Clinical Guidance

A recent report suggested that individuals with CDKN1B indels have a higher incidence of PHPT . The same study found that individuals with variants in codons 94-96 had a higher risk of developing PHPT and pituitary adenomas compared to individuals with other CDKN1B pathogenic variants.

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"

Penetrance

Penetrance is reduced and age related.

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"

Diagnostic Criteria

Suggestive Findings

Multiple endocrine neoplasia type 4 (MEN4) should be suspected in individuals with multiple/multifocal or early-onset endocrine tumors, especially those involving the parathyroid and/or pituitary gland . Varying combinations of tumors have been reported in individuals with MEN4; therefore, no clinical criteria or definition can capture all affected individuals. Parathyroid tumors manifest as hypercalcemia (primary hyperparathyroidism [PHPT]) as a result of the overproduction of parathyroid hormone. Individuals with PHPT may be asymptomatic or may present with nephrolithiasis, reduced bone mass, fatigue, muscle weakness, bone or joint pain, and/or constipation.

Anterior pituitary adenomas

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"

Differential Diagnosis

Table 3a. Hereditary Cancer Syndromes in the Differential Diagnosis of Multiple Endocrine Neoplasia Type 4

Management Guidelines

No consensus clinical practice guidelines for multiple endocrine neoplasia type 4 (MEN4) have been established. Given the clinical overlap with multiple endocrine neoplasia type 1 (MEN1), MEN1-related screening can be used as a guide, keeping in mind that MEN4 is more attenuated, with lower penetrance and later age at tumor diagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MEN4, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Multiple Endocrine Neoplasia Type 4: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

General

| • Referral to endocrinologist w/experience in MEN

• Assess for clinical manifestations of endocrine tumors (e.g., kidney stones, signs of cortisol, GH, or prolactin excess, excessive nausea, vomiting, or diarrhea)

|

PHPT | Serum calcium | In those age ≥25 yrs

Further testing (e.g., PTH, vitamin D, 24-hr urine calcium) referral to surgery for those w/laboratory findings of PHPT. |

Pituitary adenoma

| • Pituitary MRI

• Serum hormone testing (ACTH, cortisol, IGF-1, prolactin) guided by clinical suspicion

| In those age ≥25 yrs

Dynamic testing of GH or cortisol axis may be needed if screening tests indicate possible hormonal abnormalities (e.g., glucose suppression test for GH/IGF-1 or dexamethasone suppression testing for cortisol). |

Neuroendocrine tumor

| • Abdominal imaging (e.g., contrast-...

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"

Surveillance Guidelines

Table 6.

Multiple Endocrine Neoplasia Type 4: Recommended Surveillance

System/Concern | Evaluation | Frequency1

PHPT | • Serum calcium

• PTH vitamin D measurement may also be considered to ensure sufficiency.

| Biennially (every 2 yrs) starting at age 25 yrs

Pituitary adenoma

| Serum IGF-1 prolactin | Every 3-5 yrs or as symptoms indicate, starting at age 25 yrs

Pituitary MRI | Imaging every 5 yrs starting at age 25 yrs

If clinical concern for Cushing disease, perform 24-hr urine free cortisol, late night salivary cortisol, /or 1 mg overnight dexamethasone suppression test. |

Neuroendocrine tumors carcinoids

| Serum gastrin | Biannually starting at age 25 yrs

Abdominal MRI (or CT) | Imaging every 5 yrs starting at age 25 yrs, increasing to every 2.5 yrs at age 40 yrs

IGF-1 = insulin-like growth factor 1; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone

1. Abnormal findings would indicate the need for more frequent follow up (current multiple endocrine neoplasia type 1 treatment guidelines can be used as a guide).

Source: GeneReviews — "Multiple Endocrine Neoplasia Type 4"