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Cartilage-hair hypoplasia syndrome (CHH) is an autosomal recessive disorder frequently linked to n.72A>G (previously known as n.70A>G and n.71A>G), the most common RMRP variant worldwide. More than 130 pathogenic variants in this gene have already been described associated with CHH, and founder alterations were reported in the Finnish and Japanese populations. Our previous study in Brazilian CHH patients showed a high prevalence of n.197C>T variant (former n.195C>T and n.196C>T) when compared to other populations. The aim of this study was to investigate a possible founder effect of the n.197C>T variant in the RMRP gene in a series of CHH Brazilian patients. We have selected four TAG SNPs within chromosome 9 and genotyped the probands and their parents (23 patients previously described and nine novel). A common haplotype to the n.197C>T variant carriers was identified. Patients were also characterized for 46 autosomal Ancestry Informative Markers (AIMs). European ancestry was the most prevalent (58%), followed by African (24%) and Native American (18%). Our results strengthen the hypothesis of a founder effect for the n.197C>T variant in Brazil and indicate that this variant in the RMRP gene originated from a single event on chromosome 9 with a possible European origin.

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Cartilage hypoplasia syndrome is a primary immunodeficiency disease characterized by short stature, hypoplastic hair and a variable degree of immunodeficiency. Noninfectious cutaneous granulomas represent an uncommon yet well-recognized manifestation within the spectrum of primary immunodeficiency diseases. However, cutaneous granulomas as a manifestation of cartilage-hair hypoplasia syndrome, are extremely rare. We present a case of a middle-aged man with cartilage hypoplasia syndrome featuring cutaneous granulomas, manifesting as chronic, extensive and deep cutaneous ulcers. The patient was treated with anti-TNF-alpha adalimumab with partial improvement. Our case underscores the broad spectrum of clinical manifestations associated with cartilage hypoplasia syndrome and adds new evidence to the potential therapeutic efficacy of anti-TNF-alpha drugs in its treatment.

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Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia.

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Background: Specific antibody deficiency (SAD) is an inborn error of immunity, in patients older than 2 years, characterized by normal immunoglobulin levels and IgG subclasses, but with recurrent infections and decreased antibody responses to polysaccharide antigens. Case report: A 10-year-old female, previously healthy, with no significant family history. She is known in this institution for symptoms of headache, vomiting and paresis. A CT scan of the skull was performed, where 4 brain abscesses, edema and displacement of the midline were observed, a right frontal trephine was performed and abscess drainage, antimicrobial management for infectology, blood cultures, Gram staining and cultures of negative drainage material. Assessed for allergy and immunology, for abscesses in deep focus, an approach was performed to rule out inborn error of immunity, immunoglobulins, isohemagglutinins, flow cytometry and response to normal protein antigens. Antibodies against post-vaccination polysaccharide antigens are requested, where a response to only 2 serotypes (18.1% response) is observed, with normal IgG subclasses, a diagnosis of specific antibody deficiency is integrated and management with immuno- globulin at replacement doses is started, as well as annual vaccination with 13 valent. Conclusion: SAD has been considered a problem that can be resolved over time, especially in children, but in others it can evolve into more severe forms of humoral immunodeficiency. Decisions to treat with prophylactic antibiotics and/or gamma globulin are guided by clinical judgment, small studies, and recent consensus documents, which may evolve over time.

Antecedentes: La deficiencia especifica de anticuerpos (SAD) es un error innato de la inmunidad, en pacientes de más de 2 años, caracterizada por niveles de inmunoglobulinas y subclases de IgG normales, pero con infecciones recurrentes y respuestas de anticuerpos disminuidas a antígenos polisacáridos. Reporte de caso: Femenina de 10 años, previa sana, sin antecedentes heredofamiliares de importancia. Conocida en esta institución por cuadro de cefalea, vómi- tos y paresias. Se realiza TAC de cráneo, donde se observan 4 abscesos cerebrales, edema y desplazamiento de la línea media, se realiza trepano frontal derecha y drenaje de abscesos, manejo antimicrobiano por infectología, hemocultivos, tinción de Gram y cultivos de material de drenaje negativos. Valorado por alergia e inmunología, por abscesos en foco profundo, se realizó abordaje para descartar error innato de la inmunidad, inmunoglobulinas, isohemaglutininas, citometría de flujo y respuesta a antígenos proteicos normales. Se solicitan anticuerpos contra antígenos polisacáridos post vacunación, donde se observa respuesta a solo 2 serotipos (respuesta del 18.1%), con subclases de IgG normales, se integra diagnóstico de deficiencia especifica de anticuerpos y se inicia manejo con inmuno- globulina a dosis de reemplazo, asi como vacunación anual con 13 valente. Conclusión: El SAD se ha considerado un problema que puede resolverse con el tiempo, especialmente en niños, pero en otros puede evolucionar hacia formas más severas de inmunodeficiencia humoral. Las decisiones de tratar con antibióticos profilácticos y/o gammaglobulina están guiadas por el juicio clínico, estudios pequeños y documentos de consenso recientes, que pueden evolucionar con el tiempo.

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PURPOSE: There are currently more than 480 primary immune deficiency (PID) diseases and about 7000 rare diseases that together afflict around 1 in every 17 humans. Computational aids based on data mining and machine learning might facilitate the diagnostic task by extracting rules from large datasets and making predictions when faced with new problem cases. In a proof-of-concept data mining study, we aimed to predict PID diagnoses using a supervised machine learning algorithm based on classification tree boosting. METHODS: Through a data query at the USIDNET registry we obtained a database of 2396 patients with common diagnoses of PID, including their clinical and laboratory features. We kept 286 features and all 12 diagnoses to include in the model. We used the XGBoost package with parallel tree boosting for the supervised classification model, and SHAP for variable importance interpretation, on Python v3.7. The patient database was split into training and testing subsets, and after boosting through gradient descent, the predictive model provides measures of diagnostic prediction accuracy and individual feature importance. After a baseline performance test, we used the Class Weighting Hyperparameter, or scale_pos_weight to correct for imbalanced classification. RESULTS: The twelve PID diagnoses were CVID (1098 patients), DiGeorge syndrome, Chronic granulomatous disease, Congenital agammaglobulinemia, PID not otherwise classified, Specific antibody deficiency, Complement deficiency, Hyper-IgM, Leukocyte adhesion deficiency, ectodermal dysplasia with immune deficiency, Severe combined immune deficiency, and Wiskott-Aldrich syndrome. For CVID, the model found an accuracy on the train sample of 0.80, with an area under the ROC curve (AUC) of 0.80, and a Gini coefficient of 0.60. In the test subset, accuracy was 0.76, AUC 0.75, and Gini 0.51. The positive feature value to predict CVID was highest for upper respiratory infections, asthma, autoimmunity and hypogammaglobulinemia. Features with the highest negative predictive value were high IgE, growth delay, abscess, lymphopenia, and congenital heart disease. For the rest of the diagnoses, accuracy stayed between 0.75 and 0.99, AUC 0.46-0.87, Gini 0.07-0.75, and LogLoss 0.09-8.55. DISCUSSION: Clinicians should remember to consider the negative predictive features together with the positives. We are calling this a proof-of-concept study to continue with our explorations. A good performance is encouraging, and feature importance might aid feature selection for future endeavors. In the meantime, we can learn from the rules derived by the model and build a user-friendly decision tree to generate differential diagnoses.

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Se define «síndrome febril prolongado¼ a todo cuadro de hipertermia que persiste al menos 10 días sin ser diagnosticado. El síndrome de Good es una inmunodeficiencia primaria del adulto que se caracteriza por presentar hipogammaglobulinemia, disminución de linfocitos B y anormalidades en los linfocitos T. Entre el 15 y el 20% de los casos de «fiebre de origen desconocido¼ ocurren debido a neoplasias, y el cáncer de colon representa menos del 1% de todos estos casos. Se presenta una paciente de 49 años admitida en el hospital por presentar síndrome febril con un mes de evolución, con antecedentes de síndrome de Good. Se le diagnostica cáncer de colon. (AU)

A prolonged febrile syndrome (PFS) is defined as any episode of hyperthermia that persists for at least 10 days without being diagnosed. Good's syndrome is a primary immunodeficiency in adults characterized by hypogammaglobulinemia, decreased B lymphocytes, and abnormalities in T lymphocytes. Between 15 to 20% of fever of unknown origin (FOD) cases are due to neoplasms, and colon cancer represents less than 1% of all these cases. A 49-year-old patient with a history of Good's syndrome was admitted to the hospital due to a febrile syndrome lasting for a month. She was diagnosed with colon cancer. (AU)

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BACKGROUND: WHIM syndrome corresponds to an inborn error of innate and intrinsic immunity, characterized by: warts (Warts), Hypogammaglobulinemia, Infections and Myelocathexis, for its acronym in English. CASE REPORT: 4-year-old male, with severe neutropenia and B-cell lymphopenia from birth, without severe infections or warts; the panel genetic sequencing study of primary immunodeficiencies with the CXCR4 c.1000C>T (p.Arg334*) variant, which is associated with WHIM syndrome. CONCLUSIONS: The diagnosis of severe neutropenia from birth should include the search for inborn errors of immunity, through genetic sequencing studies, especially in asymptomatic or oligosymptomatic patients.

ANTECEDENTES: El síndrome WHIM corresponde a un error innato de la inmunidad innata e intrínseca, caracterizada por verrugas (Warts), hipogammaglobulinemia, infecciones y mielocatexis, por sus siglas en inglés. REPORTE DE CASO: Paciente masculino de 4 años, con neutropenia severa y linfopenia de células B desde el nacimiento, sin infecciones severas ni verrugas. El estudio de secuenciación genética informó la variante CXCR4 c.1000C>T (p.Arg334*), relacionada con el síndrome de WHIM. CONCLUSIÓN: El diagnóstico de neutropenia severa desde el nacimiento debe incluir la búsqueda de errores innatos de la inmunidad, mediante estudios de secuenciación genética, especialmente en pacientes asintomáticos u oligosintomáticos.

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PURPOSE: This study aimed to investigate the correlation between calculated globulin (CG, total protein level minus albumin level) and the gamma globulin fraction (Gamma), obtained from serum protein electrophoresis with serum IgG levels in adults (≥ 18 years). METHODS: Using linear regression models, analyses of CG and Gamma levels correlation with IgG levels in adults were performed. Receiver-operator curves were created to determine cutoff values and the respective sensitivity and specificity measures. RESULTS: A total of 886 samples were analyzed. CG and Gamma were positively and statistically correlated with IgG levels (r2 = 0.4628 for CG, and = 0.7941 for Gamma, p < 0.0001 for both analyses). For the detection of hypogammaglobulinemia, i.e., IgG level below the reference value (6 g/L), a CG cutoff value of 24 g/L showed a sensitivity of 86.2% (95% CI 69.4-94.5) and a specificity of 92% (90.0-93.6). A Gamma cutoff value of 7.15 g/L yielded a sensitivity of 100% (88.3-100) and a specificity of 96.8 (95.3-97.8). CONCLUSION: Both CG and Gamma levels determined by protein electrophoresis analysis may be used to screen for antibody deficiencies in adults, enabling earlier diagnosis of antibody deficiencies in a routine clinical setting.

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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.

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ABSTRACT Introduction Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies. Method We performed GATA2 genotyping in patients with NTM and/or FI. Results Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients. Conclusion Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient's treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.

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