Baruch Wolach

Chronic Granulomatous Disease: The European Experience

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a “respiratory burst”, essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (∼1∶250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91phox deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with γ-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.

Hematologically important mutations: X-linked chronic granulomatous disease (third update)

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by a lack of superoxide production by the leukocyte enzyme NADPH oxidase. Superoxide is used to kill phagocytosed micro-organisms in neutrophils, eosinophils, monocytes and macrophages. The leukocyte NADPH oxidase is composed of five subunits, of which the enzymatic component is gp91-phox, also called Nox2. This protein is encoded by the CYBB gene on the X chromosome. Mutations in this gene are found in about 70% of all CGD patients. This article lists all mutations identified in CYBB in the X-linked form of CGD. Moreover, apparently benign polymorphisms in CYBB are also given, which should facilitate the recognition of future disease-causing mutations.

Treatment of hemangiomas of infants with high doses of prednisone

OBJECTIVE We reviewed our experience with the use of oral corticosteroid therapy in treating hemangiomas of infants to determine the optimal effective dose. STUDY DESIGN During a 24-year period, 60 infants with hemangiomas were treated with an initial dose of either 3 or 5 mg/kg per day of orally administered prednisone for a period ranging from 6 to 12 weeks. Involution of the hemangioma and re-growth. were monitored. RESULTS Overall, excellent and rapid results were achieved in 68% of infants and good results occurred in 25%. In 7% treatment was deemed to have failed. Forty-seven of 60 patients received one course of therapy, 8 received 2 courses, and 5 required 3 courses. An initial dose of 5 mg/kg per day oral prednisone therapy was more effective than 3 mg/kg per day. Side effects were not serious and resolved after discontinuation of therapy. CONCLUSIONS High oral doses of corticosteroids (5 mg/kg per day prednisone) provide an effective, rapid, and safe modality of treatment of hemangiomas of infants. We recommend that treatment continue for 6 to 8 weeks, and in more severe cases for as long as 12 weeks.

Hematologically important mutations: The autosomal recessive forms of chronic granulomatous disease (second update)

Chronic granulomatous Disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is essential in the process of intracellular pathogen killing by phagocytic leukocytes. Four of the five genes involved in CGD are autosomal; these are CYBA, encoding p22-phox, NCF2, encoding p67-phox, NCF1, encoding p47-phox, and NCF4, encoding p40-phox. This article lists all mutations identified in these genes in the autosomal forms of CGD. Moreover, polymorphisms in these genes are also given, which should facilitate the recognition of future disease-causing mutations.

The effect of a combined intervention on body mass index and fitness in obese children and adolescents – a clinical experience

Abstract. We assessed the effect of a weight management programme on body weight, body mass index (BMI), and fitness in obese children and adolescents. The study was designed as a longitudinal, non-randomised, clinical experience of a 3 and 6 month combined dietary-behavioural-exercise intervention. A total of 177 obese children (age 6–16 years) participated in the 3 month programme, of whom 65 completed the 6 month intervention. A group of 25 age- and maturity-matched obese children who did not participate in the structured programme served as controls. Body weight, BMI, and fitness were evaluated at baseline, and after the 3 and 6 months intervention. Body weight and BMI were significantly reduced (P<0.05), and endurance time significantly increased (P<0.0005) following the 3 months intervention. Obese children who continued the programme for 6 months maintained the decrease in BMI and further improved endurance time. In contrast, obese children who did not participate in the structured programme gained weight, increased their BMI, and improved fitness less significantly. Gender, pubertal status, and the degree of obesity had no influence on BMI changes. Children without parental overweight had significantly greater decreases in BMI compared to children of obese parents. Conclusion: a combined, structured multidisciplinary intervention for childhood obesity results in decreased body weight, decreased body mass index and improved fitness.

Aspirated foreign bodies in the respiratory tract of children: eleven years experience with 127 patients

During 10 years, 127 children were admitted to the pediatric ward because of aspiration of foreign bodies (0.56% of all admissions). Eighty-one percent of the children were under 3 years of age. One hundred and one children (80%) had a positive history of foreign body aspiration. Vegetable substances, particularly peanuts and grains, were the commonest type of foreign body removed. Clinical signs and radiological studies were, in most children, pathognomonic, but sometimes not conclusive. Chest X-rays were normal in 18%; fluoroscopy was diagnostic in 92%. Rigid bronchoscopy and subsequent removal of the foreign body was the treatment instituted. Pneumonia (the commonest complication) developed before and after bronchoscopy in 28% of the children. Pneumomediastinum and subcutaneous emphysema were present on admission in 2 children. Cardiac arrhythmias, bronchospasm, and cardiac arrest were recorded during bronchoscopy. Bronchiectasis developed in one, and persistent intractable pneumonia, requiring lobectomy, developed in another patient. One death occurred.

Quantitative ultrasound measurements of bone speed of sound in premature infants.

Abstract. We measured bone speed of sound in premature infants by quantitative ultrasound. A total of 44 neonates participated in the study including 29 premature infants (median birth weight 1264 g, range 578–2420 g; median gestational age 31 weeks, range 24–36 weeks) and 15 full-term infants (median birth weight 3360 g, range 2700–3730 g; median gestational age 40 weeks, range 37–41 weeks). The left tibial speed of sound (SOS) was measured by quantitative ultrasound. Bone SOS was successfully measured in all infants. We found a significant correlation between tibial SOS and gestational age (r=0.78, P<0.0005), but a significant inverse correlation between tibial SOS and post-natal age (r=–0.78, P<0.0005). Bone SOS was significantly (P<0.05) higher in full-term infants (3101 m/s, range 2899–3314 m/s) compared to premature infants (2821 m/s, range 2516–3139 m/s), and compared to a subgroup of the premature infants who reached corrected age of full-term infants (2706 m/s, range 2516–2892 m/s, n=13). Bone SOS was lower (2745 m/s, range 2533–3036 m/s, n=16) in very low birth weight premature infants (birth weight <1500 g). Conclusion: the results indicate that tibial speed of sound was reduced in premature infants (in particular very low birth weight) compared to full-term infants even when premature infants reached the corrected age of their full-term peers. The potential role of this technique in assessing osteopenia in premature infants warrants further exploration.

Chronic granulomatous disease in Israel : Clinical, functional and molecular studies of 38 patients

Chronic granulomatous disease (CGD) is an innate immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. In the course of 21 years, 38 Israeli CGD patients were diagnosed with 17 gene mutations, seven of which were new. Clinical, functional, and molecular studies were accomplished. Although X-linked recessive (XLR)-CGD is worldwide the most common genotype of the disease (~70%), in our study only 11 patients (29%) suffered from XLR-CGD. In Israel, the higher incidence of the autosomal recessive (AR) form of CGD (63%) may be related to consanguineous marriages. In three patients (8%), all four proteins of the NADPH oxidase were present. Severe clinical expression was found both in the XLR and AR forms, but in general a milder disease was evident in AR-CGD, particularly in patients with p47(phox) deficiency. Despite early and aggressive therapy, a mortality rate of 26% was noted. Given that bone-marrow transplantation was successful in five of seven patients, it is recommended to perform it as early as possible before tissue damage is irreversible.

A congenital neutrophil defect syndrome associated with mutations in VPS45

BACKGROUND Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. METHODS We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single-nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase-chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. RESULTS All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the childs ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn-5 and syntaxin-16. The level of β1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. CONCLUSIONS Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (Funded by the National Human Genome Research Institute and others.).

Increased sodium concentrations in drinking water increase blood pressure in neonates.

Background In a previous study, we found that increased sodium concentrations in the drinking water led to an increase in mean arterial pressure (MAP) and systolic blood pressure (SBP) in fourth- and fifth-grade school children. Milk powder formulae have a low content of sodium, almost identical to that of breast milk. However, the final sodium concentration in the milk formula depends upon the concentration of sodium in the diluting water, which varies remarkably. Objective To evaluate changes in blood pressure during the first 2 months of life in neonates receiving low-sodium mineral water (LSMW), high-sodium tap water (HSTW), or breast milk. Design A randomized, prospective study in a teaching hospital. Methods Fifty-eight Jewish term infants maintained on milk formula were randomly assigned to two groups. Group 1 consisted of 25 infants whose formula was diluted with LSMW (Eden Spring Mineral Water) having a sodium concentration of 32 mg/l (1.4 mmol/l). Group 2 contained 33 infants whose formula was diluted with HSTW having a sodium concentration of 196 mg/l (8.5 mmol/l). Fifteen breastfed babies served as the control group (group 3). Weekly weight, height, head circumference, heart rate, and systolic (SBP), diastolic (DBP) and mean (MAP) blood pressures were recorded for each infant for 8 consecutive weeks after birth. After 8 weeks, group 1 reverted to a diet similar to that of group 2. At 6 months of age (week 24), a follow-up blood pressure measurement was performed in 11, 20 and seven infants in groups 1, 2 and 3, respectively. Blood pressure was measured during sleep. Urinary sodium : creatinine ratio was determined monthly during the initial 2 months. Results Increases in weight and height were equal in all groups. Heart rate did not differ between groups during the entire study period. From the age of 6 weeks until week 8, MAP, SBP and DBP were found to be significantly greater in the group 2 (HSTW). In parallel, the urinary sodium : creatinine ratio was significantly greater in this group. At week 24, blood pressure values in group 1 increased towards those of group 2. Conclusions Diluting milk formula with tap water containing a high concentration of sodium will result in the infant being fed a high-salt diet. To equilibrate with breast milk, formula should be diluted with low-salt water. Blood pressure in the neonate is increased by a high sodium intake via drinking water.