Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Incidence, pattern, and etiology of elevated liver enzymes in pediatric inflammatory bowel disease.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) often develop elevated liver enzymes (ELE), which are frequently a benign, transient finding, but may be related to treatment or IBD-associated liver diseases. Distinguishing benign from pathologic ELE is crucial for focused diagnostic and therapeutic interventions. We sought to characterize the incidence, character, chronicity, degree, and etiology of ELE in children with IBD. METHODS: Institutional review board-approved retrospective review of all of the patients with IBD (2-21 years) seen between October 2009 and October 2012 with >9 months of follow-up were included in the study. We examined body mass index, disease activity, extent, phenotype, concurrent medications, and character, chronicity, degree of enzyme elevation, and final diagnosis. RESULTS: A total of 219 of 514 patients with IBD had ≥1 episode of ELE. Five patients were excluded for preexisting liver disease, leaving 214 patients (Crohn disease [CD]: 14.8 ±â€Š3.5 years, 46% girls; ulcerative colitis [UC]: 14.4 ±â€Š4.2 years, 37% girls). One hundred forty-eight patients (69%) had a hepatic, 17 (8%) cholestatic, and 49 (23%) mixed character of ELE. There were no significant differences in character, chronicity, or degree of ELE between CD and UC (P = 0.71, P = 0.58, P > 0.33). Of the 128 patients with sufficient data to determine chronicity, 98 (77%) had transient elevations, (CD: n = 66, 75% and UC: n = 32, 80%). Episodes of ELE were idiopathic in 87% of patients with IBD. A final diagnosis of idiopathic ELE was associated with a lower degree of ELE elevation (P < 0.0001). CONCLUSIONS: Pediatric patients with IBD commonly experience transient, idiopathic ELE. Our findings suggest that higher degrees of ELE, specifically alanine aminotransferase, are associated with an etiology that requires more extensive evaluation.

Magnetic Resonance Elastography of the Liver in Children and Adolescents: Assessment of Regional Variations in Stiffness.

RATIONALE AND OBJECTIVES: We describe our experience in measuring parenchyma stiffness across the liver Couinaud segments in lieu of the conventional practice of using a single slice-wise "global" region-of-interest. We hypothesize that the heterogeneous nature of fibrosis can lead to regional stiffness within the organ, and that it can be reflected by Couinaud segment-based magnetic resonance elastography measurements. MATERIALS AND METHODS: This retrospective study involved from 173 patients (116 males, 57 females, 1.0-22.5 years, 14.7 ± 3.5 years) who underwent exams between June 2017 and September 2018. Liver stiffness across the eight Couinaud segments was measured in addition to a single-slice global measurement by two analysts. Inter- and intrarater analysis was performed in a subset of 20 cases. Individual segment stiffness values, the average across the segments, and the coefficients of variation (CoV) were compared to global single-slice-derived values using linear and Lin's concordance correlation coefficients. Linear correlations between stiffness values versus age, gender, and body-mass-index (BMI) were also evaluated. RESULTS: We observed CoVs ranging from 3.1%-79.2%, 17.2 ± 7.2%. The CoV was not correlated with age or BMI (r2 < 0.01, p = 0.99 for both). The CoV did not differ between males (17.1 ± 5.6%) and females (17.3 ± 9.8%) (p = 0.88). There were no correlations between global stiffness versus age (r2 = 0.02, p = 0.84) or BMI (r2 = 0.03, p = 0.68). A range of 0.58-0.86 was observed for Lin's concordance correlation coefficient between segmental stiffness, the average stiffness across segments, and global stiffness. Segments II and VII had the highest frequency of being the stiffest Couinaud segment. The average stiffness across the segments correlated strongly with the single-slice global measurement (r2 = 0.88, p< 0.01). CONCLUSION: There exists potential variations in parenchyma stiffness across the liver Couinaud segments, which may reflect the heterogeneous nature of fibrosis. This variation can potentially provide additional diagnostic and clinical information.

Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

Liver transplantation for erythropoietic protoporphyria liver disease.

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival.