What Are the Genetics of Multiple Endocrine Neoplasia (MEN)?

Patient Presentation
A 4-month-old female came to the resident continuity clinic for her health maintenance appointment. The patient was well but one parent had multiple endocrine neoplasia type 1 (MEN1). The family had already seen the geneticist and molecular testing was pending. They had met the resident during the genetics appointment and wanted to transfer their primary care to the regional children’s hospital so that all of their care was in one place. The past medical history revealed a healthy term female who was the first baby for these parents. The family history was positive for MEN1, and also for diabetes and lymphoma.

The pertinent physical exam showed a happy baby with growth parameters around 50% and normal vital signs.
The physical examination was normal.
The diagnosis of a healthy female with risk of MEN syndrome was made. “We know that if she has MEN then we won’t need to do a lot until she is around school age, but we think it’s best to have all of her care in one place. That way if things change then all of you can work together,” the parents explained. The resident and staff pediatricians discussed with the family that they would oversee all of her regular primary care and would work to schedule any surveillance testing needed in the future. “The oncology group has a multidisciplinary group that follows patients at risk for various cancers and once we know about the baby we can talk about possibly referring you to that team as well,” the staff physician said.

Primary care physicians often work as part of a health care team. Their job can be particularly important for helping oversee intermittent or ongoing surveillance for various diseases. Some of the challenges are changes in clinical guidelines or treatment for uncommon diseases, timelines for evaluation that are in the future (particularly several years), and communication between various health care providers especially across locations or health systems. It is not surprising that families with children with special health care needs may move closer to their providers and consolidate their care within one health care system.

Like many diseases, multiple endocrine neoplasias (MEN) have been a known entity for many years, but the understanding of their genetics has exploded in the past few years. Molecular diagnosis has made this diagnosis easier along with the important genetic counseling of family members as this is mainly an autosomal dominant disease with high penetrance. MEN requires a multidisciplinary team to monitor the patient (as well as the literature for changing practices) over many years. Some centers have clinical specialists who do cancer screening and monitoring for diagnoses which carry increased risks such as MEN, Beckwith-Widemann syndrome, etc.

Learning Point
One challenge of MEN is that there are multiple tumor types that can be observed. Below is an overview of the most common tumors and known genetics:

  • MEN Type 1
    • 2-20/100,000 persons affected
    • Genetics
      • Autosomal dominant on chromosome 11q13 with > 1000 germline mutations noted
      • Changes menin which is a cellular scaffolding and signaling protein
      • 90% are inherited and 10% sporadic
    • Penetrance
      • 0% at age 5 years
      • 50% by age 20 years
      • 95% by age 40 years
      • Onset is 5-81 years though
    • Diagnosis made with
      • > 2 MEN1 related tumor, or
      • 1 MEN related tumors and positive family history, or
      • Molecular diagnosis
    • Main tumors
      • Parathyroid – hyperparathyroidism is most commonly seen
      • Pituitary
      • Pancreatic neuroendocrine tumors
    • Treatment
      • Surveillance starts around age 5 with annual biochemical screening and scheduled imaging.
      • Tumor treatment is multi-disciplinary including oncologists, surgeons and endocrinologists
    • Outcomes poorer as tumors tend to be larger, multi-focal or more aggressive
  • MEN Type 2
    • 2.5/100,000 persons affected
    • Genetics
      • Autosomal dominant on chromosome 10q11.2 with multiple mutations
      • 95% are inherited and 5% sporadic
      • Changes RET pro-oncogene which is a transmembrane tyrosine kinase receptor
    • Penetrance
      • As early as age 3 years
    • Diagnosis made with multiple tumors, family history and molecular diagnosis
    • Main tumors
      • Medullary thyroid carcinoma – affects nearly all patients
      • MEN2A – pheochomocytoma and hyperparathyroidism (afffects 75% of all MEN2 patients)
      • MEN2B – pheochromocytoma, mucosal and gastrointestinal tumors
      • Familial – only medullary thyroid carcinoma
    • Treatment
      • Surveillance starts around age 5 with annual biochemical screening and scheduled imaging
      • Tumor treatment is multi-disciplinary including oncologists, surgeons and endocrinologists. This includes consideration of prophylactic thyroidectomy because of the high risk of medullary thyroid cancer.
    • Outcomes have improved with earlier detection especially in younger children. If detected later in adolescence, there is a decrease in survival.
  • MEN Type 4
    • Described in 2006
    • 9 pedigrees identified
    • MEN1 like tumors

Questions for Further Discussion
1. What other diseases have high potential cancer risks and patients which need monitoring?
2. What resources for genetic counseling are available locally?
3. How do you view your role on a multidisciplinary team?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Endocrine Diseases and Cancer in Children.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Giri D, McKay V, Weber A, Blair J. Multiple endocrine neoplasia syndromes 1 and 2: manifestations and management in childhood and adolescence. Arch Dis Child. 2015;100(10):994-999. doi:10.1136/archdischild-2014-307028

Concolino P, Costella A, Capoluongo E. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genetics. 2016;209(1-2):36-41. doi:10.1016/j.cancergen.2015.12.002

Wasserman JD, Tomlinson GE, Druker H, et al. Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. 2017;23(13):e123-e132. doi:10.1158/1078-0432.CCR-17-0548

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa