Diabetes and CFAP126 gene mutation; are they really linked together?

OBJECTIVES: We are reporting a rare case series of 2 siblings and their mother with diabetes having a CFAP126 gene mutation. CASE PRESENTATION: Two female siblings, presented with incidental hyperglycemia at the ages of 16 and 13. They had a strong family history of diabetes on the maternal side. The systemic examination was unremarkable. Sibling 1 had HbA1C of 12.3 % with insulin and C-peptide levels of 6.6 IU/L and 1.8 ng/mL, respectively. Sibling 2 had an HbA1C of 12.6 %, an insulin level of 7.3 IU/L, and a C-peptide level of 2.02 ng/mL. Anti-GAD-65 and IA2 antibodies were negative. Mother also shared similar clinical processes and exhibited comparable biochemical changes related to glucose metabolism with elevated HbA1C levels and negative autoimmune markers (anti-GAD65 and IA2 antibodies). Whole exome sequencing (WES) turned out to be negative for MODY variants but revealed a rare heterozygous mutation in the CFAP126 gene (c.310A>T p. (Lys104*) in this family including both siblings and mother. The pathogenicity prediction tool MutationTaster® classified the mutation as disease causing. Oral glibenclamide remarkably reduced insulin requirements and improved HbA1C levels. CONCLUSIONS: This rare genetic mutation is likely associated with diabetes and possibly a novel marker for a yet to be identified type of diabetes, that is responsive to oral sulfonylureas. The influence of this gene on insulin secretion needs to be confirmed through future research.

The Mutational Landscape Of Genetic Cholestatic Diseases In Pakistani Children.

Objectives: To report the mutational landscape of a clinically diagnosed cohort of paediatric patients with cholestasis liver diseases. METHODS: The retrospective study was conducted at the University of Child Health Sciences, The Children Hospital, Lahore, Pakistan, from December 10, 2021, to March 31, 2022, and comprised data collected from the Paediatric Gastroenterology and Hepatology unit on demographics, clinical and laboratory findings related to children of either gender aged <12 years and diagnosed with cholestatic liver disease from July 2018 to June 2021. The diagnosis was based on clinical and biochemical findings, with no evidence of biliary atresia and metabolic liver disease. Molecular characterisation was done through whole exome sequencing. RESULTS: Of the 171 children evaluated, 92(53.8%) were diagnosed with genetic cholestatic disorders. There were 52(56%) boys and 41(44%) girls. The median age at presentation was 19.5 months (interquartile range: 51 months). Consanguinity was found in 82(88.1%) cases, and positive family history with one or more affected siblings was noted in 60(64.5%). Exome sequencing identified pathogenic mutations in 13 genes underlying the hereditary cholestasis; ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, DCDC2, ACOX2, AKR1D1, HSD3B7, ABCC2, USP53, SLC10A1, and SLC51A. Of the 70 variants identified, 50(71.4%) were novel variants. The ABCB11-related hereditary cholestasis was the most frequent 27(29%), followed by ABCB4 (26(27.9%). Homozygosity was frequently seen in all except 8(8.6%) children, who had compound heterozygous pathogenic variants. There was no evidence of phenotypic expression in the carrier parents despite the severe nature of the respective mutations identified in the patients. CONCLUSIONS: Genetic heterogeneity of paediatric intrahepatic cholestasis showed recurrent and novel mutations.

Clinical and Genetic Description of Hereditary Chronic Pancreatitis in Pakistani Children.

BACKGROUND/AIMS: The purpose of this study was to identify the spectrum and frequency of pathogenic variants as well as the clinical and genetic insight of hereditary chronic pancreatitis in Pakistani children. MATERIALS AND METHODS: The deoxyribonucleic acid of affected probands of 44 unrelated Pakistani families, having hereditary chronic pancreatitis-affected children, were subjected to massive parallel sequencing for candidate reported genes (SPINK1, PRSS1, CFTR, CPA1, CTRC, CBS, AGL, PHKB, and LPL). Data were analyzed using different bioinformatics tools for the variants and in-silico analysis. All the identified variants were validated by direct sequencing of the targeted exons in the probands and their parents. RESULTS: There were 50 patients included in this study with confirmed hereditary chronic pancreatitis. Nine known mutations in SPINK1, PRSS1, CFTR, CTRC, CBS, and AGL genes, and 10 novel variants in LPL, CFTR, CTR, and PHKB genes were identified. The identified variants were found in heterozygous, compound heterozygous, and trans-heterozygous forms, with rare allele frequency in the normal population. The novel variants were [c.378C>T(p.Lys126Asn) and c.719G>A(p.Arg240Gln) in CTRC, c.586-3C>A and c.763A>G(p.Arg255Gly) in CPA1, c.1160_1161insT(p.Lys387Asnfs*26), c.784C>T(p.Gln262*), c.1139+1G>A, c.175G>A(p.Gly59Arg) in LPL, c.388C>G(p.leu130val) in CFTR, and c.2327G>A(p.Arg776His in PHKB)]. The phenotypic characteristics were variable and correlated with the relevant variant. CONCLUSIONS: The genetic composition plays a significant role in the predisposition of hereditary chronic pancreatitis. The clinical presentation varies with the genetic determinant involved. This information would help in building up a diagnostic algorithm for our population that can be used for genetic screening services in affected cohorts.

Corticosterone Methyl Oxidase Type 1 (CMO1) Deficiency Due to CYP11B2 Mutation: Two Case Reports.

Aldosterone synthase deficiency (ASD) is a rare autosomal recessive condition due to an inactivating mutation in CYP11B2. There are two types of ASD depending upon level of defect in aldosterone synthesis, corticosterone methyl oxidase type 1 (CMO 1) and type 2 (CMO 2) deficiency. We are reporting two cases of CMO 1 deficiency presented with failure to thrive. Both cases were born to consanguineous parents and presented at around 17 months and 15 months with complaints of repeated vomiting and failure to thrive. They were found to have persistent hyponatremia, hyperkalemia, low aldosterone level, raised renin levels, normal cortisol and normal 17 hydroxyprogesterone level, suggesting the diagnosis of isolated aldosterone deficiency. Whole exome sequencing revealed that Case 1 is carrying a novel homozygous mutation in CYP11B2, c.1391_1393dup p.(Leu464dup) and Case 2 has a homozygous pathogenic variant in CYP11B2, c.922T>C p.(Ser308Pro), confirming the diagnosis of CMO 1 deficiency in both cases. After initial stabilization, both cases were started on oral fludrocortisone. They responded well and showed a good catch-up in growth and development. Aldosterone synthase deficiency is a rare condition, but it shall be suspected in infants presented with failure to thrive, hyponatremia and hyperkalemia without pigmentation and virilization.

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.

Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report.

OBJECTIVES: Rabson Mendenhall syndrome  (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country. CASE PRESENTATION: An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in INSR gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding. CONCLUSIONS: RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.

The Epidemiology and Outcome of Biliary Atresia: Saudi Arabian National Study (2000-2018).

Background: The epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America. Objective: We report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia. Methods: A national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 µmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan-Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL). Results: BA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5-4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan-Meier survival curves for patients undergoing KPE at the age of <60, 61-90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88). Conclusion: The incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed.

Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly.

The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.

Kleefstra Syndrome with Severe Sensory Neural Deafness and De Novo Novel Mutation.

Kleefstra syndrome is a rare inherited neuro-developmental condition characterised by facial dysmorphism, microcephaly, hypotonia, developmental delay, and intellectual disability. It is a rare syndrome; and less than 100 cases with different genetic mutations are reported so far. We report an eight-month baby boy with Kleefstra syndrome type 2 due to a novel de novo pathogenic mutation in the KMT2C (Lysine methyltransferase 2C) gene. Key Words: Kleefstra syndrome, KMT2C gene, Neurodevelopmental disorder, Deafness.

Tricho-Hepato-Eenteric Syndrome: Same Genotype but Different Phenotypes in Two Pakistani Children.

Tricho-hepato-enteric syndrome (THES) is characterised by infantile diarrhea with characteristic facies, trichorrhexis nodosa and hepatic involvement. The underlying genetic mutation is in tetratricopeptide repeat domain 37 (TTC37) gene. It is a very rare syndrome and only 44 cases have been reported so far in the medical literature. We recently diagnosed two children with THES on genetic analysis, who had same genotype but different phenotypes. Using these cases as a precedent, we reviewed what is known about this rare syndrome, as well as the novelties in our cases and treatment options. Key Words: Chronic diarrhea, Liver disease, Genetic mutation, TTC37.

Viral dysbiosis in children with new-onset celiac disease.

Viruses are common components of the intestinal microbiome, modulating host bacterial metabolism and interacting with the immune system, with a possible role in the pathogenesis of immune-mediated diseases such as celiac disease (CeD). The objective of this study was to characterize the virome profile in children with new-onset CeD. We used metagenomic analysis of viral DNA in mucosal and fecal samples from children with CeD and controls and performed sequencing using the Nextera XT library preparation kit. Abundance log2 fold changes were calculated using differential expression and linear discriminant effect size. Shannon alpha and Bray-Curtis beta diversity were determined. A total of 40 children with CeD and 39 controls were included. We found viral dysbiosis in both fecal and mucosal samples. Examples of significantly more abundant species in fecal samples of children with CeD included Human polyomavirus 2, Enterobacteria phage mEpX1, and Enterobacteria phage mEpX2; whereas less abundant species included Lactococcus phages ul36 and Streptococcus phage Abc2. In mucosal samples however, no species were significantly associated with CeD. Shannon alpha diversity was not significantly different between CeD and non-CeD groups and Bray-Curtis beta diversity showed no significant separation between CeD and non-CeD samples in either mucosal or stool samples, whereas separation was clear in all samples. We identified significant viral dysbiosis in children with CeD, suggesting a potential role in the pathogenesis of CeD indicating the need for further studies.

A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene.

PURPOSE: We sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause. METHODS: Exome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed. RESULTS: We identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes. CONCLUSION: We describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

Robust Output Feedback Control of Single-Link Flexible-Joint Robot Manipulator with Matched Disturbances Using High Gain Observer.

This article focuses on the output feedback control of single-link flexible-joint robot manipulators (SFJRMs) with matched disturbances and parametric uncertainties. Formally, four sensing elements are required to design the controller for single-link manipulators. We have designed a robust control technique for the semiglobal stabilization problem of the angular position of the link in the SFJRM system, with the availability of only a position sensing device. The sliding mode control (SMC) based output feedback controller is devised for SFJRM dynamics. The nonlinear model of SFJRM is considered to estimate the unknown states utilizing the high-gain observer (HGO). It is shown that the output under SMC using HGO-based estimated states coincides with that using original states when the gains of HGO are sufficiently high. Finally, the results are presented showing that the designed control technique works well when the SFJRM model is uncertain and matched perturbations are expected.

Very early onset inflammatory bowel disease: Spectrum of clinical presentation, diagnostic tools and outcome in children.

OBJECTIVE: To explore the spectrum of presentation, underlying monogenetic defects and outcome in very early onset inflammatory bowel disease (VEO-IBD). METHOD: The prospective, observational study was conducted at the Children's Hospital, Lahore, Pakistan, from January 2017 to December 2018, and comprised children developing features of inflammatory bowel disease aged <6 years. Data included demography, clinical presentation, diagnostic tools and outcome. Data was analysed using SPSS 21. RESULTS: Of the 60 children with relevant symptoms, 26(43.3%) were diagnosed as having very early onset inflammatory bowel disease. Of them, 13(50%) had underlying monogenic defect, and 16(61.5%) had ulcerative colitis. There were 22(84.6%) males with median age of 1.5(11) months in monogenic inflammatory bowel disease versus 24(43) months for non-monogenic inflammatory bowel disease (p<0.05). In the monogenic group, isolated rectal bleeding was the major presentation 13(100%) versus non-monogenic who presented mainly with failure to thrive 13(100%). Upper and lower endoscopies with histopathology had good diagnostic yield and inflammatory infiltrates on the biopsied tissues were the major findings. Mutations detected among the subjects were XIAP, PRKDC, PIK3CD, RAG-1, LRBA, DOCK8, TTC7, MEFV and EPCAM. Mortality was significantly higher in the monogenic group 7(54%) than in the non-monogenic group 2(15%) (p<0.05). CONCLUSIONS: Very early onset inflammatory bowel disease should be suspected when conventional management fails to rectify common disease mimickers. Testing for underlying immunological defect and genetic mutation would be helpful for managing these rare disorders.

Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility.

We implemented a collaborative diagnostic program in Lahore (Pakistan) aiming to establish the genetic diagnosis, and to asses diagnostic yield and clinical impact in patients with suspected genetic diseases. Local physicians ascertained pediatric patients who had no previous access to genetic testing. More than 1586 genetic tests were performed in 1019 individuals (349 index cases, 670 relatives). Most frequently performed tests were exome/genome sequencing (ES/GS, 284/78 index cases) and specific gene panels (55 index cases). In 61.3% of the patients (n = 214) a genetic diagnosis was established based on pathogenic and likely pathogenic variants. Diagnostic yield was higher in consanguineous families (60.1 vs. 39.5%). In 27 patients, genetic diagnosis relied on additional biochemical testing, allowing rapid assessment of the functional effect of the variants. Remarkably, the genetic diagnosis had a direct impact on clinical management. Most relevant consequences were therapy related such as initiation of the appropriated treatment in a timely manner in 51.9% of the patients (n = 111). Finally, we report 12 candidate genes among 66 cases with no genetic diagnosis. Importantly, three of these genes were validated as 'diagnostic' genes given the strong evidence supporting causality derived from our data repository (CAP2-dilated cardiomyopathy, ITFG2-intellectual disability and USP53-liver cholestasis). The high diagnostic yield, clinical impact, and research findings demonstrate the utility of genomic testing, especially when used as first-line genetic test. For patients with suspected genetic diseases from resource-limited regions, ES can be considered as the test of choice to achieve genetic diagnosis.

Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene.

Background PHKG2-related liver phosphorylase kinase deficiency is inherited in autosomal recessive pattern and is a rare type of liver glycogenosis. We demonstrated the clinical presentation and genetic determinants involved in children with PHKG2- related liver phosphorylase kinase deficiency. Methodology Ten Pakistani children with liver phosphorylase kinase from seven different families, were enrolled over a period of 18 months. All regions of the PHKG2 gene spanning exons and splicing sites were evaluated through targeted exome sequencing. Variants were analyzed using different bioinformatics tools. Novel variants were reconfirmed by direct sequencing. Results Seven different variants were identified in PHKG2 gene including five novel variants: three stop codons (c.226C>T [p.R76*], c.454C>T [p.R152*] and c.958C>T [p.R320*]), one missense variant c.107C>T (p.S36F) and one splice site variant (c.557-3C>G). All five novel variants were predicted to be damaging by in Silico analysis. The variants are being transmitted through recessive pattern of inheritance except one family (two siblings) has compound heterozygotes. Laboratory data revealed elevated transaminases and triglycerides, normal creatinine phosphokinase and uric acid levels but with glycogen loaded hepatocytes on liver histology. Conclusion PHKG2 related liver phosphorylase kinase deficiency can mimic both liver glycogenosis type I (glucose-6-phosphatase deficiency) & III(amylo-1,6 glucosidase) and characterized by early childhood onset of hepatomegaly, growth restriction, elevated liver enzymes and triglycerides. Molecular analysis would be helpful in accurate diagnosis and proper treatment. The symptoms and biochemical abnormalities in liver glycogenosis due phosphorylase kinase deficiency tend to improve with proper dietary restrictions but need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

Antifungals in a case of basidiobolomycosis: role and limitations.

A 10-year-old Saudi boy was diagnosed to have basidiobolomycosis after a stormy course of his ailment. Therapy was initiated with intravenous antifungal, voriconazole, which was well tolerated for 6 weeks except for local excoriation at the site of ileostomy. He developed drug-induced hepatitis on oral voriconazole, therefore, switched to oral itraconazole following which he experienced severe chest pain. Alternatively, co-trimoxazole (bactrim) an antibacterial with antifungal activity was prescribed but he had the intolerance to it as well. Unfortunately, posaconazole as an alternative antifungal was not available in our centre. We report here a Saudi boy who developed an intolerance to most common antifungals used clinically 6 weeks after the therapy was initiated.

Unusual case of Juvenile Tay-Sachs disease.

Tay-Sachs disease (TSD) is a type 1 gangliosidosis (GM2) and caused by hexosaminidase A deficiency resulting in abnormal sphingolipid metabolism and deposition of precursors in different organs. It is a progressive neurodegenerative disorder transmitted in an autosomal-recessive manner. There is an accumulation of GM2 in neurocytes and retinal ganglions which result in progressive loss of neurological function and formation of the cherry-red spot which is the hallmark of TSD. We report the first case of juvenile TSD from Pakistan in a child with death of an older sibling without the diagnosis.

Hepatic Glycogenosis In Children: Spectrum Of Presentation And Diagnostic Modalities.

BACKGROUND: Objectives of the study were to determine the clinical spectrum of presentation and various modalities helpful in the diagnosis of liver glycogenosis short of genetic analysis. METHODS: All patients under 18 years of age presenting to Paediatric Gastroenterology unit of Children's Hospital, Lahore with suspicion of hepatic glycogen storage disease (GSD) were enrolled over a period of 18 months. Demographic profile and various factors under observation were recorded. Collected data was analysed using SPSS version 22. RESULTS: Among 89 enrolled patients F:M ratio was (1.28:1). The most common GSD was type I (71, 79.7%) followed by III (13, 14.6%), II (3, 3.3%), IV (1, 1.1%) and IX (1, 1.1%). The Abdominal distension was the most common presentation in 89.5% followed by hepatomegaly in 86.5%, diarrhoea in 41.6%, doll's like appearance in 31.5% and vomiting, acidotic breathing with convulsions in about 20% of children in GSD I. Hepatomegaly (100%), failure to thrive (85%), developmental delay (69%) and splenomegaly (92.3%) were leading presentation in GSD III. Elevated triglycerides (77.5%) followed by transaminesemia (56%), hypercholesterolemia (63%), hyperuricemia (32%) and hypoglycaemia (14%) were significant biochemical findings in GSD I. Consistently raised liver enzymes (92%) and creatinine phosphokinase (100%) in addition to hypertriglyceridemia (69%) were seen in GSD III. The presence of enlarged hepatocytes with clearing of cells favour GSD1 showed in 79% of children while fibrosis and steatosis usually seen in GSD-III (14.6%). CONCLUSIONS: Hepatic glycogen storage diseases are serious health issues and should be excluded in any patient who present with hepatomegaly, short stature and hyperlipidaemia to decrease the disease mortality and morbidity.

Rare presentation of haemobilia and Loeffler's pneumonia in a child by ascaris lumbricoides.

Ascariasis is a soil-sourced, second most common parasitic infection worldwide. Because of its wandering nature, it migrates from the intestine to other organs of the body like the lungs and biliary system. This results in complications such as biliary colic, acute cholecystitis, pyogenic cholangitis, liver abscesses, pancreatitis and loeffler's pneumonia. We report a unique case of an 8-year-old boy who presented with upper gastrointestinal bleed and chest infection. He was diagnosed as haemobilia and loeffler's pneumonia caused by ascaris lumbricoides.