased CD11b and CD18. These were all compatible with a diagnosis of leukocyte adhesion deficiency type I [LAD type 1].

Leukocyte adhesion deficiency syndrome: report on the first case in Chile and South America / Síndrome de deficiencia de adhesión leucocitaria: informe del primer caso en Chile y América del Sur

CONTEXT: Adhesion molecule deficiency type 1 is a rare disease that should be suspected in any patient whose umbilical cord presents delay in falling off, and who presents recurrent severe infections. Early diagnostic suspicion and early treatment improve the prognosis. CASE REPORT: The case of a four-month-old boy with recurrent hospitalizations because of severe bronchopneumonia and several episodes of acute otitis media with non-purulent drainage of mucus and positive bacterial cultures is presented. His medical history included neonatal sepsis and delayed umbilical cord detachment. Laboratory studies showed marked leukocytosis with predominance of neutrophils and decreased CD11b and CD18. These were all compatible with a diagnosis of leukocyte adhesion deficiency type I [LAD type 1].

CONTEXTO: El deficit de moleculas de adhesión tipo 1 es una enfermedad rara que debe ser sospechada en todo paciente que presente un retardo en la caída del cordón unmbilical, además de infecciones graves a repetición. Un sospecha diagnóstica precoz y un tratamiento oportuno mejorarán el pronóstico. INFORMES DE CASO: Se presenta el caso de un niño de cuatro meses de edad, con hospitalizaciones recurrentes a causa de bronconeumonía severa y varios episodios de otitis media aguda con drenaje mucoso, no purulento, y cultivos bacterianos positivos. Su historial médico incluye la sepsis neonatal y el desprendimiento tardío del cordón umbilical. Los estudios de laboratorio mostraron leucocitosis marcada con predominio neutrofílico y disminución de CD11b y CD18, todos compatibles con el diagnóstico del tipo de deficiencia de adhesión leucocitaria 1 [tipo LAD 1].

Alterações periodontais associadas às doenças sistêmicas em crianças e adolescentes: [revisão] / Periodontal problems associated with systemic diseases in children and adolescents: [review]

OBJETIVO: O objetivo deste estuo foi revisar na literatura a inter-relação entre condições sistêmicas e a ocorrência de doenças periodontais em crianças e adolescentes, destacando-se as manifestações periodontais frequentemente encontradas. FONTES DE DADOS: Artigos indexados nas bases de dados Medline, Lilacs e Bibliografia Brasileira em Odontologia, nos últimos 20 anos, além de referências clássicas. As palavraschave utilizadas foram: "doença periodontal", "periodontite", "doenças sistêmicas", "criança" e "adolescente". SÍNTESE DOS DADOS: Doenças sistêmicas como hipofosfatasia, histiocitose X, síndrome de Down, síndrome de Papillon-Lefèvre, síndrome de Ehlers-Danlos, síndrome de Chédiak-Higashi, leucemias, Aids e as deficiências quantitativas e qualitativas dos neutrófilos estão associadas ao aparecimento de alterações periodontais graves em crianças e adolescentes. Os estudos demonstraram a ocorrência de alteração periodontal na forma de periodontite em crianças e adolescentes com doenças sistêmicas, podendo levar à perda precoce de dentes. CONCLUSÕES: A ocorrência de alterações periodontais é observada em crianças e adolescentes com alterações sistêmicas, que manifestam desde inflamação gengival até formas mais destrutivas, como periodontites e perda precoce dos dentes.

OBJETIVE: The aim of this study was to review the literature regarding the relationship between systemic conditions and the occurrence of periodontal diseases among children and adolescents, and to highlight the most common periodontal alterations. DATA SOURCE: Indexed articles published in the last 20 years on the following databases were searched: Medline, Lilacs, and the archives of the Brazilian Bibliography of Dentistry, in addition to classic references. Keywords included "periodontal disease", "periodontitis", "systemic diseases", "child", and "adolescent". DATA SYNTHESIS: Systemic diseases such as hypophosphatasis, histiocytosis X; Down, Papillon-Lefèvre, Ehlers-Danlos and Chédiak-Higashi syndromes, as well as leukemia, Aids, quantitative and qualitative neutrophilic deficiencies are associated with severe periodontal alterations among children and adolescents. Several studies demonstrated the occurrence of periodontitis, which can lead to early tooth loss among children and adolescents diagnosed with systemic diseases. CONCLUSIONS: The occurrence of periodontal alterations is observed in children and adolescents with systemic diseases. There are several manifestations, ranging from gingival inflammations to more destructive patterns, such as periodontitis and early teeth losses.

[Leukocyte adhesion deficiency syndrome: case report]. / Síndrome de adhesión leucocitaria deficiente: informe de un caso.

INTRODUCTION: Leukocyte adhesion deficiency syndrome (LAD) is an altered phagocytic disorder characterised by the deficiency of one or several integrins which are included within the adhesion molecules group and cell surface receptors superfamily. OBJECTIVE: To describe the clinical features of a rare primary immunodeficiency case. CLINICAL CASE: A nineteen days-old male newborn was referred to the pediatrics infectology service because a 15 days clinical course characterised by delayed cord detachment; fever and skin lesions in several arcas that evolved to, cellulitis and dermal necrosis: Then he was admitted with the diagnosis of septicemia secondary to omphalitis. There were a partial response to antimicrobial treatment. Thereafter he had recurrent respiratory and gastrointestinal fungal and bacterial infections. Then he suffered psychomotor impairment and severe malnutrition. The patient died because septicemia at 5 months-old. WBC counts showed persistent leukocytosis between 42,000 and 133,000 cells/mm3, mostly neutrophils (64%-88%). We also found defective neutrophil quimiotaxis. By flow cytometer it was detected CDII/18 adhesins deficiency. Otherwise immunological, bone marrow biopsy and viral tests were, normal. CONCLUSIONS: Although its prevalence is rare, leukocyte adhesion defects must be considered in those patients with delayed cord detachment, recurrent severe infections and both persistent and elevated neutrophilia and with other primary and secondary immunodeficiencies previously discarded.

Síndrome de adhesión leucocitaria deficiente: informe de un caso / Leukocyte adhesion deficiency syndrome. A case report

Introducción. El síndrome de adhesión leucocitaria deficiente (ALD) es una alteración de la fagocitosis caracterizada por la deficiencia de una o varias intregrinas a la superfamilia de receptores de la superficie celular y de moléculas de adhesión. Objetivo. Describir las características clínicas de una inmunodeficiencia primaria de prevalencia rara. Caso clínico. Recién nacido masculino de 19 días de vida extrauterina referido al servicio de infectología pediátrica por un cuadro clínico de 15 días de evolución caracterizado por caída tardía del cordón umbilical, fiebre y lesiones dérmicas pápuloeritematosas en el área periumbilical, hipogástrica, inguinal, glútea y en el muslo derecho, misma que progresaron a celulitis y necrosis tisular. Ingresó al hospital con diagnóstico de septicemia secundaria a onfalitis. Hubo respuesta parcial al menejo inicial con antimicrobianos. Posteriormente tuvo infecciones bacteriana y micóticas recurrentes de las vías respiratorias y el tracto gastrointestinal. Tuvo retardo psicomotriz y deterioro severo de su estado nutricional. Falleció por septicemia a los cinco meses de edad. De los exámenes de laboratorio, la biometría hemática mostró leucocitosis persistente entre 42,000 y 133,00 células/mm3, con predominio de neutrófilos, con variaciones entre 64 y 68 por ciento. Se encontró deficiencia de la quimiotaxis de neutrófilos. Por citometría de flujo se observó deficiencia de las adhesinas CD11/18. El resto de los estudios inmunológicos, biopsia de médula ósea y viral fueron normales. Conclusión. Si bien su prevalencia es rara, los defectos de adhesión leucocitaria deben considerarse en los pacientes con caída tardía de cordón umbilical, infecciones severas recurrentes y neutrofilia muy elevada y persistente en quienes se hayan descartado otras inmunodeficiencias primarias y secundarias

Leukocyte adhesion deficiency II syndrome, a generalized defect in fucose metabolism.

Leukocyte adhesion deficiency II has been described in only 2 patients; herein we report extensive investigation of another patient. The physical stigmata were detected during prenatal ultrasonographic investigation. Sialyl-Lewis X (sLex) was absent from the surface of polymorphonuclear neutrophils, and cell binding to E- and P-selectin was severely impaired, causing an immunodeficiency. The elevation of peripheral neutrophil counts occurred within several days after birth. A severe hypofucosylation of glycoconjugates bearing fucose in different glycosidic links was present in all cell types investigated, demonstrating that leukocyte adhesion deficiency II is not only a disorder of leukocytes but a generalized inherited metabolic disease affecting the metabolism of fucose.

PCR screening for carriers of bovine leukocyte adhesion deficiency (BLAD) and uridine monophosphate synthase (DUMPS) in Argentine Holstein cattle.

BLAD (Bovine Leukocyte Adhesion Deficiency) and DUMPS (Deficiency of Uridine Monophosphate Synthase) are monogenic autosomal, recessive inherited diseases of Holstein cattle. Single nucleotide changes (point mutations) responsible for the genetic disorders were detected by polymerase chain reaction coupled with restriction fragment length polymorphism assays (PCR-RFLP). Using oligonucleotide primers, DNA fragments of predicted sizes were amplified, and the products' specificity was assessed by nucleotide sequencing. Mutations were detected in DNA samples from bovine blood and semen by the presence or absence of restriction sites within the PCR amplification products (Taq I, Hae III for BLAD, Ava I for DUMPS). The test included 104 bulls and 950 cows of Argentinean Holstein breed. Defective alleles frequencies were as follows: 2.88% BLAD in bulls used in artificial insemination, 1.79% in cows; 0.96% DUMPS in bulls and 0.11% in cows.

Leukocyte adhesion deficiency mimicking Hirschsprung disease.

An infant had clinical signs suggestive of Hirschsprung disease as the initial manifestation of leukocyte adhesion deficiency. Chromosome studies showed a deletion of the distal third of the long arm of one chromosome 21, and flow cytometric studies confirmed the defective expression of CD18.