Physical and neuropsychological development of children with Citrin deficiency / 中国当代儿科杂志

OBJECTIVES@#To study the physical and neuropsychological development of children with Citrin deficiency (CD).@*METHODS@#A total of 93 children, aged 1.9-59.8 months, who were diagnosed with CD by @*RESULTS@#For the 93 children with CD, the incidence rate of failure to thrive was 25% (23 children) and the proportion of small for gestational age was 47% (44 children). For the 100 cases of CD, the incidence rates of growth retardation, underweight, emaciation, overweight, and microcephalus were 23% (23 cases), 14% (14 cases), 4% (4 cases), 8% (8 cases), and 9% (9 cases), respectively. The incidence rate of neuropsychological developmental delay was 25% (25 cases), and the incidence rates of development delay in the five domains of adaptability, gross motor, fine motor, language, and social ability were 7% (7 cases), 15% (15 cases), 7% (7 cases), 9% (9 cases), and 7% (7 cases), respectively.@*CONCLUSIONS@#Physical and neuropsychological developmental delay can be observed in children with CD, and physical and neuropsychological development should be regularly assessed.

Clinical features and ABCC2 genotypic analysis of an infant with Dubin-Johnson syndrome / 中国当代儿科杂志

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder resulting from biallelic mutations of ABCC2 gene, with long-term or intermittent conjugated hyperbilirubinemia being the main clinical manifestation. This paper aims to report the clinical features and ABCC2 genotypes of an infant with DJS. A 9.5-month-old male infant was referred to the hospital due to abnormal liver function discovered over 9 months. The major clinical presentation was prolonged jaundice since neonatal period. A series of biochemistry analysis revealed markedly elevated total bilirubin, conjugated bilirubin and total bile acids. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined etiology. Physical examination revealed jaundiced skin and sclera, and a palpable liver 3 cm below the right subcostal margin with medium texture. The spleen was not enlarged. Genetic analysis revealed a splice-site variant c.3988-2A>T and a nonsense variant c.3825C>G (p.Y1275X) in the ABCC2 gene of the infant, which were inherited from his mother and father respectively. The former had not been previously reported. Then ursodeoxycholic acid and phenobarbital were given orally. Half a month later, as a result, his jaundice disappeared and the biochemistry indices improved. However, the long-term outcome needs to be observed. Literature review revealed that neonates/infants with DJS presented with cholestatic jaundice soon after birth as the major clinical feature, and the ABCC2 variants exhibited marked heterogeneity.

Clinical and genetic analysis of an infant with progressive familial intrahepatic cholestasis type II / 中国当代儿科杂志

Progressive familial intrahepatic cholestasis type II (PFIC-2) is an autosomal recessive disorder caused by biallelic variants of ABCB11 gene. This paper reports the clinical and laboratory features of a pediatric patient with PFIC-2. The patient was a 2.4-month-old male infant with jaundice and hepatomegaly as the main clinical manifestations. The serum levels of total bilirubin, direct bilirubin and total bile acids were increased, while the serum γ-glutamyl transpeptidase (GGT) level was normal. Next generation sequencing revealed two missense variants, c.1493T>C(p.Ile498Thr) and c.1502T>G(p.Val501Gly), in the ABCB11 gene of the patient, which were inherited from his father and mother, respectively. The latter was a novel variant which was predicted to be pathogenic by using a variety of bioinformatic tools, and the affected p.Val501 residue was highly conserved in 112 homologous peptides.

Clinical and genetic analysis of a pediatric patient with sodium taurocholate cotransporting polypeptide deficiency / 中国当代儿科杂志

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 feature and molecular diagnostic analysis of the first non-caucasian child with infantile liver failure syndrome type 1 / 中国当代儿科杂志

Infantile liver failure syndrome type 1 (ILFS1) is a Mendelian disease due to biallelic mutations in the cytoplasmic leucyl-tRNA synthetase gene (LARS). This study aimed to report the clinical and molecular features of the first non-caucasian ILFS1 patient, providing reliable evidences for the definite diagnosis of ILFS1. The 2 years and 9 months old male patient was referred to the hospital with hepatosplenomegaly over 1 year. At age 17 months, he was found to have hepatosplenomegaly and anemia. Since then, he had been managed in different hospitals. The laboratory tests showed liver dysfunction, hypoproteinemia, coagulopathy and anemia, along with histologically-confirmed cirrhosis and fatty liver; however, the etiology remained undetermined. The subsequent SLC25A13 mutation analysis by means of prevalent mutation screening and Sanger sequencing only revealed a paternally-inherited mutation c.1658G>A, and no aberrant SLC25A13 transcripts could be detected from the maternal allele on cDNA cloning analysis, ruling out the possibility of citrin deficiency. Further target exome high-throughout sequencing of genes relevant to genetic liver diseases detected a paternal c.2133_2135del (p.L712del) and a maternal c.1183G>A (p.D395N) mutation in LARS gene. This finding was then confirmed by Sanger sequencing, and ILFS1 was thus definitely diagnosed. The child has been followed up till age 4 years, and his condition became stabilized.

Clinical features and DGUOK mutations of an infant with mitochondrial DNA depletion syndrome / 中国当代儿科杂志

The aim of this study was to investigate the clinical features and DGUOK gene mutations of an infant with mitochondrial DNA depletion syndrome (MDS). The patient (more than 7 months old) manifested as hepatosplenomegaly, abnormal liver function, nystagmus and psychomotor retardation. Genetic DNA was extracted from peripheral blood samples of the patient and her parents. Targeted Exome Sequencing was performed to explore the genetic causes. Sanger sequencing was carried out to confirm the detected mutations. The sequencing results showed that the patient was a compound heterozygote for c.679G>A and c.817delT in the DGUOK gene. The former was a reportedly pathogenic missense mutation of maternal origin, while the latter, a frameshift mutation from the father, has not been described yet. The findings in this study expand the mutation spectrum of DGUOK gene, and provide molecular evidence for the etiologic diagnosis of the patient as well as for the genetic counseling and prenatal diagnosis in the family.

Clinical features and COMP gene mutation in a family with a pseudoachondroplasia child / 中国当代儿科杂志

This study aimed to report the clinical characteristics and COMP gene mutation of a family with pseudoachondroplasia (PSACH), a relatively rare spinal and epiphyseal dysplasia that is inherited as an autosomal dominant trait. Clinical information on a 5-year-2-month-old PSACH child and his parents was collected and analyzed. Diagnosis was confirmed by PCR amplification and direct sequencing of all the 19 exons and their flanking sequences of COMP gene, and the mutation was further ascertained by cloning analysis of exon 10. The child presented with short and stubby fingers, bow leg, short limb dwarfism and metaphysic broadening in long bone as well as lumbar lordosis. A mutation c.1048_1116del (p.Asn350_Asp372del) in exon 10, inherited from his father who did not demonstrate any phenotypic feature of PSACH, was detected in the child. PSACH was diagnosed definitively by means of COMP mutation analysis, on the basis of the child's clinical and imaging features. The non-penetrance phenomenon of COMP mutation was described for the first time in PSACH.

Rapid differentiation of human umbilical cord-derived mesenchymal stem cells into insulin-secreting cells under the sole induction of biological products / 生理学报

In order to explore the feasibility of inducing the human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) to differentiate into insulin-secreting cells with biological products alone, hUC-MSCs were separated and purified from the whole umbilical cord by the sequent digestion of collagenase II and trypsin followed by two-step centrifugation. hUC-MSCs were induced with IMDM culture medium containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and Ginkgo biloba extract (GBE). Before and after the induction, the morphological changes were observed under inverse microscope; the islet-related genes were detected by RT-PCR; islet-like clusters (ILCs) were identified by dithizone (DTZ) staining; PDX-1 and immunoreactive insulin (IRI) were examined by immunofluorescence method; the quantity and quality of IRI secretion were assayed by chemiluminescence immunoassay and Western blot respectively. The results showed that the purified hUC-MSCs presented long spindle-like shape and parallel or spiral arrangement which are typical morphological features of MSCs. After the induction, hUC-MSCs changed gradually into round or oval shape and gathered together to form ILCs; there were more than one hundred clusters on the growth surface of a flask of T25; ILCs were stained into positive mauve by DTZ and positive for PDX-1 and IRI; Western blot displayed that most of the IRI was proinsulin (PI). Therefore, hUC-MSCs can rapidly differentiate into insulin-secreting cells under the sole induction of EGF, bFGF, GBE and IMDM, but ILCs are not mature enough to produce sufficient true insulin.