Study of gastrointestinal polypeptides controlling gastric acid secretion in patients with primary antibody deficiency.

BACKGROUND: gastric abnormalities are a common feature in patients with primary antibody deficiency. The most important problem is the high incidence of stomach cancer found in these patients. Chronic atrophic gastritis with pernicious anemia is also a common finding that predisposes to gastric adenocarcinoma. The aim of the present study was to identify factors predictive of high risk for developing gastric cancer in patients with primary antibody deficiency. PATIENTS AND METHODS: we studied gastric hormones (gastrin, somatostatin and gastrin-releasing peptide, GRP) in 47 patients (23 children and 24 adults) with primary antibody deficiency. In accordance with the World Health Organization (WHO) classification, patients were diagnosed as having X-linked agammaglobulinemia (Bruton disease) in 13 cases, common variable immunodeficiency in 28, and hypogammaglobulinemia with hyperIgM in 6. Gastric biopsy was performed in 22 patients (16 children and 6 adults). Hormone determinations were carried out by radioimmunoassay. RESULTS: baseline serum gastrin levels were normal or increased compared with controls, but the response to stimulation with a hyperproteic diet was delayed in 18 patients and lower than in controls in 7. In 4 adult patients, all with pernicious anemia, gastric biopsy revealed chronic atrophic gastritis involving the stomach corpus and antrum (type B gastritis). The absence of a normal response of gastrin secretion to stimulation with a hyperproteic diet may be explained by this finding. Serum somatostatin and GRP levels were higher than in controls. No correlations were found between these findings and patient age, type of immunodeficiency or duration of clinical manifestations.

Study of gastrointestinal polypeptides controlling gastric acid secretion in patients with primary antibody deficiency.

BACKGROUND: Gastric abnormalities are a common feature in patients with primary antibody deficiency. The most important problem is the high incidence of stomach cancer found in these patients. Chronic atrophic gastritis with pernicious anemia is also a common finding that predisposes to gastric adenocarcinoma. The aim of the present study was to identify factors predictive of high risk for developing gastric cancer in patients with primary antibody deficiency. PATIENTS AND METHODS: We studied gastric hormones (gastrin, somatostatin and gastrin-releasing peptide, GRP) in 47 patients (23 children and 24 adults) with primary antibody deficiency. In accordance with the World Health Organization (WHO) classification, patients were diagnosed as having X-linked agammaglobulinemia (Bruton disease) in 13 cases, common variable immunodeficiency in 28, and hypogammaglobulinemia with hyperIgM in 6. Gastric biopsy was performed in 22 patients (16 children and 6 adults). Hormone determinations were carried out by radioimmunoassay. RESULTS: Baseline serum gastrin levels were normal or increased compared with controls, but the response to stimulation with a hyperproteic diet was delayed in 18 patients and lower than in controls in 7. In 4 adult patients, all with pernicious anemia, gastric biopsy revealed chronic atrophic gastritis involving the stomach corpus and antrum (type B gastritis). The absence of a normal response of gastrin secretion to stimulation with a hyperproteic diet may be explained by this finding. Serum somatostatin and GRP levels were higher than in controls. No correlations were found between these findings and patient age, type of immunodeficiency or duration of clinical manifestations.

[Primary immunodeficiencies. Clinical features and variant forms]. / Inmunodeficiencias primarias. Clínica y formas variantes.

Periodically the World Health Organization and currently the International Union of Immunology Societies publish a classification of primary immunodeficiency diseases (PID) that includes diagnostic and therapeutic guidelines. The latest of these publications dates from 1999 and includes a new group of PID, the proliferative autoimmune syndromes. Furthermore, new forms of severe combined immunodeficiency (SCID) and of recessive autosomal agammaglobulinemia are described. From the publication of this classification until the end of the year 2000 a minimum of three new PIDs have been described and a further two should probably be added. Progress in the molecular biology of these diseases has given rise not only to more accurate diagnosis but also to greater insight into the clinical spectrum of these diseases. A mutation or deletion in a gene can provoke the complete absence of its product; sometimes expression is partial or normal but functional activity is absent or defective. In certain cases, partial or defective activity causes variant forms of the disease presenting symptomatology or atypical cellular phenotype. In other cases, this is not cause of the variant form, which can appear in interfamilial cases sharing the same mutation. In these cases, these differences can be attributed to environmental factors or to other genes able to modify the affected gene. In this article we provide examples of variant forms in several PIDs. Some are late onset forms, such as X-linked agammaglobulinemias diagnosed in adults, since until diagnosis, clinical symptomatology was minimal. In adenosine-deaminase deficiency, a serious and highly lymphoproliferative form of SCID, patients have been described whose symptomatology began after the age of 20 years. Another SCID, RAG1 and RAG2 recombinase deficiency, may produce a typical form with a characteristic T-B-NK + phenotype, Omenn's syndrome, or forms with an unexpected T-B + NK + phenotype. Deficiency in common gamma chain receptor for IL-2 may produce phenotypical variants that can lead to diagnostic error. X-linked lymphoproliferative syndrome may present as fulminant infectious mononucleosis, as leukemia or lymphoma or as hipo- or agammaglobulinemia. Possibly, some patients diagnosed with common variable immunodeficiency or with x-linked agammaglobulinemia do in fact have this syndrome. Chronic granulomatous disease is usually of early-onset, but late-onset forms have been described. In one case the first clinical manifestation was produced when the patient was 60 years old. The above examples serve to highlight that, even though PIDs are usually suspected by pediatricians, in some cases the diagnosis may be missed by internists or non-pediatricians. Moreover, the clinical and laboratory findings of these variant forms must be determined to carry out an early diagnosis, which is essential for a favorable therapeutic outcome.

[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.

[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.

[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.

Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults.

The Spanish Registry for Primary Immunodeficiency Diseases (REDIP) was organized in 1993. One thousand sixty-nine cases of primary immunodeficiency diseases (PID) were registered in patients diagnosed between January 1980 and December 1995. PID diagnosis was made according to the World Health Organization criteria. The most frequent disorders were IgA deficiency (n = 394) and common variable immunodeficiency (n = 213), followed by severe combined immunodeficiency (n = 61), C1 inhibitor deficiency (n = 52), X-linked agammaglobulinemia (n = 49), IgG subclass deficiency (n = 48), and chronic granulomatous disease (n = 32). A comparative study between REDIP and data recently obtained from the European registry (ESID Report, 1995) revealed important differences between phagocytic disorders and complement deficiencies reported in both registries, 4.9 vs 8.7 and 6.0 vs 3.6, while percentages of predominantly antibody deficiencies and T cell and combined deficiencies concurred with those reported in the European registry, 69.3 vs 64.7 and 14.7 vs 20.2, respectively. The heterogeneous nature of the geographical distribution of cases submitted may indicate underdiagnosis of PID in some country areas; surprisingly, the interval between the onset of clinical symptoms and diagnosis was significant, even in immunodeficiency diseases, such as IgA deficiency, which are easy to diagnose.

[Nezelof syndrome with secondary immunodeficiency (author's transl)]. / Síndrome de Nezelof con inmunodeficiencia secundaria sobreañadida

A child with recurrent infections is presented. The frequent diarrhea leads to a severe malnutrition. The immunological work-up disclosed: absent IgA and low IgG serum levels, deficient cellular immunity and abnormal neutrophil chemotaxis. The cellular immunity and the neutrophil chemotaxis were improved with the nutritional status. At present the patient shows a partial combined immunodeficiency. The diagnosis of the case as a Nezelof's syndrome is discussed, as well as the addition of a secondary immunodeficiency caused by the recurrent infections and the malnutrition.

[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.

[Common variable immunodeficiency (author's transl)]. / Síndrome variable común de inmunodeficiencia. Diagnóstico diferencial con la agammaglobulinemia congénita ligada al sexo

In a boy initially diagnosed as X-linked hypogammaglobulinemia, the later clinical and analytical course and the application of new immunological techniques led to the new diagnosis of common variable immunodeficiency. The patient shows panhypogammaglobulinemia, a scarce number of plasma cells with a normal number of precursors and circulating B lymphocytes with membrane bound immunoglobulins and C3 receptors. Delayed hypersensitivity is absent despite normal amount of circulating T lymphocytes which were able to transform when stimulated by PHA. The anergy seems primary and not related to the clinical malnutrition. The authors make a differential diagnosis between both illnesses as a tentative pathogenetic interpretation of B cell development arrest.

[Thymus implant in a case of DiGeorge syndrome (author's transl)]. / Implante de timo en un caso de síndrome de DiGeorge.

A boy with III-IV pharingeal pouch malformative syndrome, hypocalcemia and recurrent infections is presented. The immunological work-up disclosed deficiency in the specific cellular immunity with normal serum immunoglobulin levels. An adult thymus in Millipore diffusion chambers was implanted in the rectus adominalis muscle. One week later clinical and analytical data suggesting immunological reconstitution was recorded. Two years later the patient remains in good health, T and B lymphocyte percentages are normal, being the only immunological abnormality a low serum level of IgG.

[Present-day status of glycogenosis Ib. Report of a new case]. / Estado actual de la glucogenosis Ib. Aportación de un nuevo caso.

A four-month-old boy affected by glycogen storage disease type I is presented. The child suffered from hepatomegaly, lactic acidosis, fasting hypoglycemia and failure to thrive. He had repeated infectious and cyclic neutropenia. Immunoglobulin and chemotactic neutrophil motility was impaired. Liver biopsy showed increased amounts of glycogen in hepatic cells as assessed by morphological and biochemical grounds. The activity of glucose-6-phosphatase as well as other glycogenolytic enzymes was normal in the frozen liver. The aforementioned characteristics suggested the diagnosis of glycogen storage disease type Ib. The child was first treated by enteral continuous feeding and later on by frequent meals during the daytime and enteral continuous feeding during the night time, improving the hypoglycemia as well as the other biochemical and metabolic abnormalities.

Inmunodeficiencias primarias / Primary immunodeficiencies

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