Background: Chronic Granulomatous Disease (CGD) is an inherited defect in phagocytic respiratory burst that results in severe and life-threatening infections in affected children. Single centre studies from India have shown that proportion of autosomal recessive (AR) CGD is more than that reported from the West. Further, affected patients have high mortality rates due to late referrals and difficulties in accessing appropriate treatment. However, there is lack of multicentric collaborative data on CGD from India. Objective: To describe infection patterns, immunological, and molecular features of CGD from multiple centres in India. Methods: A detailed proforma that included clinical and laboratory details was prepared and sent to multiple centres in India that are involved in the care and management of patients with inborn errors of immunity. Twelve centres provided data which were collated and analysed. Results: Of the 236 patients in the study, X-linked and AR-CGD was seen in 77 and 97, respectively. Male female ratio was 172:64. Median age at onset of symptoms and diagnosis was 8 and 24 months, respectively. Common infections documented include pneumonia (71.6%), lymphadenitis (31.6%), skin and subcutaneous abscess (23.7%), blood-stream infection (13.6%), osteomyelitis (8.6%), liver abscess (7.2%), lung abscess (2.9%), meningoencephalitis (2.5%), splenic abscess (1.7%), and brain abscess (0.9%). Forty-four patients (18.6%) had evidence of mycobacterial infection. Results of molecular analysis were available for 141 patients (59.7%) – CYBB (44.7%) gene defect was most common, followed by NCF1 (31.9%), NCF2 (14.9%) and CYBA (8.5%). While CYBA variants were documented only in Southern and Western parts of India, a common dinucleotide deletion in NCF2 (c.835_836delAC) was noted only in North Indian population. Of the 174 patients with outcome data, 67 (38.5%) had expired. Hematopoietic stem cell transplantation was carried out in 23 patients and 12 were doing well on follow-up. Conclusions: In India, AR-CGD is more common compared to Western cohorts, though regional differences in types of AR-CGD exist. Clinical profile and mortality rates are similar in both X-linked and AR-CGD. However, this may be a reflection of the fact that milder forms of AR-CGD are probably missed. Keywords: Chronic Granulomatous Disease; India; Mycobacterium tuberculosis; BCG; Survival

/pdf/clinical-immunological-and-molecular-profile-of-chronic-ul3jy8zf53.pdf

Clinical, Immunological, and Molecular Profile of Chronic Granulomatous Disease: A Multi-Centric Study of 236 Patients From India.

Chronic granulomatous disease (CGD) is an immunodeficiency disorder affecting about 1 in 250,000 individuals. CGD patients suffer from severe, recurrent bacterial and fungal infections. The disease is caused by mutations in the genes encoding the components of the leukocyte NADPH oxidase. This enzyme produces superoxide, which is subsequently metabolized to hydrogen peroxide and other reactive oxygen species (ROS). These products are essential for intracellular killing of pathogens by phagocytic leukocytes (neutrophils, eosinophils, monocytes and macrophages). The leukocyte NADPH oxidase is composed of five subunits, four of which are encoded by autosomal genes. These are CYBA, encoding p22phox, NCF1, encoding p47phox, NCF2, encoding p67phox and NCF4, encoding p40phox. This article lists all mutations identified in these genes in CGD patients. In addition, cytochrome b558 chaperone-1 (CYBC1), recently recognized as an essential chaperone protein for the expression of the X-linked NADPH oxidase component gp91phox (also called Nox2), is encoded by the autosomal gene CYBC1. Mutations in this gene also lead to CGD. Finally, RAC2, a small GTPase of the Rho family, is needed for activation of the NADPH oxidase, and mutations in the RAC2 gene therefore also induce CGD-like symptoms. Mutations in these last two genes are also listed in this article.

Hematologically important mutations: The autosomal forms of chronic granulomatous disease (third update).

Systematic review of clinical practice guidelines on the management of community acquired pneumonia in children.

American association of clinical endocrinologists and american college of endocrinology protocol for standardized production of clinical practice guidelines, algorithms, and checklists - 2017 update.

Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall. As a result, patients with LAD suffer from severe bacterial infections and impaired wound healing, accompanied by neutrophilia. In LAD-I, characterized directly after birth by delayed separation of the umbilical cord, mutations are found in ITGB2, the gene that encodes the β subunit (CD18) of the β2 integrins. In the rare LAD-II disease, the fucosylation of selectin ligands is disturbed, caused by mutations in SLC35C1, the gene that encodes a GDP-fucose transporter of the Golgi system. LAD-II patients lack the H and Lewis Lea and Leb blood group antigens. Finally, in LAD-III, the conformational activation of the hematopoietically expressed β integrins is disturbed, leading to leukocyte and platelet dysfunction. This last syndrome is caused by mutations in FERMT3, encoding the kindlin-3 protein in all blood cells, involved in the regulation of β integrin conformation. This article contains an update of the mutations that we consider to be relevant for the various forms of LAD. 

Hematologically important mutations: Leukocyte adhesion deficiency (second update).

Background
Chronic granulomatous disease (CGD) is a rare disease in China, and very little large‐scale studies have been conducted to date. We aimed to investigate the clinical and genetic features of CGD in Chinese pediatric patients.

Clinical and genetic characteristics of Chinese pediatric patients with chronic granulomatous disease.

Importance:
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase deficiency is a rare and underdiagnosed disorder with fewer than 30 patients reported worldwide. The application of whole-exome sequencing in patients could improve our understanding of this disorder.


Objective:
To identify the genetic causes and evaluate the phenotype of mitochondrial HMG-CoA synthase deficiency in a pediatric patient with uncommon features that included ketosis and elevated lactate and ammonia.


Methods:
The proband was referred to the pediatric intensive care unit of Beijing Children’s Hospital and selected for molecular testing with whole-exome sequencing. Her parents and sibling also underwent sequencing for segregation information.


Results:
We identified two novel mutations (c.1347_1351delAGCCT/p.Ala450Profs*7 and c.1201G>T/p.Glu401*) in the HMG-CoA synthase-2 gene (HMGCS2, NM_005518.3) in the proband and her brother. Both variants were classified as pathogenic variants according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Metabolic acidosis in the proband was corrected with continuous renal replacement therapy and she left hospital after 21 days of treatment.


Interpretation:
Our results extend the genotypic and phenotypic spectrum of HMGCS2 mutation in mitochondrial HMG-CoA synthase deficiency patients and serve as a reminder for physicians to consider mitochondrial HMG-CoA synthase deficiency in newborns and children with coma and hypoketotic hypoglycemia after fasting.


Key words: 
HMGCS2 mutation; Hypoketotic hypoglycemia; Mitochondrial HMG-CoA synthase deficiency; Pediatric intensive care unit; Whole-exome sequencing

Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality worldwide among children. The growing number of guidelines have been accompanied with a growing concern about variance and conflicts among guideline recommendations. There is a need to critically appraise clinical practice guidelines (CPGs) in order to ensure safe and effective practices. A literature search was systematically conducted in English and Chinese major academic databases (from January 2000 to March 2015). CPGs related to CAP in children were evaluated by four independent assessors, according to AGREE II instruments. Standardized domain scores were calculated for each guideline. Inter-rater reliability was assessed by intraclass correlation coefficient. The software used for analysis was SPSS 17.0. A total of 10 guidelines met the inclusion criteria and were appraised. Scope and purpose (69.03 %) and clarity of presentation (83.33 %) achieved relative high scores, while the scores of the other four domains were low: stakeholder involvement (42.78 %), rigour of development (44.95 %), applicability (37.60 %), and editorial independence (23.74 %). 3 guidelines were strongly recommended as a result of the overall scores were greater than 60 %. The qualities of CPGs for CAP in children were generally acceptable with several flaws. Stakeholder involvement, rigour of development, applicability and editorial independence should be considered and well described in the future development of CPGs.

/pdf/appraisal-of-clinical-practice-guidelines-on-community-1g0z7u1s3p.pdf

Appraisal of clinical practice guidelines on community-acquired pneumonia in children with AGREE II instrument.

The high clinical and genetic heterogeneity makes it difficult to reach a confirmative diagnosis of suspected pediatric respiratory inherited diseases. Many patients with monogenic respiratory disorders could be missed without genetic testing. We performed a single-center study in Beijing Children's Hospital to demonstrate the clinical utility of exome sequencing (ES) as a first-tier test by evaluating the diagnostic yields of ES for inherited diseases with respiratory symptoms. A total of 107 patients were recruited in this study. We identified 51 pathogenic or likely pathogenic variants in 37 patients by ES (with or without copy number variants sequencing). The overall diagnostic yield was 34.6% (37/107). The most frequent disorders in our cohort were primary immunodeficiency disease (PIDs) (18/37, 48.6%) and primary ciliary dyskinesia (PCD) (9/37, 24.3%). We further reviewed the directive outcomes of genetic testing on the 37 positive cases. Our study demonstrated the effectiveness of ES as a first-tier test in China for diagnosing monogenic diseases of the respiratory system. In the era of precision medicine, ES as a first-tier test can rapidly make a molecular diagnosis and direct the intervention of the positive cases in pediatric respiratory medicine.

Exome sequencing as the first-tier test for pediatric respiratory diseases: A single-center study.

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Clinical and genetic characteristics of Chinese pediatric patients with chronic granulomatous disease.

Novel HMGCS2 pathogenic variants in a Chinese family with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

Appraisal of clinical practice guidelines on community-acquired pneumonia in children with AGREE II instrument.

Exome sequencing as the first-tier test for pediatric respiratory diseases: A single-center study.