Introduction

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by the abnormal proliferation and tissue infiltration of foamy histiocytes. Since its first description in 1930, fewer than a few thousand cases have been reported worldwide, making it a challenging condition to diagnose and manage. ECD is a systemic disorder with highly variable clinical manifestations, affecting the bones, cardiovascular system, central nervous system, retroperitoneum, and endocrine organs.

Among its diverse features, endocrine dysfunction represents a major clinical hallmark, often serving as one of the earliest signs of disease. In particular, central diabetes insipidus (DI) and anterior pituitary hormone deficiencies are frequently observed due to histiocytic infiltration of the hypothalamic–pituitary axis. These manifestations can significantly impair quality of life and, if left untreated, lead to life-threatening complications.

Pathophysiology of endocrine dysfunction in ECD

Infiltration of the hypothalamic–pituitary axis by histiocytes

Erdheim-Chester disease is characterised by the accumulation of foamy histiocytes that infiltrate the pituitary stalk, hypothalamus, and pituitary gland. This infiltration disrupts the normal architecture of the hypothalamic–pituitary axis, interfering with hormone production and secretion.

Fibrosis and destruction of endocrine tissue

As the disease progresses, histiocytic infiltration leads to fibrosis and scarring of endocrine tissue. This structural damage permanently compromises pituitary function, making endocrine dysfunction often irreversible.

Mechanisms leading to specific endocrine abnormalities

• Central Diabetes Insipidus (DI): Damage to vasopressin-producing neurons in the hypothalamus or posterior pituitary reduces antidiuretic hormone (ADH) secretion, resulting in impaired water reabsorption and polyuria
• Hypopituitarism: Infiltration and fibrosis of the anterior pituitary cause deficiencies in multiple hormones, including ACTH, TSH, LH/FSH, and growth hormone, leading to secondary adrenal insufficiency, hypothyroidism, hypogonadism, and growth impairment¹

Diabetes insipidus in ECD

Prevalence

Diabetes insipidus (DI) is the most common endocrine manifestation of Erdheim-Chester disease, affecting approximately one-third to half of patients. In many cases, it is also the earliest sign of disease, appearing years before systemic involvement is recognised.

Pathogenesis

Histiocytic infiltration of the posterior pituitary and pituitary stalk disrupts the normal release of vasopressin (antidiuretic hormone, ADH). The lack of ADH secretion impairs the kidney’s ability to concentrate urine, resulting in excessive water loss.

Clinical features

Patients typically present with polyuria, polydipsia, and nocturia. If untreated, they may develop dehydration, fatigue, and electrolyte imbalances.

Diagnosis

Water deprivation: test demonstrates failure to concentrate urine.
MRI of the pituitary: often shows loss of the posterior pituitary bright spot and thickening of the pituitary stalk.

Management

Desmopressin (DDAVP) is the treatment of choice, effectively controlling polyuria and polydipsia. Ongoing monitoring of fluid balance and electrolytes is important to avoid complications.

Pituitary involvement beyond DI

Anterior pituitary hormone deficiencies

Histiocytic infiltration and fibrosis of the anterior pituitary can lead to multiple hormonal deficiencies:

• Hypogonadism: LH/FSH deficiency → amenorrhea, infertility, decreased libido
• Secondary hypothyroidism: TSH deficiency → fatigue, cold intolerance, weight gain
• Secondary adrenal insufficiency: ACTH deficiency → weakness, hypotension, risk of adrenal crisis
• Growth hormone deficiency: Reduced muscle mass, low energy, impaired quality of life²

Radiological findings

MRI may reveal a thickened pituitary stalk, pituitary enlargement, or hypothalamic mass, and loss of the normal posterior pituitary bright spot may accompany these findings.

Clinical implications

Hormone deficiencies can cause chronic fatigue, metabolic disturbances, and reproductive issues. Multiple pituitary hormone loss (panhypopituitarism) may develop over time, requiring lifelong hormone replacement therapy.

Differential diagnosis

Langerhans cell histiocytosis (LCH)

Both ECD and LCH can cause diabetes insipidus and pituitary stalk thickening. Histology and immunohistochemistry (CD68-positive, CD1a-negative in ECD) are crucial for distinction.

Sarcoidosis

Granulomatous inflammation may involve the hypothalamic–pituitary axis, mimicking stalk thickening and DI.

Germinoma

Intracranial germ cell tumors often present with DI and pituitary stalk lesions, particularly in younger patients.

Tuberculosis and other infections

Chronic infections like tuberculosis or fungal disease may infiltrate the pituitary stalk, causing endocrine dysfunction.

Autoimmune hypophysitis

Lymphocytic inflammation of the pituitary can also result in DI and hypopituitarism, often associated with other autoimmune conditions.

Therapeutic approaches

Targeted therapy for ECD

Patients with BRAF V600E mutation may benefit from BRAF inhibitors (e.g., vemurafenib, dabrafenib). Those with MAPK pathway mutations may respond to MEK inhibitors (e.g., cobimetinib, trametinib). These therapies can help reduce disease burden, including hypothalamic–pituitary involvement.

Hormone replacement therapy

• Desmopressin (DDAVP): For central diabetes insipidus
• Levothyroxine: For secondary hypothyroidism
• Hydrocortisone or equivalent: For adrenal insufficiency
• Sex steroid replacement: For hypogonadism
• Growth hormone replacement: In selected patients with GH deficiency

Multidisciplinary management

Close collaboration between endocrinologists, oncologists/haematologists, radiologists, and neurologists is essential. Regular monitoring for progression of endocrine dysfunction and systemic involvement .³

Prognosis and follow-up

Diabetes insipidus

Usually permanent, even with targeted therapy. Requires lifelong desmopressin treatment and regular electrolyte monitoring.

Anterior pituitary dysfunction

Hormonal deficiencies often progress over time. Lifelong hormone replacement therapy is frequently needed.

Disease monitoring

Regular endocrine evaluations (every 6–12 months) to detect new or worsening deficiencies. MRI follow-up for pituitary stalk and hypothalamic lesions.

Impact of targeted therapies

Systemic therapies (BRAF/MEK inhibitors) may stabilise or reduce CNS lesions but usually do not reverse established endocrine damage.

Long-term outlook

With early recognition and appropriate treatment, patients can achieve a good quality of life. Delayed diagnosis or untreated hormone deficiencies can contribute to significant morbidity.⁴

Summary

Endocrine involvement is a hallmark feature of Erdheim-Chester disease, with diabetes insipidus and pituitary dysfunction being among the most common presentations. Histiocyte infiltration and fibrosis of the hypothalamic–pituitary axis underlie these abnormalities, often leading to permanent hormone deficiencies. Diabetes insipidus is typically the earliest and most frequent manifestation, while anterior pituitary hormone deficiencies may develop progressively over time. Early recognition, timely diagnosis, and appropriate hormone replacement therapy are essential to prevent complications and improve quality of life. Although targeted therapies have improved systemic disease control, endocrine dysfunction often persists, underscoring the need for lifelong follow-up and multidisciplinary management.