The patient was a 12.9-year-old girl from Mainland China, who presented with yellow skin staining that she had for 5 days. she was the only child to the parents, who were not consanguineous. Furthermore, the patient's mother had a full-term normal pregnancy and was not diagnosed with any abnormalities. The patient's birth weight was 3.5 kg. Apart from mild joint contracture, no abnormalities were detected after birth, and she experienced normal growth and development. Her first hospital visit was at the age of 5 when she was diagnosed with ichthyosis because of repeated dry and itchy skin with desquamation. There was no significant improvement in this condition even after she was administered external and oral drugs.
In this second hospital visit, the patient was brought with a complaint of yellow skin staining, accompanied by obvious hunger. Physical examination showed yellowing all over the body, accompanied by icteric sclera, contracture of the finger and toe joints, dry skin all over the body accompanied by incessant itching, and hand and foot desquamation, which is a manifestation of ichthyosis, as shown in Figure 1.
The outpatient examination showed 230.2 mumol/L TBil, 26.7 mumol/L IBil, 32.9 g/L albumin, 31 U/L AST, 32 U/L ALT, 16 U/L GGT, and 173 mumol/L bile acid. Her renal and coagulation functions were normal; routine urine tests showed high urine bilirubin, moderate levels of urine protein, and normal urine sugar. Cranial MRI showed a slightly higher signal in the bilateral basal ganglia on T1WI. Abdominal B-ultrasound showed mild liver enlargement and abdominal CT showed full shadows in the liver and pancreas and small flaky high-density shadows in the bilateral kidneys. MRCP was normal, ruling out any organic disease of the biliary tract.
The patient was admitted after these tests. In addition to all the other symptoms, at the time of admission, we observed that the child was irritable and had a speech disorder. We speculated that this might be related to bilirubin encephalopathy. As part of the treatment process post-admission, the patient was given ursodeoxycholic acid, ornithine aspartate injection, lactulose, probiotics, atomolan, compound glycyrrhizic anhydride, fresh frozen plasma, and a non-protein diet, but there was no significant improvement in her hyperbilirubinemia and low GGT cholestasis. This finally led us to conduct a whole exon gene sequencing to shed light on this unexplained juvenile cholestasis. While awaiting the sequencing results, we started eight plasma transfusions on the 3rd day of her admission, but the bilirubin and bile acid of the patient decreased only slightly and increased again after the plasma exchange stopped (Table 1).
On the 10th day after admission, the child developed a fever and was given anti-infection treatment. Because plasma exchange could not reduce the bilirubin level, we suggested liver transplantation. However, her parents rejected this suggestion and chose to leave our hospital; the patient then underwent a liver puncture examination at another hospital; the pathological results showed intrahepatic bile duct stenosis. We later followed up with the patient and learned that her bilirubin and bile acid levels had gradually decreased upon treatment with oral ursodeoxycholic acid; our most recent follow-up revealed that the patient's bilirubin and bile acid levels were normal, but the skin symptoms did not improve.
Finally, the whole exon gene sequencing of the patient revealed that she had two heterozygous mutations in the VPSS33B gene. The first was c.1081(exon14) C > T, NM_018668, p.Q361X,257. Following ACMG guidelines, the mutation was determined to be pathogenic (PVS1 + PM2 + PP3), which was inherited from her mother. The second was c.244(exon4) T > C, NM_018668, p.C82R, which, based on ACMG guidelines, was determined to be a likely pathogenic mutation (PVS1 + PM2 + PM3 + PP3), inherited from her father (Figure 2). These two newly discovered gene mutations may be related to the mild ARC syndrome reported previously.