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.

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.

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.

Impaired metabolic function and signaling defects in phagocytic cells in glycogen storage disease type 1b.

Patients with glycogen storage disease (GSD) type 1b (1b), in contrast to patients with GSD type 1a (1a), are susceptible to recurrent bacterial infections suggesting an impairment in their immune system. In this study, phagocytic cell (neutrophil and monocyte) respiratory burst activity, as measured by superoxide anion generation, oxygen consumption, and hexose monophosphate shunt activity, was markedly reduced in both neutrophils and monocytes from GSD 1b patients as compared with either GSD 1a patients or healthy adult control cells. Degranulation, unlike respiratory burst activity, was not significantly different in neutrophils from GSD 1b patients as compared with controls. Both neutrophils and monocytes from GSD 1b patients showed decreased ability to elevate cytosolic calcium in response to the chemotactic peptide f-Met-Leu-Phe. In addition, calcium mobilization in response to ionomycin was also attenuated suggesting decreased calcium stores. Thus, reduced phagocytic cell function in GSD 1b is associated with diminished calcium mobilization and defective calcium stores. Defective calcium signaling is associated with a selective defect in respiratory burst activity but not degranulation.

Sweet syndrome associated with G-CSF treatment in a child with glycogen storage disease type Ib.

Acute febrile neutrophilic dermatosis (Sweet syndrome) is rare in children and is regularly associated with underlying malignancies or inflammtory diseases. A 5-year-old girl with glycogen storage disease type Ib, neutropenia, and recurrent infections developed characteristic skin eruption of Sweet syndrome after 2 years of granulocyte colony-stimulating factor (G-CSF) therapy. This association points to a possible role of G-CSF-induced granulopoiesis and granulodyte activation in the pathogenesis of Sweet syndrome.

Pulmonary functions in children with progressive systemic sclerosis.

The patterns of pulmonary involvement in 13 children with progressive systemic sclerosis were investigated. Eight patients (61%) had respiratory symptoms or signs and 7 patients (55%) had abnormalities on chest roentgenogram. Twelve patients (92%) had abnormal pulmonary function tests: 7 had restrictive disease, 2 had obstructive disease, 2 had small airway disease, and 1 had an isolated reduction in the diffusing capacity of carbon monoxide. Nine patients had the test performed during the first year of illness, 3 during the second year, and 1 at 5 years. All patients had abnormal pulmonary function tests when first studied. Subsequent pulmonary function tests over a period of 3 to 10 years (mean 6.2 years) showed substantial changes in only 2 patients (1 patient had initial worsening of diffusing capacity of carbon monoxide followed by normalization and another patient showed improvement of obstructive disease). Two patients died during follow-up, 1 of pulmonary hypertension, the other of severe restrictive lung disease and myocardial fibrosis. The major findings of this study were (1) high frequency of pulmonary disease in children with progressive systemic sclerosis, (2) early involvement of the lungs, (3) relatively indolent progression of lung disease, and (4) the prognostic importance of the severity of pulmonary disease. Pulmonary manifestations of progressive systemic sclerosis in children appear to be similar to those of affected adults.

Late-onset localized junctional epidermolysis bullosa and mental retardation: a distinct autosomal recessive syndrome.

We present 2 sibs with a local junctional type of epidermolysis bullosa associated with enamel defect of the teeth, dystrophic nails of the feet, and mental retardation. Subluxation of the lenses was evident in 1 of them. This combination found in a brother and a sister seems to represent a distinct autosomal recessive type of epidermolysis bullosa.

Myopathy, lactic acidosis, and sideroblastic anemia: a new syndrome.

We describe 2 sibs (brother and sister) with myopathy, sideroblastic anemia, lactic acidosis, mental retardation, microcephaly, high palate, high philtrum, distichiasis, and micrognathia. Very low levels of cytochromes a, b, and c were detected in the patients' muscle mitochondria. Deposition of iron within the mitochondria of bone marrow erythroblasts was observed on electron microscopy. Irregular and enlarged mitochondria with paracrystalline inclusions were also seen on electron microscopy of the patients' muscle specimen. Examination of DNA from the affected sibs showed no deletions in the mitochondrial DNA nor the mutations identified in the syndromes of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) or myoclonus, and epilepsy associated with rugged-red fibers (MERRF). Since the parents were first cousins and 2 of 6 sibs (male and female) were affected, we suggest that the syndrome expressed by our patients represents a previously unknown autosomal recessive disorder that includes mitochondrial myopathy, lactic acidosis, and sideroblastic anemia.

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.

Cerebrospinal fluid leukocyte aggregation in meningitis.

OBJECTIVE: To evaluate whether the difference in aggregation of cerebrospinal fluid cells from patients with bacterial, viral, aseptic and partially treated meningitis can be used for diagnostic purposes. METHODS: Cerebrospinal fluid samples of 100 patients with meningitis (15 bacterial, 13 partially treated, 10 viral and 62 aseptic) were compared on the basis of the predefined leukocyte aggregation score (LAS). RESULTS: Mean LAS was 56% in the bacterial meningitis group (range, 15 to 90%), 5.8% in the partially treated meningitis group (range, 0 to 27%), 2% in the proven viral meningitis group (range, 0 to 5%) and 2% in the aseptic meningitis group (range, 0 to 15%). All patients with bacterial meningitis had a LAS of > 15%, whereas all those with viral or aseptic meningitis had a score of < 15%. Although most patients with partially treated meningitis had a low LAS, several had higher scores, which may indicate bacterial infection. There was no statistical correlation between number of cells, type of cells (mononuclear or polymorphonuclear) or cerebrospinal fluid protein and glucose concentration and degree of leukocyte aggregation for the different groups. CONCLUSION: Measurement of the LAS may contribute to the immediate differential diagnosis of bacterial or viral meningitis, especially in patients with very high pleocytosis, as sometimes seen in enteroviral meningitis. It may also serve as a guide for the likelihood of bacterial infection in cases of partially treated meningitis. Additional studies are needed to confirm these observations.

Risk of infection during adrenocorticotropic hormone treatment in infants with infantile spasms.

We reviewed the clinical features and laboratory findings of 27 infants with infantile spasms treated with adrenocorticotropic hormone or prednisone during febrile episodes in order to evaluate the incidence of bacteremia, the risk of serious infection, determination of whether serious infections can be identified at presentation and the outcome of febrile episodes. There were 75 febrile episodes including 4 episodes of identified bacteremia (5.3%). Three children who were treated with adrenocorticotropic hormone dosage larger than recommended died. Leukocytosis and a differential count with many immature granulocytes predicted bacteremia in this population. Chest radiography was useful in identifying the cause of fever. The pathogens isolated were similar to those found in this age range. We conclude that the frequency of bacteremia in our patient population is similar to that observed in infants of the same age; however, the outcome is frequently fatal. In addition this increased mortality may be associated with the use of a larger dosage of adrenocorticotropic hormone than recommended.

Gerstmann tetrad in leopard syndrome.

We report a 12-year-old boy with multiple lentigines (Leopard) syndrome who was evaluated for learning difficulties and Gerstmann tetrad syndrome (i.e., dyscalculia, left-right disorientation, finger agnosia, and dysgraphia). Cranial computed tomography revealed left ventriculomegaly, more pronounced in the occipital horn suggesting mild atrophy of the left parietal lobe. This is the first report of an association between the Leopard and Gerstmann syndromes and one of the few to demonstrate a computed tomographic abnormality in the latter.

Transient acute cortical blindness associated with hypoglycemia.

A 7-year-old boy with glycogen storage disease type III developed transient acute cortical blindness associated with hypoglycemia on two separate occasions; the patient also demonstrated transient high-voltage slowing on the electroencephalogram over both occipital areas. This patient is the second examined in our pediatric department during a 5 year period with acute cortical blindness associated with hypoglycemia.

MRI meningeal enhancement with intracranial hypotension caused by lumbar puncture.

A 12-year-old girl with recent history of pseudotumor cerebri developed severe postural headache due to intracranial hypotension after lumbar puncture. Meningeal enhancement and thickening were demonstrated on magnetic resonance imaging. Repeated imaging 3 months later disclosed no abnormalities. This is the first report of a child with evident meningeal enhancement on magnetic resonance imaging related to lumbar puncture.

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.

Helical hairs: a new hair anomaly in a patient with Netherton's syndrome.

A new hair shaft defect, helical hair, is presented. This hair abnormality was found to accompany trichorrhexis invaginata and pili torti in an infant with Netherton's syndrome. The patient's main clinical features included erythroderma since birth, failure to thrive, recurrent infections, hepatosplenomegaly, lymphadenopathy, eosinophilia, hypergammaglobulinemia, and high serum IgE levels. A possible mechanism for the formation of helical hair is reviewed.

Penile tourniquet syndrome.

A 2 1/2-year-old boy was examined because of swelling of the penis of six weeks' duration. Several strands of hair wrapped around the penis and buried under the epithelium were found to cause a constriction. The penile tourniquet syndrome should be suspected whenever the penis is swollen, especially in children, even if a foreign body is not visible.

Presternal swelling in mumps.

A case of presternal swelling associated with mumps is presented. presternal swelling occurs secondary to obstruction of the lymphatic drainage from the anterior-superior chest wall by the enlarged cervical salivary glands. The occurrence of this complication in mumps is discussed.