Pathogenic Novel Heterozygous Variant c.1076c>T p. (Ser359Phe) chr1: 120512166 in NOTCH2 Gene, Type 2 Alagille Syndrome Causing Neonatal Cholestasis: A Case Report.

BACKGROUND Alagille syndrome (ALGS) is a multisystem hereditary illness with a dominant pattern and partial penetrance. Multiple organ abnormalities can be caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene. Notch receptor 2 (NOTCH2) gene mutations are also uncommon. ALGS is also characterized by deformed or narrowed bile ducts and is notoriously difficult to diagnose due to the wide range of symptoms and absence of unambiguous genotype-phenotype connections. Little is known about ALGS patients who have NOTCH2 mutations. We present a patient who developed progressive liver failure due to a unique pathogenic heterozygous variation of the NOTCH2 gene, c.1076c>T p. (Ser359Phe) chr1: 120512166, resulting in type 2 ALGS. CASE REPORT A Saudi Arabian newborn with bilateral hazy eyes, ectropion, dry ichthyic skin, normal male genitalia, and bilateral undescended testes was born at 31 weeks. Previous miscarriages, pregnancy-induced maternal cholestasis, fatty liver, or neonatal jaundice were not reported in the family history. He had developed worsening cholestatic jaundice by the third week of hospitalization. The extensive work-up for metabolic, infectious, and other relevant etiologies was negative. Following gram-negative sepsis, he died of multiorgan failure. A NOTCH2 gene mutation explained the phenotypic difference in our situation. Another intriguing observation was the presence of ichthysis and craniosynostosis in ALGS with a NOTCH2 mutation. CONCLUSIONS Cholestasis in newborns can be difficult to diagnose. Next-generation sequencing detects 112 copy number variants in the cholestasis gene panel blood test. More research is needed to understand why NOTCH2 mutations are relatively rare in ALGS.

Tricho-hepato-enteric syndrome: Retrospective multicenter experience in Saudi Arabia.

Background: Trichohepatoenteric syndrome (THES) is a very rare disorder that is characterized by intractable congenital diarrhea, woolly hair, intrauterine growth restriction, facial dysmorphism, and short stature. Our knowledge of THES is limited due to the small number of reported cases. Methods: Thirty patients diagnosed with THES, all molecularly confirmed by whole exome sequencing (WES) to have biallelic variants in TTC37 or SKIV2L, were included in the study. Clinical, biochemical, and nutritional phenotypes and outcome data were collected from all participants. Results: The median age of THES patients was 3.7 years (0.9-23 years). Diarrhea and malnutrition were the most common clinical features (100%). Other common features included hair abnormalities (96%), skin hyperpigmentation (87%), facial dysmorphic abnormalities (73%), psychomotor retardation (57%), and hepatic abnormalities (30%). Twenty-five patients required parenteral nutrition (83%) with a mean duration of 13.34 months, and nearly half were eventually weaned off. Parenteral nutrition was associated with a poor prognosis. The vast majority of cases (89.6%) had biallelic variants in SKIV2L, with biallelic variants in TTC37 accounting for the remaining cases. A total of seven variants were identified in TTC37 (n = 3) and SKIV2L (n = 4). The underlying genotype influenced some phenotypic aspects, especially liver involvement, which was more common in TTC37-related THES. Conclusion: Our data helps define the natural history of THES and provide clinical management guidelines.

Etiology and clinical characteristics of pediatric acute pancreatitis in Saudi Arabia: a 20-year experience from a single tertiary center.

BACKGROUND: Cases of acute pancreatitis (AP) have increased among pediatric populations worldwide; however, the natural course of this condition in Saudi Arabia was unknown. AIM: To report the characteristics as well as outcomes of pediatric AP. PATIENTS AND METHODS: A retrospective chart review study was conducted to include acute pancreatitis in patients ≤ 19 years. The period was from 1994 until 2015. Demographic, clinical, laboratory, imaging and outcome data were collected and analyzed. RESULTS: 50 patients (n = 26; 52% males vs. n = 24; 48% females) were included. The mean age at diagnosis was 11.6 years. The mean length of hospital stay was 10.5 days. 9 (18%) patients had a recurrence of AP and 4 (8%) had complications. Idiopathic AP was the most frequent etiology (n = 21; 42%), followed by cholelithiasis (n = 11; 22%). 2 patients (4%) had drug-induced AP, where one was taking isoniazid and the other had taken a large amount of erythromycin, amoxicillin and ibuprofen. 2 choledochal cysts complicated by AP (4%). Pancreaticobiliary diseases, as a complete entity, accounted for 34% (n = 17). Clinically, abdominal pain (n = 47; 94%) and vomiting (n = 38; 76%) were most commonly encountered. KUB was non-diagnostic in all patients. No patient died during their admission. CONCLUSION: Although still relatively uncommon in Saudi Arabia, there are on average 2-3 cases of pediatric AP diagnosed annually in our institution. Idiopathic AP was the most common cause. Isoniazid and choledochal cysts are rare causes of AP and were reported in the study.

Severe Crohn's Disease Manifestations in a Child with Cystathionine ß-Synthase Deficiency.

Inflammatory bowel diseases (IBDs) are idiopathic autoimmune diseases that are characterized by inflammation of both the small and large intestine. Although IBD is common in the general population, the pathophysiology remains ambiguous. Clear understanding of IBD pathophysiology would be a major step toward curative treatment in the future. Hyperhomocysteinemia has been associated with multiple autoimmune diseases including IBD, but homocystinuria has not been associated with IBD before. We report a 9-year-old girl with Crohn's disease and homocystinuria. Her gastrointestinal symptoms improved significantly upon classical homocystinuria treatment, and her last colonoscopy showed a pronounced remission. This case supports the inflammatory role of homocysteine in the gastrointestinal tract and the association between hyperhomocysteinemia and IBD manifestations.

Prevalence of celiac disease among symptom-free children from the Eastern Province of Saudi Arabia.

BACKGROUND/AIM: Epidemiological studies of celiac disease (CD) among Saudi children have been performed only within some groups who are at a high risk of developing CD. The aim of this study was to determine the prevalence of CD among symptom-free children from the public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia. PATIENTS AND METHODS: Between 2012 and 2014, serum samples were collected from 1141 students (age 6-18 years) attending nine public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia. Participants were screened for CD by testing for anti-tissue transglutaminase IgA (IgA-tTG) and IgG antibodies (IgG-tTG). Small intestinal biopsy was offered to all participants who tested positive for IgA-tTG [IgA-tTG >20 relative units (RU)/ml]. RESULTS: Of the 1141 participants, 32 were IgA-tTG positive. Thus, the estimated serology-positive prevalence was 3%. An intestinal biopsy was performed in 10 of the participants with antibody positivity. The biopsy findings of all 10 children were consistent with CD. Thus, the estimated biopsy-confirmed prevalence was about 1%. CONCLUSIONS: The prevalence of CD was estimated to be about 1% among symptom-free children from the public schools of the military campus of National Guard in the Eastern Province of Saudi Arabia.