Hand-Schuller-Christian Syndrome

Hand-Schuller-Christian Syndrome (HSC) is one variant of Langerhan's cell histiocytosis (LCH) which was previously known as Histiocytosis X.¹
Langerhan's cell histiocytosis covers a spectrum of disorders that have been separately classified in the past as:

• Eosinophilic granuloma (localised bony lesions, single or multiple)
• Hand-Schuller-Christian syndrome itself (multiple bony lesions affecting the skull, associated with proptosis and hypothalamic infiltration) and
• Letterer-Siwe disease (aggressive systemic variant with involvement of soft tissue only).²

These categories are not exclusive and overlap with progression between types.

All are diseases of abnormal Langerhan's cell proliferation, probably due to defective immunoregulation. Although no longer believed to be a truly malignant condition (most cases appear to be self-limiting), LCH does sometimes behave aggressively and its response to chemotherapy places it within oncologists' practice.

LCH is characterised by :

• Presence of clonal proliferation of Langerhans cell (monocytes lineage)
• Contain Birbeck's granule (tennis racket- shaped)
• Express surface antigens S100 and CD11 and 14 surface monoclonal antibodies
• Variable numbers of eosinophils, lymphocytes and giant cells.

• Hand-Schuller-Christian syndrome is usually a disease of childhood but may affect any age.^3,4 The peak incidence is age 2-6.⁵
• Family clusters⁶ and twin concordance⁷ have been described.
• Incidence - very rare, affects about 1:1 million children.⁵
• The cause is unknown.

With Hand-Schuller-Christian syndrome, there is a recognised triad of bone lesions, diabetes insipidus and exophthalmos. However, this full triad is only seen in about 12%.

Possible clinical features (listed by systems) and complications are:

• General features:
  • Fever
  • Weight loss or failure to thrive
  • Raised ESR
• Bone lesions:
  • Cranial lesions are very common in HSC, and may cause:
    • Otitis media
    • Diabetes insipidus (due to lesions affecting the pituitary or its stalk)
    • Exophthalmos
    • Dental lesions, e.g. loose teeth and bleeding gums
• Haematological:
  • Anaemia
  • Thrombocytopaenia
  • Lymphadenopathy
  • Hepatosplenomegaly
• Skin:^5,9
  • Pink crusted papules, nodules, mouth or genital ulceration, seborrheic rashes
• Neurological:
  • Skull lesions may impinge on CNS; bony lesions can affect spinal cord
  • Transverse myelitis
• Other organ involvement:
  • Lung
  • Liver
  • Renal
  • GI tract

Tissue biopsy, FBC, renal and liver function tests, coagulation studies, bone marrow aspirates, skeletal survey, chest X-ray and urine osmolality, hearing tests. CT or MRI may be useful, e.g. for cranial involvement.

Current recommendations are that patients be risk-stratified according to the number of organs involved, the degree of organ dysfunction and which organ system is involved.¹⁰

• Mild symptoms may not require treatment.
• Where a single system affected e.g. bone, lymphatics or skin use minimum intervention to stop progression of the lesion, e.g. curettage, excision, or intralesional steroid injection for skin or bone lesions.
• Possible treatment of skin lesions includes:⁵
  • Local treatments, e.g. topical steroids, antiseptics or antibiotics; curettage or intralesional injection of steroids
  • Phototherapy (PUVA)
  • Topical nitrogen mustard (mechlorethamine)
  • Thalidomide
• Where more than one system involved, steroids and/or chemotherapy:
  • For children, oral corticosteroids may be the first option⁵
  • Other chemotherapy agents are: methotrexate, vinblastine, etoposide or mercaptopurine.
• Management of progressive disease not responding to above: Possible use of allogenic marrow transplantation or stem cell transplantation (if match), or antithymocytic globulin, prednisolone and ciclosporin (where no donor).

Some cases resolve or regress spontaneously.¹² Neonates with isolated cutaneous lesions have an excellent prognosis.¹⁰Prognosis varies the number of organ systems involved.^8,13
For example:

• If age > 2 years of age when diagnosed, with no involvement of the blood, liver, lungs or spleen, patients often do well and/or are likely to respond to a single chemotherapy drug.⁵
• Younger children with involvement of blood, liver, lungs or spleen may require more complicated chemotherapy regimens with multiple drugs.⁵
• Initial response to chemotherapy is also a prognostic indicator.¹⁰
• Some patients with multiple organ involvement may not respond to treatment.
• About 20% of patients with multisystem involvement may have a progressive form of the disease.¹³