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1
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Khabou B, Othman H, Guirat M, Chabchoub I, Kmiha S, Mahjoub B, Abdelhadi R, Ben Mahmoud A, Kallel R, Sellami Boudawara T, Kammoun T, Fakhfakh F, Hadj Kacem H, Kammoun H. Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level. J Hum Genet 2025:10.1038/s10038-025-01338-w. [PMID: 40251428 DOI: 10.1038/s10038-025-01338-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/30/2025] [Accepted: 03/30/2025] [Indexed: 04/20/2025]
Abstract
PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.
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Affiliation(s)
- Boudour Khabou
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia.
| | - Houcemeddine Othman
- Department of Genetics, Farhat Hached University Hospital, Ibn El Jazzar St, Sousse, 4000, Tunisia
- Laboratory of cytogenetics, molecular genetics and reproductive biology (LR03SP02), Farhat Hached University Hospital, Ibn El Jazzar St, Sousse, 4000, Tunisia
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, 9 Jubilee Road, Parktown, Johannesburg, 2193, South Africa
| | - Manel Guirat
- Medical Genetic Department, Hédi Chaker University Hospital, Sfax, Tunisia
- Laboratory of Molecular and Cellular Screening Processes (LPCMC), Biotechnology Center of Sfax, Sfax, Tunisia
- Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia
| | - Imen Chabchoub
- Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Sana Kmiha
- Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Bahri Mahjoub
- Pediatric Department, Tahar Sfar Hospital, Mahdia, Tunisia
| | - Rania Abdelhadi
- Centre of Biotechnology of Sfax (Tunisia), Microorganisms and Biomolecule Laboratory, and Molecular and Cellular Screening Process Laboratory, Sfax, Tunisia
- Ksentini Private Laboratory of Cytogenetics of Sfax, Sfax, Tunisia
- Ribosite Biotech Company for Research and Development in Biotechnhology, Sfax, Tunisia
| | - Afif Ben Mahmoud
- Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Qatar Foundation, Hamad Bin Khalifa University (HBKU), Doha, Qatar
| | - Rim Kallel
- Department of Anatomy and Pathological Cytology, Habib Bourguiba Hospital, Sfax, Tunisia
| | | | - Thouraya Kammoun
- Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Faiza Fakhfakh
- Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia
| | - Hassen Hadj Kacem
- Department of Applied Biology, College of sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Hassen Kammoun
- Medical Genetic Department, Hédi Chaker University Hospital, Sfax, Tunisia
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Pandey D, Chandnani S, Gandhi H, Vishal M, Rathi PM. A Novel Compound Heterozygous Mutation in Progressive Familial Intrahepatic Cholestasis (PFIC) 4: A Rare Case Report With Literature Review. Cureus 2024; 16:e73927. [PMID: 39697951 PMCID: PMC11654999 DOI: 10.7759/cureus.73927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2024] [Indexed: 12/20/2024] Open
Abstract
A 12-year-old female, resident of western India, presented with a history of pruritus associated with jaundice for two months. On presentation, she had icterus with mild palpable hepatomegaly. Investigations revealed direct hyperbilirubinemia and elevated transaminases, while gamma-glutamyl transferase levels were normal. Serology for anti-hepatitis A, E, B, and C were negative. Autoimmune markers such as antinuclear antibody, smooth muscle antibody, and anti-liver kidney microsomal antibody were negative. Serum IgG levels were within the normal range. A normal magnetic resonance cholangiopancreatography ruled out any ductal abnormalities. A liver biopsy was also conducted but proved to be inconclusive. Despite extensive workup, the diagnosis remained unclear. However, genetic testing through whole exome sequencing identified a novel compound heterozygous variation, a novel in exon 5 and exon 4 of the Tight-Junction Protein 2 gene, and confirmed the diagnosis of cholestatic liver disease as progressive familial intrahepatic cholestasis type 4. This case highlights the importance of genetic testing for diagnosing cholestatic liver diseases, especially when conventional tests do not provide a clear diagnosis. Whole exome sequencing revealed a novel mutation in the TJP2 gene, ultimately confirming the diagnosis of PFIC4.
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Affiliation(s)
- Deepika Pandey
- Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND
| | - Sanjay Chandnani
- Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND
| | - Harsh Gandhi
- Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND
| | - Mavuri Vishal
- Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND
| | - Pravin M Rathi
- Department of Gastroenterology, Topiwala National Medical College & BYL Nair Charitable Hospital, Mumbai, IND
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3
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Abokandil MA, Waheeb S, Zaghloul W, Abdelgawad M, Abdelhady M, Mansy M, Kotb M. Progressive familial intrahepatic cholestasis type 4: a case report. J Med Case Rep 2024; 18:434. [PMID: 39243110 PMCID: PMC11380191 DOI: 10.1186/s13256-024-04662-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 05/13/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known. CASE PRESENTATION A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations. CONCLUSION Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.
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Affiliation(s)
| | - Saber Waheeb
- Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Wessam Zaghloul
- Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Manal Abdelgawad
- Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Mona Abdelhady
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Mohamed Mansy
- Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt
- Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Mostafa Kotb
- Nile of Hope Hospital for Congenital Anomalies, Alexandria, Egypt.
- Faculty of Medicine, Alexandria University, Alexandria, Egypt.
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Halabi H, Kalantan K, Abdulhaq W, Alshaibi H, Almatrafi MA. A Rare Case of Progressive Familial Intrahepatic Cholestasis Type 4: A Case Report and Literature Review. Cureus 2023; 15:e47276. [PMID: 38021987 PMCID: PMC10656038 DOI: 10.7759/cureus.47276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a group of genetic disorders characterized by progressive intrahepatic cholestasis. Different mutations in hepatocellular transport genes result in distinct PFIC subtypes with unique clinical manifestations, laboratory findings, and histopathological characteristics. Three PFIC genotypes have been commonly described (PFIC 1, 2, and 3), but in recent years, PFIC 4, 5, and 6 genetic mutations have been identified. Here, we report the first PFIC 4 case in the Middle East in a 46-day-old male infant who was successfully treated with a liver transplant. A 46-day-old, male, full-term infant presented with persistent jaundice and obstructive liver pathology suggested by liver profile and biopsy. Whole exome sequencing confirmed the diagnosis of PFIC 4. Medical treatment failed to improve the patient's symptoms. Therefore, the patient underwent hepatectomy and an unrelated liver transplant. He is currently exhibiting significant clinical improvements and is free of active complaints. PFIC is a rare disease that poses diagnostic and therapeutic challenges for clinicians. Infants presenting with unexplained cholestasis should have PFIC 4 as a differential diagnosis. Early recognition and treatment of PFIC 4 with liver transplantation may result in a more favorable prognosis.
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Affiliation(s)
- Hana Halabi
- Department of Pediatrics, Maternity and Children Hospital, Makkah, SAU
| | - Khawla Kalantan
- Department of Pediatrics, Maternity and Children Hospital, Makkah, SAU
| | - Warif Abdulhaq
- Department of Medicine and Surgery, Medical College of Umm Al-Qura University, Makkah, SAU
| | - Habeib Alshaibi
- Department of Anatomic Pathology, Maternity and Children Hospital, Makkah, SAU
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Vinayagamoorthy V, Srivastava A, Sarma MS. Newer variants of progressive familial intrahepatic cholestasis. World J Hepatol 2021; 13:2024-2038. [PMID: 35070006 PMCID: PMC8727216 DOI: 10.4254/wjh.v13.i12.2024] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/19/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defects in bile secretion and presentation with intrahepatic cholestasis in infancy or childhood. The most common types include PFIC 1 (deficiency of FIC1 protein, ATP8B1 gene mutation), PFIC 2 (bile salt export pump deficiency, ABCB11 gene mutation), and PFIC 3 (multidrug resistance protein-3 deficiency, ABCB4 gene mutation). Mutational analysis of subjects with normal gamma-glutamyl transferase cholestasis of unknown etiology has led to the identification of newer variants of PFIC, known as PFIC 4, 5, and MYO5B related (sometimes known as PFIC 6). PFIC 4 is caused by the loss of function of tight junction protein 2 (TJP2) and PFIC 5 is due to NR1H4 mutation causing Farnesoid X receptor deficiency. MYO5B gene mutation causes microvillous inclusion disease (MVID) and is also associated with isolated cholestasis. Children with TJP2 related cholestasis (PFIC-4) have a variable spectrum of presentation. Some have a self-limiting disease, while others have progressive liver disease with an increased risk of hepatocellular carcinoma. Hence, frequent surveillance for hepatocellular carcinoma is recommended from infancy. PFIC-5 patients usually have rapidly progressive liver disease with early onset coagulopathy, high alpha-fetoprotein and ultimately require a liver transplant. Subjects with MYO5 B-related disease can present with isolated cholestasis or cholestasis with intractable diarrhea (MVID). These children are at risk of worsening cholestasis post intestinal transplant (IT) for MVID, hence combined intestinal and liver transplant or IT with biliary diversion is preferred. Immunohistochemistry can differentiate most of the variants of PFIC but confirmation requires genetic analysis.
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Affiliation(s)
- Vignesh Vinayagamoorthy
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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