Diagnosis of Chronic Granulomatous Disease: Strengths and Challenges in the Genomic Era.

Chronic granulomatous disease (CGD) is a group of rare primary inborn errors of immunity characterised by a defect in the phagocyte respiratory burst, which leads to severe and life-threatening infective and inflammatory complications. Despite recent advances in our understanding of the genetic and molecular pathophysiology of X-linked and autosomal recessive CGD, and growth in the availability of functional and genetic testing, there remain significant barriers to early and accurate diagnosis. In the current review, we provide an up-to-date summary of CGD pathophysiology, underpinning current methods of diagnostic testing for CGD and closely related disorders. We present an overview of the benefits of early diagnosis and when to suspect and test for CGD. We discuss current and historical methods for functional testing of NADPH oxidase activity, as well as assays for measuring protein expression of NADPH oxidase subunits. Lastly, we focus on genetic and genomic methods employed to diagnose CGD, including gene-targeted panels, comprehensive genomic testing and ancillary methods. Throughout, we highlight general limitations of testing, and caveats specific to interpretation of results in the context of CGD and related disorders, and provide an outlook for newborn screening and the future.

Morbidity and treatment costs of cystic fibrosis in a middle-income country.

Introduction: : Asian children with cystic fibrosis (CF) managed in Malaysia have significant morbidity with limited access to life-sustaining treatments. We determined the morbidity and treatment cost of CF in a resource-limited country. Methods: This cross-sectional study included all children diagnosed with CF in our centre. Data on clinical presentation, genetic mutation, serial spirometry results and complications were collected. Out-of-pocket (OOP) and healthcare costs over 1 year were retrieved for patients who were alive. Cohen's d and odds ratio (OR) were used to determine the effect size. Results: Twenty-four patients were diagnosed with CF. Five patients died at a median (range) age of 18 (0.3-22) years. F508deletion (c. 1521_1523delCTT) was found in 20% of the alleles, while 89% of the variants were detected in nine patients. Body mass index (BMI) Z score was >-1.96 in 70.6% of patients. Two thirds (68%) were colonised with Pseudomonas aeruginosa, and this was associated with lower weight (P = 0.009) and BMI (P = 0.02) Z scores. Only 18% had FEV1 Z scores >-1.96. Early symptom onset (d = 0.74), delayed diagnosis (d = 2.07), a low FEF25-75 Z score (d = 0.82) and a high sweat conductance (d = 1.19) were associated with death. Inpatient cost was mainly from diagnostic tests, while medications contributed to half of the outpatient cost.Healthcare utilisation cost was catastrophic, amounting to 20% of the total income. Conclusion: Asian children with CF suffer significant complications such as low weight, low lung function and shortened lifespan. P. aeruginosa colonisation was frequent and associated with poor growth. Healthcare cost to parents was catastrophic.

Health-related quality of life and developmental outcome of children on home mechanical ventilation in a developing country: A cross-sectional study.

BACKGROUND: Provision of home mechanical ventilation (HMV) to children with chronic respiratory insufficiency enhances growth and quality of life. The hypothesis was that health-related quality of life (HRQoL) and the development of these children were poorer than in healthy children. OBJECTIVES: To determine the HRQoL and developmental outcome of children on HMV. METHODS: This cross-sectional study used the TNO-AZL Preschool children's Quality Of Life (TAPQOL; <5 years old) and Health Utilities Index (HUI) 2/3 (≥5 years old) to assess the quality of life and the Schedule of Growing Skills-II to assess development. Instruments were used on children currently or previously on HMV (≥3 months) and compared with age and sex-matched controls. RESULTS: Sixty-five patients and 130 controls were recruited. Patients' median (interquartile range) age was 3.12 (1.65, 5.81) years. Patients had significantly lower TAPQOL scores in the domains of lung, liveliness, positive mood, social functioning, motor functioning, and communication, and lower HUI 2/3 scores in hearing, sensation, pain, speech, mobility, ambulatory, dexterity, and self-care domains. The developmental outcome of patients was poorer in all domains. However, patients had fewer behavioral problems. Those with respiratory tract disease and without comorbidities had better HRQoL and developmental scores. Having a parent as the primary caregiver was associated with better speech and language skills. CONCLUSIONS: HRQoL and the developmental outcome are lower in children on HMV compared to controls. Children with respiratory tract disease and without comorbidities have a better outcome. Parents play a crucial role in the acquisition of speech.

Density of breast: An independent risk factor for developing breast cancer, a prospective study at two premium breast centers.

BACKGROUND: Breast cancer is the leading cause of death among women worldwide. Studies have identified breast density as a controversial risk factor of breast cancer. Moreover, studies found that breast density reduction through Tamoxifen could reduce risk of breast cancer significantly. To date, no study on the association between breast density and breast cancer has been carried out in Malaysia. If breast density is proven to be a risk factor of breast cancer, intervention could be carried out to reduce breast cancer risk through breast density reduction. PURPOSE: To determine if density of breast is an independent risk factor which will contribute to development of breast cancer. MATERIALS AND METHODS: A prospective cohort study is carried out in two hospitals targeting adult female patients who presented to the Breast Clinic with symptoms suspicious of breast cancer. Participants recruited were investigated for breast cancer based on their symptoms. Breast density assessed from mammogram was correlated with tissue biopsy results and final diagnosis of benign or malignant breast disease. RESULTS: Participants with dense breasts showed 29% increased risk of breast cancer when compared to those with almost entirely fatty breasts (odds ratio [OR] 1.29, 95% CI 0.38-4.44, P = .683). Among the postmenopausal women, those with dense breasts were 3.1 times more likely to develop breast cancer compared with those with fatty breasts (OR 3.125, 95% CI 0.72-13.64, P = .13). Moreover, the chance of developing breast cancer increases with age (OR 1.046, 95% CI 1.003-1.090, P < .05). In contrast, the density of breast decreases with increasing age (P < .05) and body mass index (P = .051). The proportion of high breast density whether in the whole sample size, premenopausal, or postmenopausal group was consistently high. CONCLUSION: Although results were not statistically significant, important association between breast density and risk of breast cancer cannot be ruled out. The study is limited by a small sample size and subjective assessment of breast density. More studies are required to reconcile the differences between studies of contrasting evidence.