Analysis of SMOC2 gene variants in familial and nonfamilial primary open angle glaucoma Pakistani patients

AIM:To find out the association of secreted protein acidic and rich in cysteine(SPARC)-related modular calcium binding 2(SMOC2)gene variants rs2255680 and rs13208776 with genotypic and phenotypic characteristics in both familial and non-familial primary open angle glaucoma(POAG)patients.METHODS:A total of 212 POAG patients,comprising 124 familial and 88 non-familial,were enrolled.For genotyping the SMOC2 variant rs2255680,amplification refractory mutation system(ARMS)-polymerase chain reaction(PCR)method and PCR-restriction fragment length polymorphism(PCR-RFLP)were utilized for analyzing rs13208776 variant.RESULTS:The mean age of familial POAG patients was 50.92±9.12y,with 78 males and 46 females.The mean age of non-familial POAG patients was 53.14±13.44y,with 52 males and 36 females.The SMOC2 gene variant rs13208776 showed the significant association with POAG between familial and non-familial groups.The homozygous G/G variant was frequent among non-familial(60.2%)whereas the heterozygous G/A variant was more frequent in familial POAG patients(46%).There were significant differences in G/A variant between familial and non-familial glaucoma patients,and the risk was decreased to 0.53-fold in non-familial glaucoma patients[odds ratio(OR):0.53;95%confidence interval(CI):0.29-0.94;P=0.033]in codominant model.The risk was further reduced to 0.49-fold(95%CI:0.28-0.86;P=0.012)in dominant model for non-familial patients.No significant association of SMOC2 gene variant rs2255680 between familial and non-familial glaucoma patients was found in our population.The haplotype analysis showed the decreased risk for TA[OR:0.48(95%CI:0.29-0.79);P=0.004]and an increased risk for TG[OR=2.28(95%CI:1.22-4.25);P=0.01]haplotypes.CONCLUSION:Current findings show significant association of SMOC2 gene variant rs13208776 with POAG between familial and non-familial Pakistani patients.

Two different mutational types of familial gastrointestinal stromal tumors:Two case reports

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal(GI)tract,and cases of GISTs tend to be of the disseminated type,with a global incidence of 10 to 15 cases/million each year.The rarer familial GISTs,which often represent a population,differ in screening,diagnosis,and treatment.Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs.However,whether the same genetic family has different phenotypes has not been reported.CASE SUMMARY We report two cases of rare GISTs in the same family:A male patient with the V561D mutation in exon 12 of the PDGFRA gene,who has been taking the targeted drug imatinib since undergoing surgery,and a female patient diagnosed with wild-type GIST,who has been taking imatinib for 3 years since undergoing surgery.The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy,and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease.CONCLUSION Different mutation types of familial GISTs in the same family are very rare,thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.

PML nuclear bodies:new players in familial amyotrophic lateral sclerosis-frontotemporal dementia?

Amyotrophi c lateral s c lerosis(ALS)and frontotemporal dementia(FTD)are two closely related disorders with overlapping clinical,genetic,and neuropathological features,forming a continuous disease spectrum(Ling et al.,2013).The major pathological hallmark of ALS and FTD are the depletion from the nucleus of the RNA-binding proteins TAR DNA‐binding protein 43(TDP-43)and FUsed in Sarcoma(FUS)and their abnormal accumulation in ubiquitin-positive cytoplasmic inclusions(Ling et al.,2013).

Development of immature ovarian teratoma after mature teratoma in a girl with familial ovarian teratoma:A case report

BACKGROUND Immature ovarian teratoma is a rare and aggressive neoplasm that affects young women.This report is the first to describe the development of immature teratoma after ovarian cystectomy for mature teratoma of the ovary in an adolescent female with a family history of ovarian teratoma.CASE SUMMARY A 16-year-old girl who had undergone bilateral ovarian cystectomy for mature teratomas 3 years ago showed bilateral adnexal tumors during her regular ultrasonography follow-up every 6 months.She received laparoscopic bilateral ovarian cystectomy,and final histopathology showed grade-1 immature teratoma of the left ovary and mature teratoma of the right ovary.Laparoscopic left salpingo-oophorectomy and staging procedures were performed again.Her mother,maternal aunt,and maternal grandmother had also received surgeries for mature ovarian teratomas.CONCLUSION It is important to have guidance on management of patient and family members with familial ovarian teratomas.

Familial hypercholesterolemia:Current limitations and future breakthroughs

Familial hypercholesterolemia(FH)is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations,presenting with xanthomas,corneal arch,and severe cardiovascular diseases.Early identification,diagnosis,and treatment are crucial to prevent severe complications like acute myocardial infarction.Statins are the primary treatment,supplemented by Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors,though their effectiveness can be limited in severe cases.Over 90%of FH cases remain undiagnosed,and current treatments are often inadequate,underscoring the need for improved diagnostic and management systems.Future strategies include advancements in gene testing,precision medicine,and novel drugs,along with gene therapy approaches like AAV-mediated gene therapy and clustered regularly interspaced short palindromic repeats.Lifestyle modifications,including health education,dietary control,and regular exercise,are essential for managing FH and preventing related diseases.Research into FH-related gene mutations,especially LDLR,is critical for accurate diagnosis and effective treatment.

Familial Forms of Spondyloarthritis Study of 100 Senegalese Multiplex Families

Introduction: Spondyloarthritis (SpA) comprises a group of chronic inflammatory rheumatic diseases characterized by predominant axial involvement. These include ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic arthritis (PsA), arthritis associated with inflammatory bowel diseases (IBD), SAPHO syndrome (Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis), juvenile spondyloarthritis (JSPA), and undifferentiated SpA. Their exact cause is unknown but is believed to stem from a combination of factors. The first familial forms were described by de Blécourt et al. in 1961. The objective was to evaluate the epidemiological, clinical, therapeutic and evolutionary aspects of familial forms of SpA and in particular, to prove the severity of the disease in family members compared to index cases in the rheumatology department of the Aristide Le Dantec University Hospital in Dakar. Methodology: This was a prospective, cross-sectional and descriptive study with an analytical aim on patients with the familial form of spondyloarthritis defined by the existence of at least one other family member with SpA outside the propositus, collected within the Aristide Le Dantec rheumatology department in Dakar over a period of 10 years between January 2012 and December 2021. There were two phases of study, the first of which consisted of collecting index cases with miserly SpA and the second of which consisted of family screening after consent. The data analysed were epidemiological, clinical, paraclinical, therapeutic and evolving. Results: Out of 100 families of 1905 members, 667 SpA patients included, i.e. a prevalence of 35%, including 225 (33.73%) men and 412 women (61.17%), i.e. a ratio of 1.8. The mean age at diagnosis among relatives was 26.3 years (range 13 and 80 years), 47.14 years among the propositus, in whom the mean age at onset was 36.26 years and that of relatives 49.9 years in the first degree, 15 years in the second degree and 1 year in the third degree. The time to diagnosis was 11.20 years in the first degree, 2.5 years in the second degree, 1 year in the third degree and 10.88 years in the case of the proposes. The number of marriages in families was 420 of which 116 were consanguineous (consanguinity rate 27.62%), 19% among the propositus. HLA-B27 positive in 92% of the proposers and 33.43% in the families;70% of the propositus had an inflammatory syndrome and 17.54% in the families;87% of sacroilliitis in the propositus and 5.54% in the families. Clinical forms were dominated by undifferentiated SpA (338 cases) and APS (295 cases). The average BASFI was 3.23 on D0;2.59 in the 3rd month and 1 in the 6th month for the propositus versus 2.55 at D0;1.86 at the 3rd month and 1.55 in the 6th month in the families. Average BASDAI was 3.92 at D0;3.12 at the 3rd month and 2.07 at the 6th month in the propositus and 3 at D0;2.21 at the 3rd month and 1 at the 6th month in the families. Autoimmune associated conditions were 18 cases, degenerative 24 cases, autoinflammatory 2 metabolic cases 18 cases. They all received: NSAIDs, methotrexate, salazopyrine (11 cases) and anti-TNF-α (1 case). The evolution was generally favourable. Conclusion: SpA is on the rise in Senegalese hospitals, frequent in young people, SPA and undifferentiated SpA are the most frequent, management is essentially based on conventional care, and the disease is less severe in family members than index cases.

Novel subtype of obesity influencing the outcomes of sleeve gastrectomy:Familial aggregation of obesity

BACKGROUND Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy(SG)between patients with familial aggregation of obesity(FAO)and patients with sporadic obesity(SO)have not been elucidated.AIM To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO.METHODS A total of 193 patients with obesity who underwent SG were selected.Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity(1 SO vs 1FAO,2SO vs 2FAO).The baseline characteristics,weight loss outcomes,prevalence of obesity-related comorbidities and incidence of major surgeryrelated complications were compared between groups.RESULTS We defined FAO as the presence of two or more first-degree relatives with obesity.Patients with FAO did not initially show significant differences in baseline data,short-term postoperative weight loss,or obesity-related comorbidities when compared to patients with SO preoperatively.However,distinctions between the two groups became evident at the two-year mark,with statistically significant differences in both percentage of total weight loss(P=0.006)and percentage of excess weight loss(P<0.001).The FAO group exhibited weaker remission of type 2 diabetes mellitus(T2DM)(P=0.031),hyperlipidemia(P=0.012),and non-alcoholic fatty liver disease(NAFLD)(P=0.003)as well as a lower incidence of acid reflux(P=0.038).CONCLUSION FAO patients is associated with decreased mid-to-long-term weight loss outcomes;the alleviation of T2DM,hyperlipidemia and NAFLD;and decreased incidence of acid reflux postoperatively.

Molecular overview of progressive familial intrahepatic cholestasis

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Familial aggregation in inflammatory bowel disease:Is it genes or environment?

Inflammatory bowel disease (IBD) develops in genetically susceptible individuals due to the influence of environmental factors, leading to an abnormal recognition of microbiota antigens by the innate immune system which triggers an exaggerated immune response and subsequent bowel tissue damage. IBD has been more frequently found in families, an observation that could be due to either genetic, environmental or both types of factors present in these families. In addition to expanding our knowledge on IBD pathogenesis, defining the specific contribution to familial IBD of each one of these factors might have also clinical usefulness. We review the available evidence on familial IBD pathogenesis.

A Retrospective and Comparative Study of Familial and Non-familial Bullous Lichen Planus

In order to compare the clinical characteristics of familial and non-familial bullous lichen planus (BLP), the archival data of 36 BLP patients with positive family history and 21 BLP patients with negative family history diagnosed according to the clinical features and histopathology were collected in our department from 1956 to 2003. The clinical features were analyzed and compared. There were significant differences between familial and non-familial BLP in age of onset, duration of disease and extension of eruption (P<0.01). It was concluded that familial BLP appeared to differ from the non-familial form in its earlier age of onset, longer duration of the disease, more extensive eruption and more tendency to involve nails. Hereditary factors may play a role in the pathogenesis of familial BLP.

Novel mutation in a Chinese patient with progressive familial intrahepatic cholestasis type 3

Genotyping is conclusive for the diagnosis of progressive familial intrahepatic cholestasis type 3(PFIC3). Here we report a Chinese patient of PFIC3 with compound mutations in the ABCB4 gene. Liver biopsy was performed on a 17-year-old male patient with intrahepatic cholestasis of unknown etiology. Liver histology findings are indicative of intrahepatic cholestasis with extensive fibrosis. Genotyping revealed c.175C>T(p.L59L) mutation in exon 4, c.504C>T(p.N168N) mutation in exon 6, c.711A>T(p.I237I) mutation in exon 8, c.874A>T(p.K292X) in exon 9 and a novel mutation, c.1804G>T(p.G602W) in exon 15. Based on these findings, the patient was diagnosed with PFIC3. The novel mutation p.G602 W in exon 15 was predicted as probably damaging by Poly Phen-2 with a score of 0.986(sensitivity: 0.54; specificity: 0.94) and was predicted to affect protein function with a SIFT score of 0.01.

Expanding etiology of progressive familial intrahepatic cholestasis

BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes,resulting in a hepatocellular form of cholestasis.While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause,recent scientific advancements have uncovered multiple specific responsible proteins.The variety of identified defects has resulted in an ever-broadening phenotypic spectrum,ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.AIM To review current data on defects in bile acid homeostasis,explore the expanding knowledge base of genetic based diseases in this field,and report disease characteristics and management.METHODS We conducted a systemic review according to PRISMA guidelines.We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding,diagnosis,and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC.English only articles were accessed in full.The manual search included references of retrieved articles.We extracted data on disease characteristics,associations with other diseases,and treatment.Data was summarized and presented in text,figure,and table format.RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults.A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1(ATP8B1),BSEP(ABCB11),and MDR3(ABCB4)transporter deficiencies,as well as more recently described gene mutations--TJP2(TJP2),FXR(NR1H4),MYO5B(MYO5B),and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.

APC gene mutations in Chinese familial adenomatous polyposis patients

AIM:To study the characteristics of APC(adenomatous polyposis coli)gene germline mutation in Chinese patients with familial adenomatous polyposis(FAP).METHODS:APC gene from 14 FAP families was amplified by polymerase chain reaction(PCR)and underwent direct sequencing to determine the micromutation type.For the samples without micromutation,the large fragment deletion of APC gene was examined by multiplex ligation-dependent probe amplification(MLPA).RESULTS:There were gene micromutations in 9 families with a micromutation detection rate of 64.3%(9/14),including 6 frameshift mutations(66.7%),1 nonsense mutation(11.1%)and 2 splicing mutations(22.2%).Large fragment deletions were detected by MLPA in 2 families.The total mutation detection rate of micromutations and large fragment deletions was 78.6%(11/14).CONCLUSION:The detection rate of APC gene germline mutation can be improved by direct sequencing combined with MLPA large fragment deletion detection.

Progressive familial intrahepatic cholestasis

BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic cholestasis'and'PFIC'was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.

Risk of ileal pouch neoplasms in patients with familial adenomatous polyposis

Restorative proctocolectomy is the most common surgical option for patients with familial adenomatous polyposis(FAP). However,adenomas may develop in the ileal pouch mucosa over time,and even carcinoma in the pouch has been reported. We therefore reviewed the prevalence,nature,and treatment of adenomas and carcinoma that develop after proctocolectomy in the ileal pouch mucosa in patients with FAP. In 25 reports that were reviewed,the incidence of adenomas in the ileal pouch varied from 6.7% to 73.9%. Several potential factors that favor the development of pouch polyposis have been investigated,but many remain controversial. Nevertheless,it seems certain that the age of the pouch is important. The risk appears to be 7%to 16% after 5 years,35% to 42% after 10 years,and75% after 15 years. On the other hand,only 21 cases of ileal pouch carcinoma have been recorded in the literature to date. The diagnosis of pouch carcinoma was made between 3 to 20 years(median,10 years) after pouch construction. Although the risk of malignant transformation in ileal pouches is probably low,it is not negligible,and the long-term risk cannot presently be well quantified. Regular endoscopic surveillance,especially using chromoendoscopy,is recommended.

Familial pancreatic cancer: Concept, management and issues

Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome(HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (<20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish>Caucasian) and a younger onset are common also in FPC. In European countries, "anticipation" is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (Pan IN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990 s and several surveillance projects for highrisk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.

Familial adenomatous polyposis and changes in the gut microbiota: New insights into colorectal cancer carcinogenesis

Patients with familial adenomatous polyposis(FAP),an autosomal dominant hereditary colorectal cancer syndrome,have a lifetime risk of developing cancer of nearly 100%.Recent studies have pointed out that the gut microbiota could play a crucial role in the development of colorectal adenomas and the consequent progression to colorectal cancer.Some gut bacteria,such as Fusobacterium nucleatum,Escherichia coli,Clostridium difficile,Peptostreptococcus,and enterotoxigenic Bacteroides fragilis,could be implicated in colorectal carcinogenesis through different mechanisms,including the maintenance of a chronic inflammatory state,production of bioactive tumorigenic metabolites,and DNA damage.Studies using the adenomatous polyposis coliMin/+mouse model,which resembles FAP in most respects,have shown that specific changes in the intestinal microbial community could influence a multistep progression,the intestinal“adenoma-carcinoma sequence”,which involves mucosal barrier injury,low-grade inflammation,activation of the Wnt pathway.Therefore,modulation of gut microbiota might represent a novel therapeutic target for patients with FAP.Administration of probiotics,prebiotics,antibiotics,and nonsteroidal anti-inflammatory drugs could potentially prevent the progression of the adenoma-carcinoma sequence in FAP.The aim of this review was to summarize the best available knowledge on the role of gut microbiota in colorectal carcinogenesis in patients with FAP.

Surgical treatment of familial adenomatous polyposis: Dilemmas and current recommendations

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome characterized by multiple adenomatous polyps (predisposing to colorectal cancer development) and numerous extracolonic manifestations. The underlying genetic burden generates variable clinical features that may influence operative management. As a precancerous hereditary condition, the rationale of performing a prophylactic surgery is a mainstay of FAP management. The purpose of the present paper is to bring up many controversial aspects regarding surgical treatment for FAP, and to discuss the results and perspectives of the operative choices and approaches. Preferably, the decision-making process should not be limited to the conventional confrontation of pros and cons of ileorectal anastomosis or restorative proctocolectomy. A wide discussion with the patient may evaluate issues such as age, genotype, family history, sphincter function, the presence or risk of desmoid disease, potential complications of each procedure and chances of postoperative surveillance. Therefore, the definition of the best moment and the choice of appropriate procedure constitute an individual decision that must take into consideration patient&#x02019;s preferences and full information about the complex nature of the disease. All these facts reinforce the idea that FAP patients should be managed by experienced surgeons working in specialized centers to achieve the best immediate and long-term results.

Rhabdomyolysis following severe hypokalemia caused by familial hypokalemic periodic paralysis

Rhabdomyolysis continues to appear with increasing frequency and represents a medical emergency requiring rapid appropriate treatment. One of the unusual causes of nontraumatic rhabdomyolysis is hypokalemic periodic paralysis without secondary causes. Primary hypokalemic periodic paralysis is a rare genetic disease characterized by episodic attacks of muscle weakness due to decreases in serum potassium. A 30-year-old woman who had 3 episodic attacks of hypokalemic periodic paralysis was admitted in emergency room with sudden onset symmetrical muscle weakness. After several hours, she started to complain myalgia and severe ache in both calves without any changes. Laboratory test showed markedly elevated creatine phosphokinase, lactic dehydrogenase levels with hypokalemia, rhabdomyolysis resulting from hypokalemia was diagnosed. Here, we report an unusual case of rhabdomyolysis caused by severe hypokalemia, which was suggested a result of familial hypokalemic periodic paralysis.

Ductopenia and cirrhosis in a 32-year-old woman with progressive familial intrahepatic cholestasis type 3: A case report and review of the literature

Progressive familial intrahepatic cholestasis type 3 is caused by a mutation in the ATP-binding cassette, subfamily B, member 4 (ABCB4) gene encoding multidrug resistance protein 3. A 32-year-old woman with a history of acute hepatitis at age 9 years was found to have jaundice during pregnancy in 2008, and was diagnosed as having intrahepatic cholestasis of pregnancy. In 2009, she underwent cholecystectomy for gallstones and chronic cholecystitis. However, itching and jaundice did not resolve postoperatively. She was admitted to our hospital with fatigue, jaundice, and a recently elevated γ-glutamyl transpeptidase level. Liver biopsy led to the diagnosis of biliary cirrhosis with ductopenia. Genetic testing revealed a pathogenic heterozygous mutation, ex13 c.1531G > A (p.A511 T), in the ABCB4 gene. Her father did not carry the mutation, but her mother's brother carried the heterozygous mutation. We made a definitivediagnosis of familial intrahepatic cholestasis type 3. He symptoms and liver function improved after 3 mo o treatment with ursodeoxycholic acid.