PTEN hamartoma syndrome

PTEN hamartoma syndrome includes Cowden syndrome including Lhermitte-Duclos disease = adult-onset manifestation, Bannayan-Riley-Ruvalcaba syndrome [Ruvalcaba-Mhyre syndrome, Riley-Smith syndrome] = childhood-onset manifestation, and SOLAMEN syndrome = type 2 segmental Cowden syndrome.


Characterized by macrocephaly, cutaneous and visceral hamartomas, and a predisposition to malignancy. Slow-flow (VM, LM, CM) and fast-flow (AVM) malformations are often present.

Genetic basis

The different clinical phenotypes are based on an interaction of germline mutations (= constitutional mutations) and somatic/postzygotic “second-hit” mutations of the tumor suppressor gene PTEN (phosphatase and tensin homolog) deleted on chromosome 10. While the autosomal-dominant hereditary “constitutional” PTEN mutations are present and detectable in all cells, including blood, “second hit” mutations are present as a mosaic only in hamartomas or tumors or vascular malformations. The second hit mutations affect the second allele of the PTEN gene and thus lead to its complete loss.

The PTEN gene encodes a protein and lipid phosphatase that is important for the regulation of cell cycle and apoptosis. PTEN is an antagonist of PIK3. Loss-of-function mutations lead to activation of the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR pathway.

Cowden syndrome is based on a constitutional mutation plus further random mutations of single somatic cells (somatic mutations), which – depending on the affected tissue – are the basis of hamartomas/tumors/malignancies.

SOLAMEN syndrome (segmental overgrowth, lipomatosis, arteriovenous malformation, epidermal nevus), syn.: type 2 segmental Cowden syndrome, represents a special form: In addition to a constitutional PTEN mutation, a “second hit” occurs early in embryonic development, which leads to the loss of the second PTEN allele in a cell and is “inherited” by its successor cells (type 2 mosaic). This results in a segmental occurrence.

Diagnostic criteria of COWDEN syndrome

(National Comprehensive Cancer Network [NCCN 2015])

Revised criteria: Pilarski et al. 2013.

Pathognomonic criteria

  • Mucocutaneous hamartomatous lesions (facial trichilemmoma, acral keratosis, papillomatosis of skin/mucosa)
  • Dysplastic gangliocytoma of the cerebellum in adults (Lhermitte-Duclos disease))

Main criteria

  • Macrocephaly
  • Pigmented spots on the penis including the glans
  • Breast carcinoma or non-medullary thyroid carcinoma or endometrial carcinoma

Secondary criteria

  • Thyroid changes (goiter, adenomas, Hashimoto's thyroiditis)
  • Intelligence impairment (IQ: ≤ 75).
  • Hamartomatous intestinal polyps (incl. ganglioneuromas, adenomas, hyperplastic polyps)
  • Colon cancer
  • Fibroadenomas of the breast, fibrocystic mastopathy
  • Lipomas/lipomatosis
  • Fibromas
  • Genitourinary tract tumors (especially renal cell carcinoma)
  • Melanomas
  • Cysts of the ovaries, less frequently of the vagina and vulva
  • Uterine fibroids
  • Genitourinary tract malformations (horseshoe kidneys, bicornate uterus)
  • Vascular malformations (capillary, venous, arteriovenous, lymphatic)
  • Glycogen acanthosis of the esophagus
  • Autism spectrum disorder

The manifestations are strongly age-dependent. There is a lifetime risk of 25–50% for breast carcinoma, 10–20% for colorectal carcinoma, about 10% for thyroid carcinoma, and 5–10% for endometrial carcinoma. Renal cell carcinoma and malignant melanoma occur less frequently. Dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease) cause hydrocephalus and neurological disorders.

The accompanying vascular malformations do not always occur but, in addition to the increased likelihood of tumor occurrence, are often determinant of the disease course or symptomatology. Relatively characteristic are the often progressive, circumscribed soft tissue changes known as PHOST (PTEN Hamartoma Of Soft Tissue), which histologically present as mixed vascular and soft tissue malformations (capillary, venous and lymphatic malformations) embedded in atypically increased hyperplastic adipose tissue. Concomitant arteriovenous fast-flow malformations are characterized by more spherical, intranidal, or venous “flow-related” aneurysms and frequently recur after treatment.


  • Lifelong cancer screening (intensified early detection program).
  • If necessary, therapy of vascular malformations, which tend to recur, however, especially in AVM
  • Resection of PHOST after preoperative interventional treatment.
  • Consider mTOR inhibition as a therapeutic option.