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. PHTS is characterized by the clinical symptoms of macrocephaly, gastrointestinal polyposis, lipomas, vascular malformations, and mental retardation / autism spectrum disorder. 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.

Key Data

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Synonym
Gene PTEN
Gene product PTEN (phosphatase and tensin homolog)
Function Tumor suppressor: negative regulation of the PI3K/AKT/mTOR signaling pathway
Heredity 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.
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Diagnosis

Clinical Diagnosis: Cowden Syndrome in Adults

The National Comprehensive Cancer Network (NCCN) lists 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 detection of a heterozygous germline mutation in the PTEN gene through sequence analysis or deletion/duplication analysis. The use of panel examinations consisting of multiple genes as well as exome or genome sequencing may be helpful.

Differential Diagnoses

Clinical Presentation

Cowden Syndrome (CS)

Cowden syndrome is characterized by mucocutaneous manifestations and a predisposition to benign and malignant tumors of the thyroid, breast, and endometrium. 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)

Breasts
  • The risk of benign breast diseases is 67%.
  • The lifetime risk of mammary carcinomas is 85%, with a penetrance of 50% at the age of 50.
Thyroid
  • Benign diseases (multinodular goiter, adenomatous nodules, or follicular adenomas) are present in 75% of patients.
  • The lifetime risk of epithelial thyroid carcinomas is approximately 3% and the average age at the time of diagnosis 37, with the earliest occurrence documented at 7 years of age.
Endometrium
  • Uterine myomas are common.
  • The lifetime risk of endometrial carcinomas is 28%.
Gastrointestinal neoplasia
  • Endoscopic polyps have been found in over 90% of patients. The histology of the polyps is widely varied (ganglioneuromatous, harmartomatous, juvenile, adenomatous).
  • The lifetime risk of a colorectal carcinoma is 9%.
Renal cell carcinomas
  • The lifetime risk of renal cell carcinomas is 35%.
  • Most of them are papillary renal cell carcinomas.
Other
  • The lifetime risk of a cutaneous melanomas is 5%.
  • Brain tumors and vascular malformations have been described as part of CS.
  • A tumor associated with Lhermitte-Duclos disease (LDD, cerebral dysplastic gangliocytoma) may 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.

Therapeutic Considerations

The mucocutaneous manifestations with 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.

Surveillance Recommendations

Surveillance Recommendations

Cowden Syndrome

Children and Adolescents < 18 Years of Age:

  • 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

Additionally for Women Age 30 and Older:

  • Monthly breast self-examination

  • Annual breast cancer screening, MRI, or at least a mammogram

  • Annual transvaginal 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.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with PTEN hamartoma tumor syndrome that we can recommend to you for more information.

Support Groups