A Japanese boy weighing 1,968 g was born via vaginal delivery. His mother was a 29-year-old primigravida woman. She had no prenatal care, including testing for syphilitic infection. The Apgar scores at 1 and 5 min were 5 and 7, respectively. The gestational age was estimated to be 36 weeks and 2 days using the Dubowitz method.
After birth, maternal serological tests for syphilis, rapid plasma reagin (RPR), and T. pallidum antibody (TPAb) test were positive. Maternal serological tests for human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus were negative. The infant had peeling skin on his face, hands, and feet. Hepatosplenomegaly and cervical lymphadenopathy were also observed. Initial laboratory examination showed a white blood cell count of 13.3 x 109/L, a hemoglobin level of 12.8 g/dl, and a platelet count of 124 x 109/L. C-reactive protein (CRP) and immunoglobulin M (IgM) levels were elevated to 4.24 and 331 mg/dl, respectively. The hepatic function test results were normal, with an aspartate aminotransferase (AST) level of 41 IU/L, alanine aminotransferase level of 4 IU/L, total bilirubin (TB) level of 2.9 mg/dl, and a direct bilirubin (DB) level of 1.1 mg/dl. The results of the coagulation studies were normal. Cytomegalovirus, rubella virus, herpes simplex virus, hepatitis B virus, hepatitis C virus, and HIV serological tests were negative. His RPR, TPAb, and fluorescent treponemal antibody-absorption serum tests were positive. Although cerebrospinal fluid (CSF) examinations showed normal lymphocytosis and protein levels, the CSF Venereal Disease Research Laboratory test was also reactive. Furthermore, histopathological examination of the placenta and umbilical cord revealed severe chorioamnionitis and necrotizing funisitis. Numerous T. pallidum cells were detected in Wharton jelly by immunohistochemistry, using an antibody against T. pallidum. Given these findings, he was diagnosed with CS and treated with penicillin G for 2 weeks.
After penicillin G therapy, CRP levels decreased rapidly to 0.09 mg/dl at day 14. However, he developed cholestasis at 1 month of age, with elevated serum TB (7.0 mg/dl), DB (5.6 mg/dl), AST (416 IU/L), ALT (187 IU/L), gamma-glutamyl transferase (139 IU/L, reference range: 13 to 64 IU/L), and total serum bile acid (141.8 mumol/L, reference range: <10 mumol/L) levels. Common causes of neonatal cholestasis, such as hypothyroidism, galactosemia, and alpha1-antitrypsin deficiency, were excluded by blood examination. He needed to receive a formula containing medium-chain triglycerides to achieve adequate body weight gain. He was treated with ursodeoxycholic acid, and supplementation with vitamins D and K was started. However, his cholestasis progressively worsened (Figure 1A), and acholic stools were observed. His gallbladder was found to be normal and no triangular cord sign was observed by ultrasonography, suggesting a lower possibility of biliary atresia (BA). However, considering that ultrasonography cannot completely rule out BA, surgical intervention was performed at 1.5 months of age. Operative cholangiography showed a normal gallbladder and biliary tree, thus excluding BA. Liver pathology tests showed intrahepatic cholestasis with a few bile plugs within the bile ducts (Figures 2A-C). Moderate inflammatory cell infiltration was also observed, mainly consisting of CD68-positive macrophages and small numbers of CD20-positive B lymphocytes (Figures 2D,E). Azan staining showed mild pericellular fibrosis surrounding hepatocytes, with slight fibrosis in the portal vein area (Figures 2F,G). Bile duct paucity was not observed, and T. pallidum was not detected in the liver. To further delineate the etiology, we also performed targeted next-generation DNA sequencing for neonatal and infantile cholestasis, and no significant causative mutations were identified. Therefore, cholestasis was determined to be associated with CS.
DB, AST, and ALT levels peaked at 2 months of age and improved gradually thereafter (Figure 1A). The serum RPR test results were negative at 2 months of age. The levels of serum markers of liver fibrosis, including procollagen type III peptide (P-III-P, 622 ng/mL, reference range: 3.6 to 9.5 ng/mL) and type IV collagen (1,154 ng/mL, reference range: <150 ng/mL), increased at 3 months of age; however, they gradually decreased thereafter (Figure 1B). He was discharged at 3.5 months of age with DB, ALT, and AST levels of 5.4 mg/dl, 117 IU/L, and 166 IU/L, respectively. The level of DB was within the normal range at 5 months of age, and the levels of AST and ALT were within the normal range at 9 months of age. At the 10-month follow-up, he had no apparent sequelae of CS.
Our case highlights the importance of correct differential diagnosis and management of cholestasis associated with CS. However, the long-term prognosis and effects of cholestasis associated with CS on liver function are still unknown.