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

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

Risk factors of breast cancer in Mexican women

OBJECTIVE: To investigate the association between family history (FH) of neoplasia, gyneco-obstetric factors and breast cancer (BC) in a case--control study. In cases, to analyze those variables in relation with early onset of BC, the manner of detection (self-examination, prompted by pain, or casual), the size of tumor, and the elapsed time to seek medical attention. MATERIAL AND METHODS: Data from 151 prevalent BC cases and 235 age-matched controls were analyzed by multiple logistic regression, to assess the influence of BC risk factors. RESULTS: Ten per cent of patients and 1% of controls had first-degree relatives (FDR) with BC. Family history of FDR with BC (OR, 11.2; 95% CI 2.42-51.92) or with gastric or pancreatic cancer (OR, 17.7; 95% CI 2.2-142.6) was associated with BC risk. Breastfeeding at or under 25 years of age was protective against BC (OR, 0.40; 95% CI 0.24-0.66). The manner of tumor detection did not influence its size at the time of diagnosis. CONCLUSIONS: Our study confirms that FH of BC and/or of gastric or pancreatic carcinoma are risk factors for BC, while lactation at 25 years of age or earlier is protective

Risk factors of breast cancer in Mexican women Factores de riesco de cáncer de mama en mujeres mexicanas

OBJECTIVE: To investigate the association between family history (FH) of neoplasia, gyneco-obstetric factors and breast cancer (BC) in a case--control study. In cases, to analyze those variables in relation with early onset of BC, the manner of detection (self-examination, prompted by pain, or casual), the size of tumor, and the elapsed time to seek medical attention. MATERIAL AND METHODS: Data from 151 prevalent BC cases and 235 age-matched controls were analyzed by multiple logistic regression, to assess the influence of BC risk factors. RESULTS: Ten per cent of patients and 1% of controls had first-degree relatives (FDR) with BC. Family history of FDR with BC (OR, 11.2; 95% CI 2.42-51.92) or with gastric or pancreatic cancer (OR, 17.7; 95% CI 2.2-142.6) was associated with BC risk. Breastfeeding at or under 25 years of age was protective against BC (OR, 0.40; 95% CI 0.24-0.66). The manner of tumor detection did not influence its size at the time of diagnosis. CONCLUSIONS: Our study confirms that FH of BC and/or of gastric or pancreatic carcinoma are risk factors for BC, while lactation at 25 years of age or earlier is protective.<br>OBJETIVO: Investigar la asociación entre la historia familiar de neoplasias, factores ginecobstétricos y cáncer mamario (CM) en un estudio de casos y controles. Además, en los casos, estudiar estas variables en relación con inicio temprano del cáncer, forma de detección (autoexamen, exploración individual por dolor o casual), tamaño del tumor. MATERIAL E MÉTODOS: Entre enero y marzo de 1997 se estudiaron 151 casos prevalentes de CM y 235 controles pareados por edad provenientes del Hospital de Especialidades del Centro Médico del Noreste, Instituto Mexicano del Seguro Social, o del Hospital Universitario de la Universidad Autónoma de Nuevo León, ambos localizados en Monterrey, México. Los factores de riesgo se analizaron con regresión logística múltiple. RESULTADOS: Diez por ciento de casos y 1% de controles tuvieron historia familiar de primer grado para CM; este antecedente (razón de momios --RM, 11.2; IC 95%; 2.42-51.92) y el de carcinoma gástrico o pancreático (RM, 17.7; IC 95%; 2.2-142.6) se asociaron con riesgo de CM. El amamantar a los 25 años o menos fue factor protector (RM, 0.40; IC 95%; 0.24-0.66). La forma de detección del tumor no influyó en el tamaño del tumor al momento del diagnóstico. CONCLUSIONES: Se mostró que la historia familiar de CM y de carcinoma gástrico o pancreático son factores de riesgo para CM, mientras que la lactancia a los 25 años o antes, es protectora

Multifocal Recurrent Osteomyelitis and Hemophagocytic Lymphohistiocytosis in a Boy with Partial Dominant IFN-γR1 Deficiency: Case Report and Review of the Literature

Mutations in the genes coding for cytokines, receptors, second messengers, and transcription factors of interferon gamma (IFN-γ) immunity cause Mendelian susceptibility to mycobacterial disease (MSMD). We report the case of a 7-year-old male patient with partial dominant (PD) IFN-γ receptor 1 deficiency who had suffered from multifocal osteomyelitis attributable to bacille Calmette–Guérin vaccination since the age of 18 months. He developed hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory complication, and died with multiorgan dysfunction, despite having been diagnosed and treated relatively early. Patients with PD IFN-γR1 deficiency usually have good prognosis and might respond to human recombinant subcutaneous IFN-γ. Several monogenic congenital defects have been linked to HLH, a catastrophic “cytokine storm” that is usually ascribed to lymphocyte dysfunction and thought to be triggered by interferon gamma. This is the sixth patient with both MSMD and HLH of whom we are aware. The fact that patients with macrophages that cannot respond to IFN-γ still develop HLH, bring these assumptions into question

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

<p><b>Background</b>: 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.</p> <p><b>Methods</b>: 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.</p> <p><b>Results</b>: 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.</p> <p><b>Conclusions</b>: Delayed diagnosis and atypical manifestations in XLA might be related to mutation type and BTK expression.</p

First Report of the Hyper-IgM Syndrome Registry of the Latin American Society for Immunodeficiencies: Novel Mutations, Unique Infections, and Outcomes

Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Jeffrey Modell FoundationLatin American Advisory Board on Primary Immunodeficiencies initiativeUniv São Paulo, Inst Biomed Sci, Dept Immunol, BR-05508000 São Paulo, BrazilCtr Invest & Estudios, Dept Biomed Mol, Mexico City, DF, MexicoDr Ricardo Gutierrez Childrens Hosp, Buenos Aires, DF, ArgentinaHosp Nacl Ninos Dr Carlos Saenz Herrera, San Jose, Costa RicaPediat Allergy & Immunol Clin, Caxias Do Sul, RS, BrazilAlbert Sabin Hosp, Fortaleza, Ceara, BrazilHosp Base Dist Fed, Brasilia, DF, BrazilIntegrated Ctr Pediat Specialties, Curitiba, PR, BrazilHosp Ninos VJ Vilela, Rosario, ArgentinaHosp Ninos Luis Calvo Mackenna, Santiago, ChileUniv Fed Parana, Dept Pediat, BR-80060000 Curitiba, Parana, BrazilUniv Estadual Campinas, Sch Med, Dept Pediat, Campinas, SP, BrazilConceicao Childrens Hosp, Dept Pediat, Div Allergy & Immunol, Porto Alegre, RS, BrazilChildrens Hosp Lucidio Portela, Teresina, PI, BrazilPontificia Univ Catolica Chile, Div Pediat, Santiago, ChileUniv Estadual Campinas, Sch Med, Dept Med, Campinas, SP, BrazilUniv São Paulo, Ribeirao Preto Med Sch, BR-14049 Ribeirao Preto, SP, BrazilHosp Nacl Edgardo Rebagliati Martins Alergia & In, Lima, PeruUniv Fed Rio de Janeiro, Sch Med, Dept Pediat, Rio de Janeiro, BrazilInst Nacl Pediat, Unidad Invest Inmunodeficiencias, Mexico City, DF, MexicoIMSS, Unidad Med Alta Especialidad 25, Monterrey, Nuevo Leon, MexicoClin Montefiori, Unidad Inmunol, Lima, PeruUNAL, Univ Hosp, Monterrey, Nuevo Leon, MexicoFac Med ABC, Santo Andre, SP, BrazilChildrens Hosp, Dept Pediat, New Orleans, LA USAHop Necker Enfants Malad, INSERM, Unite U768, Paris, FranceUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USASeattle Childrens Res Inst, Seattle, WA USAUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, Div Allergy Immunol & Rheumatol, São Paulo, BrazilFAPESP: 2012/50515-4FAPESP: 2006/57643-7FAPESP: 2012/51745-3Web of Scienc