Clinical characteristics.

Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. Parathyroid adenomas and parathyroid hyperplasia manifest as hypercalcemia (primary hyperparathyroidism) as a result of the overproduction of parathyroid hormone. Anterior pituitary adenomas can secrete adrenocorticotrophic hormone (ACTH), growth hormone (GH), prolactin, or are nonfunctional (nonsecreting) adenomas. Well-differentiated endocrine tumors of the gastroenteropancreatic tract, carcinoid tumors, and adrenocortical tumors can also occur.

Diagnosis/testing.

The diagnosis of MEN4 is established in a proband with a germline heterozygous pathogenic variant in CDKN1B identified by molecular genetic testing.

Management.

Treatment of manifestations: Parathyroidectomy for primary hyperparathyroidism; cinacalcet may be considered in those with symptomatic hypercalcemia who are not surgical candidates; surgical resection for pituitary adenomas that secrete ACTH or GH; cabergoline for prolactin-secreting tumors; surgical resection for neuroendocrine and carcinoid tumors if possible; some individuals may be treated with somatostatin analogs; proton pump inhibitors for individuals with gastrin-secreting tumors.

Surveillance: Biennial serum calcium and gastrin starting at age 25 years; IGF-1 and prolactin every three to five years or as symptoms indicate, starting at age 25 years; pituitary MRI every five years starting at age 25 years; abdominal MRI or CT every five years starting at age 25 years and increasing frequency to every 2.5 years starting at age 40 years.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the CDKN1B pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment.

Genetic counseling.

MEN4 is inherited in an autosomal dominant manner. Most individuals diagnosed with MEN4 have an affected parent; some individuals diagnosed with MEN4 may have the disorder as the result of a de novo CDKN1B pathogenic variant. Each child of an individual with MEN4 has a 50% chance of inheriting the CDKN1B pathogenic variant. Once the CDKN1B pathogenic variant has been identified in an affected family member, testing of at-risk asymptomatic family members (strongly recommended for all first-degree relatives of an affected person with an identified CDKN1B pathogenic variant) and prenatal and preimplantation genetic testing are possible.

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 (see Clinical Description). 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

• Adrenocorticotrophic hormone-secreting anterior pituitary adenomas are mostly associated with Cushing disease.
• Growth hormone-secreting anterior pituitary adenomas cause gigantism in children and signs and symptoms of acromegaly in adults.
• Prolactinomas (prolactin-secreting anterior pituitary adenomas) manifest as oligomenorrhea/amenorrhea and galactorrhea in females, and sexual dysfunction and (more rarely) gynecomastia in males.
• Nonfunctioning (nonsecreting) anterior pituitary adenomas manifest as enlarging tumors, compressing adjacent structures such as the optic chiasm and causing visual disturbances, headaches, and/or hypopituitarism.

Note: The imaging test of choice for all types of pituitary tumors is MRI.

Well-differentiated endocrine tumors of the gastroenteropancreatic tract (including tumors of the stomach, duodenum, pancreas, and intestinal tract) manifest as the following clinical presentations (from most to least frequent):

• Nonfunctioning pancreatic endocrine tumors are the most frequently seen tumors in MEN4. They are not found during biochemical testing but may be detected on abdominal imaging studies (CT, MRI, ultrasound) performed for other specific indications.
• Zollinger-Ellison syndrome (ZES; peptic ulcer with or without chronic diarrhea) resulting from a gastrin-secreting duodenal mucosal tumor (gastrinoma)

Note: Endoscopic ultrasound examination is the most sensitive imaging procedure for the detection of small (≤10 mm) pancreatic endocrine tumors in asymptomatic individuals with multiple endocrine neoplasia type 1 (MEN1) [Jensen 1999]; however, this has not been directly evaluated in individuals with MEN4.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

No clinical diagnostic criteria can accurately distinguish MEN4 from multiple MEN1 or coincidental tumor co-occurrence. Therefore, the diagnosis of MEN4 is established in a proband with a germline heterozygous pathogenic (or likely pathogenic) variant in CDKN1B identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous CDKN1B variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include single-gene testing and a multigene panel depending on the phenotype.

• Single-gene testing. Sequence analysis of CDKN1B is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes CDKN1B and other genes of interest (see Differential Diagnosis) may also be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Multiple endocrine neoplasia type 4 (MEN4) is characterized by the development of endocrine tumors, especially those involving the parathyroid and/or pituitary gland. The clinical presentation has significant overlap with multiple endocrine neoplasia type 1 (MEN1). While there are some conflicting reports, most indicate that, by comparison, MEN4 is more attenuated, with lower penetrance and later ages of diagnosis [Alrezk et al 2017, Singeisen et al 2023]. The mean age of first endocrine tumor presentation is 43.5 years (range: 5-76 years) [Singeisen et al 2023], compared to 31.8 years (range: 9-71 years) in MEN1 [Marini et al 2018].

To date, 65 individuals have been identified with a disease-causing variant in CDKN1B [Singeisen et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Primary hyperparathyroidism (PHPT). MEN4-associated PHPT is often mild, with hypercalcemia often detected in asymptomatic individuals. PHPT is the most common MEN4-associated endocrinopathy and is the first manifestation in approximately 56% of individuals. The pathology most often shows a single adenoma. The median age of PHPT diagnosis in individuals with MEN4 is 51 years (range: 15-74 years). Multiglandular disease or recurrent PHPT are much less common in MEN4 (14% and 6%, respectively) compared to MEN1. MEN4-associated PHPT has been reported more often in women than in men (80% vs 58%) [Singeisen et al 2023].

Anterior pituitary adenomas are the second most common feature in MEN4 and are the presenting feature in approximately 23% of individuals. MEN4-associated anterior pituitary adenomas are more likely to be microadenomas. The median age of MEN4-associated anterior pituitary adenoma diagnosis is 39 years (range: 5-79 years). Adrenocorticotrophic hormone-secreting adenomas leading to hypercortisolism and Cushing disease are the most common, followed by prolactinomas and nonfunctional tumors [Singeisen et al 2023].

A study of mostly children with Cushing disease identified CDKN1B variants in up to 2.6% of individuals [Chasseloup et al 2020].

Well-differentiated neuroendocrine tumors of the gastroenteropancreatic tract (GEP-NET). Nonfunctioning GEP tract tumors are the most frequent type of neuroendocrine tumor in MEN4, followed by gastrin-secreting tumors (gastrinomas). Most GEP-NETs occur in the pancreas; however, gastric tumors have also been reported. MEN4-associated GEP-NETs are less likely to be multifocal. Furthermore, the age of tumor diagnosis is considerably later than the age of tumor diagnosis in those with MEN1, with the youngest reported MEN4-associated pancreatic neuroendocrine tumor diagnosed at age 42 years. However, approximately half of GEP-NETs are metastatic at diagnosis [Singeisen et al 2023]. A lack of standardized screening guidance for individuals with MEN4 may contribute to this finding.

Carcinoid tumors. Approximately 4%-7% of individuals with MEN4 develop carcinoid tumors of the thymus, bronchus, and ileum, some of which were metastatic at the time of diagnosis [Singeisen et al 2023].

Adrenocortical tumors. Approximately 4%-7% of individuals with MEN4 develop adrenocortical tumors, which are either nonfunctional or cortisol secreting [Singeisen et al 2023].

Other. Singeisen et al [2023] reported papillary thyroid cancer in 8% of individuals with MEN4. Three of four individuals had multifocal thyroid cancer, and all four individuals were women who were diagnosed with papillary thyroid cancer in their fifties or sixties. This may represent an emerging association, but further research is needed in this area.

Individuals with MEN4 have been found to have breast cancer, colon cancer, testicular cancer, prostate cancer, cervical neuroendocrine carcinoma, meningioma, and renal angiomyolipoma. Further research is needed to determine if these tumors are part of the phenotype or occurred by coincidence in an individual with MEN4.

Chevalier et al [2020] also reported a possible association between germline CDNK1B variants and autoimmune disease. Further research is needed to determine if risk of autoimmune disease is part of the MEN4 phenotype.

Cutaneous manifestations associated with MEN1 have not been reported in individuals with MEN4. Further research is needed to determine if cutaneous tumors are absent from the MEN4 phenotype versus underassessed in clinical reports.

Genotype-Phenotype Correlations

A recent report suggested that individuals with CDKN1B indels have a higher incidence of PHPT [Halperin et al 2022]. 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.

Penetrance

Penetrance is reduced and age related.

Prevalence

MEN4 is likely both rare and underdiagnosed. To date, 65 individuals have been reported with a disease-causing variant in CDKN1B [Singeisen et al 2023]. However, 13 of these individuals belong to a large Danish family [Frederiksen et al 2019]. A further complication is that many case reports describe individuals with MEN4 whose CDKN1B variant is currently classified as a variant of uncertain significance.

Disease-causing variants in CDKN1B have been identified in a very small percentage (<5%) of individuals with features suggestive of MEN1 and negative MEN1 molecular testing [Georgitsi et al 2007, Agarwal et al 2009, Molatore et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MEN4, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the CDKN1B pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of surveillance and treatment. Early detection and treatment of the potentially malignant neuroendocrine tumors should reduce the morbidity and mortality of MEN4.

When molecular genetic testing for a CDKN1B pathogenic variant is not possible or is not informative, individuals at 50% risk (i.e., first-degree relatives of an individual with MEN4) should undergo surveillance.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.

Mode of Inheritance

Multiple endocrine neoplasia type 4 (MEN4) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with MEN4 have an affected parent.
• Some individuals diagnosed with MEN4 may have the disorder as the result of a de novo CDKN1B pathogenic variant. The proportion of MEN4 caused by a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status, determine their need for appropriate clinical surveillance (see Management), and allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MEN4 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. However, penetrance appears to be reduced (see Penetrance), and the types of MEN4-related tumors can vary among affected family members.
• If the CDKN1B pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the CDKN1B pathogenic variant but are clinically unaffected, sibs of a proband are still presumed to be at increased risk for MEN4 because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with MEN4 has a 50% chance of inheriting the CDKN1B pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CDKN1B pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic individuals. Molecular genetic testing of at-risk asymptomatic family members is strongly recommended for all first-degree relatives of an affected person with an identified CDKN1B pathogenic variant so that individuals with a CDKN1B pathogenic variant can receive the appropriate clinical surveillance (see Management). Given the apparently low risk of childhood tumors and the emerging nature of associated risks, it may be appropriate to follow the American Society of Clinical Oncology (ASCO) recommendation to delay genetic testing in at-risk individuals until they reach age 18 years and are able to make informed decisions regarding genetic testing [American Society of Clinical Oncology 2003]. Education and genetic counseling of all at-risk individuals and their families prior to genetic testing is appropriate.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the CDKN1B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CDKN1B encodes the p27 nuclear protein, which is a cyclin-dependent kinase inhibitor that blocks cell cycle progression from the G1 to S phase. CDKN1B acts as a tumor suppressor gene.

Mechanism of disease causation. Most reports suggest that the mechanism of tumorigenesis is loss or reduced p27. In many MEN4-related tumors, there is no loss of heterozygosity or acquired second hit. Further research is needed to determine whether the mechanism of disease causation is haploinsufficiency versus loss of function due to epigenetic silencing of CDKN1B in addition to a germline variant.

CDKN1B-specific laboratory technical considerations. CDKN1B variants with functional evidence of pathogenicity have been reported to exist outside the coding region of the gene, such as in the 5' UTR [Chasseloup et al 2020, Singeisen et al 2023].

Revision History

• 21 September 2023 (sw) Review posted live
• 3 March 2023 (pb) Original submission

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