Letterer-Siwe Disease

Definition

  • Historical name for acute disseminated multisystem LCH
  • Most often under 2 years of age
  • Most severe end of the LCH spectrum

Pathology

  • Clonal Langerhans-type cells with grooved coffee bean nuclei
  • Mixed eosinophils, lymphocytes and macrophages
  • CD1a, langerin (CD207) and S100 positive
  • Tennis racket Birbeck granules on electron microscopy
  • MAPK pathway mutations, most often BRAF V600E, place LCH among myeloid neoplasms

Clinical Features

  • Fever, failure to thrive and irritability
  • Seborrhoeic rash of scalp, trunk and skin creases, sometimes purpuric
  • Hepatosplenomegaly and lymphadenopathy
  • Pancytopenia from marrow infiltration, with bleeding and infection
  • Otitis media and otorrhoea
  • Pulmonary involvement
  • Multiple lytic bone lesions, particularly of the skull

Investigations

Eosinophilic Granuloma, histology of eosinophilic granuloma (langerhans cell histiocytosis)
Histology of eosinophilic granuloma (Langerhans cell histiocytosis). Image by No machine-readable author provided. KGH assumed (based on copyright claims)., Wikimedia Commons, CC BY-SA 3.0.
  • FBC, liver function, coagulation and albumin
  • Skeletal survey, whole body MRI or PET
  • Bone lesions are punched out lytic defects without a sclerotic rim
  • Chest and abdominal imaging for lung, liver and spleen
  • Marrow examination when cytopenias are present
  • Biopsy the most accessible lesion, often skin or bone

Classification

  • Histiocyte Society system stratifies by disease extent
  • Multisystem LCH with risk organ involvement (liver, spleen, haematopoietic system) is high risk
  • This high risk group corresponds to Letterer-Siwe disease

Differential Diagnosis

  • Leukaemia and metastatic neuroblastoma
  • Haemophagocytic lymphohistiocytosis
  • Congenital infection
  • Non-accidental injury with multiple skeletal lesions

Management

  • Vinblastine and prednisolone first line under paediatric oncology
  • Cytarabine or cladribine for refractory disease
  • BRAF and MEK inhibitors for refractory high risk disease
  • Transfusion and infection management
  • Orthopaedic role is biopsy and spinal or long bone lesions at fracture risk

Prognosis

  • Depends on risk organ involvement and early treatment response
  • Poor responders with risk organ dysfunction have substantial mortality
  • Late effects include diabetes insipidus, orthopaedic deformity and neurodegenerative disease

Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 10 October 2026.