Protein S deficiency causing arterial ischemic stroke during pregnancy is uncommon. Delay or omission of treatment with perfusion therapies may worsen outcomes for both the mother and the fetus. In this paper, we report a case of an early pregnant woman with protein S deficiency and multiple history of chronic cerebrovascular disease who underwent successful thrombolysis and mechanical thrombectomy. The patient is a 35-year-old woman, eight weeks pregnant, with a history of protein S deficiency and chronic cerebrovascular disease, presenting with rightsided weakness and aphasia. Initial National Institutes of Health Stroke Scale was 10 with cranial magnetic resonance imaging findings of acute infarcts on the left caudate, lentiform nucleus, insula, and frontal lobe with a large vessel occlusion on the proximal M1 segment of the left middle cerebral artery. Intravenous thrombolysis and mechanical thrombectomy were performed with complete recanalization. The patient improved and delivered without any complications after 8 months. Protein S deficiency can contribute to arterial thrombosis including ischemic stroke. Arterial ischemic stroke and large vessel occlusion can cause significant disability if not treated appropriately. Reperfusion therapies in pregnant women show favorable outcomes and should be performed if the benefits outweigh the risks.

For the first time, this study evaluated the gender differences and mechanisms of the antidepressant effects of raw Rehmanniae Radix(RRR) based on the classic depression model with traditional Chinese medicine syndrome of Yin deficiency and internal heat. The depression model with Yin deficiency and internal heat was established by the widely recognized and applied method of thyroxine induction of the classic depression model with Yin deficiency and internal heat(chronic unpredictable mild stress). Male and female mice were simultaneously treated with RRR. The study analyzed indicators of nourishing Yin and clearing heat, conventional antidepressant efficacy test indicators, and important biomolecules reflecting the pathogenesis and prevention and treatment mechanisms of depression, and conducted a correlation analysis of antidepressant efficacy, Yin-nourishing and heat-clearing efficacy, and biological mechanism in different genders, thereby comprehensively assessing the antidepressant effects of RRR on depression of Yin deficiency and internal heat, as well as its gender differences and mechanisms. RRR exhibited antidepressant effects in both male and female mouse models, and its antidepressant efficacy showed gender differences, with a superior effect observed in females. Moreover, the effects of RRR on enhancing or improving hippocampal neuronal pathology, nucleus-positive areas, postsynaptic dense area protein 95, and synaptophysin protein expression were more significant in females than in males. In addition, RRR significantly reversed the abnormal upregulation of nuclear factor(NF)-κB/cyclooxygenase 2(COX2)/NOD-like receptor thermal protein domain associated protein 3(NLRP3) pathway proteins in the hippocampus of both male and female mouse models. The antidepressant effects of RRR were more pronounced in depression female mice with Yin deficiency and internal heat syndrome, possibly due to the improvement of neuronal damage and enhancement of neuroplasticity. The antidepressant mechanisms of RRR for depression with Yin deficiency and internal heat syndrome may be associated with the downregulation of the NF-κB/COX2/NLRP3 pathway to reduce neuronal damage and enhance neuroplasticity.
Male ; Female ; Mice ; Animals ; Yin Deficiency ; NLR Family, Pyrin Domain-Containing 3 Protein ; Sex Factors ; Cyclooxygenase 2 ; NF-kappa B ; Antidepressive Agents/pharmacology*

OBJECTIVE: To explore the genetic etiology of a child with D bifunctional protein deficiency (DBPD) born to a consanguineous pedigree. METHODS: A child with DBPD who was admitted to the First Affiliated Hospital of Hainan Medical College on January 6, 2022 due to hypotonia and global developmental delay was selected as the study subject. Clinical data of her pedigree members were collected. Peripheral blood samples of the child, her parents and elder sisters were collected and subjected to whole exome sequencing. Candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 2-year-and-9-month-old female, had featured hypotonia, growth retardation, unstable head lift, and sensorineural deafness. Serum long-chain fatty acids were elevated, and auditory brainstem evoked potentials had failed to elicit V waves in both ears with 90 dBnHL stimulation. Brain MRI revealed thinning of corpus callosum and white matter hypoplasia. The child's parents were secondary cousins. Their elder daughter had a normal phenotype and no clinical symptoms related to DBPD. Elder son had frequent convulsions, hypotonia and feeding difficulties after birth, and had died one and a half month later. Genetic testing revealed that the child had harbored homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene, for which both of her parents and elder sisters were carriers. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.483G>T (p.Gln161His) was rated as a pathogenic variant (PM1+PM2_Supporting+PP1+PP3+PP4). CONCLUSION The homozygous c.483G>T (p.Gln161His) variants of the HSD17B4 gene caused by the consanguineous marriage probably underlay the DBPD in this child.
Female ; Humans ; Pedigree ; Muscle Hypotonia ; Hearing Loss, Sensorineural ; Protein Deficiency ; Mutation

OBJECTIVE: To investigate the possible causes of abnormal hemoglobin electrophoresis results. METHODS: The hemoglobin electrophoresis results of 5 696 patients in the First Affiliated Hospital of Chengdu Medical College from September 2018 to July 2021 were collected, and the abnormal results and clinical significance were analyzed. RESULTS: The results of 486 patients (accounting for 8.53%) were abnormal, of which 300 cases had increased HbA2, 135 cases had decreased HbA2, 44 cases had increased F alone, and 7 cases had abnormal hemoglobin bands. Among the 486 patients, 246 patients were thalassemia gene positive (the positive rate was 50.62%), including 29 cases of α thalassemia, 208 cases of β thalassemia and 9 cases of αβ thalassemia. Among the patients with elevated HbA2, 68.67% were detected β thalassemia, 3.00% αβ thalassemia, 9.33% were suspected to be caused by macrocytosis, 6.33% by thyroid dysfunction, and 12.67% by uncertainty of the method. Among the patients with reduced HbA2, 21.48% were detected α thalassemia, 60.00% iron deficiency anemia, 8.15% were suspected to be caused by thyroid dysfunction, and 10.37% by uncertainty of the method. Among the patients with elevated F alone, the results of thalassemia gene detection were negative, 40.91% of them were suspected to be caused by macrocytosis, 27.27% by hereditary persistence of fetal hemoglobin, 29.55% by special physiological condition of pregnant women, and 2.27% by hyperthyroidism. Abnormal hemoglobin bands were detected in 7 patients, including 4 cases of hemoglobin D, 2 cases of hemoglobin E, and 1 case of hemoglobin J. CONCLUSION Thalassemia, iron deficiency anemia, macrocytosis such as megaloblastic anemia and non-severe aplastic anemia, thyroid dysfunction, hereditary persistence of fetal hemoglobin, abnormal hemoglobin diseases, the uncertainty of the method are all important causes of abnormal hemoglobin electrophoresis results. In clinical work, the patient's indicators should be comprehensively analyzed to determine the possible cause.
Humans ; Female ; Pregnancy ; beta-Thalassemia/genetics* ; Anemia, Iron-Deficiency ; Fetal Hemoglobin/analysis* ; alpha-Thalassemia ; Blood Protein Electrophoresis ; Hemoglobin A2/analysis* ; Hemoglobins, Abnormal/analysis*

OBJECTIVE: To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage. METHODS: Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents. RESULTS: The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4). CONCLUSION The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.
Female ; Pregnancy ; Humans ; Protein C Deficiency ; Fetus ; Genetic Counseling ; Genomics ; Hydrocephalus/genetics* ; Mutation

Humans ; Protein C Deficiency ; Mutation

Reduced protein S activity is one of the high-risk factors for venous thromboembolism.Hereditary protein S deficiency is an autosomal dominant disorder caused by mutations in the PROS1 gene.We reported a female patient with a mutation of c.292 G>T in exon 3 of the PROS1 gene,which was identified by sequencing.The genealogical analysis revealed that the mutation probably originated from the patient's mother.After searching against the PROS1 gene mutation database and the relevant literature,we confirmed that this mutation was reported for the first time internationally.
Humans ; Female ; Protein S/genetics* ; Protein S Deficiency/genetics* ; Pedigree ; Mutation

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.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Infant, Newborn ; Male ; Pedigree ; Protein S/genetics* ; Protein S Deficiency/genetics* ; Pulmonary Embolism/genetics* ; Retrospective Studies

Objective: To investigate the molecular pathogenesis and clinical features of unrelated 12 patients with inherited coagulation protein C (PC) deficiency in Chinese population. Methods: The PC activity (PC:A) and PC antigen (PC:Ag) were detected by chromogenic substrate and enzyme linked immunosorbent assay, respectively. The nine exons and flanking sequences of the protein C (PROC) gene were amplified by polymerase chain reaction with direct sequencing, and the suspected mutations were validated by reverse sequencing (clone sequencing for deletion mutations) . Results: The PC:A of the 12 probands decreased significantly, ranging from 18% to 55%, and the PC:Ag of the 10 probands decreased significantly. Eleven mutations were found, out of which four mutations [c.383G>A (p.Gly128Asp) , c.997G>A (p.Ala291Thr) , c.1318C>T (p.Arg398Cys) , and c.532G>C (p.Leu278Pro) ] were discovered for the first time. Six mutations were in the serine protease domain, four mutations were located in epidermal growth factor (EGF) -like domains, and one mutation was located in activation peptide. There were two deletion mutations (p.Met364Trp fsX15 and p.Lys192del) , and the rest were missense mutations. Mutations p.Phe181Val and p.Arg189Trp were identified in three unrelated families. All mutations may be inherited, and consanguineous marriages were reported in two families. Among the probands, nine cases had venous thrombosis, two cases had poor pregnancy manifestations, and one case had purpura. Conclusion: Patients with PC deficiency caused by PROC gene defects are prone to venous thrombosis, especially when there are other thrombotic factors present at the same time.
Humans ; Mutation ; Mutation, Missense ; Pedigree ; Phenotype ; Protein C/genetics* ; Protein C Deficiency/genetics*

Objective: To analyze the clinical manifestations and molecular pathogenesis of 18 patients with inherited protein S (PS) deficiency. Methods: Eighteen patients with inherited PS deficiency who were admitted to the Institute of Hematology & Blood Diseases Hospital from June 2016 to February 2019 were analyzed: activity of protein C (PC) and antithrombin (AT) , PS activity were measured for phenotype diagnosis; high throughput sequencing (HTS) was used for screening of coagulation disease-related genes; Sanger sequencing was used to confirm candidate variants; Swiss-model was used for three-dimensional structure analysis. Results: The PS:C of 18 patients ranged from 12.5 to 48.2 U/dL. Among them, 16 cases developed deep vein thrombosis, including 2 cases each with mesenteric vein thrombosis and cerebral infarction, and 1 case each with pulmonary embolism and deep vein thrombosis during pregnancy. A total of 16 PROS1 gene mutations were detected, and 5 nonsense mutations (c.134_162del/p.Leu45*, c.847G>T/p.Glu283*, c.995_996delAT/p.Tyr332*, c.1359G> A/p.Trp453*, c.1474C>T/p.Gln492*) , 2 frameshift mutations (c.1460delG/p.Gla487Valfs*9 and c.1747_1750delAATC/p.Asn583Wfs*9) and 1 large fragment deletion (exon9 deletion) were reported for the first time. In addition, the PS:C of the deep vein thrombosis during pregnancy case was 55.2 U/dL carrying PROC gene c.565C>T/p.Arg189Trp mutation. Conclusion: The newly discovered gene mutations enriched the PROS1 gene mutation spectrum which associated with inherited PS deficiency.
Antithrombin III/genetics* ; Female ; Genetic Testing ; Humans ; Mutation ; Pregnancy ; Protein C/genetics* ; Protein S/genetics* ; Protein S Deficiency/genetics*