OBJECTIVE: To summarize the clinical features and management of two brothers affected with X-linked inhibitor of apoptosis protein (XIAP) deficiency. METHODS: This study retrospectively analyzed the clinical presentations, treatment, and follow-up of two brothers with XIAP deficiency diagnosed at Shanghai Children's Hospital in 2020, and summarized similar cases recorded in databases such as PubMed, Wanfang, Chinese Medical Association Journals, and WIP from January 2006 to November 2024. This study was approved by the Medical Ethics Committee of our hospital (Ethics No.: 2025R128-E01). RESULTS: Patient 1 was the younger brother, who presented at 8 years of age with growth retardation, folliculitis, erythema nodosum, and perineal abscess. Sequencing revealed that he has carried a hemizygous c.566T>C (p.Leu189Pro) variant of the XIAP gene, which was inherited from his mother. He was allergic to infliximab treatment and underwent allogeneic stem cell transplantation (HSCT) in January 2021. During a follow-up of 3 years and 10 months post-transplantation, he showed no gastrointestinal symptoms and had a good outcome. Patient 2 was the elder brother, who presented at 10 years and 6 months of age with growth retardation, rash, and anal fistula. Genetic testing revealed the same variant. He was treated with oral azathioprine but did not have regular follow-ups. At 14-years-and-6-months of age, he had developed severe gastrointestinal infection and hemophagocytic lymphohistiocytosis, which was alleviated after treatment with antibiotics, glucocorticoids, immunoglobulin, and rituximab. He is currently being prepared for HSCT. A total of 13 publications were retrieved, which involved 64 patients from 23 families, with 23 different variants identified. The main clinical manifestations included splenomegaly (34 cases, 53.1%), hemophagocytic lymphohistiocytosis (27 cases, 42.2%), and inflammatory bowel disease or colitis (20 cases, 31.8%). There were significant phenotypic differences among patients from the same family. Thirteen patients (20.3%) underwent HSCT, with a survival rate of 61.5%. CONCLUSION For male children with early onset, poor treatment response, especially those with unexplained splenomegaly and IBD-like symptoms, early genetic testing is recommended. HSCT is a safe and effective treatment for XIAP deficiency. For patients with developmental delay, early onset, and severe IBD phenotype, early transplantation is recommended.
Humans ; Male ; X-Linked Inhibitor of Apoptosis Protein/deficiency* ; Child ; Genetic Diseases, X-Linked/therapy* ; Phenotype ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) cause a severe neurodevelopmental disorder, yet the impact of truncating mutations remains unclear. Here, we introduce the Cdkl5^492stop mouse model, mimicking C-terminal truncating mutations in patients. 492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors, alongside other behavioral deficits. After creating cell lines with various Cdkl5 truncating mutations, we found that these mutations are regulated by the nonsense-mediated RNA decay pathway. Most truncating mutations result in CDKL5 protein loss, leading to multiple disease phenotypes, and offering new insights into the pathogenesis of CDKL5 disorder.
Animals ; Disease Models, Animal ; Mice ; Protein Serine-Threonine Kinases/deficiency* ; Mutation/genetics* ; Epileptic Syndromes/genetics* ; Humans ; Dendritic Spines/pathology* ; Spasms, Infantile/genetics* ; Male ; Seizures/genetics* ; Mice, Inbred C57BL

Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). This study investigates the role of high mobility group box 1 (HMGB1) in oligodendrocyte precursor cells (OPCs) in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier (BBB) by using OPC-specific HMGB1 knockout (KO) mice. We found that HMGB1 released from OPCs promotes BBB disruption, subsequently allowing increased immune cell infiltration. The migration of CD4+ T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes (OLs). OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS, leading to less damage to the myelin sheath and mitigated EAE progression. CD4+ T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs. Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; HMGB1 Protein/deficiency* ; Mice, Knockout ; Oligodendrocyte Precursor Cells/immunology* ; Mice, Inbred C57BL ; CD4-Positive T-Lymphocytes/immunology* ; Cell Movement ; Blood-Brain Barrier/immunology* ; Mice ; Myelin Sheath/pathology* ; Disease Models, Animal ; Coculture Techniques ; Oligodendroglia/metabolism* ; Female ; Cells, Cultured

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.

Hereditary protein S deficiency (PSD) is an autosomal dominant disorder caused by mutations in the PROS1 gene which can cause venous thrombosis. Individuals with PSD usually present with recurrent deep vein thrombosis and/or pulmonary embolism, but thrombosis may occur at unusual sites, such as the mesenteric and portal veins. Here we report a case of hereditary protein S deficiency patient with predominant mesenteric venous thrombosis. A 57-year-old man was admitted for abdominal pain and bilateral lower limber swelling. His sister had a history of thrombotic disease. On admission, His temperature was 37.4 ℃, the pulse was regular, and the blood pressure was 130/79 mmHg. Abdominal examination showed right lower abdomen tenderness, rebound tenderness and suspected muscle rigidity. Abdominal computed tomography (CT) angiography found that the patient had superior mesenteric venous thrombosis (MVT) and perforation of intestine. Vascular ultrasound of lower limb indicated bilateral deep venous thrombosis. Although treatment of fasting, water restriction, parenteral nutrition solution, acid suppression, anti-biotic treatment and low molecular weight heparin for anticoagulation were given, abdominal pain were not relieved. Small intestine resection and anastomosis was done after. Pathology of intestine did not show changes indicative of vasculitis. To investigate the cause of multiple thrombosis, a work-up for hypercoagulability (protein C and S activities, antithrombin, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein Ⅰ antibody) was done and the result showed increased dRVVT ratio and the significantly decreased protein S levels. Anti-phospholipid syndrome (APS) was suspected because of the thrombosis and positive lupus anticoagulant, but at the time of the test the patient was on oral anticoagulants which might influence the result of lupus anticoagulant. The lupus anticoagulant was normal after discontinuing oral anticoagulants and APS was excluded. Because of his personal and family history of thrombotic disease, a hereditary thrombophilia was suspected and a laboratory analysis showed a reduced protein S activity. Further examination of the whole exome sequencing indicated a heterozygous mutation in the PROS1 gene. He was diagnosed with hereditary protein S deficiency and was started on anticoagulant therapy with rivaroxaban. He had been followed up for 1 year, and his condition kept stable without newly developed thrombosis or bleeding.
Humans ; Male ; Protein S Deficiency/genetics* ; Middle Aged ; Venous Thrombosis/etiology* ; Mesenteric Veins ; Protein S/genetics* ; Mutation ; Abdominal Pain/etiology*

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

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*

Humans ; Protein C Deficiency ; Mutation

Objective: To analyze the clinical characteristics and risk factors of protein energy wasting (PEW) in children with chronic kidney disease (CKD). Methods: Clinical data of 231 children with chronic kidney disease hospitalized in Beijing Children's Hospital affiliated to Capital Medical University from January 2018 to January 2023 were retrospectively analyzed to explore the incidence of PEW. According to the diagnostic criteria of CKDPEW, they were divided into a CKDPEW group and a non PEW group. The comparison between the groups was performed by independent-sample t test and Chi-squared test, and the risk factors were analyzed by multivariate Logistic regression. Results: Among the 231 children, there were 138 males and 93 females, with a visiting age of 9.9 (7.9, 16.0) years; 6 cases were in stage 1, 14 cases in stage 2, 51 cases in stage 3, 36 cases in stage 4, and 124 cases in stage 5. A total of 30 children (13.0%) with CKD PEW were diagnosed at the age of 7. 1 (3.8, 13.2) years, including 1 case in stage 1, 1 case in stage 2, 5 cases in stage 3, 5 cases in stage 4, and 18 cases in stage 5. There were a total of 201 cases (87.0%) in the non PEW group, diagnosed at the age of 11.8 (8.5, 12.2) years, including 5 cases in stage 1, 13 cases in stage 2, 46 cases in stage 3, 31 cases in stage 4, and 106 cases in stage 5. The Chi-squared test and t test showed that the systolic blood pressure, diastolic blood pressure, birth weight and carbon dioxide binding capacity of the CKD PEW group were lower than those of the non PEW group ((109±22) vs. (120±20) mmHg (1 mmHg=0.133 kPa), (72±19) vs. (79±16) mmHg, (2.9±0.5) vs. (3.2±0.6) kg, (17±4) vs. (19±4) mmol/L,t=2.85, 2.14, 0.67, 2.63, all P<0.05). Multivariate logistic regression analysis showed that carbon dioxide binding capacity and birth weight were independent protective factors of CKDPEW in children (OR=0.81 and 0.36, 95%CI=0.73-0.90 and 0.17-0.77, respectively; both P<0.01); the risk of PEW in CKD children decreased by 0.187 times for every 1 mmol/L increment in carbon dioxide binding capacity, and 0.638 times for every 1 kg increment in birth weight. Conclusions: The incidence of protein energy expenditure in children with chronic kidney disease is lower than that in the previous researches. PEW can appear in CKD 1-2 stage, and attention should be paid to it in the early stage of CKD in clinical practice. Low birth weight CKD children are susceptible to PEW, and actively correcting metabolic acidosis can reduce the risk of CKDPEW.
Renal Insufficiency, Chronic/epidemiology* ; Humans ; Child ; Energy Metabolism ; Protein-Energy Malnutrition/epidemiology* ; Risk Factors ; Adolescent ; Male ; Female ; Proteins/metabolism* ; China/epidemiology*

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