A family of hereditary protein S deficiency with the onset of pulmonary embolism and literature review / 中华儿科杂志

ABSTRACT

Objective: To explore the clinical characteristics and genotype of PROS1 gene related hereditary protein S deficiency (PSD) with the onset of pulmonary embolism in children. Methods: A family with pulmonary embolism was diagnosed as hereditary PSD in the Department of Pediatrics of Peking University First Hospital in November 2020, and the clinical data, including clinical manifestations, laboratory tests, imaging and genetic results, were collected for a retrospective research. The family members were also screened for protein S activity and PROS1 gene mutations. A literature search with "PROS1" "protein S deficiency" "homozygous" and "complex heterozygous" as key words was conducted at PubMed, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform (up to October 2021). Case reports of patients with PROS1 gene homozygous or complex heterozygous variants and related clinical features, protein S activity, and genotype were reviewed and analyzed. Results: The proband, a 14-year-old girl, was admitted to the hospital for a 9-day history of coughing and a 4-day history of chest pain in November 2020. After admission, laboratory tests showed that D-dimer was 8.38 mg/L (reference<0.24 mg/L). An urgent CT pulmonary angiography confirmed bilateral pulmonary embolism and right lower pulmonary infarction, while an ultrasonography showed deep vein thrombosis in her left leg. Further examination revealed that protein S activity was less than 10%. The proband's second sister, a 12-year-old girl, was admitted to the hospital in December 2020. Her protein S activity was 8% and an ultrasonography showed deep vein thrombosis in her right leg. The protein S activity of the proband's father and mother were 36% and 26%, respectively. Trio-whole-exome sequencing detected compound heterozygous PROS1 gene variants (c.-168C>T and c.200A>C (p.E67A)) for the proband and her second sister, that were inherited from her father and mother, respectively. The proband's third sister's protein S activity was 28%; she and the proband's grandfather both carried c.200A>C (p.E67A) variants. The proband and her younger sister were treated with rivaroxaban and responded well during the 3-month follow-up. A total of 1 Chinese report in literature and 18 English literature were retrieved and 14 patients with protein S deficiency caused by homozygous or complex heterozygous variants of PROS1 gene were enrolled, including 8 male and 6 female patients. The ages ranged from 4 days to 35 years. Three patients experienced fulminant purpura or severe intracranial hemorrhage in early neonatal-period, while the remaining 11 patients developed venous thromboembolism in adolescence. Protein S activity was examined in 11 patients, and all showed less than 10% of activity. Missense variants was the most common type of gene variants. Conclusions: For children with pulmonary embolism, if there are no clear risk factors for thrombosis, hereditary protein S deficiency should be considered, and protein S activity should be examined before oral anticoagulant drugs. If protein S activity is less than 10%, protein S deficiency caused by homozygous or complex heterozygous variants should be considered.