Johanson-Blizzard syndrome caused by novel UBR1 mutation in four Saudi patients.

Johanson-Blizzard syndrome (JBS) is a rare genetic disorder caused by Ubiquitin Protein Ligase E3 Component N-Recognin1 (UBR1) gene mutations. It is characterized by exocrine pancreatic insufficiency, craniofacial deformities, sensorineural hearing loss, and a broad variety of intellectual disabilities. The aim of our study is to report four pediatric cases (three of which are siblings, and the fourth patient is unrelated) that presented some features of JBS. The cases have been confirmed by genetic testing to have mutations in the UBR1 gene. This case series study was conducted retrospectively, giving a detailed description of the demographic and clinical information of these four cases, and reflecting our experience with this subset of patients. All these cases have been treated at the King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, and were identified by their clinical and laboratory markers that favor JBS. A novel homozygous missense mutation c.2075 T > C (p. lle692Thr) in exon 18 (UBR1: NM_174916.3) was identified and confirmed by Sanger sequencing in all our cases outlined in this paper. These presented cases illustrate the phenotypic variability and complexity of JBS and the importance of physical examination to reach a diagnosis. The identified novel mutation in this study broadens the spectrum of UBR1 mutations that contribute to JBS.

Bile salt export pump-reactive antibodies form a polyclonal, multi-inhibitory response in antibody-induced bile salt export pump deficiency.

UNLABELLED: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) is caused by mutations in ABCB11, encoding the bile salt export pump (BSEP). In 2009, we described a child with PFIC-2 who developed PFIC-like symptoms after orthotopic liver transplantation (OLT). BSEP-reactive antibodies were demonstrated to account for disease recurrence. Here, we characterize the nature of this antibody response in 7 more patients with antibody-induced BSEP deficiency (AIBD). Gene sequencing and immunostaining of native liver biopsies indicated absent or strongly reduced BSEP expression in all 7 PFIC-2 patients who suffered from phenotypic disease recurrence post-OLT. Immunofluorescence, western blotting analysis, and transepithelial transport assays demonstrated immunoglobulin (Ig) G-class BSEP-reactive antibodies in these patients. In all cases, the N-terminal half of BSEP was recognized, with reaction against its first extracellular loop (ECL1) in six sera. In five, antibodies reactive against the C-terminal half also were found. Only the sera recognizing ECL1 showed inhibition of transepithelial taurocholate transport. In a vesicle-based functional assay, transport inhibition by anti-BSEP antibodies binding from the cytosolic side was functionally proven as well. Within 2 hours of perfusion with antibodies purified from 1 patient, rat liver showed canalicular IgG staining that was absent after perfusion with control IgG. CONCLUSIONS: PFIC-2 patients carrying severe BSEP mutations are at risk of developing BSEP antibodies post-OLT. The antibody response is polyclonal, targeting both extra- and intracellular BSEP domains. ECL1, a unique domain of BSEP, likely is a critical target involved in transport inhibition as demonstrated in several patients with AIBD manifest as cholestasis.

Prevalence of hepatopulmonary syndrome in children.

OBJECTIVE: The hepatopulmonary syndrome is defined as a triad of liver disease, hypoxemia, and intrapulmonary vascular dilation. The reported prevalence of hepatopulmonary syndrome in adults with cirrhosis ranges from 4% to 29%; however, the prevalence of hepatopulmonary syndrome and its outcome in children is unknown. The objective of this study was to describe prospectively the prevalence of intrapulmonary vascular dilation and hepatopulmonary syndrome in children with liver disease. METHODS: Pulse oximetry was undertaken in children with liver disease, and those with oxygen saturation < or = 97%, those with cirrhosis, and those with clinically severe portal hypertension from other causes underwent contrast-enhanced echocardiography for detection of intrapulmonary vascular dilations. Patients with intrapulmonary vascular dilation underwent arterial blood gas analysis and technetium-99m-labeled macroaggregated albumin scan. RESULTS: Oxygen saturation was measured in 301 children and was < or = 97% in 8. These 8 and an additional 18 patients with cirrhosis or portal hypertension underwent contrast-enhanced echocardiography. Seven (27%) patients had intrapulmonary vascular dilation detected by contrast-enhanced echocardiography; 2 of these patients had abnormal arterial blood gas analysis and thus met diagnostic criteria for hepatopulmonary syndrome (representing 8% of patients with cirrhosis or severe portal hypertension). Both patients with hepatopulmonary syndrome had abnormal pulse oximetry. Technetium-99m-labeled macroaggregated albumin scans for 6 patients showed a median 6.5% (range: 4%-12%) tracer uptake outside the lungs. CONCLUSIONS: Hepatopulmonary syndrome occurs in an important minority of children with cirrhosis or severe portal hypertension. Additional studies should be undertaken to determine the importance of intrapulmonary vascular dilation without hepatopulmonary syndrome and the impact of hepatopulmonary syndrome on the outcomes of affected children.