Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two.

Mutations in PIK3R1 gene have been associated to two different conditions: a primary immunodeficiency, called APDS2, of recent description and SHORT syndrome. 47 patients with APDS2 have been reported to date, only one of them sharing both PIK3R1-related phenotypes. Here we describe two more patients affected by APDS2 and SHORT syndrome, which highlights that this association may not be so infrequent. We recommend that patients with mutations in PIK3R1 gene should be assessed by both clinical immunologists and clinical geneticists.

Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation.

BACKGROUND: Complement (C) factor I deficiency is a rare immunodeficiency state frequently associated with recurrent pyogenic infections in early infancy. This deficiency causes a permanent uncontrolled activation of the alternative pathway resulting in massive consumption of C3. PATIENT: A 23-year-old woman with monthly recurrent meningitis episodes, mostly in the perimenstrual period, since August 1999. Previously, at age 16 years, she had meningococcal sepsis, also coinciding with menstruation. OBJECTIVES: To study the patient and her family to elucidate the molecular defects in the pedigree and to evaluate her clinical evolution. RESULTS: We describe clinical, immunological, and treatment follow-up during this period. First, we characterized the existence of a total complement factor I deficiency defined by undetectable levels by enzyme immunosorbent assay. This total deficiency was also found in her sister. Her parents and brother had approximately half of the normal levels. In addition, the patient had very low levels of C3; factor B; and an important reduction of factor H, properdin, C5, C7, and C8 complement components. Additional studies in the patient's sera evidenced high levels of immune complexes containing C1q and immunoglobulin (Ig) G, as well as C3b/factor H, C3b/properdin, C3b/IgG, and properdin/IgG complexes. Treatment with prophylactic antibiotics, antiestrogen medication, plasma infusions, or intravenous immunoglobulin has been unsuccessful in avoiding consecutive meningitis episodes. CONCLUSION: For the first time to our knowledge, these data present an unusual relationship between meningitis episodes and menstruation in factor I immunodeficiency.

[Molecular diagnosis of primary immunodeficiencies]. / Diagnóstico molecular de inmunodeficiencias primarias.

Knowledge of the molecular defects responsible for some primary immunodeficiency diseases (PIDs) offers undoubted advantages in establishing a reliable diagnosis. Such knowledge would allow us not only to establish a prognosis but also to instigate the most appropriate therapy. After molecular diagnosis, some patients could benefit from gene therapy. However, apart from the diagnosis of the disease, molecular biological techniques also enable more reliable identification of carriers and, when suggested by the family history and when the familial defect is already known, prenatal diagnosis will also be possible, thus establishing the earliest possible treatment. Using the single-stranded conformational polymorphism technique followed by direct sequencing, we found 22 different mutations in 22 patients from unrelated families and with a phenotype compatible with x-linked agammaglobulinemia. Fourteen of these are new, previously undescribed mutations and the remaining eight are already included in the data base (http://www.uta.fi/imt/bioinfo/Btkbase). Analysis of the female carrier was performed in all the mothers and the mutation was de novo in only one patient. Study of the BtK gene enabled differential diagnosis with common variable immunodeficiency disease in some patients who showed absent or very low lymphocyte B counts as well as forms of autosomal recessive agammaglobulinemia. Using the same techniques, we were able to identify mutations in the CD40 ligand gene in three families in which one of the members had clinical and biological phenotype compatible with X-linked hyper-IgM. Molecular diagnosis was very useful in identifying carriers in these families as well as in making the differential diagnosis among patients with common variable immunodeficiency disease. Purely on this were we able to provide appropriate genetic counseling.

Diagnóstico molecular de inmunodeficiencias primarias / Molecular diagnosis of primary immunodeficiencies

El conocimiento de los defectos moleculares responsables de algunas inmunodeficiencias primarias (IDP) tiene indudables ventajas para establecer un diagnóstico seguro de la enfermedad, lo que nos permitirá no sólo establecer un pronóstico, sino también instaurar el tratamiento más adecuado. Una vez realizado el diagnóstico molecular algunos de estos enfermos podrán beneficiarse de la terapia génica. Pero aparte del diagnóstico de la enfermedad, vemos cómo las técnicas de biología molecular nos facilitan el poder establecer la condición de portadoras con la mayor fiabilidad y, cuando la historia familiar lo sugiera y el defecto en la familia ya sea conocido, podremos hacer el diagnóstico prenatal que permitirá establecer el tratamiento lo más precozmente posible.Utilizando la técnica de polimorfismos en la conformación de la cadena sencilla (SSCP) seguida de secuenciación directa, hemos encontrado 22 mutaciones diferentes en otros tantos enfermos de familias no relacionadas y con fenotipo compatible con agammaglobulinemia ligada al cromosoma X (ALX).Catorce de estas mutaciones son nuevas, no descritas previamente y las otras 8 ya están recogidas en la base de datos (http://www.uta.fi/imt/bioinfo/Btkbase).El análisis de portadora se llevó a cabo en todas las madres y sólo en uno de los enfermos la mutación fue de novo. El estudio del gen de la Btk nos permitió el diagnóstico diferencial con el síndrome variable común de inmunodeficiencia (SVCID) en algunos pacientes que cursan con ausencia o muy bajo número de linfocitos B, así como con formas de agammaglobulinemia autosómica recesiva.Utilizando la misma tecnología, hemos podido encontrar mutaciones en el gen del CD40 ligando (CD40L), en tres familias en las que alguno de sus miembros tenía un fenotipo clínico y analítico compatible con el síndrome de hiper-IgM ligado al cromosoma X (HIM-X). El diagnóstico molecular nos ha sido de gran utilidad a la hora de establecer la condición de portadoras en estas familias así como para hacer el diagnóstico diferencial, en los afectos, con el SVCID.Sólo así se ha podido dar el consejo genético adecuado (AU)

Knowledge of the molecular defects responsible for some primary immunodeficiency diseases (PIDs) offers undoubted advantages in establishing a reliable diagnosis. Such knowledge would allow us not only to establish a prognosis but also to instigate the most appropriate therapy. After molecular diagnosis, some patients could benefit from gene therapy. However, apart from the diagnosis of the disease, molecular biological techniques also enable more reliable identification of carriers and, when suggested by the family history and when the familial defect is already known, prenatal diagnosis will also be possible, thus establishing the earliest possible treatment. Using the single-stranded conformational polymorphism technique followed by direct sequencing, we found 22 different mutations in 22 patients from unrelated families and with a phenotype compatible with x-linked agammaglobulinemia. Fourteen of these are new, previously undescribed mutations and the remaining eight are already included in the data base (http://www.uta.fi/imt/bioinfo/Btkbase). Analysis of the female carrier was performed in all the mothers and the mutation was de novo in only one patient. Study of the BtK gene enabled differential diagnosis with common variable immunodeficiency disease in some patients who showed absent or very low lymphocyte B counts as well as forms of autosomal recessive agammaglobulinemia. Using the same techniques, we were able to identify mutations in the CD40 ligand gene in three families in which one of the members had clinical and biological phenotype compatible with X-linked hyper-IgM. Molecular diagnosis was very useful in identifying carriers in these families as well as in making the differential diagnosis among patients with common variable immunodeficiency disease. Purely on this were we able to provide appropriate genetic counseling (AU)

[Neutropenia as early manifestation of X-linked agammaglobulinemia. Report on 4 patients]. / Neutropenia como manifestación precoz de una agammaglobulinemia ligada al cromosoma X. Descripción de cuatro pacientes.

OBJECTIVE: The aim of this study was to determine the frequency of neutropenia associated to X-linked agammaglobulinemia (XLA) and to describe the clinical characteristics of the children diagnosed in our unit. PATIENTS AND METHODS: A revision of the medical records registered in our unit during a 28 year period (1970-1998) according to the diagnostic criteria of XLA was performed. We included in the study group those patients that expressed a neutropenia. Immunological studies by standard techniques were performed. RESULTS: Of the 37 patients fulfilling the diagnostic criteria of XLA, 4 cases had experienced episodes of neutropenia (10.81%). The frequency of neutropenia within the group without familiar antecedents was 15% and within the group with familiar antecedents 5.88%. In all cases, the neutropenia was present during a serious acute infectious disease. The neutropenia was transient and resolved promptly after the onset of antibiotic therapy in all patients. None of the patients experienced neutropenia while under therapy with intravenous gammaglobulin. CONCLUSIONS: The association of XLA and neutropenia seems to be sufficiently frequent as to include it in the differential diagnosis of neutropenia during infancy. It is important to consider a primary immunodeficiency diagnosis when a child presents neutropenia and a serious acute infectious disease. Quantification of serum immunoglobulin levels and enumeration of lymphocyte subpopulations can lead to an early diagnosis.

[Prospective immunologic study of mothers of HIV positive children]. / Estudio inmunológico prospectivo en madres e hijos VIH positivos.

From a cohort of 162 children born to 161 mothers belonging to risk groups for human immunodeficiency virus (HIV) infection, we have studied 32 asymptomatic HIV seropositive and 19 HIV seronegative mothers and their offspring seropositive mothers when compared with the seronegative group had lower counts of leukocytes, lymphocytes, CD4+ cells and CD4+/CD8+ ratio as well as higher IgG and IgM serum levels. The offspring from HIV seropositive mothers differed from children born to HIV seronegative mothers in having higher lymphocyte counts, serum IgG level and spontaneous in vitro IgG production. The number of lymphocytes and the IgG serum level correlated in the child HIV seropositive mother pairs. Two children born to HIV seropositive mothers had a CD4+/CD8+ ratio below 0.8. The significance of these abnormalities and its possible relationship with active HIV infection in children is at present unknown.

[Treatment of primary immunodeficiencies with intravenous gamma globulin]. / Tratamiento de inmunodeficiencias primarias con gammaglobulina intravenosa.

Thirty five patients affected by primary immunodeficiency diseases were treated with a polyethylenglicol treated intravenous gammaglobulin. Number of infusions administered during a period of 665 months/patients, was 110. In those cases previously treated with intramuscular gammaglobulin, serum IgG levels were higher after intravenous gammaglobulin administration. Therapeutic response was favourable in most cases. Intravenous gammaglobulin was well tolerated, noticing only two serious and two mild adverse reactions. Patients that suffered adverse reactions with intramuscular gammaglobulin tolerated well intravenous preparation used, except for one patient that after two years in treatment developed IgE mediated antibodies against IgA. Need of an individualized dosage is emphasized.