Biallelic pathogenic variants in AKR1D1 cause Δ4-3-oxosteroid 5β-reductase deficiency, disrupt bile acid synthesis, and result in Congenital Bile Acid Synthesis defect type 2 (CBAS2). CBAS2 presents in infancy with cholestasis, coagulopathy, and failure to thrive. We report an infant who unexpectedly died at age 8 weeks with hepatic dysfunction and intracerebral hemorrhage. Characteristic of CBAS2, postmortem biochemical findings showed near-absent primary bile acids and accumulation of atypical bile acid intermediates. Subsequent genetic testing found compound heterozygous AKR1D1 variants: NM_005989.3:c.[593C>T];[782G>A], p.(Pro198Leu);(Arg261His). This highlights the diagnostic challenge posed by bile acid synthesis disorders, the need for early diagnosis, and the potential for fatal outcomes without early intervention. Given the treatable nature of CBAS2, we advocate for expanded newborn screening or for rapid targeted bile acid or genetic screening in infants presenting with cholestasis, prolonged jaundice, or hyperbilirubinemia.

Bile acid synthesis disorders represent a rare subset of cholestatic conditions that, if unrecognised, may progress to end-stage liver disease requiring transplantation. These disorders result from deficiencies in one of the 17 enzymes involved in the conversion of cholesterol into primary bile acids. We present a case series of three first-degree relatives diagnosed with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency), a disorder characterised by impaired steroid 5β-reductase activity. After initiating cholic acid, all patients demonstrated significant clinical improvement.

Congenital bile acid synthesis defect type 2 (CBAS2) is an autosomal recessive disorder caused by biallelic mutations of AKR1D1 gene, which encodes the Δ4-3-oxo-steroid 5β-reductase. Cholestatic jaundice is the main clinical manifestation, accompanied by malabsorption of fat and fat-soluble vitamins. This paper reported the clinical and genetic features of a CBAS2 patient definitely diagnosed by AKR1D1 genetic analysis. An 8-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 7 months. On physical examination, growth retardation and malnutrition were discovered besides mild jaundice of the skin and sclera. The liver was palpable 8 cm below the right subcostal margin with medium texture, and the spleen was not enlarged. On liver function test, elevated levels of bilirubin (predominantly conjugated bilirubin) and transaminases were detected, but serum total bile acids and γ-glutamyl transpeptidase levels were within the normal ranges. Liver histopathologic analysis showed disorganized bile ducts, obvious multinucleated giant cells, significant cholestasis in hepatocytes, together with portal and interstitial fibrosis and lymphocytic infiltration. Via next generation sequencing analysis and Sanger sequencing confirmation, the infant proved to be a compound heterozygote of the AKR1D1 variants c.579+2delT and c.853C>T(p.Q285X), two novel mutations originated from his mother and father, respectively. CBAS2 was thus definitely diagnosed, and chenodeoxycholic acid was given orally. As a result, the abnormal liver function and hepatomegaly were improved gradually. On a follow-up 3 months later, a soft liver was palpable 2.5 cm below the right subcostal margin, and all liver function indices recovered to normal ranges. 先天性胆汁酸合成障碍2型（CBAS2）是编码Δ4-3-氧固醇5β-还原酶的AKR1D1基因突变导致的常染色体隐性遗传病，以胆汁淤积性黄疸为主要临床表现，伴脂肪和脂溶性维生素吸收障碍。本文报道了1例CBAS2患儿的临床特点及AKR1D1基因突变分析结果。患儿为8个月男婴，因发现全身皮肤、巩膜黄染7月余就诊。体查发现患儿发育、营养差；皮肤、巩膜轻度黄染；肝右肋下8 cm，质地中等，脾脏不大。血生化结果发现转氨酶和总胆红素升高，以结合胆红素升高为主，但γ-谷氨酰转肽酶和总胆汁酸水平基本正常。肝脏组织学检查见胆管排列紊乱，多核巨细胞易见，肝细胞内明显淤胆，伴间质纤维组织增生及淋巴细胞浸润。代谢性肝病组套二代测序及Sanger测序验证结果证实患儿AKR1D1基因型为c.579+2delT/c.853C > T（p.Q285X），两个突变均为新突变，且分别来源于其母亲和父亲。患儿最终确诊为CBAS2，给予鹅去氧胆酸治疗后，肝功能明显好转，肝肿大逐渐改善。3个月后随访，肝脏右肋下2.5 cm可及，质软，肝功能各项指标已恢复正常。