Clinical and Genetic Spectra of Progressive Familial Intrahepatic Cholestasis With Normal GGT: 31 Pediatric Patients
Nehal M Elkoofy1, Mortada H El-Shabrawi1, Mohamed A Elmonem2
1Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.
Insights
This study details the first phenotype-genotype analysis of Progressive Familial Intrahepatic Cholestasis (PFIC) with normal gamma-glutamyltransferase (GGT) in Egyptian children. It identifies genetic variants and highlights varying disease severity among different PFIC types.
Area of Science:
- Genetics
- Pediatrics
- Hepatology
Background:
- Progressive Familial Intrahepatic Cholestasis (PFIC) syndromes are rare, autosomal recessive liver diseases.
- Understanding the genetic basis and clinical presentation of PFIC, especially variants with normal gamma-glutamyltransferase (GGT), is crucial for diagnosis and management.
- This research focuses on a specific population in Egypt, addressing a gap in global phenotypic and genotypic data for normal GGT/PFIC.
Purpose of the Study:
- To conduct the first detailed phenotype-genotype characterization of PFIC children with normal GGT in an African population.
- To identify disease-causing genetic variants and correlate them with clinical manifestations and disease progression.
- To expand the global knowledge base of normal GGT/PFIC syndromes and inform clinical care strategies in Egypt.
Main Methods:
- Systematic analysis of clinical, biochemical, histopathological, and genetic data from 31 pediatric patients across 28 unrelated Egyptian families.
- Genotyping was performed to identify variants in genes associated with PFIC, including ABCB11, ATP8B1, TJP2, MYO5B, and USP53.
- Phenotypic data, including symptoms like pruritus and hepatomegaly, and disease progression markers, were correlated with identified genotypes.
Main Results:
- Thirty-one patients (15 males, 16 females) with normal GGT/PFIC were studied, with a mean age of 55 months at diagnosis.
- Common clinical features included severe pruritus, hepatomegaly, sleep disturbances, and splenomegaly.
- Genetic variants were identified in ABCB11 (PFIC2), ATP8B1 (PFIC1), TJP2 (PFIC4), MYO5B (PFIC10), and USP53 (PFIC7), with 16 novel variants reported among 25 disease-causing variants.
- PFIC1 patients exhibited more severe outcomes, including higher rates of growth retardation, sibling deaths, skin changes, and need for biliary diversion compared to other PFIC types.
- Conversely, PFIC2 patients did not progress to biliary diversion, and PFIC10 patients maintained normal liver transaminases.
Conclusions:
- This study provides comprehensive phenotype-genotype data for normal GGT/PFIC in Egyptian children, expanding global understanding of these rare disorders.
- Specific genetic variants are associated with distinct clinical severities and progression patterns, notably PFIC1 and PFIC2.
- The findings will aid in improving diagnostic accuracy and tailoring management strategies for PFIC patients in Egypt and similar populations.
Abstract:
Progressive familial intrahepatic cholestasis (PFIC) syndromes are rare autosomal recessive disorders. We present the first detailed phenotype-genotype of PFIC children with normal gamma-glutamyltransferase (GGT) [normal GGT/PFIC] in an African population. Thirty-one pediatric patients belonging to 28 unrelated Egyptian families with normal GGT/PFIC were reported. Clinical, biochemical, histopathological, and genetic data were systematically analyzed. Patients were 15 males/16 females (55 ± 52 months at diagnosis). Apart from cholestasis, clinical features included severe pruritus (visual analogue scale 7.5 ± 3.4), hepatomegaly (80.6%), sleep deprivation (41.9%), and splenomegaly (19.4%). 13/28 families had ABCB11 variants (PFIC2), 6/28 families had ATP8B1 (PFIC1) and TJP2 (PFIC4) variants each, 2/28 had MYO5B variants (PFIC10), and one family had USP53 variants (PFIC7). Twenty-five disease-causing variants were reported, including 16 novel variants. PFIC1 patients were more severely affected compared to other PFIC syndromes, as the incidence of growth retardation, sibling deaths, skin changes, and progression to biliary diversion were all significantly higher (p value 0.006, 0.012, 0.037, and 0.012, respectively). In contrast, none of the 13 PFIC2 children progressed to biliary diversion, and all four PFIC10 children had normal liver transaminases. Our study expands the global phenotypic and genotypic knowledge of normal GGT/PFIC and will facilitate better care for the syndrome in Egypt.
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