What is PTEN hamartoma tumor syndrome?

PTEN hamartoma tumor syndrome (PHTS) includes multiple diseases caused by mutations – or genetic changes – in the PTEN gene, namely Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), with PTEN-associated Proteus syndrome (PS) and Proteus-like syndrome usually included as well. Clinically, PHTS is characterized by a large head circumference (macrocephaly), numerous polyps in the gastrointestinal tract, benign fatty tissue tumors, vascular malformations, and mental retardation / autism-related disorders. In addition, there is an increased risk with regard to numerous other diseases, such as cancers of the breast, endometrial, colon, kidney, skin, and thyroid.

How is PTEN hamartoma tumor syndrome diagnosed?

There are individual diagnostic criteria for the various diseases associated with PHTS along with findings indicative of the syndrome.

Clinical Diagnosis: Cowden Syndrome (Adults)

CS-specific Criteria:

  • Lhermitte-Duclos tumors (LDD, cerebellar dysplastic gangliocytoma), a rare cerebellar tumor

  • Lesions of the skin and mucous membranes

    • Trichilemmomas (benign tumors of hair root sheaths) in the face
    • Keratosis (keratinization disorder) of the hands or feet
    • Papillomatosis (benign lesions of the uppermost skin and mucosal layers)
    • Lesions in the mucous membranes

Major Criteria

  • Breast cancer

  • Thyroid carcinoma (non-medullary, mainly follicular)

  • Macrocephaly (large head circumference, ≥ 97th percentile)

  • Endometrial cancer

Minor Criteria

  • Other thyroid lesions (e.g. adenomas, nodules)

  • Mental retardation (IQ ≤ 75)

  • Polyps in the gastrointestinal tract

  • Changes in mammary gland tissue

  • Lipomas (benign fatty tissue tumors)

  • Fibromas (benign connective tissue tumors)

  • Urogenital tumors (especially renal cell carcinoma)

  • Urogenital malformations

  • Myomas (benign tumors) of the uterus

Making the Diagnosis

CS can be clinically diagnosed as soon as one of the following criteria has been met:

  • A CS-specific lesion of the skin or mucous membranes combined with one of the following findings

    • ≥ 6 papules (skin nodules) in the face, of which ≥ 3 are trichilemmomas
    • Papules in the face and papillomatosis of the oral mucous membrane
    • Papillomatosis of the oral mucous membrane and keratosis of the hands or feet
    • ≥ 6 instances of keratosis of the hands or feet
  • ≥ 2 major criteria

  • 1 major criterion and ≥ 3 minor criteria

  • ≥ 4 minor criteria

If there is CS in the family, the clinical diagnosis can be made as soon as one of the following criteria has been met:

  • 1 CS-specific criterion

  • ≥ 1 major criterion

  • ≥ 2 minor criteria

  • A positive history of Bannayan-Riley-Ruvalcaba syndrome

Clinical Diagnosis: Cowden Syndrome (Children)

Macrocephaly and at least one of the following findings:

  • Autism or developmental delays

  • Skin manifestations such as lipomas, trichilemmomas, papillomas of the oral mucous membrane, or a pigmentation disorder of the penis

  • Vascular malformations

  • Polyps in the gastrointestinal tract

Clinical Diagnosis: Bannayan-Riley-Ruvalcaba Syndrome

There are no standard diagnostic criteria to date. The existence of BRRS is suspected with presentation of the following:

  • Macrocephaly

  • Numerous polyps in the gastrointestinal tract

  • Lipomas

  • Pigmentation disorder on the penis

Clinical Diagnosis: PTEN-associated Proteus Syndrome

The existence of PS is suspected with presentation of the following:

  • Asymmetrical, excessive growth

  • Thickening of the connective tissue along with deep grooves (cerebriform connective tissue nevi) or skin thickening with a brownish color (epidermal nevi)

  • Abnormal increase in fatty tissue, lipomas

  • Vascular malformations

Genetic Diagnostics

The diagnosis of “PTEN hamartoma tumor syndrome” is confirmed by detection of a mutation – or genetic change – in the PTEN gene.

What is the risk of cancer?

Cowden Syndrome (CS)

Patients with Cowden syndrome have an increased risk of benign and malignant tumors of the thyroid, breast, and endometrium. Due to the frequent occurrence of polyps in the gastrointestinal tract, there is also an increased risk of colon cancer. Kidney cancer can occur as part of CS as well.

Risk of Tumors

  • Breast

    • The risk of benign breast diseases is 67%.
    • The lifetime risk of breast cancer is around 85%. 50% of CS patients have developed breast cancer by the age of 50.
  • Thyroid

    • 75% of patients have benign diseases (nodules, adenomas).
    • The lifetime risk of thyroid cancer is approximately 35% and the average age at diagnosis is 37, with the earliest occurrence documented at 7 years of age.
  • Endometrium

    • Myomas (benign tumors) are common.
    • The lifetime risk of endometrial cancer is 28%.
  • Tumors in the gastrointestinal tract

    • Polyps have been found in over 90% of patients during a gastroscopy or colonoscopy.
    • The lifetime risk of colon cancer is approximately 9%.
  • Kidney cancer

    • The lifetime risk of kidney cancer is 35%.
  • Other

    • The lifetime risk of a skin cancer is over 5%.
    • Brain tumors and vascular malformations have been described as part of CS.

In addition to the increased risk of tumors, Cowden syndrome is also characterized by anomalies of the skin and mucous membranes. Nearly all patients exhibit these anomalies (trichilemmomas, papillomas, cornification disorders) around the age of 30.

What is also striking in patients with CS is the large head with a head circumference above the 97th percentile (macrocephaly) and a long, narrow head shape (dolicocephaly).

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

The risk of malignant tumors is comparable to that of Cowden syndrome. In addition, BRRS is also characterized by the following clinical signs:

  • Macrocephaly

  • Numerous polyps in the gastrointestinal tract in 45% of patients, these do not lead to an increased risk of colon cancer

  • Lipomas

  • Pigmentation disorder of the penis

  • High birth weight

  • Developmental delays and mental retardation (in 50% of patients)

  • Weakness of muscles near the trunk (in 60% of patients)

  • Over-articulated joints, a funnel chest, and a spinal deformity (in 50% of patients)

PTEN-associated Proteus Syndrome

PS is associated with various tumors. In addition, it is also characterized by non-uniform, excessive growth of various tissues, with the skeleton, skin, fat, and central nervous system most commonly affected. There are generally no anomalies at birth, as the excessive growth usually does not begin until early childhood. Other typical clinical signs are diseases of the lungs, an increased risk of venous thrombosis, and lung embolisms.

What causes PTEN hamartoma tumor syndrome?

PTEN hamartoma tumor syndrome is caused by mutations – or genetic changes – in the PTEN gene. This gene encodes for the PTEN protein, which is involved in transmitting signals between the cells of our body. The activity of the PTEN protein specifically initiates cell death in certain cells, thereby controlling the proliferation of cells in our body. For this reason, the PTEN protein is classified as a tumor suppressor. Now if the PTEN gene is altered, the PTEN protein will no longer be able to function properly, resulting in uncontrolled cell proliferation and thus the development of tumors and other diseases.

PHTS can be passed on by parents to their children. In these cases, it is inherited as an autosomal dominant disease. It is also possible for the genetic change in the PTEN gene to occur as a spontaneous or new mutation, called a de novo mutation.

Is there a treatment?

The treatment of benign and malignant tumors associated with PHTS is no different from the treatment of similar, sporadically occurring tumors.

With Cowden syndrome, the manifestations in the skin and mucous membranes are rarely life-threatening. Therefore, the following treatment is recommended:

  • For asymptomatic manifestations, regular observation is sufficient.

  • If a malignant tumor is suspected, it should be removed.

  • Symptomatic manifestations can be treated using medications acting locally, surgery, or laser therapy.

Surveillance Recommendations for the Early Detection of Cancer

Surveillance Recommendations

Cowden Syndrome

  • Children and adolescents < 18 years of age

    • Annual clinical examination following diagnosis
    • Annual ultrasound of the thyroid from age 7 (whereby the examination interval can be extended to every 2 years during childhood and adolescence if the findings are normal)
    • Annual examination of the skin once the diagnosis is made
  • Adults

    • Annual ultrasound of the thyroid
    • Annual examination of the skin
    • Colonoscopy from the age of 35, with the frequency depending on the number and tissue structure of the polyps found
    • CT or MRI of the kidneys every 2 years from the age of 40
  • Additionally, for women 30 years of age and older

    • Monthly breast self-examination
    • Annual breast cancer screening, MRI, or at least a mammogram
    • Annual transvaginal ultrasound examination or biopsy of the endometrium

Bannayan-Riley-Ruvalcaba Syndrome

There are no standard surveillance recommendations for BRRS to date, which is why following the same treatment regimen as that of Cowden syndrome is advised. Moreover, special care should be taken to check for complications that may arise from polyps in the gastrointestinal tract (e.g. bleeding, intestinal obstruction).

Proteus Syndrome / Proteus-like Syndrome

There are no standard surveillance recommendations for PS to date, which is why following the same treatment regimen as that of Cowden syndrome is advised.

Self-Care and Support

What should I pay special attention to?

You should consult a doctor as soon as you notice changes in the skin, thickened cervical lymph nodes, nodules in the breast, vaginal bleeding, or intestinal bleeding. However, non-specific symptoms such as abdominal pain or muscle weakness should be noted and reported to a doctor as well. You should also see a doctor right away if you notice any other newly occurring abnormalities or symptoms, such pain in the legs.

Support Groups and Additional Information