Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.1.5
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: MEN1
• Condition: Multiple Endocrine Neoplasia Type I
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• MEN1 ⇔ 0007540 (multiple endocrine neoplasia type 1): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: MEN1 ⇔ 0007540 (OMIM:131100)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity from parathyroid adenoma / Biochemical surveillance to guide parathyroidectomy decision	1	3C	3B	3	10CB
Morbidity from other MEN1-related tumors (gastrinoma excluded) / Biochemical surveillance	2	2C	2B	3	9CB
Morbidity from other MEN1-related tumors (gastrinoma excluded) / Imaging surveillance	2	2C	2B	2	8CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Multiple endocrine neoplasia, type 1 (MEN1) has an estimated prevalence of 1:10,000 to 1:100,000. [1, 2, 3]

Clinical Features

MEN1 is a hereditary cancer syndrome caused by inactivating pathogenic variants in the MEN1 gene. Manifestations include varying combinations of more than 20 endocrine and non-endocrine tumors. As such, no single definition of manifestations fits all index cases and families. Associated endocrine tumors include parathyroid tumors, anterior pituitary neuroendocrine tumors (PitNET), well-differentiated endocrine tumors of the gastro-entero-pancreatic tract, carcinoid tumors, and adrenocortical tumors. Parathyroid tumors, resulting in primary hyperparathyroidism (PHPT), are the most common feature of MEN1, affecting 95% of patients; pancreatic islet tumors (40%) and anterior pituitary tumors (30%) are the next most prevalent tumors. Clinical features are related to the sites of the tumors and the type of endocrine secretion and can include peptic ulcer, polyuria, polydipsia, constipation, nausea, abdominal pain, fatigue, depression, confusion, hypo- or hyperglycemia, increased fracture risk, shortened QT interval, syncope, kidney stones, visual changes, flushing, diarrhea, wheezing, edema, and anorexia. Pituitary tumors may cause menstrual dysfunction in females and sexual dysfunction in males. Pancreatic neuroendocrine tumors (NET) are associated with high levels of morbidity and mortality. Non-endocrine tumors include facial angiofibromas, collagenomas, lipomas, meningiomas, ependymomas, and leiomyomas. With the exception of gastrinomas, most tumors associated with MEN1 are non-metastasizing. [1, 2, 3, 4, 5, 6, 7]

Natural History

Parathyroid tumors, which cause PHPT, are the most common feature and the first clinical manifestation in 90% of individuals with MEN1 with onset typically between ages 20 and 25 years. Almost all (95-100%) individuals with MEN1 can expect to have PHPT by age 50 years. However, MEN1 affects all age groups, with a reported age range of 5 to 81 years; 17% of MEN1 tumors are diagnosed under age 21. Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by age 50. The cause of death in 50-70% of cases is due to a malignant tumor process or sequelae of the disease, with malignancies accounting for 30% of all deaths. MEN1-associated NET are more difficult to treat surgically, are more associated with occult metastatic disease, and may be larger, more aggressive, and more resistant to treatment than non-MEN1 associated tumors. MEN1 affects both sexes equally, though carcinoid tumors, which are a late manifestation of disease, affect the sexes unequally, with a 20:1 male:female ratio for thymic carcinoids and a 1:4 male:female ratio for bronchial carcinoids. Additionally, MEN1 pituitary adenomas occur more frequently in women than men (50% vs 31%). A more recent meta-analysis of case series has estimated the male:female ratio of thymic NET to be a more modest 79:20. Smoking increases the carcinoid risk. Thymic carcinoids tend to be aggressive, particularly in males who smoke. [2, 3, 4, 5, 6, 7]

2. How effective are interventions for preventing harm?

Patient Management

To establish extent of disease in patients at diagnosis, initial assessment should include evaluation for presence of the most common manifestations: multiglandular parathyroid disease, prolactinoma, thymic NET, gastrinoma and other entero-pancreatic NET. (Tier 2) (Tier 2) [7]

Patients with MEN1 should be managed by a multidisciplinary team consisting of relevant specialists (such as endocrinologist, gastroenterologist, oncologist, clinical geneticist) with experience in the management of endocrine disorders. (Tier 2) [6]

Treatment is guided by manifestations and may include: surgery; medical therapy to counteract the effects of secretions; radiotherapy, chemotherapy, or other tumor specific treatments in the case of tumors incurable by surgery; and quality of life management. Parathyroidectomy is the treatment of choice for the hyperparathyroidism manifestations, though the recommended timing and extent of surgery is controversial. A randomized controlled trial comparing surgical outcomes in 32 patients with various surgical approaches found no differences in persistent hyperparathyroidism (2-5%) between these procedures. (Tier 2) [6, 7]

In the general population, where PHPT is also most commonly caused by parathyroid adenoma, parathyroidectomy is also considered the only definitive therapy for PHPT, and improvements have been shown for both asymptomatic and symptomatic patients. Surgical cure results in improved kidney function, bone mineral density, and patient-reported quality of life, as well as reduced cardiovascular manifestations and mortality, neurocognitive and neuropsychiatric symptoms, patient-reported symptoms, and all-cause mortality. (Tier 2) [8]

At the time of parathyroidectomy for hyperparathyroidism, prophylactic thymectomy is also suggested to be undertaken. There are reports of thymic carcinoids occurring after prophylactic surgery, suggesting that surveillance after surgery is still necessary. (Tier 2) [6]

Although pheochromocytoma occurs rarely in MEN1, it is appropriate to measure urinary catecholamines prior to surgery to diagnose and treat a pheochromocytoma and thus avoid dangerous and potentially lethal blood pressure peaks during surgery. (Tier 4) [4]

Surveillance

The surveillance guidelines outlined below for asymptomatic patients are noted to be dependent on patient preferences, local resources, and clinical judgement. Surveillance is used to guide timing and choice of intervention, which may include surgery. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection as earlier diagnosis and treatment of these tumors may help reduce morbidity and mortality. There is a recent (last 20 years) trend toward decreasing mortality in MEN1, presumably the result of enhanced surveillance and early intervention. In a multicenter study of 258 heterozygotes for a MEN1 pathogenic variant, it was found that patients born during the second half of the 20th century tend to have their tumors diagnosed earlier than carriers of the same age born in the first half. Surgical morbidity has been shown to be reduced in other hereditary cancer syndromes when presymptomatic early surgical intervention is performed. (Tier 2) [3, 6]

Regular clinical surveillance for symptoms of insulinoma, such as syncope and hypoglycemia, along with annual biochemical surveillance in the form of fasting blood glucose and insulin is recommended starting at age 5. (Tier 2) [3, 6]

Regular clinical surveillance for symptoms of PitNET, such as headaches and visual changes, along with annual biochemical surveillance in the form of prolactin and IGF1 and imaging via brain MRI in 3-5 year intervals is recommended starting at age 5. (Tier 2) [3, 6, 7]

Regular clinical surveillance for symptoms of parathyroid adenoma, such as back pain, fatigue, nausea, and multiple fractures, along with annual assessment of plasma calcium and/or parathyroid hormone concentrations to screen for primary hyperthyroidism, is recommended with a suggested starting age of 8 years. (Tier 2) [3, 6, 7]

Regular clinical surveillance for the rare symptomatic presentation of pancreatic NET, such as profuse diarrhea, hyperglycemia, nausea, and polyuria, along with annual abdominal MRI, CT, or endoscopic ultrasound is recommended, starting by age 10. Frequent (1-3 years) biochemical surveillance in the form of chromogranin A, glucagon, proinsulin, pancreatic polypeptide, and VIP has also been recommended, though it is noted that due to the nonsecretory nature of many of these tumors, the added sensitivity through this screening has not been demonstrated. Concurrent annual imaging surveillance via abdominal CT or MRI for adrenal adenoma is recommended, also starting by age 10. (Tier 2) [3, 6, 7]

Regular clinical surveillance for symptoms of gastrointestinal, bronchial, and thymic NETs and carcinoids, such as flushing, diarrhea, wheezing, edema or abdominal pain, is recommended along with imaging surveillance (interval: 1-3 years) via chest/abdominal CT/MRI , starting at age 15-20 years. (Tier 2) [3, 6, 7]

In a meta-analysis of MEN1 patients derived from cases series (n = 2710), 99 of whom had thymic NETs, older age at diagnosis (HR = 1.4, 95% CI = 1.0-1.8, p = .03), maximum tumor diameter (HR = 1.5, 95% CI = 1.0-2.3, p = .04), and presence of metastasis (HR = 1.6, 95% CI = 1.0-2.5, p = .04) were all significantly associated with worse outcome, suggesting that early detection may be beneficial. (Tier 1) [9]

Clinical surveillance for symptoms of gastrinoma, such as abdominal pain, gastric ulcers and proton-pump inhibitor usage, is recommended along with annual biochemical surveillance via fasting gastrin with or without gastric pH, starting at age 20. (Tier 2) [3]

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Pediatric context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2, 3, 4, 5, 6]

Prevalence of Genetic Variants

Population prevalence of MEN1 pathogenic variants was not reported. However, in familial cases of MEN1 80-90% have a MEN1 variant detectable by sequence analysis; 65% of simplex cases of MEN1 have a MEN1 variant detectable by sequence analysis. An additional 1-4% of all cases of MEN1 have a MEN1 variant detectable by copy number variant analysis. Thus, the prevalence of MEN1 variants should approach but be less than that of the reported prevalence of the disorder (1:10,000-1:100,000). (Tier 3) [4]

Penetrance

The overall disease penetrance has been variously reported. Disease penetrance for a first manifestation of MEN1 among heterozygotes for a MEN1 pathogenic variant is estimated at 45%, 82%, and 96% at 30, 50, and 70 years, respectively. Still others have estimated age related penetrance for all clinical features at 50% by age 20 years and 95% by age 40 years. Of all MEN1 associated tumors, 17% are diagnosed under age 21. (Tier 3) [3, 4, 6]

In a meta-analysis of case series of patients with MEN1 (N = 2710), the pooled prevalence of thymic NETs was 3.7% (N = 99). (Tier 1) [9]

For other specific tumor manifestations, penetrance estimates are:
•parathyroid adenoma or PHPT (90-98%)
•enteropancreatic tumor (30–75%), pituitary adenoma (30–55%)
•adrenocortical tumor (40%)
•gastrinoma (40%)
•pheochromocytoma (<1%)
•bronchopulmonary NET (2%)
•gastric NET (10%)
•insulinoma (10%) (Tier 3) (Tier 3) [3, 4, 6, 7]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Variable expressivity has been described among affected members of the same families (bearing the same MEN1 pathogenic variant) and even between homozygous twins. (Tier 3) [4, 6]

4. What is the Nature of the Intervention?

Nature of Intervention

Annual surveillance recommendations are primarily biochemical (phlebotomy), clinical, and non-invasive imaging in nature, though some imaging mechanisms (such as CT). [3, 6]

Medical management of manifestations is dependent on tumor type and extent of disease. Most patients will require parathyroidectomy; in this procedure, postoperative bleeding or hoarseness due to injury to the recurrent laryngeal nerve may occur in about 1% of patients. Prophylactic thymectomy is also recommended. Surgical interventions for other manifestations of disease can include local resection up to total gastrectomy. [6, 7]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

For patients with gastrinoma as a manifestation, around half have metastasized before diagnosis. Due to early age of tumor development in many patients, and surveillance recommendations outside typical clinical care, there is a reasonable probability that patients could escape detection. (Tier 3) [3, 4, 6]

Date of Search: 01.15.2019

Reference List

1. Multiple endocrine neoplasia. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=276161

2. Multiple endocrine neoplasia type 1. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=652

3. Wasserman JD, Tomlinson GE, Druker H, Kamihara J, Kohlmann WK, Kratz CP, Nathanson KL, Pajtler KW, Parareda A, Rednam SP, States LJ, Villani A, Walsh MF, Zelley K, Schiffman JD. Multiple Endocrine Neoplasia and Hyperparathyroid-Jaw Tumor Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. Clin Cancer Res. (2017) 23(13):e123-e132.

4. F Giusti, F Marini, ML Brandi. Multiple Endocrine Neoplasia Type 1. 2005 Aug 31 [Updated 2015 Feb 12]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1538

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MULTIPLE ENDOCRINE NEOPLASIA, TYPE I; MEN1. MIM: 131100: 2017 Feb 21. World Wide Web URL: http://omim.org.

6. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, Brandi ML. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. (2012) 97(9):2990-3011.

7. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Neuroendocrine and Adrenal Tumors. NCCN Evidence Blocks. Version 1.2019. Publisher: National Comprehensive Cancer Network (NCCN). (2019) Accessed: 2019-03-08. Website: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine_blocks.pdf

8. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, Doherty GM, Herrera MF, Pasieka JL, Perrier ND, Silverberg SJ, Solorzano CC, Sturgeon C, Tublin ME, Udelsman R, Carty SE. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. (2016) 151(10):959-968.

9. Ye L, Wang W, Ospina NS, Jiang L, Christakis I, Lu J, Zhou Y, Zhu W, Cao Y, Wang S, Perrier ND, Young WF Jr, Ning G, Wang W. Clinical features and prognosis of thymic neuroendocrine tumours associated with multiple endocrine neoplasia type 1: A single-centre study, systematic review and meta-analysis. Clin Endocrinol (Oxf). (2017) 87(6):706-716.