Early onset and liver failure indicating poor prognosis of infant liver failure syndrome type 1.

Background: Infantile liver failure syndrome type 1 (ILFS1, OMIM #615,438), caused by leucyl-tRNA synthase 1 (LARS1, OMIM *151,350) deficiency, is a rare autosomal-recessive disorder. The clinical manifestations, molecular-genetic features, and prognosis of LARS1 disease remain largely elusive.

Methods: Three new instances of ILFS1 with confirmed variants in LARS1, encoding LARS1, were identified.

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

Background: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited.

Methods: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed.

Results: Three new patients were identified to be carrying five new variants.

Comprehensive Bile Acid Profiling of ABCB4-mutated Patients and the Prognostic Role of Taurine-conjugated 3α,6α,7α,12α-Tetrahydroxylated Bile Acid in Cholestasis.

Background And Aims: We asked if comprehensive bile acid profiling could provide insights into the physiopathology of -mutated patients and evaluated the prognostic value of taurine-conjugated tetrahydroxylated bile acid (tauro-THBA) in cholestasis.

Methods: Serum bile acid profiles were evaluated in 13 -mutated patients with 65 healthy controls by ultra-high-performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC/MRM-MS). The concentration of tauro-THBA was compared between -mutated patients with different prognoses.

Recurrent AKR1D1 c.580-13T>A Variant: A Cause of Δ-3-Oxosteroid-5β-Reductase Deficiency.

Δ-3-oxosteroid 5β-reductase (AKR1D1) deficiency presents with neonatal cholestasis and liver failure in early infancy and features high levels of 3-oxo-Δ-bile acids in urine. Genetic analysis is needed for definitive diagnosis, because in the neonatal period it can be difficult to distinguish a primary from a secondary enzyme deficiency. By re-analysis of the gene-sequencing data, one AKR1D1 noncanonical splice-site variant (NM_005989.

Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome.

Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.

Methods: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age.

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients.

Background And Aims: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed.

Methods: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2.

NBAS disease: 14 new patients, a recurrent mutation, and genotype-phenotype correlation among 24 Chinese patients.

Aim: Neuroblastoma amplified sequence (NBAS)-associated disease has a wide phenotypic spectrum, including infantile liver failure syndrome type 2 (ILFS2, OMIM #616483), short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome (OMIM #614800), and a combined phenotype overlapping ILFS2 and SOPH syndrome. The mutation spectra of NBAS and its genotype-phenotype correlation among Chinese were not clear.

Methods: Clinical and genetic data were retrospectively collected from the medical charts of patients with biallelic NBAS mutations, as well as from Chinese patients in previously published reports.

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression.

Background & Aims: ABCB11 deficiency presenting in infancy is believed generally to manifest as persistent/progressive cholestasis. We describe a group of patients with biallelic ABCB11 variants whose disorder manifested as transient neonatal cholestasis (TNC).

Methods: Neonatal intrahepatic cholestasis in 68 children (31 males) with biallelic predictedly pathogenic variants (PPV) in ABCB11 was classified as transient (TNC group, n = 23, 11 males), intermittent (benign recurrent intrahepatic cholestasis [BRIC] group, n = 3, 1 male) or persistent/ progressive (progressive familial intrahepatic cholestasis [PFIC] group, n = 42, 19 males).

TJP2 hepatobiliary disorders: Novel variants and clinical diversity.

To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro.

Novel Melanocortin 2 Receptor Variant in a Chinese Infant With Familial Glucocorticoid Deficiency Type 1, Case Report and Review of Literature.

Familial glucocorticoid deficiency type 1 (FGD1) is an autosomal recessive disorder caused by mutations in the melanocortin 2 receptor () gene, characterized by a low or undetectable serum cortisol level and a high adrenocorticotropic hormone (ACTH) level. Clinical manifestations include hypoglycemia, seizure, skin hyperpigmentation, hyperbilirubinemia, cholestasis, and a tall stature. Some dysmorphic features such as, a prominent forehead, hypertelorism, a broad nasal bridge, and small tapering fingers, have been reported.