PTEN Hamartoma Tumor Syndrome – Definition

PTEN hamartoma tumor syndrome (PHTS, OMIM +601728) includes multiple diseases caused by mutations in the PTEN gene, namely Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), whereby PTEN-associated Proteus syndrome (PS) and Proteus-like syndrome are usually included as well. The clinical symptoms of macrocephaly, gastrointestinal polyposis, lipomas, vascular malformations, and intellectual disability/autism spectrum disorder characterize PHTS. In addition, there is a predisposition to numerous malignant diseases such as mammary and endometrial carcinoma, colorectal carcinoma, renal cell carcinoma, melanoma, and thyroid carcinoma.

Synonym:

Gene:

PTEN

Gene ­product:

PTEN (Phosphatase and Tensin homolog)

Function:

Tumor suppressor: negative regulation of the PI3K/AKT/mTOR signaling pathway

Erb­gang:

Autosomal dominant

Prevalence:

1:200,000 for Cowden Syndrome

Genotype-phenotype correlation:

Missense variants and mutations in the phosphatase region appear to include ≥ 5 organs and therefore have a more severe progression.
> 90% of families with overlapping CS/BRRS have a PTEN mutation.

Penetrance:

Nearly complete
Almost all patients with a PTEN mutation develop at least one manifestation by early adulthood.

Overview of the Chapters on This Page:

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

PTEN Hamartoma Tumor Syndrome – Diagnosis

Clinical Diagnosis: Cowden Syndrome in Adults

The National Comprehensive Cancer Network (NCCN) specifies the following diagnostic criteria:

Pathognomonic Criteria:

  • Tumors associated with Lhermitte-Duclos disease (LDD, cerebral dysplastic gangliocytoma)
  • Mucocutaneous lesions
    • Facial trichilemmomas (benign tumors of the hair root sheaths)
    • Acral keratosis
    • Papillomatous lesions
    • Mucosal lesions

Major Criteria

  • Mammary carcinoma
  • Epithelial thyroid carcinoma (non-medullary), mainly follicular
  • Macrocephaly (head circumference ≥ 97th percentile)
  • Endometrial carcinoma

Minor Criteria

  • Another thyroid lesion (e.g., adenoma, multinodular goiter)
  • Mental retardation (IQ ≤ 75)
  • Hamartomatous intestinal polyps
  • Fibrocystic mastopathy
  • Lipomas
  • Fibromas
  • Urogenital tumors (especially renal cell carcinoma)
  • Urogenital malformations
  • Uterine myomas

The clinical diagnosis of CS can be made as soon as one of the following criteria has been met:

  • Pathognomonic mucocutaneous lesion combined with one of the following criteria
    • ≥ 6 facial papules, of which ≥ 3 are trichilemmomas
    • Cutaneous facial papules and oral mucosal papillomatosis
    • Oral mucosal papillomatosis and acral keratosis
    • ≥ 6 instances of palmar-plantar keratosis
    • ≥ 2 major criteria
  • 1 major criterion and ≥ 3 minor criteria
  • ≥ 4 minor criteria

When there is a concomitant family history of CS, the clinical diagnosis can be made as soon as one of the following criteria has been met:

  • 1 pathognomonic criterion
  • ≥ 1 major criterion
  • ≥ 2 minor criteria
  • A positive history of Bannayan-Riley-Ruvalcaba syndrome

Clinical Diagnosis: Cowden Syndrome in Children

Macrocephalus and at least one of the following findings:

  • Autism or developmental delay
  • Dermatological manifestations such as lipomas, trichilemmomas, oral papillomas, or penile freckling
  • Vascular manifestations such as arteriovenous malformations or hemangiomas
  • Gastrointestinal polyps

Clinical Diagnosis: Bannayan-Riley-Ruvalcaba Syndrome

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

  • Macrocephaly
  • Hamartomatous intestinal polyposis
  • Lipomas
  • Pigmented maculae of the glans penis

Clinical Diagnosis: PTEN-Associated Proteus Syndrome

The existence of PS is suspected with the following findings:

  • Asymmetrical, excessive growth
  • Cerebriform connective tissue nevi (CCTN) or linear verrucous epidermal nevi (LVEN)
  • Abnormal increase in fatty tissue, lipomas
  • Arteriovenous malformations

Genetic Diagnostics

The diagnosis of “PTEN hamartoma tumor syndrome” is confirmed by the detection of a heterozygous germline mutation in the PTEN gene through sequence analysis or deletion/duplication analysis. Panel examinations consisting of multiple genes, as well as exome or genome sequencing, may be helpful.

Differential Diagnoses

Clinical Presentation

Cowden Syndrome (CS)

Mucocutaneous manifestations and a predisposition to benign and malignant tumors of the thyroid, breast, and endometrium characterize Cowden syndrome. Due to the frequently occurring hamartomatous and mixed intestinal polyps as part of CS, there is an increased risk of colorectal carcinomas. Renal cell carcinomas may occur as well. In addition, patients with CS generally suffer from macrocephaly and dolichocephaly.

In their third decade of life, nearly all patients exhibit mucocutaneous manifestations in the form of trichilemmomas, papillomatous papules, or cases of acral and plantar keratosis.

Overview of Tumor Risks with Cowden Syndrome (CS)

Breast
  • The risk of benign breast disease is 67%.
  • The lifetime risk of breast cancer is 85%, with a penetrance of 50% at the age of 50.
Thyroid gland
  • Benign diseases (multinodular goiter, adenomatous nodules, or follicular adenomas) occur in around 75% of patients.
  • The lifetime risk for epithelial thyroid carcinomas is around 35%, the average age at diagnosis is 37 years, the earliest occurrence is documented at 7 years.
Endometrial
  • Uterine fibroids are common.
  • The lifetime risk of endometrial cancer is 28%.
Gastrointestinal neoplasia
  • Polyps were found endoscopically in over 90% of patients. The histology of the polyps is very variable (ganglioneuromatous, hamartomatous, juvenile, adenomatous).
  • The lifetime risk of colorectal carcinoma is 9%.
Renal cell carcinoma
  • The lifetime risk of renal cell carcinoma is 35%.
  • Most of these are papillary renal cell carcinomas.
Others
  • The lifetime risk of cutaneous melanoma is over 5%.
  • Brain tumors and vascular malformations have been described in the context of CS.
  • A Lhermitte-Duclos tumor (LDD, cerebellar dysplastic gangliocytoma) can be pathognomonic.

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

The following are clinical signs of BRRS:

  • Macrocephaly
  • Intestinal polyposis (hamartomatous polyps in 45% of patients, whereby these polyps do not increase the risk of colorectal carcinomas at all)
  • Lipomas
  • Pigmented maculae of the glans penis
  • High birth weight
  • Developmental delays and mental retardation (in 50% of patients)
  • Myopathic processes in the proximal muscles (in 60% of patients)
  • Hyperextensive joints, pectus excavatum, and scoliosis (in 50% of patients)

The risk of malignant tumors is comparable to that of Cowden syndrome.

PTEN-Associated Proteus Syndrome

PS is characterized by the progressive segmental growth of various tissues. The skeleton, skin, fat, and central nervous system are most commonly affected. There are generally no anomalies at birth, as the excessive growth usually does not begin until early childhood.

In addition, PS is also associated with various tumors, pulmonary complications, an increased risk of deep vein thrombosis, and pulmonary embolisms.

Special Features of Treatment

The mucocutaneous manifestations of Cowden syndrome are rarely life-threatening. Therefore, the following treatment is recommended:

  • For asymptomatic manifestations, regular observation is sufficient.
  • If the tumor is suspected to be malignant, it should be excised.
  • Symptomatic manifestations can be treated using topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation.

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

Diagnosis ofPTEN Hamartoma Tumor Syndrome- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Diagnosis ofPTEN Hamartoma Tumor Syndrome- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Recommendations for Early Detection in Your Patients

PTEN

Children and Adolescents <18 Years:

  • Annual clinical examination following diagnosis
  • Annual thyroid ultrasound from 7 years of age (whereby the examination interval can be extended to every 2 years during childhood and adolescence, providing the findings are normal)
  • Annual dermatological examination following diagnosis

Adults:

  • Annual thyroid ultrasound
  • Annual dermatological examination
  • Colonoscopy as of age 35, with the frequency depending on the number and histology of the polyps found
  • Renal CT or MRI every 2 years as of age 40

For Women Aged 30 and Over:

  • Monthly breast self-examination
  • Annual breast cancer screening, MRI, or at least a mammogram
  • Transvaginal yearly ultrasound or endometrial biopsy

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. In addition, a close watch should be kept for the complications that can arise from gastrointestinal hamartomatous polyposis.

Proteus Syndrome / Proteus-like Syndrome

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

PTEN Hamartoma Tumor Syndrome – Further Information

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