Clinical spectrum and diagnostic challenges of vitamin D dependent rickets type 1A (VDDR1A) caused by CYP27B1 mutation in resource limited countries.

OBJECTIVES: Vitamin D dependent rickets type 1A (VDDR1A) is a rare autosomal recessive condition due to inactivating mutation of CYP27B1. It mimics clinically, biochemically and rediologically to nutritional and hypophosphatemic rickets. In developing countries like Pakistan, VDDR1A is often misdiagnosed as nutritional rickets or hypophosphatemic rickets due lack of free access to 1,25 (OH) 2 D level and genetic testing. This study was aimed to determine the clinical spectrum and diagnostic challenges of VDDR1A due to CYP27B1 mutation in developing countries. METHODS: Retrospective review of all cases of VDDR1A due to CYP27B1 mutation over a period of two years presenting in the Pediatric Endocrine clinic of Hameed Latif Hospital, Lahore, Pakistan. RESULTS: Six cases of VDDR1A (4 males) were identified. Mean age of clinical manifestation was 14 (9-24) months. Mean age of presentation to endocrine department was 5.5 (1.5-11.8) years. Growth failure and bony deformities were the most common presentation (n=6), followed by repeated diarrheas and abdominal distension (n=3) and recurrent fractures (n=1). All cases shared same biochemical profile of low/normal calcium, hypophosphatemia, raised alkaline phosphatase, raised PTH, normal/high 25(OH)D and tubular reabsorption of phosphate (TRP) <85%. Patients treated with calcitriol showed rapid healing as compared to those treated with 1-alfacalcidol. CONCLUSIONS: We should have a high index of suspicion of VDDR1A in rickets not responding to cholecalciferol therapy.

A 3' untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma.

Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR)GG = 3.55, 95% confidence interval (CI) = 1.79-7.06] and XPC rs2228001 (ORAC = 2.38, 95% CI = 1.43-3.94) with UBC. In stratified analysis with respect to smoking status, OGG1 rs2304277 and XPC rs2228001 exhibited increased risk in smokers [(rs2304277 ORGG = 4.96, 95% CI = 1.51-16.30) (rs2228001 ORAC = 2.19, 95% CI = 1.02-4.72)] as well as nonsmokers [(rs2304277 ORGG = 2.95, 95% CI = 1.26-6.90) (rs2228001 ORAC = 2.57, 95% CI = 1.31-5.04)]. These polymorphisms were also associated with both low-grade [(rs2304277 ORGG = 3.73, 95% CI = 1.72-8.09) (rs2228001 ORAC = 2.18, 95% CI = 1.21-3.92)] and high-grade tumors [(rs2304277 ORGG = 3.45, 95% CI = 1.52-7.80) (rs2228001 ORAC = 2.81, 95% CI = 1.48-5.33)] as well as with non-muscle-invasive bladder cancer [(rs2304277 ORGG = 4.03, 95% CI = 1.87-8.67) (rs2228001 ORAC = 2.14, 95% CI = 1.20-3.81)] and muscle-invasive bladder cancer [(rs2304277 ORGG = 3.06, 95%CI = 1.31-7.13) (rs2228001 ORAC = 2.95, 95%CI = 1.51-5.75)]. This is the first study on DNA repair gene polymorphisms and UBC in the Pakistani population. It identifies OGG1 rs2304277 and replicates XPC rs2228001 as significant modulators of UBC susceptibility.

Identification of novel potential genetic predictors of urothelial bladder carcinoma susceptibility in Pakistani population.

Urothelial bladder carcinoma (UBC) is the most common among urinary bladder neoplasms. We carried out a preliminary study to determine the genetic etiology of UBC in Pakistani population, for this 25 sequence variants from 17 candidate genes were studied in 400 individuals by using polymerase chain reaction-based techniques. Multivariate logistic regression analysis was performed for association analysis of the overall data as well as the data stratified by smoking status, tumor grade and tumor stage. Variants of GSTM1, IGFBP3, LEPR and ACE were found to be associated with altered UBC risk in the overall comparison. CYP1B1 and CDKN1A variants displayed a risk modulation among smokers; IGFBP3 and LEPR variants among non-smokers while GSTM1 polymorphism exhibited association with both. GSTM1 and LEPR variants conferred an altered susceptibility to low grade UBC; GSTT1, IGFBP3 and PPARG variants to high grade UBC while ACE polymorphism to both grades. GSTM1 and LEPR variants exhibited risk modulation for non-muscle-invasive bladder cancer (NMIBC); GSTT1 and PPARG variants for muscle-invasive bladder cancer (MIBC), and ACE variant for NMIBC as well as MIBC. In general, the susceptibility markers were common for low grade and NMIBC; and distinct from those for high grade and MIBC indicating the distinct pathologies of both groups. In brief, our results conform to reports of previously associated variants in addition to identifying novel potential genetic predictors of UBC susceptibility.

Childhood primary angiitis of the central nervous system.

OBJECTIVE: To analyze the clinical course and magnetic resonance angiographic (MRA) abnormalities in children with primary angiitis of the central nervous system (cPACNS). STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Neurosciences and Neuroradiology Department of the Children's Hospital, Lahore, from January 2009 to December 2010. METHODOLOGY: The cohort comprised consecutive patients diagnosed as having cPACNS based on clinical findings and identification of arterial stenosis on magnetic resonance angiography (MRA) in the absence of an underlying condition that could cause these findings. The treatment protocol for ischaemic infarcts consisted of induction therapy with intravenous steroids pulses and intravenous immunoglobulin followed by maintenance therapy with azathioprine and low dose aspirin. When indicated, they were treated with anticoagulants at least for 4 weeks along with induction therapy. Patients were followed at a single centre and systemically assessed for clinical presentation, classification of disease as progressive or non-progressive, adverse effects of anticoagulants, aspirin, azathioprine and their hospital course. RESULTS: Sixty-eight children with medium-large vessel cPACNS (62% boys, 38% girls) with mean age of 8.5 ± 3.5 years were enrolled in this study. Motor deficit (70%); headache (64%) and fever (20%) were the commonest symptoms; whereas hemiparesis (60%); seizures 55% (focal 35%, generalized 20%) and decreased conscious level (30%), were the commonest neurological findings. Neuroradiological findings were ischaemic strokes in 50 (73.5%), haemorrhagic strokes in 10 (14.7%) and ischaemic haemorrhagic lesions in 8 cases (11.8%). Angiographically 51 (51/68, 75%) of the cohort had non-progressive (obliterative) and 17 (17/68, 25%) had evidence of progressive arteriopathy at the time of admission. No secondary haemorrhagic lesions were documented among infarcts strokes, which were treated with heparin and oral anticoagulants. Outcome was survival in 56 cases (81.5%) and death in 12 cases (18.5%). All survivors were discharged on long-term oral aspirin; 15 of them were also commenced on azathioprine. Neurological findings among the 56 survivors were; normal 20%, minor disabilities in 25%, moderate disabilities in 20% and severe disabilities in 35%. CONCLUSION: The spectrum of cPACNS includes both progressive and non-progressive forms with significant morbidity and mortality. This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with medium-large vessel childhood primary angiitis of the CNS.

The spectrum of neurodegeneration in children.

OBJECTIVE: To find out the spectrum of diagnosis, clinical presentation and role of neuroimaging in neurodegenerative disorders of childhood. DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Neurology, Children's Hospital, Lahore from June, 2004 to May, 2005. PATIENTS AND METHODS: A total of 1273 patients were admitted in the Neurology Department in the said period. Out of them, 66 children fulfilled the inclusion criteria. History, clinical examination and relevant investigations were carried out and proformas were filled. Data was analyzed for descriptive statistics. RESULTS: In a total sample of 66, the male to female ratio was 1.4:1. Age range was one to twelve years. Metachromatic leukodystrophy was the predominant type seen in 14 (21%), followed by 11 cases of adrenoleukodystrophy (16%) and 8 patients with SSPE (12%). Six children (9.8%) had Wilson's disease. Five cases (7.5%) were diagnosed as Friedrich ataxia, 4 cases (4%) as lipidosis, 3 case as Gaucher's disease (4.5%), and two cases (3%) each as Alexander disease, and Hellervorden-spatz disease; and one case each as multiple sclerosis and ataxia telangiectasia. In 6 cases, final diagnosis could not be made. MRI and CT scan of brain were done in 71% and 41% patients only. Furdos copy (in 65%), CSF examination in 59% and EEG in 56% were main non-imaging investigations utilized for diagnosis. CONCLUSION: Degenerative brain diseases are not an uncommon entity in paediatric population. Commonest presentation is regression of milestones, though, it may be variable. Because of limited diagnostic modalities, brain imaging has significant value. Facilities for enzyme studies should also be available at tertiary care hospitals.