Hereditary Thyroid Cancer: Part 2

In Part 1 of this series on hereditary thyroid cancer we discussed risk factors that increase the likelihood of an hereditary predisposition to thyroid cancer.  In this post we outline four hereditary cancer syndromes that increase the risk to develop thyroid cancer, and their features. 

 

Hereditary Cancer Syndromes that Involve the Thyroid

1. Multiple Endocrine Neoplasia Type 2 (MEN2)

RET gene (Source: GHR)

RET gene (Source: GHR)

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

  • MEN2A
    •  Medullary thyroid cancer (70-100% lifetime risk),
    • Pheochromocytoma (benign tumors of the medulla of the adrenal gland via Mayo Clinic
    • Parathyroid gland tumors, that often result in hyperparathyroidism.
    • The MEN2A subtype constitutes approximately 70%-80% of cases of MEN2
  • MEN2B
    • Medullary thyroid cancer, notably more aggressive than in MEN2A
    • Pheochromocytoma 
    • Benign growths of nerve tissue on the tongue, intestine and elsewhere called neuromas or ganglioneuromas
    • The MEN2B subtype accounts for approximately 5% of cases of MEN2
  • Familial Medullary Thyroid Carcinoma (FMTC)
    • Hereditary medullary thyroid cancer is the only feature
    • The FMTC 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 a RET mutation. 
  • 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, ~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.

 

2. 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.

PTEN Gene (Source: SyndromesPedia)

PTEN Gene (Source: SyndromesPedia)

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 in an individuals 20s or 30s.

Cowden Syndrome and Thyroid Findings:

  • The risk to develop thyroid cancer in individuals with Cowden Syndrome is ~3 - 35% over their lifetime (general population risk = 1 - 2%).
  • Screening for thyroid cancer can be performed in adults and children with Cowden Syndrome using ultrasound and a 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 alterations.

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 be variable individuals in the same family.

3. Familial Adenomatous Polyposis (FAP) and Attenuated Familial Adenomatous Polyposis (AFAP)

APC gene (Source: Genetics 4 Medics)

APC gene (Source: Genetics 4 Medics)

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. 

Individuals with Attenuated FAP (AFAP) develop 10-100 colon polyps and have ~70% lifetime risk to develop colorectal cancer without preventive removal of the colon. 

Other cancers and benign findings can be seen in both conditions.  These include:  

  • 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/AFAP and Thyroid Findings:

  • The risk to develop thyroid cancer in individuals with FAP/AFAP is ~1 - 12% over their lifetime (general population risk is 1 - 2%).
  • Screening for thyroid cancer in individuals with FAP/AFAP 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 or AFAP usually inherit the condition from a parent.   However, up to 25% of individuals with FAP or AFAP are the first in the family to have the condition.  Someone with FAP or AFAP has a 50% chance to pass the condition to each of his/her children.  Familial adenomatous polyposis does not skip generations.

 4. Carney complex, type I

Carney complex is caused by mutations in the PRKAR1A gene.

PRKAR1A gene (Source: nichd.nih.gov)

PRKAR1A gene (Source: nichd.nih.gov)

The findings associated with Carney complex include: 

  • a number of 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), the thyroid, testes, ovaries and the pituitary gland;
  • adrenal disease (PPNAD) that results too much of the hormone cortisol which can lead to the development of Cushing syndrome. This syndrome 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.