The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Intermittent Volvulus with Obstruction Due to a Meckel's Diverticulum and Band Presenting as Feeding Intolerance in a Neonate with Trisomy 13.

Individuals born with trisomy 13 tend to be susceptible to Meckel's diverticulum. It is rarely symptomatic and reported cases are extremely rare. We describe here a neonate with feeding intolerance and bilious aspirates as a result of Meckel's diverticulum and peritoneal band which caused intermittent volvulus with obstruction.

MIRAGE Syndrome Enteropathy Responding to Pancrelipase Despite Normal Pancreatic Fecal Elastase: A Case Report.

BACKGROUND Major findings of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE) syndrome is a rare genetic condition caused by a gain-of-function mutation in the SAMD9 gene. It acts as a growth repressor expressed in the endothelial cells. Pathogenic variants in the SAMD9 gene lead to profound growth-restricting activity intrinsic to the protein, which further reduces cellular proliferation and instigates this growth-limiting condition. Gastrointestinal features include chronic diarrhea, severe diaper rash, and colonic dilatation. Until now, there has been no description of exocrine pancreatic insufficiency as a possible cause of enteropathy in MIRAGE syndrome. CASE REPORT We report a case of MIRAGE syndrome affecting multiple systems in an infant who had severe enteropathy which responded well to porcine-derived pancreatic enzyme supplements despite normal pancreatic fecal elastase level. The infant is being followed up by multidisciplinary teams in our outpatient department. CONCLUSIONS Porcine-derived pancreatic enzyme is beneficial in enteropathy due to MIRAGE syndrome and is worth considering.

Rapid whole genome sequencing of critically ill pediatric patients from genetically underrepresented populations.

We describe a case series of five infants (age range: 1-90 days; 4 females and 1 male) who presented to Al Jalila Children's intensive care units (ICU) with complex multisystem disorders. Patients were Emirati, Kenyan, Jordanian, Filipino, or Pakistani. Trio rapid whole genome sequencing (rWGS) was performed on all five patients and their parents within the hospital's genomics facility. Results were returned within ~37 h from blood sample draws and were diagnostic in 3 out of 5 patients. Positive findings were a homozygous pathogenic variant in POMT1 gene causing muscular dystrophydystroglycanopathy, a mosaic tetrasomy of the short arm of chromosome 12 (12p13.33p11.1) causing Pallister-Killian syndrome, and compound heterozygous pathogenic variants in the LIPA gene causing lysosomal acid lipase deficiency and Wolman disease. The rWGS analysis provided fast and precise diagnostic findings in those 3 patients and also aided in devising better management plans for them in the intensive care setting. For example, the 3-month-old infant with pathogenic variants in the LIPA gene is now a candidate for an FDA-approved, potentially lifesaving enzyme replacement therapy (sebelipase alfa). Our case series emphasize the feasibility and utility of rWGS in pediatric intensive care setting, in a diverse population that has long been underserved in genomic services. Significant investments in local healthcare infrastructure are needed, globally, for more equitable access of genomic medicine among vulnerable patients.

A rare anomaly: duodenal Dieulafoy's lesion in a preterm baby.

Neonatal Dieulafoy's lesion is a rare but serious condition that can be life-threatening if not diagnosed and intervened in a timely manner. It presents with episodes of sudden acute gastrointestinal haemorrhage in the form of blood in vomit and/or blood in stool. In general, most of the lesions are successfully treated with endoscopic or angiographic intervention. Surgery is usually reserved for cases that fail endoscopic or angiographic intervention. We present a neonatal case of duodenal Dieulafoy's lesion that occurred in a 29-week-old male baby with birth weight of 1.2 kg. He developed melena and haematemesis at 4 weeks of life. He required normal saline boluses and transfusion of blood products for acute blood loss. The lesion was successfully treated with endoscopic intervention.

Nitroglycerin patch use in digital ischemia secondary to sepsis: a case report.

Sepsis results in intense disturbances in homoeostasis and is responsible for considerable morbidity and mortality in early infancy. Owing to insufficiency on part of infant to develop adequate inflammatory response to localize the infection, they usually progress to disseminated systemic infection, pneumonia and/or meningitis. We present the case of a 26 weeks preterm boy with acute digital ischemia in right index finger progressing to impending gangrene as a manifestation of septicemia. Use of topical nitroglycerin patch with meticulous monitoring successfully alleviated the impending peripheral gangrene without any adverse effects.

Unexplained abdominal distention in a neonate: culprit femoral central venous line extravasation.

Central venous lines are an essential part of neonatal intensive care and are used for infusion of medications and parenteral nutrition (PN). PN is usually given via either peripherally inserted central lines or umbilical venous lines. Occasionally, central venous catheters (CVCs) are inserted in the femoral veins. Extravasation of femoral venous catheter leading to ascites is a rare entity. This report describes the case of a neonate with a femoral CVC, who developed ascites as a result of extravasation of PN. Ascites resolved following the removal of the catheter.

A stability-indicating LC–MS/MS method for zidovudine: Identification, characterization and toxicity prediction of two major acid degradation products / 药物分析学报

Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guideline. Successful separation of AZT and its degradation products was achieved by gradient elution mode on reverse phase C18 column using 10 mM ammonium acetate: acetonitrile as the mobile phase at 0.8 mL/min flow rate, 25 μL injection volume, 30 °C column temperature and 285 nm detection wavelength. Two major acid degradation products were identified and characterized by liquid chromatography–electrospray ionization mass spectro-metry (LC–ESI/MS/MS) and accurate mass measurements. The probable mechanisms for the formation of degradation products were identified based on a comparison of the fragmentation pattern of the [M + H] + ions of AZT and its degradation products. One of the degradation products, DP-1, was isolated by semi-preparative high performance liquid chromatography (HPLC) using Waters XBridge Prep C18 (250 mm×10 mm, 5 μm). Degradation products showed higher toxicity compared to the drug in some models assessed by TOPKAT software. The method validation was performed with respect to robustness, specificity, linearity, precision and accuracy as per ICH guideline Q2 (R1).

Role of Diffusion Weighted Imaging (DWI) for Hepatocellular Carcinoma (HCC) Detection and its Grading on 3T MRI: A Prospective Study.

BACKGROUND: Limited studies have evaluated the role of diffusion weighted imaging (DWI) and apparent diffusion coefficient (ADC) for histologically grading the hepatocellular carcinoma (HCC). OBJECTIVE: To compare the efficacy of DWI with dynamic contrast enhanced magnetic resonance (DCEMR) in detection of HCC in cirrhosis, and to evaluate whether DWI can be used instead of DCEMR. METHODS: 20 patients of either sex with cirrhosis and suspected of having HCC on screening USG were included in this prospective study approved by the Institutional Ethics Committee. All patients underwent DCEMR of the abdomen on 3T scanner and fine needle aspiration of the lesions. MR protocol included T1WI, T2WI, DWI, and dynamic CEMR. The results of diffusion weighted imaging were compared with DCEMR to find the efficacy of DWI vis-à-vis CEMR. RESULTS: DWI had a sensitivity and specificity of 100%, for diagnosis of lesions in cases having single lesion on CEMR, and sensitivity of 75% and specificity of 100% for diagnosis of lesions in cases having multiple lesions. There was a decreasing trend of ADC values with increasing grade of the tumor; however, the decreasing trend was not statistically significant. A cut-off ADC value of 0.8705 resulted in a sensitivity of 75% and specificity of 50% for differentiating between well-differentiated and other grades of HCC. CONCLUSION: DWI can be used as an alternative for the detection and characterization of HCC, especially in patients with impaired renal function or contrast allergies precluding the use of contrast. In addition, DWI with ADC measurement may be helpful for non-invasive and preoperative prediction of the degree of differentiation of HCC.

Role of geospatial technology in identifying natural habitat of malarial vectors in South Andaman, India.

BACKGROUND & OBJECTIVES: Malaria is a serious disease which has repeatedly threatened Andaman, an island territory of India. Uncharted dense vegetation and inaccessibility are the salient features of the area and the major areas are covered by remotely sensed data to identify the malaria vector's natural habitat. The present investigation appraises the role of geospatial technologies in identifying the natural habitat of malarial vectors. METHODS: The base map was prepared from Survey of India's toposheets, the landuse map was prepared from indices techniques like normalised difference vegetation index (NDVI), normalised difference water index (NDWI), modified normalised difference water index (MNDWI), normalised difference pond index (NDPI), and normalized difference turbidity index (NDTI) in conjugation with visual interpretation. The soil moisture content map was reproduced from the soil atlas of Andaman and Nicobar Islands followed by generation of an aspect profile from ASTER-GDEM satellite data. Both the landuse map and aspect profile were validated for accuracy in the field. RESULTS: A weighted overlay analysis of the classes like landuse, soil moisture and aspect profile of the study area resulted in identification of the potential natural habitat map of malaria vector surrounding the areas of Tushnabad, Garacharma, Manglutan, Chouldari, Ferrargunj and Wimberlygunj hamlets. INTERPRETATION & CONCLUSION: The natural habitat of malaria vector indicated that Tushnabad, Garacharma, Manglutan, Chouldari, Ferrargunj and Wimberlygunj hamlets are within the proximity of 2.5 km from the prime habitat location with more number of malaria positive cases. Also these hamlets are surrounded by dense evergreen forest and the land surface is draped by clay loam and clay soil texture exhibiting high soil moisture content warranting high rates of survival and proliferation of the vector ensuring resurgence of malaria every year. It is thus concluded that application of geospatial technologies plays an important role in identifying the natural habitat of malaria vector.

Imaging of portal cavernoma cholangiopathy.

Portal cavernoma cholangiopathy (PCC) refers to the biliary changes which occur in the setting of extrahepatic portal vein obstruction and secondary portal cavernoma formation. The main radiological findings include the vascular changes in the form of portosystemic collaterals and biliary changes in the form of extrinsic impressions and strictures. Till date, conventional cholangiography has been the gold standard for the diagnosis of PCC. However, it is an invasive procedure and is associated with complications. At present there is a transition towards non-invasive modalities like ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). The recent advances in these modalities provide an excellent delineation of both the vascular and the biliary changes non-invasively in a short time. The findings of PCC using these newer modalities are not so well described in literature. The findings of PCC also overlap with malignant conditions of biliary tract such as cholangiocarcinoma and compression of biliary tract by malignant adenopathies. In this article we describe the vascular and biliary changes associated with PCC on US, CT and MRI. We also describe the imaging findings using each modality along with their advantages and disadvantages.