Homozygous deletion of RAG1, RAG2 and 5' region TRAF6 causes severe immune suppression and atypical osteopetrosis.

Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5' region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor-associated family member, plays an important role in T cell signaling and in RANKL-dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.

Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children.

AIM: Few studies have focused on paediatric hyposplenism/asplenism, in which splenic phagocytic activity is diminished or absent in an anatomically present spleen. This study aimed to evaluate clinical findings, laboratory tests and prognosis of children with functional hyposplenism/asplenism. METHODS: The study group comprised 74 children who had liver/spleen technetium-99m sulphur colloid scintigraphy from 2002 to 2008. Information collected included demographic features, background diseases, blood smear findings, indications for scintigraphy and outcome. Children with functional hyposplenism were followed until 2012. RESULTS: We found that 34 patients had functional hyposplenism/asplenism. The main indications for scintigraphy in the hyposplenic patients were persistent thrombocytosis and recurrent infections. Associated conditions included immunodeficiencies, autoimmune diseases, malignancies and genetic disorders. Main infections were sinopulmonary infections, bacteraemia and sepsis. The major pathogens were Streptococcus pneumoniae and Haemophilus influenza group A. There was no correlation between the presence of Howell-Jolly bodies in blood smear with clinical disease severity or scintigraphic findings. Repeated scintigraphy showed spontaneous normalisation in 40% of patients. CONCLUSION: Functional hyposplenism is an important and underdiagnosed immunodeficiency condition in children, associated with various clinical conditions including prolonged unexplained thrombocytosis, immune deficiency and autoimmunity. Technetium-99m sulphur colloid scintigraphy is the method of choice for evaluating splenic function.

Anaphylaxis in Israel: experience with 92 hospitalized children.

Little is known about the courses, causes, and clinical features of anaphylaxis in children outside the USA and Europe. Our objective was to evaluate the events of anaphylaxis in children admitted to the Schneider Children's Medical Center of Israel, a major tertiary facility, over a 12-year period. Ninety-two children with anaphylaxis (50 boys, 42 girls) aged 14 days to 18 yr (mean, 7.4 yr) were hospitalized during the study period. The event occurred at home in 52 children (56%), in a medical institution in 24 (26%), outdoors in 13 (15%), at school in 2 (2%), and in an unspecified location in 1 (1%). The main causes were foods (43%), mainly milk and nuts, medications (22%), and hymenoptera venom (11%); in five children, anaphylaxis occurred during general anesthesia, and in 5, the causative agent could not be determined. Food-induced anaphylaxis tended to occur in younger children. Forty-eight children (52%) had a history of atopy (mainly asthma). Hospital treatment consisted of corticosteroids (85%), antihistamines (75%), epinephrine (72%), and ß2 agonists (42%). Seven patients were admitted to intensive care units. There were no fatalities. EpiPen was used by only one of the 16 patients with more than one episode of anaphylaxis, indicating that patient and parent education in the application of the EpiPen needs to be improved.

MHC class 2 deficiency and X-linked agammaglobulinaemia in a consanguineous extended family.

Manifestations of immunodeficiency within the same family are presumed to be the same disease. We report a consanguineous extended family where four patients have immunodeficiency, three have X-linked agammaglobulinaemia and one has major histocompatibility complex class 2 deficiency. Within one family, two rare genetic diseases with similar clinical manifestations can occur.

Cell migration to the chemokine CXCL8: paxillin is activated and regulates adhesion and cell motility.

The chemokine CXCL8 is a powerful inducer of directional cell motility, primarily during inflammation. In this study, we found that CXCL8 stimulation led to paxillin phosphorylation in normal neutrophils, and that both CXCL8 receptors (CXCR1 and CXCR2) mediated CXCL8-induced paxillin phosphorylation. In CXCR2-transfected cells, the process depended on G(alphai) and G(alphas) coupling to CXCR2. Dominant negative (DN) paxillin increased CXCL8-induced adhesion and migration, indicating that endogenous paxillin keeps migration at submaximal levels. Furthermore, using activating antibodies to beta1 integrins, analyses with focal adhesion kinase (FAK) DN variant (FRNK) and co-immunoprecipitations of FAK and paxillin, we found that beta1 integrin ligation cooperates with CXCL8-induced stimulation, leading to FAK activation and thereafter to FAK-mediated paxillin phosphorylation. Our findings indicate that paxillin keeps directional motility at a restrained magnitude, and suggest that perturbations in its activation may lead to chemotactic imbalance and to pathological conditions associated with excessive or reduced leukocyte migration.

Extended family studies for the identification of allogeneic stem cell transplant donors in Jewish and Arabic patients in Israel.

HLA-identified donors are the best source of allogeneic hematopoietic stem cell transplants, and are available in approximately 40% of cases. If no HLA-identical core family member is found, an extended family search may be performed. The aim of the study was to summarize the 10-year (1990-1999) experience of our tertiary care center with extended family donor search. During this period, 356 patients and 2659 of their family members were tissue-typed; 239 patients were Jewish (67%) and 117 were Arabic (33%). An HLA-identical core-family donor was identified for 168 patients (47%): 95 Jewish (40%) and 73 Arabic (62%) (p < 0.0001); 49 patients (14%) had more than one potential donor. An extended family search (grandmother/grandfather, aunts, uncles, etc.) was performed in 38 of the remaining families, which were found to be consanguineous: five Jewish and 33 Arabic. One HLA match was found in the Jewish families (20%) and 21 in the Arabic families (64%). The odds ratio for an Arabic patient to find a donor in the extended family search was 8.75, as opposed to a Jewish patient. Overall, HLA-matched donors were found by core and extended family search for 53% of the patients. The rate for Arabic patients was 80% and for Jewish patients, 40% (p < 0.001). This difference may be explained by the greater number of siblings and higher rate of consanguinity in the Arabic population. In conclusion, an extended family search for potential HLA-matched donors is worthwhile, especially in distinct ethnic populations with high consanguinity, such as Israeli Arabs.

Clinical presentations of mitochondrial cardiomyopathies.

UNLABELLED: To determine the clinical manifestations and interfamilial variability of patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of 14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996 to 2001. All patients underwent a metabolic evaluation including blood lactate, pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed for mutations. The age at presentation ranged between 6 months and 24 years. Six of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6. Eleven patients had family members with mitochondrial disorders. All the patients had additional involvement of one or more systems. Seven patients exhibited a deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point mutation (3243) was found in one patient. Blood lactic acid levels were increased in 5. Brain MRI abnormalities were observed in 4. CONCLUSIONS: Mitochondrial dysfunction frequently affects the heart and may cause both hypertrophic and dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem involvement and may rarely be isolated. The course may be stable for many years, but rapid deterioration may occur. Understanding the biochemical and genetic features of these diseases will enable us to comprehend the clinical heterogeneity of these disorders.

Ganciclovir treatment in Ménétrier's disease.

UNLABELLED: A 2-y-old girl with severe edema, oliguria and hypoalbuminemia caused by protein-losing gastritis was diagnosed with cytomegalovirus-associated Ménétrier's disease. After almost two weeks, during which the patient required repeated albumin transfusions, she was treated with intravenous ganciclovir. Within five days her condition had improved, and no additional albumin replacement was needed. Complete recovery was observed after several weeks. CONCLUSION: In patients with severe Ménétrier's disease, a course of ganciclovir treatment may be of benefit and should be considered.

Streptococcus acidominimus infection in a child causing Gradenigo syndrome.

UNLABELLED: Gradenigo syndrome is a rare presentation of acute petrositis. The clinical triad of Gradenigo syndrome consists of acute suppurative otitis media, severe unilateral headache and abducens nerve palsy. We report the first case of Gradenigo syndrome caused by Streptococcus acidominimus, a Gram-positive coccus of the Streptococcus viridans group, which rarely causes deep-seated infection in humans. CONCLUSION: Gradenigo syndrome may complicate acute otitis media and should be suspected in case of unilateral headache and abducens nerve palsy. Conservative medical treatment without surgery may be considered in some patients.

Transient hypoparathyroidism due to amphotericin B-induced hypomagnesemia in a patient with beta-thalassemia.

OBJECTIVE: To report a case of transient hypoparathyroidism that developed in a beta-thalassemic patient due to amphotericin B-induced hypomagnesemia. CASE SIJMMARY: A 21-year-old man with beta-thalassemia was treated with amphotericin B for Candida albicans intravenous line sepsis. After five days of treatment (cumulative dose 160 mg), he developed hypomagnesemia, which caused hypoparathyroidism and hypocalcemia; all three abnormalities resolved after the drug was withdrawn. DISCUSSION: Patients with beta-thalassemia may develop endocrinologic abnormalities due to excessive iron deposition. Some may have subclinical hypoparathyroidism that clinically emerges after even a mild homeostasis disturbance. Amphotericin B is associated with variable adverse effects including renal tubular insult, which may induce hypomagnesemia following relatively short treatment. The resolution of hypomagnesemia, hypocalcemia, and hypoparathyroidism in our patient after discontinuation of amphotericin B treatment suggests that the endocrine dysfunction was due to a drug-related adverse effect and not to parathyroid dysfunction caused by iron deposition. CONCLUSIONS: This case demonstrates a known but rarely reported adverse effect of amphotericin B, namely hypomagnesemia, that may occur even at a low cumulative dose. It also emphasizes that patients with an underlying disease, such as thalassemia, may be more susceptible to hypoparathyroidism and hypocalcemia during treatment with amphotericin B.

Concomitant aseptic meningitis and bacterial urinary tract infection in young febrile infants.

We evaluated the incidence and implications of coexistent bacterial urinary tract infection and aseptic meningitis in 1629 young febrile infants (age 1 to 60 days) who underwent sepsis work-up. Urinary tract infection was diagnosed in 13.2% and aseptic meningitis in 8.8%. Eleven patients (0.7%) had both infections. In view of possible coinfection initial laboratory results may be insufficient for decision-making regarding treatment in young febrile infants.

Hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis.

A 2-year-old child presented with fever and hepatosplenomegaly. Laboratory findings showed pancytopenia, hypertriglyceridemia, hyperferritinemia, and high levels of soluble-IL2 receptors. Initial bone marrow aspiration and biopsy revealed mild hemophagocytosis. A diagnosis of hemophagocytic lymphohistiocytosis was made and appropriate treatment was begun. Repeated marrow aspiration performed because of lack of clinical response revealed Leishmania amastigotes in macrophages in addition to active hemophagocytosis. Treatment with liposomal amphotericin resulted with rapid recovery. Visceral leishmaniasis should be considered in the differential diagnosis of hemophagocytic syndrome.

[Pulmonary involvement in Osler-Weber-Rendu syndrome].

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is a group of autosomal dominant diseases with variable penetration, characterized by vascular malformations. Recently hereditary hemorrhagic telangiectasia has been found to be a phenotypic expression of mutations in genes located on chromosomes 9 and 12, and possibly of other genes located on other chromosomes. We describe 2 patients with hereditary hemorrhagic telangiectasia and pulmonary involvement who presented with repeated complaints of dyspnea and cyanosis and were diagnosed as having long-standing asthma. Both were treated with therapeutic catheterization and embolization with good clinical outcomes.

Soluble CD14 in children with status asthmaticus.

BACKGROUND: Inflammation is a major component in the pathogenesis of asthma. CD14 is an endotoxin (lipopolysaccharide) receptor, and is expressed mainly on monocytes and macrophages. Binding of LPS to CD14 activates the monocyte or macrophage and causes the release of different cytokines. The soluble form of CD14 is present in serum, and its concentration increases in several clinical conditions, including infections, autoimmune disorders, allergic disorders, and lung diseases. The possible role of CD14/sCD14 in asthma has been investigated in a few adult patients only. OBJECTIVES: To measure serum concentrations of sCD14 in children with status asthmaticus. METHODS: We compared serum concentration of sCD14 in 10 children with status asthmaticus measured within 24 hours of admission and after recovery from the acute episode. RESULTS: Levels of sCD14 were significantly higher during acute asthma attacks than at recovery. CONCLUSIONS: The elevated serum levels of sCD14 during status asthmaticus may be the result of the activation of monocytes, macrophages or other cells. The influence of medications on serum sCD14 cannot be ruled out. The possible use of sCD14 as a marker of lung inflammation in asthma warrants further investigation.

Erythema nodosum in Israeli children.

BACKGROUND: Erythema nodosum, although uncommon in children, is the most frequent form of panniculitis in pediatrics. EN has been associated with various infections and chronic inflammations, and its course varies with age, gender, and racial and geographic factors. There is no information on EN in Israeli children. OBJECTIVES: To examine the clinical course of EN and the conditions with which it is associated in Israeli children. METHODS: We conducted a retrospective study of 24 children with a diagnosis of EN who presented at our Center over a 10 year period (1989-98). RESULTS: EN was more frequent in females than males (ratio 2:1) due to a cluster of adolescent girls. The mean duration of the skin manifestation was 18 days. The course was benign in all patients. Streptococcal infection was the most common cause (25%), followed by Epstein-Barr virus infection (18%) and inflammatory bowel disease (13%). In one-third of cases, no specific cause could be identified. Tuberculosis, an important cause of EN in the past, was not found in our patients. CONCLUSIONS: Most cases of EN in Israeli children are related to streptococcal and EBV infections or to chronic inflammatory conditions. Despite the increase in tuberculosis morbidity in Israel during recent years, we found no association of EN and tuberculosis in our study.

Prevalence of asthma in 13-14 yr-old schoolchildren across Israel.

There is evidence that the incidence and severity of asthma are increasing worldwide, but there are limited data on asthma in Israel. The aim of this study was to investigate the prevalence and severity of asthma and asthma symptoms in 13-14 yr-old schoolchildren in Israel. The self-completed questionnaire used was a modified version of that developed by the International Study of Asthma and Allergies in Childhood (ISAAC), and was administered to a national sample of 12,918 children. The prevalence of asthma ever, wheezing ever and wheezing in the last 12 months were 13.7, 23.8 and 17.9% respectively. Significantly higher rates of a history of asthma and asthma symptoms were observed in Jews compared with Arabs. Although asthma ever was more prevalent in males than in females, asthma symptoms were significantly more common in females. The type of area of residence had no effect on the prevalence of wheezing. The ethnic differences in the prevalence of asthma persisted after controlling for sex, district of residence and level of urbanization. The prevalence of both asthma and asthma symptoms in Israel are slightly above the mean reported from 10 other countries in Europe and the Far-East.

Toxic epidermal necrolysis associated with acetaminophen ingestion.

OBJECTIVE: To report a case of toxic epidermal necrolysis (TEN) associated with acetaminophen ingestion. SUMMARY: A seven-year-old girl developed TEN after acetaminophen ingestion. The diagnosis was based on clinical evaluation and skin biopsy. A later acetaminophen challenge, undertaken by an allergist who questioned the diagnosis, resulted in a similar skin reaction. DISCUSSION: TEN is a severe disease with a high mortality rate. TEN may be either idiopathic or associated with several clinical conditions, such as viral infections, autoimmune disorders, malignancy, and drug hypersensitivity. Because of the rarity of its association with acetaminophen, the diagnosis in our patient was questioned by an allergist who performed an oral acetaminophen rechallenge test despite the potential risk. This caused a severe skin reaction that required rehospitalization. CONCLUSIONS: TEN can be caused by over-the-counter medications such as acetaminophen. Rechallenge with the causative drug carries a risk of severe complications and should be avoided.

Constrictive pericarditis. Early experience in 12 patients in light of modern cardiology.

The last several decades have witnessed major advances in the understanding and management of constrictive pericarditis. The aim of the present study was to compare the diagnosis, treatment and outcome of constrictive pericarditis of 40 years ago to today. The study population consisted of 12 patients with a diagnosis of constrictive pericarditis who presented at the Institute of Cardiology of Beilinson Hospital, from 1961 to 1970. Their main physical findings, electrocardiographic and chest X-ray changes, and hemodynamic study results are discussed in relation to the surgical outcome of patients with constrictive pericarditis today. New noninvasive imaging modalities, such as M mode, two-dimensional and Doppler echocardiography, computed tomography and magnetic resonance imaging are presented, and their advantages and disadvantages in the diagnosis of constrictive pericarditis and its differentiation from restrictive cardiomyopathy are explained.

Low serum C3, leukopenia, and thrombocytopenia: unusual features of henoch-schonlein purpura.

Henoch-Schonlein purpura (HSP) affects predominantly the skin, joints, gastrointestinal tract and kidney. Although the pathogenesis is probably of immune origin and complement activation is thought to play a role, laboratory findings including the serum level of the complement components are usually normal. We present a patient with a severe form of HSP nephritis who had unusual laboratory findings of a low level of C3, mild leukopenia and thrombocytopenia. These findings may further support the importance of complement activation in the pathogenesis of HSP.