A 7-month-old female infant was referred to our hospital due to prolonged jaundice for approximately 4 months and growth retardation for 1.5 months. Her jaundice (yellow skin and sclera) drew the attention of her parents at the age of 3.3 months. A liver function test at the local hospital revealed elevated cholestatic indices, including gamma-glutamyl transpeptidase (GGT), direct bilirubin (Dbil) and total bile acid (TBA) (). Due to the prolonged jaundice and unresolved laboratory abnormalities, the infant was referred to another hospital at the age of 4 months, where magnetic resonance cholangiopancreatography revealed the dilatation of common hepatic and bile ducts. Laparoscopy was thus performed when the infant was aged 4.5 months, and an intraoperative cholangiography displayed biliary tree dilatation and filling defect in the common bile duct, along with an accessory hepatic duct (AHD) joining the cystic duct (). A cholecystectomy was subsequently performed, an intrabiliary thick plug in the color of dark green was removed, and bile duct irrigation and choledochostomy with T-tube drainage was carried out. Pathological analysis of the plug confirmed the diagnosis of inspissated bile syndrome (IBS). Thereafter, the infant’s jaundice subsided and the laboratory indices gradually improved (); the infant was discharged at the age of 5 months. Half a month later, nevertheless, a physical examination revealed that her body weight was 5.34 kg (−3.6 SD), her length was 59 cm (−3.2 SD) and her head circumference was 39 cm (−2.5 SD). Another anthropometric test at the age of 6 months revealed a weight of 6.0 kg (−2.5 SD) and a length of 62.0 cm (−2.2 SD). The growth retardation continued in the following month, and the infant was referred to our hospital at the age of 7 months for further evaluation, following the removal of the drainage T-tube.\nThe infant was born to a non-consanguineous couple after 37 weeks of uneventful gestation with a birth weight of 2.25 kg. On the first day after birth, the infant was admitted to hospital due to vomiting and respiratory distress. Contrast imaging of the upper digestive tract revealed the existence of esophageal atresia (EA) (), which was then resolved by a gastroesophagostomy under general anesthesia. The couple had experienced 2 pregnancies prior to this one, but both were aborted in the first trimester. Both parents appeared healthy, without any clinical symptoms or signs of CTLN2. There was no known family history of any genetic disease.\nPhysical examination at referral revealed a weight of 6.25 kg (−2.6 SD), a length of 63.0 cm (−3.3 SD) and a head circumference of 42 cm (−1.0 SD). There was no dysmorphic appearance, only a slightly chubby face. There was no evidence of jaundice (yellow skin and sclera) and there were no visible petechiae or ecchymoses. No pallor or cyanosis of the lips were observed. There was no tachypnea or dyspnea, and no stridor, wheezes, crackles or crepitus could be heard on auscultation of the both lungs. The heart sounds were normal without audible murmurs or arrhythmia. Upon abdominal inspection, no dilated veins or abdominal distention were observed. The liver was palpated with a soft edge 2 cm below the right costal margin in the mid-clavicular line. Her spleen was not palpable. A neurological examination revealed slightly reduced muscle tone. There was no neck stiffness, knee reflex was normal and there was no positivity for Brudzinski’s or Kernig’s sign.\nFollowing biochemical analysis, no abnormal liver function index was observed, although the serum GGT level was elevated, suggesting the existence of cholestasis, as shown in . Taking into consideration her prolonged jaundice, growth retardation and chubby face, and the 2 first-trimester miscarriages of her mother, SLC25A13 gene analysis was performed on the family to evaluate the possibility of a diagnosis of CD. A lactose-free and MCT-enriched therapeutic formula was subsequently introduced, while a diet rich in protein and lipids was also encouraged. A clinical following-up 4 months later revealed that the weight of the infant was 7.9 kg (−1.6 SD), her length was 70 cm (−1.5 SD) and her head circumference was 44 cm (−0.8 SD), along with a marked improvement (complete recovery) of the cholestatic indices, GGT, TBA and Dbil ().
Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.