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 .
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 ().