Primary pulmonary nuclear protein of the testis (NUT) midline carcinoma (NMC) is an extremely rare, highly aggressive thoracic malignancy that presents significant diagnostic and therapeutic challenges, characterized by heterogeneous clinical manifestations, frequent misdiagnosis, and a poor prognosis. This case report details two patients with advanced primary pulmonary NMC treated with a multimodal strategy combining anti-angiogenic agents, platinum-based chemotherapy, and radiotherapy—achieving overall survival (OS) of 32 and 13 months, respectively, which far exceeds the currently reported median OS of approximately 6.7 months for advanced NMC. A systematic literature review of 86 published cases (2011–2024) was also conducted, summarizing current diagnostic methods (such as immunohistochemistry for nuclear NUT expression and fluorescence in situ hybridization (FISH) for NUTM1 rearrangement) and treatment modalities for NMC. Findings indicate that multimodal therapy incorporating anti-angiogenic agents yields superior clinical outcomes compared to conventional monotherapy, especially for patients ineligible for surgery. The report also highlights diagnostic pitfalls, such as overlapping histopathological features with squamous cell carcinoma, and underscores how integrating anti-angiogenic therapy addresses the aggressive biology of NMC, offering a new therapeutic direction for this refractory malignancy.

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS) are rare autosomal recessive disorders causing unconjugated hyperbilirubinemia due to reduced UGT1A1 enzyme activity, with CNS type 2 (CNS2) carrying a higher risk of gallbladder stones and cholecystitis than the typically benign GS. This case report details a 28-year-old male patient with recurrent right upper abdominal pain and lifelong persistent jaundice, diagnosed with CNS2 complicated by gallbladder stones and cholecystitis after genetic testing revealed rare double homozygous mutations—A(TA)₇TAA (rs3064744) and P229Q (rs35350960)—in the UGT1A1 gene. Pedigree analysis showed the patient’s parents, who had mildly elevated bilirubin levels, carried compound heterozygous mutations of the same two variants and were diagnosed with GS. Bioinformatics analysis indicated A(TA)₇TAA, located in the UGT1A1 promoter’s TATA-box region, impairs gene transcriptional initiation, while P229Q alters the protein’s three-dimensional structure and is likely pathogenic. The double homozygous mutations in the patient resulted in a more severe phenotype than the compound heterozygous mutations in his parents. The case highlights the need to suspect inherited hyperbilirubinemia causes after ruling out biliary obstruction, and suggests early bilirubin reduction (to < 103 μmol/L (6 mg/dL)) may lower CNS2 patients’ risk of complications like cholecystitis, though longer follow-up studies are required to confirm this.