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 1. A 9-day-old female infant was admitted to the Neonatal Section of our Department of Pediatrics due to jaundice over 6 days. At her age of 3 days, jaundiced skin and sclera was noticed, which was then aggravated progressively. As the second product of a non-consanguineous couple, the infant was spontaneously delivered at the gestation age of 38 weeks and 2 days, with a birth weight of 2.85 kg and a body length 48 cm. The Apgar score was 9 points at 1 min after umbilical ligation, and 10 points at 5 min, while the amniotic fluid was clear. The patient had a 9-year-old brother, who was physically healthy with normal social performance. The parents were healthy, and there was not family history of any genetic disease.\nPhysical examination found a body temperature (T) 36.5°C, heart rate (HR) 140 beats/min , respiratory rate (RR) 45 breaths/min, and a body weight (WT) 2940 g. Jaundice was observed in the skin and sclera. The anterior fontanelle was flat and soft, and no malformation of the head, ears, nose, mouth, and eyes could be observed. No positive signs were found in the two lungs and the heart. Her liver and spleen were not enlarged. The extremities were warm, and the distal perfusion was excellent.\nAfter admission, the liver function test revealed indirect hyperbilirubinemia and markedly elevated serum TBA level. Her jaundice was alleviated soon in a response to phototherapy, but the TBA elevation persisted, even on the following-up in the clinic after she was discharged at the age of 19 days (Table ). When aged 25 days, the infant underwent SLC10A1 analysis to evaluate the possibility of NTCP deficiency. Sanger sequencing of the UGT1A1 gene was performed (), but no pathogenic variant was detected.