{
  "abstract": "Background: The leukemia inhibitory factor receptor (LIFR) is a key signaling receptor within the IL-6 cytokine-family, and its integrity is essential for STAT3 and ERK activation in developmental and immune pathways. Recessive, predominantly truncating variants in LIFR cause Stüve-Wiedemann syndrome (SWS), historically a neonatal-lethal skeletal dysplasia. As more individuals survive beyond infancy, the clinical spectrum and its biological basis remain incompletely defined.\n\nMethods: We describe the clinical heterogeneity with considerable survival beyond infancy and phenotypic expansions in neurodevelopment and immune dysregulation and determine how missense variants alter cytokine and receptor trafficking. To define the expanded disease spectrum and underlying mechanisms, we assembled an international cohort of 22 previously unreported individuals with biallelic LIFR variants, combined with functional characterization of missense alleles using cellular receptor abundance and STAT/ERK signaling assays, and proteomic profiling of patient-derived bronchoalveolar lavage (BAL) cells.\n\nResults: We identified a markedly expanded phenotype among survivors beyond infancy, including neurodevelopmental disorders, allergy, and hyperinflammatory courses, including COVID-19–associated multisystem inflammatory syndrome in children (MIS-C). In cellular assays, the hypomorphic missense variant p.Cys270Gly showed reduced cell-surface LIF-receptor abundance, STAT/ERK phosphorylation and cellular proliferation upon LIF stimulation. Analysis of additional missense variants revealed functional domain-specific effects: N-terminal extracellular variants retained partial activity, whereas C-terminal cytoplasmic variants showed near-complete loss-of-function. Patient bronchoalveolar-cell proteomics identified dysregulations in endolysosomal recycling of defective LIF-receptor.\n\nDiscussion: Our cohort’s findings may position LIFR deficiency as a survivable multisystem disorder with relevant neurological and autoimmune-inflammatory vulnerability. Variant-level functional stratification and proteomic signatures provide a coherent biological framework to support risk assessment and long-term clinical management in affected individuals.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne",
    "Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf",
    "Division of Genetics and Metabolic, Department of Paediatrics, Tawam Hospital",
    "CENTOGENE GmbH",
    "Max-Planck-Institute for Biology of Ageing and Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases",
    "Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne",
    "Center of Excellence in Nephrology, University Hospitals Aachen",
    "Institute of Human Genetics, Faculty of Medicine and University Hospital, University of Cologne",
    "Medical Genomic Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA)",
    "Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children’s Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA)",
    "Division of Medical Genetics, Sakarya Research and Training Hospital",
    "Department of Clinical Genetics & Genetic Counseling Mediscan Systems",
    "Institute of Clinical Genetics and Tumor Genetics, Medizinisches Versorgungszentrum (MVZ)",
    "Division of Genetics and Genomics, Boston Children’s Hospital",
    "Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre",
    "Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India and Suma Genomics Private Limited",
    "Department of Child Neurology, University Hospital",
    "Genetics Department, Center for Genomic Medicine, University of Medicine and Pharmacy “Victor Babes”",
    "Witten/Herdecke University, Department of Pediatrics, Faculty of Health, Helios University Hospital Wuppertal, Children’s Hospital",
    "Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin",
    "Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin",
    "Institute of Cell- and Neurobiology, Charité – Universitätsmedizin Berlin",
    "Section Central Nervous System (CNS) Development and Neurologic Disease, Partner Site Berlin, German Center for Child and Adolescent Health (Deutsches Zentrum für Kinder- und Jugendgesundheit)",
    "Dr von Hauner’s Children’s Hospital, Ludwig-Maximilians-Universität München Munich",
    "Department of Pediatrics, Helios Klinikum",
    "Department of Immunology, Great Ormond Street Hospital for Children NHS Foundation Trust",
    "HMU Health and Medical University, Campus Düsseldorf/Krefeld",
    "Université Paris Cité, Institut Imagine, Laboratory of human genetics of infectious diseases, Necker branch, INSERM UMR 1163",
    "Department of Paediatric Neurology, Evelina London Children’s Hospital",
    "Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine, King’s College London",
    "Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne",
    "Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne"
  ],
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      ],
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    },
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      "name": "Katta M. Girisha"
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      "name": "Adela Chirita-Emandi"
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      "name": "Raphael Hirtz"
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  "doi": "10.3389/fimmu.2026.1927542",
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  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
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  "title": "Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability",
  "title_text": "Hypomorphic biallelic LIFR variants define a multisystem disorder with survival beyond infancy and hyperinflammatory vulnerability",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:02Z",
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  "venue": "Frontiers in Immunology",
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