Nelson's syndrome

Nelson's syndrome is a rare and challenging neuroendocrine disorder, and it is associated with elevated Adrenocorticotropic hormone (ACTH) level, skin hyperpigmentation, and pituitary neuroendocrine tumor growth.

Nelson's syndrome (NS) is a long-term complication of bilateral adrenalectomy in patients with Cushing's disease.

● a rare condition that follows 10–30% of total bilateral adrenalectomies (TBA) performed for Cushing’s disease.

● classic triad: hyperpigmentation (skin &mucus membranes), abnormal ↑ ACTH, and progression of pituitary tumor (the last criteria is now controversial)

● treatment options: surgery (transsphenoidal or transcranial), XRT, medication.

Usually occurs 1–4 years after TBA (range: 2 mos-24 years) ¹⁾. Theoretical explanation (unproven) ²⁾: following TBA, hypercortisolism resolves, and CRH levels increase back to normal from the (reduced) suppressed state; corticotroph adenomas in patients with NS have an increased & prolonged response to CRH resulting in increased growth. Also, corticotrophs in NS and CD show reduced inhibition by glucocorticoids. It is controversial if some cases may be related to insufficient glucocorticoid replacement after TBA ³⁾.

1. hyperpigmentation (due to melanin stimulating hormone (MSH) cross-reactivity of ACTH and actually increased levels of MSH due to increased proopiomelanocortin production). Often the earliest sign that Nelson’s syndrome is developing. Look for linea nigra (midline pigmentation from the pubis to umbilicus) and hyperpigmentation of scars, gingivae, and areolae. DDx of hyperpigmentation includes: primary adrenal insufficiency (high levels of ACTH), ectopic ACTH secretion, hemochromatosis (more bronze color), jaundice (yellowish)

2. tumor growth →increased mass effect or invasion: the most serious consequence. These corticotroph tumors are among the most aggressive of pituitary tumors ⁴⁾. May produce any of the problems associated with macroadenomas (optic nerve compression, cavernous sinus invasion, pituitary insufficiency, H/A, bony invasion…) as well as necrosis with precipitous intracranial hypertension ⁵⁾; see pituitary apoplexy.

3. malignant transformation of the corticotroph tumor (very rare).

4. hypertrophy of adrenal tissue rests: may be located in the testes → painful testicular enlargement and oligospermia. Rarely the rests can secrete enough cortisol to normalize cortisol levels or even cause a recurrence of Cushing’s disease despite the adrenalectomy.

1. Laboratories

a) ACTH > 200 ng/L (usually thousands of ng/L)(normal:usually < 54 ng/L)

b) exaggerated ACTH response to CRH (not required for diagnosis)

c) other pituitary hormones may be affected as with any macroadenoma causing mass effect and endocrine screening should be done

2. Formal visual field testing: should be done in patients with suprasellar extension or in those being considered for surgery (as a baseline for comparison)

Nelson's syndrome treatment.

Nelson's syndrome is considered a severe side effect that can occur after total bilateral adrenalectomy in patients with Cushing's disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. Mirallas et al. present the case of a 48-year-old man diagnosed with Nelson's syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide ⁶⁾.