"PTEN Hamartoma Tumor Syndrome" – What Is It?

PTEN hamartoma tumor syndrome (PHTS) comprises several diseases based on pathogenic variants, i.e., genetic changes in the PTEN gene. Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are these diseases. In most cases, PTEN-associated Proteus syndrome (PS) and Proteus-like syndrome are also included. 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/disorders from the autistic spectrum. There is also an increased risk of numerous malignant diseases such as breast and endometrial cancer, bowel, kidney, skin, and thyroid cancer.

Overview of the Chapters on This Page:

  • PTEN Hamartoma Tumor Syndrome – What Is It? (This Section)
  • How Is "PTEN Hamartoma Tumor Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "PTEN Hamartoma Tumor Syndrome"
  • Is There Any Treatment Available?
  • Medical Measures for Early Detection
  • PTEN Hamartoma Tumor Syndrome – What You Can Do Yourself
  • Links and Further Information (e.g., From Support Groups)
  • PTEN Hamartoma Tumor Syndrome – What Is It? (This Section)
  • How Is "PTEN Hamartoma Tumor Syndrome" Diagnosed?
  • What Is the Risk of Cancer?
  • What Is Known About the Development of "PTEN Hamartoma Tumor Syndrome"?
  • Is There Any Form of Treatment Available?
  • Medical Measures for Early Detection
  • PTEN Hamartoma Tumor Syndrome – What You Can Do Yourself
  • Links (e.g., From Support Groups) and Further Information

How Is "PTEN Hamartoma Tumor Syndrome" Diagnosed?

There are individual diagnostic criteria or findings indicative of the syndrome for the various diseases within PHTS.

Clinical Diagnosis: Cowden Syndrome (Adults)

Criteria Specific to CS:

  • Lhermitte-Duclos tumors (LDD, cerebellar dysplastic gangliocytoma), a rare cerebellar tumor
  • Lesions on the skin and mucous membranes
    • Trichilemmomas (benign tumors of the hair root sheaths) on the face
    • Keratosis (cornification disorder) on the hands or feet
    • Papillomatosis (benign lesions of the uppermost layers of the skin and mucous membranes)
    • Lesions of the mucous membrane

Major Criteria

  • Breast cancer
  • Thyroid cancer (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 the 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

A clinical diagnosis of CS can be made as soon as one of the following criteria is met:

  • A CS-specific lesion of the skin or mucous membranes combined with one of the following findings ≥6
    • papules (skin nodules) on the face, of which ≥3 are trichilemmomasPapules
    • on the face and papillomatosis of the oral mucosaPapillomatosis
    • of the oral mucosa and keratosis on the hands or feet≥6
    • keratoses on the hands or feet
  • ≥2 major criteria
  • 1 major criterion and ≥3 minor criteria
  • ≥4 minor criteria

In the case of CS in the family, the clinical diagnosis can be made as soon as one of the following criteria is met:

  • 1 criterion specific to CS
  • ≥1 major criterion
  • ≥2 minor criteria
  • Positive history of Bannayan-Riley-Ruvalcaba syndrome

Clinical Diagnosis: Cowden Syndrome (Children)

Macrocephaly and at least one of the following findings:

  • Autism or developmental delay
  • Skin manifestations such as lipomas, trichilemmomas, papillomas of the oral mucosa, or pigmentation disorders on the penis
  • Vascular malformations
  • Polyps of the gastrointestinal tract

Clinical Diagnosis: Bannayan-Riley-Ruvalcaba Syndrome

There are currently no standardized diagnostic criteria. The presence of BRRS is suspected if the following findings are present:

  • Macrocephaly
  • Numerous polyps of the gastrointestinal tract
  • Lipomas
  • Pigmentation disorder on the penis

Clinical Diagnosis: PTEN-Associated Proteus Syndrome

The presence of PS is suspected in the following findings:

  • Uneven, excessive growth
  • Thickening of the connective tissue with deep furrows (cerebriform connective tissue nevi) or skin thickening with brownish coloration (epidermal nevi)
  • Conspicuous increase in fatty tissue, lipomas
  • Vascular malformations

Genetic Diagnostics

The “PTEN hamartoma tumor syndrome” diagnosis is confirmed when a pathogenic variant, i.e., genetic change, is detected 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 gland, breast, and endometrium. Due to the frequent occurrence of polyps in the gastrointestinal tract, there is also an increased risk of bowel cancer. Kidney cancer can also occur as part of CS.

Tumor Risk

  • Breast
    • The risk of benign breast disease is 67%.
    • The lifetime risk of breast cancer is 85%. By the age of 50, 50% of CS patients have developed breast cancer.
  • Thyroid gland
    • Benign diseases (nodules, adenomas) occur in around 75% of patients
    • The lifetime risk of thyroid cancer is around 35%, and the average age at diagnosis is 37 years, with the earliest documented occurrence being 7 years.
  • Endometrium
    • Myomas (benign tumors) are common.
    • The lifetime risk of endometrial cancer is 28%.
  • Tumors of the gastrointestinal tract
    • Polyps were found in over 90% of patients during a gastroscopy or colonoscopy.
    • The lifetime risk of bowel cancer is 9%.
  • Kidney cancer
    •  The lifetime risk of kidney cancer is 35%
  • Other
    • The lifetime risk of skin cancer is over 5%.
    • Brain tumors and vascular malformations have been described in the context of CS.

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

Patients with CS are also characterized by a large head with a head circumference above the 97th percentile (macrocephaly) and a long, narrow head shape (long skull).

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

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

  • Macrocephaly
  • Numerous polyps in the gastrointestinal tract in 45% of patients; these polyps do not cause an increased risk of colorectal cancer.
  • Lipomas
  • Pigmentation disorders on the penis
  • High birth weight
  • Developmental delay and mental retardation (in 50% of patients)
  • Muscle weakness of the muscles close to the trunk (in 60% of patients)
  • Excessively mobile joints, funnel chest, and deformation of the spine (in 50% of patients)

PTEN-Associated Proteus Syndrome

PS is associated with various tumors. It is also characterized by uneven, excessive growth of different tissues, most commonly the skeleton, skin, fat, and central nervous system. There are usually no abnormalities at birth, but excessive growth usually begins in infancy. Typical clinical signs also include lung diseases, an increased risk of venous thrombosis, and pulmonary embolism.

What Is Known About the Development of "PTEN Hamartoma Tumor Syndrome"?

PTEN hamartoma tumor syndrome is caused by pathogenic variants, i.e., genetic changes in the PTEN gene. This gene codes for the PTEN protein, which is involved in signal transmission between the cells of our body. The activity of the PTEN protein explicitly triggers cell death in specific cells, thereby controlling the proliferation of cells in our body. The PTEN protein is, therefore, one of the so-called tumor suppressors. Suppose the PTEN gene is present in an altered form. In that case, the PTEN protein can no longer function correctly as a tumor suppressor, resulting in uncontrolled cell proliferation and the development of tumors and other diseases.

PHTS can be passed on from parents to their children. The inheritance is autosomal dominant. A genetic change in the PTEN gene can also occur as a spontaneous or new pathogenic variant, known as a de novo mutation.

Is There Any Form of Treatment Available?

Treating benign and malignant tumors in PHTS does not differ from that of corresponding sporadically occurring tumors.

The skin and mucous membrane manifestations in Cowden syndrome are rarely life-threatening. The following therapy is therefore recommended:

  • Regular observation is sufficient for asymptomatic manifestations.
  • If a malignant tumor is suspected, it should be removed.
  • Symptomatic manifestations can be treated with local medication, surgery, or laser therapy.

Diagnosis of " PTEN Hamartoma Tumor Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Diagnosis of "PTEN Hamartoma Tumor Syndrome" What's Next?

If you have been diagnosed with this cancer predisposition syndrome, it is important to see a specialist. The following section explains whether cancer screening tests or other measures are needed and how they should be carried out. We also give you some valuable tips on what you can do yourself. If you have any questions, please do not hesitate to contact us or your doctor.

Medical Measures for Early Detection

Below are recommendations from the International PHTS Consensus Guidelines Working Group and AACR Guidelines 2024.

In general

  • Avoid smoking, obesity and alcohol
  • At the time of diagnosis: Full clinical examination and information about possible symptoms

Thyroid gland

  • Risk-reducing removal of the thyroid gland NOT recommended
  • Ultrasound from 12 years of age with regular checks every 1-5 years depending on the clinical findings or according to ATA-Guidelines
  • Annual TSH may be added from 18 years of age

Kidneys

  • Ultrasound every 2 years from age 35-40 may be considered
  • MRI of the kidneys may be considered

Gastrointestinal tract

  • Risk-reducing removal of colon sections NOT recommended
  • Colonoscopy:
    • Baseline at 35-40 years
    • with high polyp burden or significant polyps every 1-3 years
  • No routine gastroscopy

Dermatological examination

  • Annual from 18 years of age

Gynecology

  • Hysterectomy may be considered for uterine leiomyoma, endometrial hyperplasia with atypia
  • Patient education from 30-35 years: abnormal vaginal bleeding, postmenopausal bleeding requires investigation
  • Breast self-examination from 18 years of age
  • Clinical breast examination yearly from age 25
  • Breast MRI yearly from age 25
  • Additional mammography from age 40 to 75-80
  • Risk-reducing mastectomy may be considered, only from age 25

PTEN Hamartoma Tumor Syndrome – What You Can Do Yourself

You Should Pay Attention to This

You should consult a doctor as soon as changes in the skin, thickened cervical lymph nodes, breast lumps, vaginal bleeding, or intestinal bleeding occur. In addition, non-specific symptoms such as abdominal pain or muscle weakness should also be noticed and reported to a doctor. You should also consult a doctor if you experience any other new abnormalities or complaints, e.g., breathing difficulties or leg pain.

Further Information

Patients can also register for the CPS registry at any time or have this done by their doctors in charge.

Any further questions?

You can reach us by e-mail and telephone, or you can come to our consultation hours in person. For more information, please visit our contact page.