Effectiveness of single dose oral dexamethasone versus multidose prednisolone for treatment of acute exacerbations of asthma among children.

Introduction: Asthma is one of the most common chronic diseases in children and worldwide its prevalence has increased dramatically in the last three decades. We aimed to compare single dose oral dexamethasone versus multiple doses of oral prednisolone in children with acute exacerbation of asthma in terms of post treatment requirement of systemic steroids. Materials and methods: This Randomized control trial has been conducted in the Department of paediatrics, KRL Hospital, Islamabad from Dec 2018 to June 2019.312 patients between the age of 2-12 years patients were randomized into Group A receiving a STAT single dose of oral dexamethasone 0.3 mg/kg and Group B receiving prednisolone 1 mg/kg/day followed by two doses on Day 2 and 3. further dose of systemic steroids were ascertained through PRAM score. Results: In this study mean age in Group A was 8 years with SD ± 5.68 while mean age in Group B was 7 years with SD ± 6.12. In Group A 58% patients were male and 42% patients were female. Whereas in Group B 59% patients were male and 41% patients were female. In Group A 12% patients had further requirement of systemic steroids while in Group B 18% patients had further requirement of systemic steroids while 82% patients didn't had further requirement of systemic steroids. Conclusion: Our study concludes that post treatment requirement of systemic steroids is less in single dose oral dexamethasone as compare to multiple doses of oral prednisolone in children with acute exacerbation of asthma.

Genetic analysis of osteopetrosis in Pakistani families identifies novel and known sequence variants.

Osteopetrosis is a genetically heterogenous, fatal bone disorder characterized by increased bone density. Globally, various genetic causes are reported for osteopetrosis with all forms of inheritance patterns. A precise molecular diagnosis is necessary for prognosis and for prescribing treatment paradigms in osteopetrosis. Here we report on thirteen individuals diagnosed with infantile malignant osteopetrosis coming from ten unrelated Pakistani families; nine of whom are consanguineous. We performed whole exome sequencing and Sanger sequencing in all families and identified homozygous variants in genes previously reported for autosomal recessive inheritance of osteopetrosis. All the identified variants are expected to affect the stability or length of gene products except one nonsynonymous missense variant. TCIRG1 was found as a candidate causal gene in majority of the families. We report six novel variants; four in TCIRG1 and one each in CLCN7 and OSTM1. Our combined findings will be helpful in molecular diagnosis and genetic counselling of patients with osteopetrosis particularly in populations with high consanguinity.

Ellis-Van Creveld Syndrome in a Neonate.

Ellis-van Creveld syndrome is a rare form of skeletal and chondroectodermal dysplasia which affects all the three ectodermal, mesodermal, and endodermal derivatives. It has an autosomal recessive inheritance. This is caused by mutations in 1 of 2 genes, EVC 1 or EVC 2. This syndrome has a constellation of characteristic features that include bilateral post-axial polydactyly, mainly involving the upper limbs, hypoplastic nails and teeth, congenital heart defects, and chondroectodermal dysplasia. It is mainly a disorder of Amish population where incidence of this disease is 1/5000 and its incidence in non-Amish population is 7/1000000. Our patient had all the major characteristic features consistent with Ellis-van Creveld syndrome including post-axial polydactyly, teeth and nail abnormalities, congenital heart defect and skeletal dysplasia. Until now, only five cases have been reported from this region of the world, none of them diagnosed in neonatal life and having characteristic common atrium.

Identification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani family.

BACKGROUND: Osteopetrosis is a rare inherited bone disorder mainly described as an increased bone density caused by defective osteoclastic bone resorption. To date, genetic variants of eleven genes have been reported so far to be associated with different types of osteopetrosis. However, malignant infantile osteopetrosis, a lethal form of the disease, is mostly (50%) caused by mutation(s) in TCIRG1 gene. In this study, we investigated a consanguineous Pakistani family clinically and genetically to elucidate underlying molecular basis of the infantile osteopetrosis. METHODS: DNA samples from five family members were subjected to SNP-array based whole genome homozygosity mapping. Data was analyzed and potentially pathogenic mutation was identified by Sanger sequencing of two affected as well as three phenotypically healthy individuals in the family. The significance of identified pathogenic variation and its impact on protein structure and function was studied using various bioinformatics tools. RESULTS: DNA samples from five family members were subjected to genome-wide SNP array genotyping and homozygosity mapping which identified ~4 Mb region on chr11 harboring the TCIRG1 gene. Sanger sequencing unveiled a novel homozygous deletion c. 624delC in exon 6 of the TCIRG1 gene encodes a3 subunit of V-ATPase complex. The identified deletion resulted in a frame shift producing a truncated protein of 208 aa. In silico analysis of premature termination of the a3 subunit of V-ATPase complex revealed deleterious effects on the protein structure, predicting impaired or complete loss of V-ATPase function causing infantile osteopetrosis. CONCLUSIONS: Since a3 subunit of V-ATPase complex plays a crucial role in bone resorption process, structurally abnormal a3 subunit might have adversely affected bone resorption process, leading to infantile osteopetrosis in Pakistani family. Therefore, the present study not only expands the genotypic spectrum of osteopetrosis but also improve understandings of the role of V-ATPase a3 subunit in bone resorption process. Moreover, our findings should help in genetic counseling and provide further insight into the disease pathogenesis and potential targeted therapy.