[1][5][6] The condition is traditionally associated with a combination of three features; bulging eyes, breakdown of bone (lytic bone lesions often in the skull), and diabetes insipidus (excessive thirst and passing urine), although around 75% of cases do not have all three features.

[5] Other features may include a fever and weight loss, and depending on the organs involved there may be rashes, asymmetry of the face, ear infections, signs in the mouth and the appearance of advanced gum disease.

[7] The traditional combination of three features are seen in 25% of people with the condition, which usually presents between the ages of two and six; one or both bulging eyes, breakdown of bone (lytic bone lesions often in the skull in a 'punched out' pattern), and diabetes insipidus (excessive thirst and passing urine).

[5] These include mouth ulcers, bad breath, swollen gums, loose teeth and an unpleasant taste.

[5] Destruction of part of the jaw bone may give the appearance of advanced gum disease.

The perivascular space may appear prominent, the pituitary gland cystic and there may be signs in the white matter, a mass in the hypothalamus and enhancement of the meninges.

[7] The prognosis is poor if the disease presents in a young person with many affected organs, unless a newborn with skin lesions only, when the outlook is better.

[5] MRI and CT scan findings in a mummy have revealed evidence of the disease dating back to 900–790.

In 1940, Louis Litchtenstein and Henry L. Jaffe described a self-limiting disease characterised by "isolated bone lesions".

[9] A common feature of all these conditions was revealed to be the histological findings of large numbers of histiocytes in the tissue biopsies, leading Litchtenstein to propose that the three described conditions were part of a spectrum of a disease he named "Histiocytosis X", where "X" denoted the unknown cause.

[10] Hand–Schüller–Christian disease is now considered a subtype of LCH, chronic multifocal Langerhans cell histiocytosis.