A rare case report: multiple intrahepatic masses in a pediatric patient with citrin deficiency.

Deficiency of citrin, the liver-type aspartate-glutamate carrier, arises from biallelic mutations of the gene SLC25A13. Although citrin deficiency (CD) is associated with higher risk of hepatocellular carcinoma (HCC) in adult patients, this association remains inconclusive in pediatric cases. The patient in this paper had been diagnosed to have CD by SLC25A13 analysis at the age 10 months, and then in response to dietary therapy, her prolonged jaundice and marked hepatosplenomegaly resolved gradually. However, she was referred to the hospital once again due to recurrent abdominal distention for 2 weeks at her age 4 years and 9 months, when prominently enlarged liver and spleen were palpated, along with a strikingly elevated serum alpha-fetoprotein (AFP) level of 27605 ng/mL as well as a large mass in the right liver lobe and a suspected tumor thrombus within the portal vein on enhanced computed tomography. After 4 rounds of adjuvant chemotherapy, right hepatic lobectomy and portal venous embolectomy were performed at her age 5 years and 3 months, and metastatic hepatoblastoma was confirmed by histopathological analysis. Afterwards, the patient underwent 5 additional cycles of chemotherapy and her condition remained stable for 7 months after surgery. Unfortunately, hepatoblastoma recurred in the left lobe at the age 5 years and 10 months, which progressed rapidly into liver failure, and led to death at the age 6 years and 1 month. As far as we know, this is the the first case of hepatoblastoma in a patient with CD, raising the possibility of an association between these two conditions.

Molecular Epidemiology of Na+-Taurocholate Cotransporting Polypeptide Deficiency in Guangdong Province, China: A Pilot Study by Screening for Four Prevalent Variants of the Causative Gene SLC10A1.

Na+-taurocholate cotransporting polypeptide deficiency (NTCPD) is an autosomal recessive disorder arising from biallelic SLC10A1 mutations. As a newly-described inborn error of bile acid metabolism, the epidemiology of this condition remains largely unclear in Chinese population so far. In this study, a total of 2,828 peripheral blood samples were collected from 12 cities in Guangdong, a province with the largest population in China, and the four prevalent SLC10A1 variants c.800C > T (p.Ser267Phe), c.263T > C (p.Ile88Thr), c.595A > C (p.Ser199Arg) and c.665T > C (p.Leu222Ser) were screened for by using polymerase chain reaction (PCR)- restriction fragment length polymorphism (RFLP). As a result, 663 mutated SLC10A1 alleles were detected, and the mutated allele frequency was calculated to be 11.72% (663/5,656), with a carrier frequency 20.69% (1/5) and a theoretical morbidity rate 1.37% (1/73) of NTCPD in Guangdong province. The variant c.800C > T (p.Ser267Phe) exhibited highest allele frequency among the four prevalent variants (χ2 = 1501.27, p < 0.0001) as well as higher allele frequency in the peripheral region than that within the Pearl River Delta (χ2 = 4.834, p < 0.05). The results suggested that NTCPD might be a disorder rather common in Guangdong province. The findings depicted the molecular epidemiologic features of NTCPD, providing preliminary but significant laboratory evidences for the subsequent NTCPD diagnosis and management in Guangdong population.

Clinical characterization of NTCP deficiency in paediatric patients : A case-control study based on SLC10A1 genotyping analysis.

Na+ -taurocholate cotransporting polypeptide deficiency (NTCPD) is a newly described disorder arising from biallelic mutations of the SLC10A1 gene. As a result of a lack of compelling evidence from case-control studies, its genotypic and phenotypic features remain open for in-depth investigation. This study aimed to explore the genotypic and clinical phenotypic characteristics of paediatric patients with NTCPD. The SLC10A1 genotypes of all NTCPD patients were confirmed by screening for the prevalent variant c.800C>T and Sanger sequencing when necessary. The clinical presentations and laboratory changes were collected, reviewed and analysed, and then qualitatively and quantitatively compared with the relevant controls. A total of 113 paediatric NTCPD patients were diagnosed while c.374dupG and c.682_683delCT were detected as two novel pathogenic mutations. Hypercholanemia was observed in 99.12% of the patients. Indirect hyperbilirubinemia in affected neonates exhibited higher positive rates in comparison to controls. Moreover, transient cholestatic jaundice, elevated liver enzymes and 25-hydroxyvitamin D (Vit D) deficiency during early infancy were more commonly observed in patients than in controls. All NTCPD patients exhibited favourable clinical outcomes as a result of symptomatic and supportive treatment. The findings enriched the SLC10A1 mutation spectrum and provided comprehensive insights into the phenotypic characteristics of NTCPD. NTCPD should be considered and SLC10A1 gene should be analysed in patients with above age-dependent clinical features. Furthermore, over investigation and intervention should be avoided in the management of NTCPD patients.

Identification of a novel large deletion of the mitochondrial DNA in an infant with Pearson syndrome: a case report.

Pearson syndrome (PS), also known as Pearson marrow-pancreas syndrome, is a rare, multi-systemic disorder caused by large-scale deletion of mitochondrial DNA (mtDNA) ranging from 2.3 kb to 9 kb, with 4,977 bp in length as the most common variant. This paper reported a novel mtDNA deletion of 4,734 bp in size, spanning from nucleotide 11,220 to 15,953. The infant suffered from chronic hepatomegaly, liver dysfunction, anemia and lactic acidosis over 1 year. Evidences of any infections were negative. Bone marrow aspiration and whole exome sequencing covering nearly 20,000 nucleus genes were performed when aged 3.3 and 6 months, respectively, but no genetic cause was identified. However, at his age 13 months, multiplex ligation-dependent probe amplification assay of the mtDNA in the patient detected a large deletion of 4,734 bp in size spanning the mitochondrial genes MTND4, MTTH, MTTS2, MTTL2, MTND5, MTND6, MTTE, MTCYB and MTTT which were functionally crucial for the intact oxidative phosphorylation pathway and adenosine triphosphate production, and PS was thus definitely diagnosed. This large deletion was negative in his parents and elder brother. Oral ursodeoxycholic acid, fat-soluble vitamins and blood transfusions were administrated, his clinical and laboratory presentations remained stable so far, but the long-term prognosis needed to be followed up. These findings enriched the variant spectrum of mtDNA, and demonstrated the importance of considering mitochondrial disorder in patient with intractable anemia, liver dysfunction and lactic acidosis as well as the significance of appropriate choosing of relevant genetic tools in the etiology diagnosis of such patients.

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency: In vivo and in vitro studies of the aberrant transcription arising from two novel splice-site variants in SLC25A13.

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) is an autosomal recessive disease resulting from biallelic SLC25A13 mutations, and its diagnosis relies on genetic analysis. This study aimed to characterize the pathogenicity of 2 novel splice-site variants of SLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del]; [69+5G > A] in patient C0476 and c.[1453-1G > A]; [1751-5_1751-4ins (2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by computational analysis. The alternative splice variants in monocyte-derived macrophages from patient C0476 demonstrated exon 2 skipping [r.16_69del; p.(Val6_Lys23del)] in vivo, while minigene analysis revealed both exon 2-skipping and retained products from c.69+5G > A in vitro. In the patient C0556, an aberrant transcript [r.1453del; p.(Gly485Valfs*22)] resulting from c.1453-1G > A was detected on minigene splicing study. Thus, c.69+5G > A and c.1453-1G > A were both proved to be pathogenic. The 2 novel splice-site variants expanded the SLC25A13 mutation spectrum and provided reliable molecular markers for the definite diagnosis and genetic counseling of NICCD in the affected families.

Sodium Taurocholate Cotransporting Polypeptide (NTCP) Deficiency Hidden Behind Citrin Deficiency in Early Infancy: A Report of Three Cases.

Sodium taurocholate cotransporting polypeptide (NTCP), a carrier protein encoded by the gene SLC10A1, is expressed in the basolateral membrane of the hepatocyte to uptake bile acids from plasma. As a new inborn error of bile acid metabolism, NTCP deficiency remains far from being well understood in terms of the clinical and molecular features. Citrin deficiency is a well-known autosomal recessive disease arising from SLC25A13 mutations, and in neonates or infants, this condition presents as transient intrahepatic cholestasis which usually resolves before 1 year of age. All the three patients in this paper exhibited cholestatic jaundice and elevated total bile acids in their early infancy, which were attributed to citrin deficiency by SLC25A13 genetic analysis. In response to feeding with lactose-free and medium-chain triglycerides-enrich formula, their clinical and laboratory presentations disappeared gradually while the hypercholanemia persisted, even beyond 1 year of age. On subsequent SLC10A1 analysis, they were all homozygous for the well-known pathogenic variant c.800C > T (p.Ser267Phe), and NTCP deficiency was thus definitely diagnosed. The findings in this paper indicated that NTCP deficiency could be covered up by citrin deficiency during early infancy; however, in citrin-deficient patients with intractable hypercholanemia following resolved cholestatic jaundice, NTCP deficiency should be taken into consideration.

Clinical and molecular characterization of four patients with NTCP deficiency from two unrelated families harboring the novel SLC10A1 variant c.595A>C (p.Ser199Arg).

Sodium taurocholate cotransporting polypeptide (NTCP), a carrier protein encoded by solute carrier family 10 member 1 (SLC10A1), is expressed in the basolateral membrane of hepatocytes, where it is responsible for the uptake of bile acids from plasma into hepatocytes. The first patient with NTCP deficiency was described in 2015. A limited number of such patients have been reported in the literature and their genotypic and phenotypic features require further investigation. The current study investigated 4 patients with NTCP deficiency from two unrelated families. The patients were subjected to SLC10A1 genetic analysis and it was revealed that all patients were compound heterozygous for the c.800C>T (p.Ser267Phe) and c.595A>C (p.Ser199Arg) SLC10A1 variants. To the best of the authors' knowledge, the latter variant had not been previously reported. Further analysis in 50 healthy individuals did not identify carriers. The c.595A>C (p.Ser199Arg) variant exhibited co­segregation with hypercholanemia and exhibited a relatively conserved amino acid when compared with homologous peptides. Moreover, SWISS­MODEL prediction revealed that the mutation affected the conformation of the NTCP molecule. The 4 patients demonstrated varying degrees of hypercholanemia while a downward trend in the plasma levels of total bile acids (TBA) in 2 pediatric patients and occasionally normal TBA level in an adult case were observed. The results indicated an autosomal recessive trait for NTCP deficiency, supported the primary role of NTCP in the uptake of bile acids from plasma and suggested that hepatic uptake of bile acids may occur by means other than NTCP uptake. Moreover, the novel missense variant c.595A>C(p.Ser199Arg) enriched the SLC10A1 mutation spectrum and may serve as a new genetic marker for the molecular diagnosis and genetic counseling of NTCP deficiency.

Intrahepatic Cholestasis of Pregnancy as a Clinical Manifestation of Sodium-Taurocholate Cotransporting Polypeptide Deficiency.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Although the etiology of ICP is not fully understood thus far, some genetic factors might contribute to the development of this condition. Sodium-taurocholate cotransporting polypeptide (NTCP), the protein encoded by the gene Solute Carrier Family 10, Member 1 (SLC10A1), is the primary transporter expressed in the basolateral membrane of the hepatocyte to uptake conjugated bile salts from the plasma. NTCP deficiency arises from biallelic SLC10A1 mutations which impair the NTCP function and cause intractably elevated levels of total bile acids (TBA) in the plasma (hypercholanemia). In this study, all the SLC10A1 exons and their flanking sequences were analyzed by Sanger sequencing to investigate the etiology for hypercholanemia in two male infants aged 2 and 20 months, respectively, from two unrelated families. As a result, both patients are homozygous for the reported pathogenic variant c.800C>T (p.Ser267Phe) that could impair the NTCP function to uptake bile acids, and the diagnosis of NTCP deficiency was thus made. Their mothers are also homozygotes of the same variant and both had been diagnosed to have ICP in the third trimester, with one of them undergoing cesarean section. The father of the first patient in this paper has the same SLC10A1 genotype c.800C>T/c.800C>T, also exhibiting slight hypercholanemia with a plasma TBA level of 21.5 µmol/L. In conclusion, we suggest that with hypercholanemia being a common laboratory change, NTCP deficiency may be a genetic factor leading to ICP and even cesarean section in clinical practice.

Monozygotic Twins Suffering From Sodium Taurocholate Cotransporting Polypeptide Deficiency: A Case Report.

Sodium taurocholate cotransporting polypeptide (NTCP) is a carrier protein encoded by the human SLC10A1 gene, acting as the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although NTCP was cloned as early as in 1994 and its function has been studied extensively, clinical description of NTCP deficiency remains rather limited thus far. The patients in this paper were 2 female monozygotic twins, who were referred to our hospital at the age 2 years with the complaint of persistently-raised total bile acids (TBA) for 21 months. At age 3 months, they were both diagnosed to have cholestatic liver disease due to raised serum TBA and direct bilirubin (DBIL) with the fraction >20% of the elevated total bilirubin (TBIL). Thereafter, their jaundice subsided and the DBIL levels recovered gradually, while serum TBA remained raised persistently. In view of their refractory hypercholanemia but negative symptoms and signs, SLC10A1 genetic analysis was performed for all family members to evaluate the possibility of NTCP deficiency. As a result, the twins were both homozygotes, while the parents, carriers, of the reportedly pathogenic variant c.800C>T (p.Ser267Phe). These findings suggested that NTCP deficiency may be a unique genetic factor causing transient cholestasis in early infancy, as well as, persistent hypercholanemia in pediatric patients.

[Clinical and genetic analysis of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency].

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is an inborn error of bile acid metabolism caused by mutations of SLC10A1 gene. This paper reports the clinical and genetic features of a patient with this disease. A 3.3-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 3 months. Physical examination revealed moderate jaundice of the skin and sclera. The liver was palpable 3.5 cm below the right subcostal margin with a medium texture. Serum biochemistry analysis revealed markedly elevated bilirubin (predominantly direct bilirubin) and total bile acids (TBA), as well as decreased 25-OH-VitD level. On pathological analysis of the biopsied liver tissue, hepatocyte ballooning and cholestatic multinucleate giant cells were noted. The lobular architecture was distorted. Infiltration of inflammatory cells, predominantly lymphocytes, was seen in the portal tracts. In response to the anti-inflammatory and liver protective drugs as well as fat-soluble vitamins over 2 months, the bilirubin and transaminases levels were improved markedly while the TBA kept elevated. Because of persisting hypercholanemia on the follow-up, SLC10A1 gene analysis was performed at his age of 17.2 months. The child proved to be a homozygote of the reportedly pathogenic variant c.800C>T (p. Ser267Phe), while the parents were both carriers. NTCP deficiency was thus diagnosed. The infant was followed up until 34.3 months old. He developed well in terms of the anthropometric indices and neurobehavioral milestones. The jaundice disappeared completely. The liver size, texture and function indices all recovered. However, the hypercholanemia persisted, and the long-term outcome needs to be observed.

[Clinical and genetic study of an infant with Alagille syndrome: identification of a novel chromosomal interstitial deletion including JAG1 gene].

Alagille syndrome (ALGS) is an autosomal dominant disease affecting multiple systems including the liver, heart, skeleton, eyes, kidneys and face. This paper reports the clinical and genetic features of an infant with this disease. A 3-month-and-10-day-old female infant was referred to the hospital with jaundiced skin and sclera for 3 months. Physical examination revealed wide forehead and micromandible. A systolic murmur of grade 3-4/6 was heard between the 2th and 3th intercostal spaces on the left side of the sternum. The abdomen was distended, and the liver palpable 3 cm under the right subcostal margin with a medium texture. Serum biochemistry analysis revealed abnormal liver function indices, with markedly elevated bilirubin (predominantly direct bilirubin), total bile acids (TBA) and gamma-glutamyl transpeptidase (GGT). Atrial septal defect and pulmonary stenosis were detected on echocardiography. Next generation sequencing detected entire deletion of the JAG1 gene, and then chromosomal microarray analysis revealed a novel interstitial deletion of 3.0 Mb in size on chr20p12.3p12.2, involving JAG1 gene. The child had special facial features, heart malformations, and cholestasis, and based on the genetic findings, ALGS was definitively diagnosed. Thereafter, symptomatic and supportive treatment was introduced. Thus far, the infant had been followed up till his age of 11 months. The hyperbilirubinemia got improved, but GGT and TBA were persistently elevated, and the long-term outcome needs to be observed. This study extended the JAG1 mutation spectrum, and provided laboratory evidences for the diagnosis and treatment of the patient, and for the genetic counseling and prenatal diagnosis in the family.

[Sodium taurocholate cotransporting polypeptide deficiency manifesting as cholestatic jaundice in early infancy: a complicated case study].

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency is caused by SLC10A1 mutations impairing the NTCP function to uptake plasma bile salts into the hepatocyte. Thus far, patients with NTCP deficiency were rarely reported. The patient in this paper was a 5-month-19-day male infant with the complaint of jaundiced skin and sclera for 5.5 months as well as abnormal liver function revealed over 4 months. His jaundice was noticed on the second day after birth, and remained visible till his age of 1 month and 13 days, when a liver function test unveiled markedly elevated total, direct and indirect bilirubin as well as total bile acids (TBA). Cholestatic liver disease was thus diagnosed. Due to unsatisfactory response to medical treatment, the patient underwent exploratory laparotomy, cholecystostomy and cholangiography when aged 2 months. This revealed inspissated bile but unobstructed bile ducts. Thereafter, his jaundice subsided, but the aminotransferases and TBA levels gradually rose. Of note, his mother also had mildly elevated plasma TBA. Since the etiology was unclear, no specific medication was introduced. The infant has been followed up over 2 years. The aminotransferases recovered gradually, but TBA levels fluctuated within 23.3-277.7 µmol/L (reference range: 0-10 µmol/L). On SLC10A1 genetic analysis at 2 years and 9 months, both the infant and his mother proved to be homozygous for a pathogenic variant c.800C>T(p.S267F), and NTCP deficiency was thus definitely diagnosed. The findings suggest that, although only mildly increased plasma TBA is presented in adults with NTCP deficiency, pediatric patients with this disorder exhibit persistent and remarkable hypercholanemia, and some patients might manifest as cholestatic jaundice in early infancy.

Sodium taurocholate cotransporting polypeptide (NTCP) deficiency: Identification of a novel SLC10A1 mutation in two unrelated infants presenting with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia.

Sodium taurocholate cotransporting polypeptide (NTCP) is encoded by the gene SLC10A1 and expressed in the basolateral membrane of the hepatocyte, functioning to uptake bile acids from plasma. Although SLC10A1 has been cloned and NTCP function studied intensively for years, clinical description of NTCP deficiency remains rather limited. This study reported the genotypic and phenotypic features of two neonatal patients with NTCP deficiency. They both presented with neonatal indirect hyperbilirubinemia and remarkable hypercholanemia, and harbored the SLC10A1 variants c.800C>T (p.S267F) and c.263T>C (p.I88T). On genetic analysis of the two family trios, the latter missense variant was detected in trans with the former, a reported loss-of-function variant. Having not been reported in any databases, the c.263T>C (p.I88T) variant demonstrated an allele frequency of 0.67% (1/150) in healthy controls. Moreover, this variant involved a relatively conservative amino acid, and was predicted to be pathogenic or deleterious by changing the conformation of the NTCP molecule. In conclusion, the novel variant c.263T>C (p.I88T) in this study enriched the SLC10A1 mutation spectrum; the clinical findings lent support to the primary role of NTCP in hepatic bile acid clearance, and suggested that NTCP deficiency might be a contributing factor for the development of neonatal indirect hyperbilirubinemia.

Clinical and molecular study of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency.

The human solute carrier family 10 member 1 (SLC10A1) gene encodes sodium taurocholate cotransporting polypeptide (NTCP), the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although the function of NTCP has been studied extensively and a number of SLC10A1 variations have been identified in humans, information regarding NTCP deficiency is limited. To date, only one patient with NTCP deficiency has been described; however, in the present study a pediatric patient who experienced intractable and striking hypercholanemia is presented. Analysis of the SLC10A1 gene in the patient revealed a homozygous p.Ser267Phe (c.800C>T) variation, which proved to be a single-nucleotide polymorphism (SNP) in the allele frequency of 4.7% of healthy controls. This variation involved a conserved amino acid residue on the orthologous alignment that was predicted to be 'disease-causing' by functional analysis using a number of bioinformatic tools. Next generation sequencing was performed; however, no other genetic causes were identified that would affect the bile acid homeostasis in the patient. Moreover, an adult, with the same genotype as the pediatric patient, was identified for the first time as experiencing mild hypercholanemia. The molecular and clinical findings in the present study suggest, for the first time, that there is an association between p.Ser267Phe SNP and hypercholanemia, and this information may be used to clinically identify NTCP deficiency worldwide.

[Identification of a novel JAG1 mutation in a family affected by Alagille syndrome].

Alagille syndrome (ALGS) is an autosomal dominant disorder which is mainly caused by JAG1 gene mutation and can affect multiple systems including the liver, heart, eyes, skeleton and face. This paper reports the clinical and genetic features of an ALGS patient. A 2-year-and-9-month-old boy was referred to the hospital with the complaint of abnormal liver function and heart murmur discovered over two years. Jaundice of the skin and sclera was not observed. The child had a prominent forehead, left esotropia, depressed nasal bridge and micromandible. The two lungs were clear on auscultation, but a systolic cardiac murmur of grade 2/6 could be heard between the 2nd and 3rd intercostal space at the left sternal border. Neither abdominal distension nor enlarged liver or spleen was discovered. X-ray radiography uncovered butterfly malformation of the 6th and 8th thoracic vertebrae. Serum biochemistry analysis revealed elevation of total bile acids, bilirubin and transaminases. Based on the clinical characteristics and the consultation opinion of the ophthalmologist, the child was diagnosed to have ALGS with Duane retraction syndrome. DNA direct sequencing detected a novel JAG1 mutation c.2419delG(p.Glu807AsnfsX819) in the child. Symptomatic and supportive therapy was performed thereafter and clinical follow-up was conducted until he was 4 years and 2 months. In the follow-up visits, his general condition remained stable, but the facial malformations, left esotropia, cardiac murmur and abnormal liver function persistend. The long-term outcome needed to be observed.

[Clinical feature and ATP8B1 mutation analysis of a patient with progressive familial intrahepatic cholestasis type I].

Progressive familial intrahepatic cholestasis type I (PFIC1) is an autosomal recessive disorder caused by biallelic mutations of ATP8B1 gene, with progressive cholestasis as the main clinical manifestation. This paper reports the clinical and genetic features of a PFIC1 patient definitely diagnosed by ATP8B1 genetic analysis. The patient, a boy aged 14 months, was referred to the hospital with the complaint of jaundiced skin and sclera over 10 months. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. On physical examination, hepatosplenomegaly was discovered in addition to jaundice of the skin and sclera. The liver was palpable 4 cm below the right subcostal margin and 2 cm below the xiphoid while the spleen 2 cm below the left subcostal margin. The liver function test revealed elevated levels of serum total bile acids, bilirubin, and transaminases; however, the γ-glutamyl transferase level was normal. The diagnosis was genetic cholestasis of undetermined origin. At the age of 1 year and 8 months, a Roux-en-Y cholecystocolonic bypass operation was performed, and thereafter the jaundice disappeared. At 5 years and 1 month, via whole genome sequencing analysis and Sanger sequencing confirmation, the boy was found to be a homozygote of mutation c.2081T>A(p.I694N) of ATP8B1 gene, and thus PFIC1 was definitely diagnosed. The boy was followed up until he was 6 years, and jaundice did not recur, but the long-term outcome remains to be observed.

Idiopathic eruptive macular pigmentation in a child with citrin deficiency.

Idiopathic eruptive macular pigmentation (IEMP) is a rare dermatological disorder with generally unclear etiology and pathogenesis. A 5½-year-old girl was referred to hospital with a 10 month history of brown skin rashes. In early infancy, citrin deficiency had been diagnosed with the SLC25A13 genotype c.851_854del4/c.998G > A, but all clinical and laboratory abnormalities recovered following the introduction of a lactose-free and medium-chain triglyceride-enriched formula. Physical examination at referral indicated symmetric, multiple and non-scaly brown macules on the neck, trunk, buttocks and proximal parts of the extremities. Histopathology indicated epidermal basal layer hyperpigmentation with an irregular distribution, along with a large number of melanophages in the upper dermis. The diagnosis of IEMP was thus made. Within 2 years of follow up, the rashes disappeared spontaneously and gradually. To our knowledge, this is the first description of IEMP in a patient with silent citrin deficiency.

[Advances in the diagnosis and treatment of Alagille syndrome].

Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is an autosomal dominant disease with multisystem involvement. In this disease, the Notch signalling pathway is impaired due to mutation in JAG1 (ALGS type 1) or NOTCH2 (ALGS type 2) gene, affecting multiple organs or systems such as liver, heart, eyes, vertebrate and face. The main clinical features of ALGS include chronic cholestasis, congenital heart disease, mild vertebral segmentation abnormalities, characteristic face, postcorneal embryotoxon and poor kidney development. This article reviews the recent advances in the pathogenesis, clinical presentations, diagnosis and treatment of this syndrome.

Inspissated bile syndrome in an infant with citrin deficiency and congenital anomalies of the biliary tract and esophagus: identification and pathogenicity analysis of a novel SLC25A13 mutation with incomplete penetrance.

Biallelic mutations of the SLC25A13 gene result in citrin deficiency (CD) in humans. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major CD phenotype in pediatrics; however, knowledge on its genotypic and phenotypic characteristics remains limited. The present study aimed to explore novel molecular and clinical characteristics of CD. An infant suspected to have NICCD as well as her parents were enrolled as the research subjects. SLC25A13 mutations were investigated using various methods, including cDNA cloning and sequencing. The pathogenicity of a novel mutation was analyzed bioinformatically and functionally with a yeast model. Both the infant and her father were heterozygous for c.2T>C and c.790G>A, while the mother was only a c.2T>C carrier. The novel c.790G>A mutation proved bioinformatically and functionally pathogenic. The infant had esophageal atresia and an accessory hepatic duct, along with bile plug formation confirmed by laparoscopic surgery. However, the father seemed to be healthy thus far. The findings of the present study enrich the genotypic and phenotypic characteristics of CD patients, and provided clinical and molecular evidence suggesting the possible non-penetrance of SLC25A13 mutations and the likely involvement of this gene in primitive foregut development during early embryonic life.