Cowden syndrome Q87.86

An autosomal dominant inherited genodermatosis (PTEN hamartoma tumor syndrome; PTEN = phosphatase and tensin homolog) with pathognomonic mucocutaneous changes such as:

• facial tricho-lemnomas
• oral papillomatosis
• acral keratoses 
• Hamartomatous tumors of the breast and thyroid
• polyps in the gastrointestinal tract
• Café-au-lait spotsare occasionally detected (Murata J et al. 1999)
• Linear verrucous nevi(Cowden nevus) are also occasionally observed (Cavaillé M et al. 2023)

The main diagnostic criteria include thyroid carcinomas, breast and endometrial carcinomas, dysplastic gangliocytoma of the cerebellum, and macrocephaly (Lhermitte-Duclos syndrome). The extent to which associations with Lhermitte-Duclos syndrome represent merely a variant of Cowden syndrome or constitute a distinct syndrome remains unclear at this time (Suzuki H et al. 2017; Murata J et al. 1999).

CS is the most commonly diagnosed syndrome within the PHTS group, despite its low incidence (1 in 200,000)—which is why it is considered rare—and the fact that, among other things, its exact incidence remains unknown. 

Cowden syndrome (CS) isoneof thePTEN hamartoma tumor syndromes (PHTS). These syndromes are characterized by mutations in the PTEN1 tumor suppressor gene (phosphatase and tensin homolog gene). This gene is mapped to the 10q23.3 locus, resulting in the suppression of protein tyrosine phosphatase (PTEN), a protein that physiologically promotes cell death. This autosomal dominant genetic predisposition arises from heterozygous germline mutations in the PTEN tumor suppressor gene and leads to dysregulation of the PI3K/AKT/mTOR signaling pathway, thereby promoting the excessive growth of numerous and heterogeneous tissue types.
Suppression of the PTEN protein thus stimulates cell proliferation and hamartomatous growth. In addition to CS, PTEN-hamartoma tumor syndrome encompasses various other clinical phenotypes, including:

• Bannayan-Riley-Ruvalcaba syndrome (BRRS)
• Proteus syndrome (PS) and
• Proteus-like syndrome.

The clinical spectrum of CS ranges from benign to malignant conditions affecting nearly every system of the human body, including the skin (Pîrlog LM et al. 2024).

Dermatologic leading symptoms: Papular, centrofacial and acral lesions. Periorificial and acral lentigines (café-au-lait spots), marked papillomatosis of the oral mucosa and intestinal tract. Tricholemmomas, trichoepitheliomas of the face. Frequent lipomas, hemangiomas and vitiligo.

Extracutaneous manifestations: bird face, microstomia, maxillary and mandibular hypoplasia, narrow nose, antimongoloid eyelid axis. Lingua plicata, tooth position anomalies. Multiple cysts in hyperplastic mammae, liver, thyroid and bones.

Gruber Syndrome

Marfan syndrome.

High correlation with malignant tumors, particularly with breast and thyroid carcinomas.

Linear Cowden's nevus, also known as linear PTEN nevus, is a form of epidermal nevus first described in 2007 that occurs in patients with Cowden's syndrome. It is considered a type 2 form of segmental mosaicism (Plana-Pla A det al. 2023).

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2. Canadas LMC et al. (2006) Multiple oral fibropapillomatosis as an initial manifestation of Cowden syndrome. Case report. Oral Medicine and Pathology 11: 319-324
3. Cavaillé M et al. (2023) Diagnosis of PTEN mosaicism: the relevance of additional tumor DNA sequencing. A case report and review of the literature. BMC Med Genomics 16:166.
4. Fistarol SK et al. (2002) Cowden disease or multiple hamartoma syndrome—cutaneous clue to internal malignancy. Eur J Dermatol 12: 411–421
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10. Plana-Pla A et al. (2023) Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome. Pediatr Dermatol 40:179–181.
11. Schaller J et al. (2003) Identification of human papillomavirus DNA in cutaneous lesions of Cowden syndrome. Dermatology 207: 134–140
12. Suzuki H et al. (2017) A Case of Cowden Syndrome Associated with Lhermitte-Duclos Disease. Brain Nerve 69:1442–1446
13. Vega A et al. (2003) A Novel Loss-of-Function Mutation (N48K) in the PTEN Gene in a Spanish Patient with Cowden Disease. J Invest Dermatol 121: 1356–1359