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.
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
- Juvenile polyposis syndrome (JPS)
- Peutz-Jeghers syndrome (PJS)
- Birt-Hogg-Dubé syndrome (BHD)
- Neurofibromatosis type 1 (NF1)
- Gorlin syndrome
- AKT1-associated Proteus syndrome
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 |
|
| Thyroid gland |
|
| Endometrial |
|
| Gastrointestinal neoplasia |
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| Renal cell carcinoma |
|
| Others |
|
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 of PTEN 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
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
- Risk-reducing thyroidectomy NOT recommended
Thyroid ultrasound
- From 12 years of age:
- No nodules: every 3-5 years
- Clinically inactive nodules: every 2-3 years
- Clinically active nodules: Follow ATA guidelines
- Benign nodules: Continue surveillance every 1-2 years
- Annual TSH may be added from 18 years of age
Kidneys
- Sonography every 2 years from age 35-40 may be considered
- MRI of the kidneys may be considered
Colectomy
- Risk-reducing colectomy NOT recommended
Colonoscopy
- Baseline at 35-40 years
- High polyp burden (>5 tubular adenomas), polyps ≥1cm in diameter, high grade dysplasia: Interval 1-3 years
- No routine gastroscopy
Dermatological examination
- Annual from 18 years of age
Hysterectomy
- risk-reducing hysterectomy NOT routinely recommended
- Hysterectomy may be considered for uterine leiomyoma, endometrial hyperplasia with atypia
Endometrium
- Patient education from 30-35 years: abnormal vaginal bleeding, postmenopausal bleeding requires investigation
Breast self-examination
- From 18 years of age
Breast MRI
- Yearly from age 25
Mammography
- Additional from age 40 to 75-80
Risk-reducing mastectomy
- May be considered, only from age 25
