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.

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.

Novel IDS Variants Identified in Three Unrelated Pakistani Patients Affected with Mucopolysaccharidosis Type II (Hunter Syndrome).

INTRODUCTION: Mucopolysaccharidosis type II (MPS-II) or Hunter syndrome is a rare X-linked recessive disorder caused by genetic lesions in the IDS gene, encoding the iduronate-2-sulfatase (IDS) enzyme, disrupting the metabolism of certain sulfate components of the extracellular matrix. Thus, the undegraded components, also known as glycosaminoglycans, accumulate in multiple tissues resulting in multisystemic abnormalities. OBJECTIVE: To uncover causative genetic lesions in probands of three unrelated Pakistani families affected with rare X-linked recessive Hunter syndrome. METHODS: Screening of the IDS gene was performed in six individuals (three patients and their mothers) through whole genomic DNA extraction from peripheral blood followed by PCR and Sanger sequencing. MutationTaster, PROVEAN, Human Splicing Finder, Swiss-Model, and SwissPdbViewer were used for in silico analysis of identified variants. RESULTS: All probands were presented with coarse facies, recurrent respiratory tract infection, and reduced IDS activity. Molecular screening of IDS identified three different pathogenic variants including a novel duplication variant c.114_117dupCGTT, a novel splice site variant c.1006 + 1G>C, and a nonsense variant c.1165C>T. In silico analysis unanimously revealed the pathogenic nature of the variants due to their deleterious effects upon the encoded enzyme. CONCLUSION: Identified variants predictably lead to either the expression of a nonfunctional enzyme due to partial loss of SD1 and complete loss of SD2 subdomains or a complete lack of the IDS enzyme as a result of nonsense-mediated mRNA decay. Our study provides the first genetic depiction of MPS-II in Pakistan, expands the global IDS mutation spectrum, may provide insights into the three-dimensional structure of IDS, and should benefit the affected families in genetic counseling and prenatal diagnosis.

Genetic Analysis of Tyrosinemia Type 1 and Fructose-1, 6 Bisphosphatase Deficiency Affected in Pakistani Cohorts.

Background: Inborn errors of metabolism are inherited disorders that present in early childhood and are usually caused by monogenic recessive mutations in specific enzymes that metabolize dietary components. Distinct mutations are present in specific populations.Objective: To determine which genomic variants are present in Pakistani cohorts with hepatorenal tyrosinemia type 1 (HT1) and fructose 1,6-bisphosphatase deficiency (FBPD).Materials and Methods: We sequenced the fumaryl acetoacetate hydrolase encoding gene (FAH) including flanking regions in four unrelated HT1 cohorts and the fructose 1,6-bisphosphatase gene (FBP1) in eight FBPD cohorts.Results: We mapped two recessive mutations in FAH gene for HT1; c.1062 + 5G > A(IVS12 + 5G > A) in three families and c.974C > T(pT325M) in one. We identified three mutations in FBP1 gene; c.841G > A(p.E281K) in five FBPD families, c.472C > T(p.R158W) in two families and c.778G > A(p.G260R) in one.Conclusion: Knowledge of common variants for HTI and FBDP in our study population can be used in the future to build a diagnostic algorithm.

Haemobilia: secondary to micro aneurysms of hepatic artery.

Hepatic artery is the fourth most common site of the intraabdominal aneurysm, after infra renal aorta, iliac artery and splenic artery aneurysms. Rupture of the aneurysm may lead to the upper gastrointestinal haemorrhage. Here we report a 5 years old boy, who presented with fever, abdominal distension and unexplained upper GI bleed. Upper GI endoscopy revealed a normal esophagus and stomach with clear evidence of haemobilia with blood oozing from the ampulla. Fluoro- guided angiography followed by embolization of hepatic artery branches with 5 metallic coils was performed in this case by an interventional radiologist.

Mutational spectrum of SMPD1 gene in Pakistani Niemann-Pick disease patients.

OBJECTIVE: Genetic variation analysis of rare autosomal recessive Niemann-Pick disease (NPD) Pakistani patients. METHODS: We sequenced the SMPD1 gene including its all coding and flanking regions in seven unrelated sporadic patients suffering from Niemann-Pick disease through targeted exome sequencing. Genetic variants mapping and their protein predictions were evaluated using different bioinformatics tools and clinical phenotypes were correlated. The study was conducted from January 2018 to March 2019 at The Children's Hospital Lahore. RESULTS: We have mapped five different mutations in SMPD1 gene of enrolled patients with a novel homozygous missense variant (c.1718G>C) (p.Trp573Ser) in one patient. A missense mutation (c.1267C>T) (p.His423Tyr) has been identified in three unrelated patients. A nonsense mutation (c.1327C>T) (p.Arg443Term) and one missense mutation (c.1493G>A) (p.Arg498His) mapped in one patient each. A compound heterozygous mutation has been mapped in one patient (c.740G>A) (p.Gly247Asp); (c.1493G>A) (p.Arg498His). Pathogenic effect of novel variant has been predicted through in-silico analysis and has not been reported in general overall population in the globe. CONCLUSION: This is the first report of genetic demographic assessment of Niemann-Pick disease in Pakistan. The mapped mutations would be helpful to build a disease variants algorithm of Pakistani population. This will be used for determining disease clinical magnitude along with provision of genetic screening services in affected families.

Clinical Spectrum Of Solitary Rectal Ulcer In Children Presenting With Per-Rectal Bleed.

BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a benign and chronic disorder well known in young adults and less common in children. The objective of this study was to determine the frequency and clinical spectrum of solitary rectal ulcer in children with bleeding per rectum. METHODS: This study was conducted in the Department of Paediatric Gastroenterology Hepatology& Nutrition; The Children's Hospital & The Institute of Child Health, Lahore, from January-December 2015. Total 187 children presenting with per-rectal bleeding who underwent colonoscopy were entered in the study. Demographic and presenting clinical features; colonoscopy and histopathology findings were recorded. Data was analysed using SPSS-20. RESULTS: Out of a total of 187 children with bleeding per rectum, 21 (11.23%) were diagnosed with solitary rectal ulcer. Males were 15 (71.43%) and females were 6 (28.57%) with age range 8-12 years. Mucus in stool 14 (66.7%), constipation 12 (57.1%) and tenesmus 10 (47.6%) were the most common clinical presentations. Colonoscopic finding are solitary erythmatous ulcerative lesion was seen in 8 (38.09%) children, multiple ulcerative lesions in colon 6 (28.57%), multiple ulcerative lesions in rectum 5 (23.81%), polypoidal growth in colon and hyperaemic rectal mucosa in 1 (4.76%) each. Histopathological findings were consistent with SRUS in all the cases. CONCLUSIONS: The frequency of SRUS was high (19.6%) in patients with per-rectal bleed. Mucus in stool, constipation and tenesmus were the most common clinical presentations. Colonoscopic and histopathological findings were helpful in the confirmation of the underlying aetiology.

Congenital hepatic fibrosis: clinical presentation, laboratory features and management at a tertiary care hospital of Lahore.

OBJECTIVE: To describe the clinical presentations, laboratory features and management of congenital hepatic fibrosis patients at a tertiary care hospital. METHODS: The case series was conducted at The Children Hospital and Institute of Child Health, Lahore, Pakistan, from July 2013 to June 2015, and comprised patients of congenital hepatic fibrosis diagnosed on the basis of liver biopsy. SPSS 20 was used for statistical analysis. RESULTS: The mean age of 25 patients in the study was 8.5±2.74 years, and the male-to-female ratio was 3:1. Parents of 21(84%) patients had consanguineous marriage, and 14(56%) patients had family history of hematemesis and melena. Besides, 15(60%) patients presented with hematemesis, 12(48%) had abdominal distension, 5(20%) were picked up on screening of siblings and 5(20%) were referred from general practitioners on feeling of hepatosplenomegaly during routine examination. All had hepatomegaly with a mean size of 7.2 ±2.3cm palpable in midline. Splenomegaly was present in 24(96%). Overall, 15(60%) patients had oesophageal varices. Endoscopic band ligations were done in oesophageal variceal patients who were successfully managed, while 5(20%) patients required portosystemic shunt surgeries. CONCLUSIONS: Congenital hepatic fibrosis was not uncommon in our population having high rate of consanguinity and most of them were familial cases.

Celiac Crisis: A Rare Or Rarely Recognized Disease.

BACKGROUND: Celiac crisis is a serious life threatening complication of celiac disease characterized by profuse diarrhoea, severe dehydration and metabolic disturbances leading to neuromuscular weakness, cardiac arrhythmias and sudden death. It has been described as rare condition and not well documented in the literature. To improve awareness and facilitate diagnosis of this condition, we studied risk factors, pattern of presentation and management plans of celiac crisis. METHODS: It was a descriptive cross sectional study. Patients presenting in emergency room(ER) with profuse diarrhoea leading to severe dehydration, neuromuscular weakness, and metabolic acidosis and electrolyte abnormalities enrolled in the studies after positive serology and small bowel biopsy suggestive of celiac disease. RESULTS: Total 126 patients out of 350 fulfilled the criteria including 54 (42.8%) male and 71 (56.3%) female. The mean age at presentation was 5.25±1.18 years. Risk factors were poor social status (97.60%), consanguinity (96.77%), early weaning with gluten contained diet (93.54%), and Presenting complaints were loose motion (100%), loss of neck holding (96.77%), dehydration (96.77%), polyuria (95.96%), inability to walk (67.74%), abdominal distension (85.86%). Electrolytes imbalances were hypokalaemia (2.4±0.55), hypocalcaemia (7.29±0.66), hypomagnesaemia (1.89±0.50), hypophosphatemia (2.8±0.68), hypoalbuminemia (3.05±0.48) and metabolic acidosis (96%). One hundred & twenty patients were stabilized with GFD and correction of dehydration, acidosis and electrolyte imbalance. Six patients needed parenteral steroids ant total parenteral nutrition (TPN). Recovery time from crisis was mean 5.4±2.73 days (range 3-20 days). CONCLUSIONS: Celiac crisis is a common but under recognized problem in developing countries. Commonest presenting feature is neuromuscular paralysis and biochemical abnormality is hypokalaemia.

Spontaneous Perforation Of Bile Duct, Clinical Presentation, Laboratory Work Up, Treatment And Outcome.

BACKGROUND: Spontaneous perforation of bile duct (SPBD) is a rare and often misdiagnosed entity. Though rare, it is the second most common surgical cause of jaundice in infants, after biliary atresia. This study was planned to determine the clinical presentation, study different diagnostic modalities, treatment and outcome of patients with spontaneous perforation of bile duct. METHODS: This descriptive case series, comprising 22 patients with spontaneous perforation of bile duct over a period of 24 months. Clinical presentation, biochemical abnormalities, imaging details, treatment options and outcome were studied. RESULTS: Total 22 patients (12 Males and 10 Females) between ages of 1.5-36 months were studied. Associated anatomical defects included choledochal cyst in 7 (31.8%) while acquired biliary atresia in 1 (4.5%). Elevated liver enzymes (ALT and AST) were present in 16 patients (72.7%) and 5 (22.7%) had bilirubin above 3 mg/dl. Coagulopathy was seen in 8 (36.6%) patients. Abdominal USG showed presence of ascites in all 22 (100%), hydrocele in 2 (9.0%), inguinal hernia in 1 (4.5%), choledochal cyst in 7 (31.8%) and atretic gall bladder suggestive of acquired biliary atresia in one (4.5%) patient. HIDA scan was diagnostic in all 17 (77.27%) in which it was performed. MRCP was done in 3 (13.6%) patients. Mortality frequency was 3/22 (13.6%); one died of post-surgical sepsis second one was cirrhotic at time of presentation and didn't make It. Two were lost to follow up one which died at home while we lost contact with fourth patient. CONCLUSIONS: Spontaneous perforation of bile duct can present and should be suspected as an important cause of neonatal biliary ascites or peritonitis. Most patients can be managed with intravenous antibiotics, percutaneous drainage and ttube insertion while patients with choledochal cysts required cholecystectomy with roux en y choledochjejunostomy. Timely recognition and intervention is associated with favourable outcome.

CLINICAL PRESENTATION, AETIOLOGY AND COMPLICATIONS OF PANCREATITIS IN CHILDREN.

BACKGROUND: Childhood Pancreatitis is an uncommon but serious condition with incidence on the rise. It manifests as acute or chronic form with epigastric pain, vomiting and elevated serum -amylase and lipase. This study was conducted with the aim to determine the clinical presentation, aetiology, and complications of pancreatitis in children. METHODS: This descriptive case series was conducted in the Department of Paediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital & the Institute of Child Health, Lahore from 1st January to 31st December 2014. Seventy-two patients up to the age of 15 years having abdominal pain, Amylase >200 IU/L and/or lipase >165 IU/L, with features of acute or chronic pancreatitis on abdominal imaging; were included in study. Data analysis was done using SPSS-20. RESULTS: Of the total 72 patients, 43 (60%) had acute pancreatitis, males were 25 (58%) and females 18 (42%) and chronic pancreatitis was diagnosed in 29 (40%), males 10 (34%) and females 19 (66%). Common clinical features were abdominal pain (100%), nausea and vomiting (79%). Common aetiologies were idiopathic (40%) while choledochal cyst 8%, hyperlipidaemia 7%, biliary tract stones/sludge 7% and abdominal trauma 6%. Complications were more frequently associated with acute pancreatitis (60%) than with chronic pancreatitis (34%). Common complications were pseudo-pancreatic cyst (36%), ascites (17%) and pleural effusion (4%). CONCLUSION: Abdominal pain, nausea and vomiting were common presenting features of childhood pancreatitis. Common aetiologies were idiopathic hyperlipidemia, biliary tract stones/sludge, choledochal cyst and abdominal trauma. Common complications were Pseudo-pancreatic cyst, ascites and pleural effusion.

Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants in RBL2 , including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly, Drosophila melanogaster , to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harboring RBL2 variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila , and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in an RBL2 -linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches may ameliorate aspects of RBL2 LOF patient symptoms.

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.

Secondary findings in a large Pakistani cohort tested with whole genome sequencing.

Studies on genomic secondary findings (SFs) are diverse in participants' characteristics, sequencing methods, and versions of the ACMG SF list. Based on whole genome sequencing and the version 3.1 of the ACMG SF list, we studied SFs in 863 individuals from five different regions in Pakistan. We identified 24 ACMG SFs in 23 (2.7%) of 863 individuals: 18 of 24 were related to cardiovascular disease and four to cancer syndromes. In addition to ACMG SFs, we identified 16 (1.9%) participants with pathogenic and likely pathogenic variants in genes that were not related to the participants' clinical conditions but with clear medical actionability (non-ACMG SFs): 4 of 16 were related to eye diseases, two to metabolic disorders, and two to urinary system disorders. By testing a large Pakistani cohort with whole genome sequencing, we concluded that in countries such as Pakistan, the ACMG SF list could be expanded, and our non-ACMG SF list is one example.

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.

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.

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.

An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.