The endocrine system is the bodily system that regulates our metabolism, growth and development, sexual function, reproduction, sleep, mood, and more. Glands that produce hormones and regulate these functions include:

  • Pineal gland

  • Pituitary gland

  • Thyroid

  • Thymus

  • Adrenal glands

  • Pancreas

  • Reproductive glands (ovaries and testes)

 Let’s focus on one endocrine gland – the thyroid – and the hereditary syndromes that can cause an individual to be at an increased risk for thyroid cancer. When thyroid cancer or benign thyroid tumors/conditions occur, it is important to document them in your family history and report them to your physician. This information can help determine whether genetic counseling may be appropriate and can help your genetics team determine if genetic testing may be right for you and your family. Accurate family history information also aids in interpreting your genetic test results correctly.

The following list includes red flags that increase the likelihood of a genetic predisposition to thyroid cancer:

  • Medullary thyroid cancer at any age, even with no other history of cancer

  • Thyroid cancer (non-medullary) AND one feature of Carney complex (see Table 3 here) in the same person

  • Thyroid cancer (non-medullary) AND two features of Cowden syndrome (see Table 4 here) in the same person

  • Papillary thyroid cancer (cribriform-morular variant)

When any one of these red flags is present in you and/or your family history, consider meeting with a genetic counselor.

A known family history of any of the following hereditary cancer syndromes also increases the risk to develop thyroid cancer:

Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN2 is caused by a mutation in the RET gene and is separated into three subtypes:

  1. MEN2A

    • Medullary thyroid cancer (~95% lifetime risk)

    • Pheochromocytoma (benign tumors of the medulla of the adrenal gland)

    • Parathyroid gland tumors that often result in hyperparathyroidism

    • This subtype constitutes approximately 70–80% of cases of MEN2

  2. MEN2B

    • 100% lifetime risk of medullary thyroid cancer; notably more aggressive than in MEN2A

    • Pheochromocytoma (50% lifetime risk)

    • 40% of individuals have ganglioneuromatosis, a condition characterized by widespread benign growths in the GI tract

    • This subtype accounts for approximately 5% of cases of MEN2

  3. Familial Medullary Thyroid Carcinoma (FMTC)

    • Hereditary medullary thyroid cancer is the only feature

    • This subtype constitutes approximately 10–20% of cases of MEN2

MEN2 and Thyroid Findings: 

  • Medullary thyroid cancer can develop during childhood or early adulthood and can spread early

  • Removal of the thyroid is recommended for virtually all individuals with MEN2

  • The recommended age for thyroid removal surgery is dependent on the specific mutation found in the individual/family and family history

  • In the most aggressive forms of MEN2, thyroid removal is recommended as soon as possible within the first year of life

  • Other types of screening may be recommended after surgery, and a consultation with an endocrinologist and genetics expert familiar with MEN2 is recommended.

People with MEN2 usually inherit the condition from a parent. However, about 5% of individuals with MEN2A and up to 50% of individuals with MEN2B are the first in the family to have the condition. Someone with MEN2 has a 50% chance to pass the condition to each of his/her children. MEN2 does not skip generations.

 

PTEN Hamartoma Tumor Syndrome (PHTS)

 

PHTS is the parent name for several syndromes caused by mutations in the PTEN gene. The specific syndrome diagnosed in each family with a PTEN mutation will depend on the clinical findings in that individual/family. One syndrome associated with PTEN mutations is Cowden syndrome.

 

Cowden syndrome (CS) is associated with:

  • An increased risk to develop cancer of the breast, endometrium (the inner lining of the uterus), thyroid, kidney, colon, and skin (melanoma)

  • Macrocephaly (a larger than average head size)

  • Increased risk for autism spectrum disorder and/or intellectual disability

  • Non-cancerous skin findings, including trichilemmomas, acral keratosis, papillomatous papules, and fibromas that generally appear when an individual is in their 20s or 30s

Cowden Syndrome and Thyroid Findings: 

  • The lifetime risk to develop thyroid cancer is about 3–35% (general population risk is 1–2%)

  • Screening for thyroid cancer can be performed in adults and children using ultrasound, as well as thorough manual examination of the thyroid by a clinician to detect any changes or unusual lumps

  • It was once thought that thyroid nodules and/or goiters were common in individuals with PHTS; however, these are also common findings in the general population, and more research is needed to find out if they are truly linked with PTEN mutation.

People with PHTS usually inherit the condition from a parent. However, up to 10–50% of individuals with PHTS are the first in the family to have the condition. Someone with PHTS has a 50% chance to pass the condition to each of his/her children. PHTS does not skip generations; however, the signs and symptoms can vary in individuals in the same family.

Familial Adenomatous Polyposis (FAP) 

Individuals with classic FAP develop hundreds to thousands of colorectal polyps and have a virtually 100% lifetime risk of colorectal cancer without preventive removal of the colon. Other cancers and benign findings can be seen with this condition, including:

 

 

 

 

 

  • Cancers of the colon, stomach, pancreas, and thyroid

  • Non-cancerous abdominal soft tissue tumors, called desmoid tumors, that tend to regrow in the area in which they develop

  • Benign pigmented lesions at the back of the eye (retina) called congenital hypertrophy of the retinal pigment epithelium (CHRPE)

  • Tumors of the skull and jaw bone

FAP and Thyroid Findings: 

  • The lifetime risk to develop thyroid cancer in individuals with FAP is about 1–12%

  • Screening for thyroid cancer in individuals with FAP generally begins in the late teens, with a thorough examination of the thyroid by a clinician to detect any changes or unusual lumps

  • A thyroid ultrasound may also be considered

People with FAP usually inherit the condition from a parent. However, up to 25% of individuals with FAP are the first in the family to have the condition. Someone with FAP has a 50% chance to pass the condition to each of his/her children. Familial adenomatous polyposis does not skip generations.

Carney Complex, Type I

 Carney complex is caused by mutations in the PRKAR1A gene. The findings associated with Carney complex include: 

  • Benign tumors and hormone-related problems

  • An increased risk of papillary and follicular thyroid cancers

  • Changes in skin coloring that result in dark brown areas on the skin

  • Noncancerous tumors, called myxomas, that can develop in the skin, breasts, internal organs, and in the heart (which can block the flow of blood)

  • Tumors in hormone-producing glands, such as the adrenal glands (located on top of each kidney), thyroid, testes, ovaries, and pituitary gland

  • Adrenal disease (PPNAD) that results in too much of the hormone cortisol, which can lead to the development of Cushing syndrome, which causes high blood pressure, abdominal obesity, a round red face, slowed growth in children, fragile skin, fatigue, and other health problems.

Carney Complex and Thyroid Findings:

  • Up to 75% of individuals with Carney complex have multiple thyroid nodules, most of which are thyroid follicular adenomas

  • Thyroid cancer (both papillary and follicular types) can occur, although exact lifetime risks have not been determined

  • Screening for thyroid nodules and cancer can be performed in individuals with Carney complex using ultrasound and a thorough examination of the thyroid by a clinician to detect any changes or unusual lumps

People with Carney complex usually inherit the condition from a parent. However, up to 20% of individuals are the first in the family to have the condition. Someone with Carney complex has a 50% chance to pass the condition to each of his/her children. Carney complex does not skip generations.

DICER 1

DICER1 tumor predisposition syndrome is caused by mutations in the DICER1 gene. The findings associated with DICER1 include:

  • A type of childhood lung cancer called pleuropulmonary blastoma (PPB)
  • Cysts in the lungs
  • An increased risk to develop thyroid tumors (multinodular goiter, adenomas, and/or thyroid cancer)
  • An increased risk to develop ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma) 
  • An increased risk to develop benign kidney tumors called cystic nephroma 
  • Other tumors of the central nervous system 

DICER1 and Thyroid Findings:

  • Up to 75% of women and 17% of men with DICER1 will develop thyroid goiter by age 40
  • Thyroid cancer (including papillary and follicular thyroid cancer) can occur 
  • Screening for thyroid tumors by thyroid ultrasound is recommended beginning at age eight. People who have had chemotherapy should begin thyroid ultrasound within three to five years after treatment. 

People with DICER1 tumor predisposition syndrome usually inherit the condition from a parent. However, up to 20% of individuals are the first in the family to have the condition. Someone with DICER1 tumor predisposition syndrome has a 50% chance to pass the condition to each of his/her children. DICER1 tumor predisposition syndrome does not skip generations.