Patient 3 was a 1-year-and-2-month-old female referred to our hospital because of abnormal liver function discovered for 12.7 months. At the age 1.3 months, she went through a liver function test because of prolonged jaundice for 1 month, which showed raised levels of AST, GGT, ALP, TBIL, DBIL, and IBIL (). When aged 1.8 months, her TBA level was found to be as high as 172.0 µmol/L besides the cholestatic alterations (), and the MS-MS analysis revealed increased levels of tyrosine, citrulline, and methionine while large quantities of urinary 4HPPV and 4HPL were detected on GC-MS analysis. NICCD was consequently suspected, and breast-feeding was stopped while a lactose-free and MCT-enriched formula was suggested. Following that, her cholestatic jaundice got alleviated rapidly and the laboratory alterations recovered to normal levels by the age 5 months, while the hypercholanemia was intractable, even beyond 1 year of age ().\nAs the first child of a non-consanguineous couple, the infant was delivered by cesarean section at the gestation age of 38 weeks and 2 days with the birth weight 2,750 g. Her father was clinically healthy with an elevated serum TBA level of 21.1 µmol/L (0–10 µmol/L), and her mother was physically and biochemically healthy (). There was no family history of any genetic diseases.\nPhysical examination at referral revealed a body weight 10.1 kg, length 80 cm and head circumference 46 cm. No jaundice was observed in the skin and sclera. Examinations of the heart, the lungs, the abdomen, and nervous system were all normal.\nBiochemical test at referral revealed a TBA level 50.9 µmol/L with otherwise normal indices (). On genetic analysis, the patient was a compound heterozygote of the SLC25A13 mutations c.852_855del4 and c.1638_1660dup, which was inherited from the father and mother, respectively (); moreover, the patient and her father were both homozygous for the SLC10A1 variant c.800C > T (p.Ser267Phe), while her mother was a carrier (). Hence, citrin deficiency and NTCP deficiency were definitely diagnosed for the infant. No specific therapy was given, and his TBA level tended downward to 25.6 µmol/L at the age of 3 years and 4 months (), still remaining beyond the upper limit. The patient also had a fondness of protein-rich foods while an aversion to carbohydrate-rich foods from the age 1 year.\nThe molecular findings above were further confirmed by Sanger sequencing () and illustrated as family tree diagrams (). The clinical and molecular features of all the 3 patients were summarized in .
Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].