Progressive Familial Intrahepatic Cholestasis (PFIC) Type 4 is a rare autosomal recessive liver disorder caused by mutations in the TJP2 gene, responsible for maintaining tight junctions in hepatocytes. These mutations disrupt bile flow, leading to cholestasis, liver damage, and sometimes liver failure. The clinical manifestations of TJP2 mutations vary widely depending on age, zygosity, and other factors. Below, we discuss five cases of TJP2 mutations, illustrating the spectrum of phenotypes and highlighting unique characteristics of each case. The cases presented below were identified and compiled using Adenine AI: Organized Evidence for Medical Genetics.
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Severe Neonatal Presentation of PFIC Type 4
- Age/Sex: Neonate, male
- Ethnicity: Omani
- Zygosity: Homozygous mutation in TJP2
- Phenotype: Severe cholestasis, coagulopathy, multiple intracranial bleeds
- Unique characteristic: Presented with bleeding tendency due to vitamin K deficiency, requiring internal biliary diversion
This case highlights a severe neonatal presentation in an Omani infant with PFIC Type 4. The patient had persistent cholestasis and intracranial bleeds, with a homozygous TJP2 mutation, necessitating advanced intervention.
PMID: 38090248
- Mutation: TJP2:c.2417G>A (p.Trp806Ter)
Benign Recurrent Intrahepatic Cholestasis with a Novel TJP2 Mutation
- Age/Sex: 15-year-old female
- Ethnicity: Canadian
- Zygosity: Heterozygous TJP2 mutation
- Phenotype: Recurrent episodes of jaundice, vomiting, intense pruritus, weight loss
- Unique characteristic: First known case of benign recurrent intrahepatic cholestasis (BRIC) caused by a heterozygous TJP2 mutation
This case describes a unique presentation of BRIC in a teenager, with recurring jaundice and pruritus. Genetic analysis revealed a heterozygous TJP2 mutation, previously not associated with BRIC.
PMID: 37205944
- Mutation: TJP2:c.3067_3068delinsTT (p.Ala1023Phe)
New TJP2 Variant Causing PFIC in Adults
- Age/Sex: 19-year-old male
- Ethnicity: Danish
- Zygosity: Homozygous for novel TJP2 variant
- Phenotype: Liver cirrhosis, variceal bleeding, primary liver cancer
- Unique characteristic: Variable expression of PFIC4 among siblings, with some showing cirrhosis and others only elevated liver enzymes
This family case report from Denmark presents a novel TJP2 variant in multiple siblings, with the index patient developing cirrhosis and liver cancer at 19. Other family members had varying levels of disease expression, suggesting age-dependent penetrance.
PMID: 32089630
- Mutation: TJP2:c.3334C>T (p.Gln1112Ter)
Compound Heterozygote TJP2 Mutations in a Chinese Child
- Age/Sex: 5-year-old female
- Ethnicity: Chinese
- Zygosity: Compound heterozygous mutations in TJP2
- Phenotype: Jaundice, pruritus, failure to thrive
- Unique characteristic: Novel compound heterozygous mutations, both leading to loss of TJP2 protein translation
This young child presented with PFIC, exhibiting jaundice and pruritus, and was found to have compound heterozygous mutations in TJP2. Both mutations were predicted to result in the loss of TJP2 protein function.
PMID: 30658709
- Mutations: TJP2:c.2448+1G>C and TJP2:c.2639delC (p.Tyr880Serfs*12)
Two Novel Pathogenic TJP2 Variants in PFIC Patients
- Age/Sex: Multiple patients
- Ethnicity: Chinese
- Zygosity: Biallelic pathogenic variants in TJP2
- Phenotype: PFIC with cytoskeletal abnormalities in liver cells
- Unique characteristic: Molecular mechanisms explored using CRISPR-cas9 and siRNA techniques to demonstrate the role of TJP2 in cytoskeletal regulation
This study explored the underlying molecular mechanisms of TJP2 mutations in PFIC Type 4 patients, identifying novel pathogenic variants that disrupted the cytoskeleton and affected cell proliferation.
PMID: 34504838
- Mutations: TJP2:c.1202A>G (p.Lys401Arg) and TJP2:c.2668-11A>G
These studies highlight the diverse clinical presentations of TJP2 mutations and the importance of genetic screening in diagnosing and managing PFIC-related conditions.