Neuroendocrine Neoplasms (NEN) – genetic related syndromes

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Definitions – the differences between Hereditary vs Familial vs Genetic Disorders

I wanted to start with these definitions because people may unintentionally use these three terms interchangeably which is sometimes not the correct use of the information being conveyed. However, after studying this subject, I can tell you it is a very complex area and difficult to explain and then understand in a single paragraph.  Even these widely accepted definitions don’t make it any more understandable!  

The terms ‘hereditary’ and ‘familial’ look like synonyms and are frequently used interchangeably but are two different concepts. ‘Hereditary’ is most commonly used when referring to diseases with a known genetic cause whereas ’Familial’ disorders are those which appear to have a genetic component, affecting more family members than would be expected by chance alone. However, a single genetic cause or explanation is not known. 

But not all genetic disorders are hereditary. The main difference between these two terms lies in the fact that hereditary diseases have the potential of being carried from one generation to another whereas a genetic disease can either be hereditary or not, but there will always be a mutational change in the genome.   

The US National Cancer Insitute defines the terms as follows:

A Hereditary cancer syndrome is a type of inherited disorder in which there is a higher-than-normal risk of certain types of cancer. Hereditary cancer syndromes are caused by mutations (changes) in certain genes passed from parents to children. In a hereditary cancer syndrome, certain patterns of cancer may be seen within families. These patterns include having several close family members (such as a mother, daughter, and sister) with the same type of cancer, developing cancer at an early age, or having two or more types of cancer develop in the same person.

A Familial Disease occurs in families more often than would be expected by chance. These cancers often occur at an early age and may indicate the presence of a gene mutation that increases the risk of cancer. They may also be a sign of shared environmental or lifestyle factors.

A Genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. Genetic disorders can be caused by a mutation in one gene (monogenic disorder), by mutations in multiple genes (multifactorial inheritance disorder), by a combination of gene mutations and environmental factors, or by damage to chromosomes (changes in the number or structure of entire chromosomes, the structures that carry genes).

Autosomal dominant inheritance. This term very frequently comes up when discussing genetic syndromes related to NENs.  One of the ways a genetic trait or a genetic condition can be passed down (inherited) from parent to child. In autosomal dominant inheritance, a genetic condition can occur when the child inherits one copy of a mutated (changed) gene from one parent. A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene.

You may also appreciate this simple explanation here:  Click

Note: This is not meant to be an all-encompassing information source as the subject is VAST. But I hope to provide at least an overview of the subject for the average patient; but also to provid sufficient extra detail and links for those who are interested in delving more into the detail. I know I have two different types of readers! I hope I got the balance right. 

Genetically related syndromes in Neuroendocrine Tumours (NET)

Several genetic-related syndromes involve the endocrine or neuroendocrine glands. It’s difficult to put a number on the chances of a NET being hereditary but most texts I’ve read seem to put it around 5-10% (one European study went as high as 20%).  These percentages need to be put into context as they could be higher or lower in certain types, e.g. pancreatic NETs and Pheochromocytoma figures may be above this average. The average across all cancers looks to be around 5%. 

It’s clear that most hereditary and familial Neuroendocrine Neoplasms (NEN) will be from well-differentiated Neuroendocrine Tumours (NET) rather than poorly differentiated Neuroendocrine Carcinomas (NEC).  It’s also worth noting that hereditary and familial syndromes are not tumours but the mutational change in the genome can lead to tumours.

These include:

  • Multiple endocrine neoplasia type 1 (MEN1),
  • Multiple endocrine neoplasia type 2 (MEN2),
  • Multiple endocrine neoplasia type 4 (MEN4),
  • Familial pheochromocytoma (PHEO) and paraganglioma (PGL) syndrome (FPPL),
  • Carney-Stratakis syndrome (CSS),
  • Von Hippel-Lindau Disease (VHL),
  • Neurofibromatosis Type 1 (NF1),
  • Tuberous sclerosis (TSC).

Descriptions of each are provided below.  I have also included a section on the Small Intestine Familial Clinical Trial going on at the National Institute of Health in USA.  You will find it below. 

Multiple Endocrine Neoplasia (MEN)

Multiple endocrine neoplasia (MEN) syndromes describe a group of heterogeneous disorders, characterised by a predisposition for tumours involving two or more endocrine glands. The four recognised disorders (MEN1–4) are autosomal dominant and are distinguished phenotypically by the development of synchronous or metachronous tumours in specific endocrine glands. A MEN syndrome is diagnosed if any one of the following clinical, familial or genetic criteria are met:

  • the occurrence of two or more MEN-associated tumours,
  • a single MEN-associated tumour in a first-degree relative of a patient with a clinical diagnosis of MEN or a germline pathogenic variant in an associated MEN gene, even in the absence of symptoms and radiological or biochemical abnormalities.

MEN type 1 (MEN1)

Sometimes called Wermer syndrome, Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome with the following main features:

Parathyroid tumors and primary hyperparathyroidism (PHPT).  The most common features and often the first presenting signs of MEN1 are parathyroid tumors, which result in PHPT. These tumors occur in 80% to 100% of patients by age 50 years. MEN1-associated parathyroid tumors are typically multiglandular and hyperplastic. This differs from sporadic parathyroid tumors, which often present with a solitary adenoma.[9] The mean age of PHPT onset is 20 to 25 years in individuals with MEN1. In contrast, PHPT onset occurs in the general population at age 50 to 59 years.

Duodenopancreatic neuroendocrine tumors (NETs).  Duodenopancreatic NETs (i.e. duodenal and pancreatic) are the second most common endocrine manifestation in MEN1, occurring in 30% to 80% of patients by age 40 years.  The figures may be lower or higher in different age grouping and/or different MEN1 pathogenic variants. These manifestations also include functional pancreatic NETs including:

  • Gastrinomas (approximately 40 percent of adults with MEN type 1 develop multiple gastrinomas, usually located in the first portion of duodenum, and more rarely in the pancreas. Approximately, 50% of MEN1-gastrinomas have already metastasized at the time of clinical diagnosis),
  • Insulinomas (10%),
  • Vasoactive intestinal peptide tumors (VIPomas) (1%),
  • Glucagonomas (1%),
  • Somatostatinomas (<1%),
  • Non-functional pancreatic NETs are said to range between 20-55%

Pituitary tumors.  Approximately 15% to 50% of MEN1 patients will develop a pituitary tumor. Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting. Other pituitary tumors can include somatotropinomas and corticotropinomas, or they may be nonfunctioning

Other locations. MEN1 is often labeled as the 3 P’s but other tumours may be found, including manifestations of foregut NETs typically bronchial or thymic, and sometimes gastric. 

Approximately 10-15% of individuals with MEN type 1 develop slow-growing NETs. These tumors usually develop in the stomach (gastric), the large tubes that carry air to and from the lungs (bronchial tubes) (bronchial), and the thymus, a small gland located in the upper chest just behind the breastbone. NETs of the bronchial tubes primarily affect women; thymic NETs primarily affect men. In most cases, these tumors do not produce hormones (i.e. non-functioning tumors)

Skin lesions are also common and can include facial angiofibromas (up to 80% of MEN1 patients) and collagenomas (~75% of MEN1 patients), Lipomas (~30% of MEN1 patients) and adrenal cortical lesions (up to 50% of MEN1 patients), including cortical adenomas, diffuse or nodular hyperplasia, or rarely, a carcinoma.

Prevalence. MEN1 affects males and females in equal numbers. It affects approximately 1 in 30,000 individuals. Some researchers believe that many cases of MEN1 go undiagnosed, making it difficult to determine its true frequency in the general population. 

Genes Involved

MEN1

MEN type 2 (MEN2) – Overview

Historically, individuals with MEN2 were given one of the following clinical subtypes based on the presence or absence of certain endocrine tumors in the individual/family:

  1. MEN2A.
  2. Familial medullary thyroid cancer (FMTC).
  3. MEN2B (sometimes referred to as MEN3).

However, the current classification now includes two MEN2 syndromes: MEN2A and MEN2B but MTC is involved in most.

This syndrome includes two main clinical subtypes, characterized by different clinical characteristics (phenotype):

MEN2A (accounting for 95% of all MEN2 cases); characterized by the uniform presence of MTC in association with pheocromocytoma (PHEO) or primary hyperthyroidism (PHPT) or both in some patients. MEN2A includes four subvariants:

  • Classical MEN2A (MTC with PHEO or PHPT, or both)
  • MEN2A with cutaneous lichen amyloidosis
  • MEN2A with Hirschsprung disease
  • Familial medullary thyroid cancer; FMTC (families or individuals with RET germline mutations who develop only MTC)

MEN2B (accounting for less than 5% of all MEN2 cases); characterized by a 100% prevalence of an earlier onset and more severe MTC, PHEO but not PHPT.

Medullary thyroid cancer (MTC)

MTC develops in the C cells and is sometimes the result of a genetic syndrome called multiple endocrine neoplasia type 2 (MEN2). This tumor has very little, if any, similarity to normal thyroid tissue. MTC can often be controlled if it is diagnosed and treated before it spreads to other parts of the body. MTC accounts for about 3% of all thyroid cancers.

About 25% of all MTC is familial (i.e. 75% are sporadic). This means that family members of the patient will have a possibility of a similar diagnosis. The RET proto-oncogene test can confirm if family members also have familial MTC (FMTC). Those diagnosed with FMTC should also be tested for MEN2A and 2B.

By definition, FMTC must occur in at least four members of a family in the absence of additional signs and symptoms MEN2A or MEN2B such as PHEO or parathyroid adenoma. MTC is less aggressive in this variant than other MEN2A variants and MEN2B familial form then when it is associated with MEN types 2A or 2B. Onset is usually during adulthood. 

MEN type 2A (MEN2A)

MEN2A is diagnosed clinically by the occurrence of two specific endocrine tumors in addition to Medullary Thyroid Cancer (MTC). These are Pheochromocytoma and/or parathyroid adenoma/hyperplasia in a single individual or in close relatives.

The classical MEN2A subtype makes up about  95% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome. Since genetic testing for RET pathogenic variants has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC.

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC. In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 years and 25 years (mean, 15 y). If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain between the ages of about age 5 years and 20 years. More than 50% of such patients have cervical lymph node metastases. Diarrhea, the most frequent systemic symptom, occurs in patients with a markedly elevated plasma calcitonin level or bulky disease and/or hepatic metastases and implies a poor prognosis. Up to 30% of patients with MTC present with diarrhea and advanced disease.

MEN2-associated PHEOs are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia. They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts. MEN2-associated PHEOs usually present after MTC, typically with intractable hypertension.

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium. A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group. The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism. Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid cancer in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, 4 double adenomas, and 25 hyperplastic glands.

MEN2A with cutaneous lichen amyloidosis

A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.

MEN2A with Hirschsprung disease (HSCR)

HSCR, a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, occurs in a small number of individuals with MEN2A-associated RET pathogenic variants. Pathogenic variants at specific cysteine residues in exon 10 (i.e., codons 609, 618, and 620) are most commonly associated with HSCR, although individuals with pathogenic variants in other exons can still be affected.HSCR can occur outside of a diagnosis of MEN2A and infants with HSCR may benefit from their own genetic evaluation regardless of the likelihood of MEN2A because HSCR can present as part of other syndromes. Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline pathogenic variants in the RET proto-oncogene. Certain loss-of-function RET variants have been associated with isolated HSCR, indicating that not all individuals with HSCR and a germline RET variant necessarily have MEN2A.

Prevalence

The prevalence of all MEN2 worldwide is 1 in 35,000.  MEN2A accounts for 95% of all cases.  The epidemiology of MEN2B is unknown and is estimated to be between 1 in 600,000 to 1 in 4 million. 

Genes Involved

RET.  Fewer than 5% of people with MEN2A are thought to have a de novo mutation in the RET gene.

MEN type 2B (sometimes called MEN3)

MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC. In cases of de novo pathogenic variants, the diagnosis of MEN2B is often delayed, after the development of MTC. The MTC is often fatal, particularly in the presence of metastatic disease, which is common at the time of diagnosis. It is important, therefore, for pediatricians to recognize the endocrine and nonendocrine clinical manifestations of the syndrome as an earlier diagnosis may result in lifesaving treatment of MTC, before metastatic spread.

The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome. MEN2B is characterized by the early development of an aggressive form of MTC in all patients. Patients with MEN2B who do not undergo thyroidectomy at an early age (at approximately age 1 y) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN2B was 21 years. PHEOs occur in about 50% of MEN2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon. Patients with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.

Patients with MEN2B may have diffuse ganglioneuromatosis of the gastrointestinal tract with associated symptoms that include abdominal distension, megacolon, constipation, and diarrhea. A review of the literature reported the presence of constipation as a common symptom in 72.7% of patients with MEN2B. Additionally, gastrointestinal symptoms occurred during the first year of life in 52.3% of patients with MEN2B. Intestinal biopsy led to the diagnosis of ganglioneuromatosis in 27.3% of patients.

About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.

A retrospective review of the clinical presentation of 35 cases of MEN2B with de novo pathogenic variants treated at a single institution found that 22 cases were diagnosed because of endocrine manifestations of the syndrome. The diagnosis of PHEO, a neck mass, and/or skeletal abnormalities led to the identification of MTC. The remaining 13 patients presented with a nonendocrine manifestation, including oral neuromas, corneal nerve abnormalities, persistent diarrhea, failure to thrive, or skeletal abnormalities with frequent falls. Of the entire cohort, 21 patients had one or more physician referrals for the evaluation of an MEN2B-related feature, an average of 5 years before the diagnosis of MEN2B.

It is critical for pediatricians to maintain a high index of suspicion when evaluating patients with any of the clinical manifestations associated with MEN2B. In a child, the presence of oral and ocular neuromas and/or a tall and lanky appearance may warrant further investigation. Some authors have recommended referral to genetic counseling for an individual with MTC or any of the following features:

    • Benign oral and submucosal neuromas.
    • Elongated face and large lips.
    • Ganglioneuromatosis.
    • Inability to cry tears (biologic mechanism unknown).

Prevalence

The prevalence of all MEN2 worldwide is 1 in 35,000.  MEN2A accounts for 95% of all cases.  The epidemiology of MEN2B is unknown and is estimated to be between 1 in 600,000 to 1 in 4 million. 

Genes Involved

Most people with MEN2B do not have any family history of the condition. They have a de novo (new) mutation in the RET gene. 

MEN type 4 (MEN4)

Multiple endocrine neoplasia type 4 (MEN4) is a novel, rare syndrome with clinical features that overlap with the other MEN syndromes. The most common phenotype of the 19 established cases of MEN4 that have been described to date is primary hyperparathyroidism (PHPT), followed by pituitary adenomas. MEN4 is caused by germline pathogenic variants in the tumor suppressor gene CDKN1B (12p13.1). This syndrome was discovered initially in rats (MENX) and later in humans (MEN4). The syndrome has the phenotype of being multiple endocrine neoplasia type 1 (MEN1)-like. The incidence of CDKN1B variants in patients with a MEN1-related phenotype is difficult to estimate, but it is likely to be in the range of 1.5% to 3.7%. Pathogenic variants leading to the MEN4 phenotype are transmitted in an autosomal dominant fashion.

PHPT due to parathyroid neoplasia affects approximately 80% of the reported cases of MEN4. PHPT occurs at a later age in MEN4 than in MEN1 (mean age ~56 y vs. ~25 y, respectively), with a female predominance. There have been no reports of PHPT recurrence after surgical resection, which might indicate that PHPT in MEN4 represents an overall milder disease spectrum than in MEN1. Pituitary involvement in MEN4 is the second most common manifestation of the disease, affecting approximately 37% of the reported cases. Pituitary adenomas in MEN4 vary and include nonfunctional, somatotropinoma, prolactinoma, or corticotropinoma types. The age at diagnosis for these lesions also varies widely, from 30 years to 79 years. The youngest patient reported to have MEN4 presented at age 30 years with acromegaly. Pancreatic neuroendocrine tumors (NETs) have been rare, with only a few cases reported. These include duodenopancreatic or gastrointestinal NETs that could be nonfunctioning or hormonally active and may secrete several substances, including gastrin, insulin, adrenocorticotropic hormone, or vasoactive intestinal polypeptide. Although adrenal neoplasia is a frequent finding in MEN1, only one case of nonfunctional bilateral adrenal nodules has been reported in MEN4. Skin manifestations that are commonly reported in MEN1, such as lipomas, angiofibromas, and collagenomas, have not been reported in MEN4. There is no known genotype-phenotype correlation.

Prevalence

Ultra rare

Genes Involved

CDKN1B

Pheochromocytoma (PHEO) and Paraganglioma (PGL): Hereditary Factors

It’s necessary to have this separate section within MEN2 devoted to PHEO and PGL given the strong connection between these NET types and MEN2a/2b and MTC/FMTC.   Actually, PHEO/PGL appears to be even more genetically complex than MEN syndromes and other genetic disorders can be related. 

A pheochromocytoma is a NET of the adrenal glands. Adrenal glands have 2 main parts that function separately: the outer adrenal cortex and the inner adrenal medulla. Each part produces a different set of hormones. A pheochromocytoma begins in the chromaffin cells of the adrenal medulla. The cells release hormones called catecholamines during times of stress. Most people develop a pheochromocytoma in 1 adrenal gland, but some can develop in both.  They usually grow slowly but can metastasize.

A paraganglioma is a NET that develops from the same type of cells that pheochromocytomas do (see above). However, paragangliomas form outside the adrenal glands. The majority of paragangliomas form in the abdomen. They can also form in other parts of the body, including near the carotid artery, along nerve pathways in the head and neck, and in the chest, heart, and abdomen. Paragangliomas are less common than pheochromocytomas. Paragangliomas are typically slow growing but depending on the tumor’s location in the body and certain genetic mutations, about 20% to 40% of paragangliomas can metastasize, or spread. 

Inherited syndromes and gene changes. Up to 40% of pheochromocytomas and paragangliomas are linked to hereditary syndromes. Changes to certain genes have also been associated with tumours when they are not connected to known hereditary syndromes. Syndromes and gene changes that raise the risk of developing a pheochromocytoma or paraganglioma include:

    • Multiple endocrine neoplasia type 2 (MEN2). Approximately 50% of people with MEN2 develop a pheochromocytoma.  See the sections above for info on MEN2.

    • Von Hippel-Lindau syndrome (VHL). Approximately 10% to 20% of people with VHL will develop pheochromocytoma. They often occur in both adrenal glands.

    • Neurofibromatosis type 1 (NF1). Approximately 1% to 13% of people with NF1 are diagnosed with a pheochromocytoma or paraganglioma.

    • Succinate dehydrogenase (SDHx) syndromes. Germline, or inherited, mutations in the SDH family of genes have also been associated with an increased risk of pheochromocytoma and paraganglioma. The increased risk can range from very low up to 45%, depending on the specific mutation.

      • The Carney-Stratakis syndrome.  Related to SDHx syndromes. Sometimes known as Carney dyad. Linked with paragangliomas and gastrointestinal stromal tumour (GIST) – the latter is classified as a sarcoma, not a NET.  Carney triad is a usually sporadic association of pulmonary chondroma, gastrointestinal stromal tumours, and paraganglioma. The majority of patients have two of these tumours, the gastric and pulmonary tumours being the most common combination. Carney Stratakis syndrome is an association of familial paraganglioma and gastric stromal sarcoma and it is considered to be a distinct condition from Carney triad as it is dominantly inherited and not associated with pulmonary chondroma.

    • Other mutations. There are many other, less common genetic mutations that may increase the risk of pheochromocytoma or paraganglioma.

Misc and less common hereditary/familial/genetic disorders related to NETs

  • Neurofibromatosis type 1 (NF1).  See PHEO/PGL section above.  Also sometimes found in pancreatic NETs.
  • Carney-Stratakis syndrome (CSS).  See PHEO/PGL section above. 
  • Von Hippel-Lindau Disease (VHL). An autosomal dominant disease with a predisposition to multiple neoplasms. Germline pathogenic variants in the VHL gene predispose individuals to specific types of both benign and malignant tumors and cysts in many organ systems. These include central nervous system hemangioblastomas; retinal hemangioblastomas; clear cell renal cell carcinomas and renal cysts; pheochromocytomas (see Pheo section above), cysts, cystadenomas, and neuroendocrine tumors of the pancreas; endolymphatic sac tumors; and cystadenomas of the epididymis (males) and of the broad ligament (females).
  • Tuberous sclerosis.  This is listed in various texts but finding precise information on the connection with NENs is difficult. It is a rare genetic multisystem disorder that is typically apparent shortly after birth. The disorder can cause a wide range of potential signs and symptoms and is associated with the formation of benign (non-cancerous) tumors in various organ systems of the body. The skin, brain, eyes, heart, kidneys and lungs are frequently affected. These tumors are often referred to as hamartomas. Hamartoma is a general term for a tumor or tumor-like growth that is made up of cells normally found in the area of the body where the hamartoma forms. Hamartomas are not malignant; they do not typically metastasize and spread to other areas of the body. However, these abnormal growths can grow larger and can damage the affected organ system.  I can find references linking it to pancreatic NETs, particularly in Gastrinomas, MEN1 (facial angiofibromas) and Insulinomas.

The familial Small Intestine NET Clinical Trial

I wanted to include this ongoing clinical trial conducted by the National Institute of Health in USA.  The first results have actually been around since 2015 and involved families where there are more than 2 instances of small intestine NETs found in blood relatives.  You can read more in this article. 

Click – NIH study finds genetic link for rare intestinal cancer | National Institutes of Health (NIH)   

The output from the study suggests there might be a genetic link with small intestinal Neuroendocrine Tumour (SI NET) (one of the most common types of NET). SI NETs are rarely associated with familial syndromes; however, detailed family history remains important as a small number may be associated with a mutation in inositol polyphosphate multikinase. It is likely that other cases are associated with genetic mutations which have not as yet been characterised. Given that only a very small proportion can be genetically explained, there is no justification for testing all patients with SI NETs. 

It looks like they want to keep testing for better data and those in the US with more than 2 instances of small intestinal NETs in blood-related family members and are interested in joining, should make contact as per the details in the NIH article above.  The inclusion and exclusion criteria can be found in the clinical trials document below:

Click – Natural History of Familial Carcinoid Tumor – Full-Text View – ClinicalTrials.gov (it’s an old document, apologies for use of the ancient term carcinoid)

The study picked up potential genetic linkages with Lung NET and I understand that Lung NETs with a 2nd blood relative with a proven diagnosis of midgut NET through a pathology report, may also enter this study (you would need to confirm that with NIH).

How will I know if I am affected? 

Some people do worry about this, often because of what they find on the internet including inside patient forums.  I suspect many people already know about genetic issues via family connections. But there are tumour dispositions that might be similar to known genetic presentations with NETs. For example, I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise suspicion for (say) the MEN1 syndrome and be investigated. Many people say how do I know, how do I check, and this is obviously a delicate subject.  Of course, your first port of call should be your NET specialist if you suspect or know of any connection.  This is in fact one of the suggested 10 questions I list in my questions article (see more here). However, as I hinted above, there are known connections that increase suspicions, and many people will have already been told of their risk from parents and siblings.  

But before you all run off and get tested, you need to understand two things, firstly you need professional testing and not the sort of thing you find cheap online. Secondly, there are known linkages between genetic issues with NETs so always talk to your doctors first to avoid nugatory effort and expense.  Thus, why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.”  

When reading, you’ll find it’s actually much more than that! Check it out here:

Crossref DOI link: https://doi.org/10.1007/s11154-017-9430-3

Disclaimer

I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.  Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional as they are not members of the private group or followers of my sites in any official capacity.  Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.

General Clinical Trials Disclaimer

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact.  If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net

The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan. 

 
 

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