Cowden syndrome Q87.86

Autosomal-dominantly inherited genodermatosis (PTEN-Hamartoma-Tumor-Syndrome/ PTEN= phosphatase and tensin homologue) with pathognomic mucocutaneous changes such as:

• facial tricholemmomas
• oral papillomatosis
• acral keratoses
• Hamartous tumors of the breast and thyroid gland
• polyps in the gastrointestinal tract
• Occasionally, café-au-lait spots are also detected (Murata J et al. 1999)
• Occasionally, linear verrucous nevi (Cowden nevus) are also detected (Cavaillé M et al. 2023)

The main diagnostic criteria include thyroid carcinoma, breast and endometrial carcinoma, dysplastic gangliocytoma of the cerebellum and macrocephaly(Lhermitte-Duclos syndrome). The extent to which associations with Lhermitte-Duclos syndrome are merely a variant of Cowden syndrome or an independent syndrome remains open ( Suzuki H et al. 2017; Murata J et al. 1999).

Mutations of the PTEN1 tumor suppressor gene (phosphatase and tensin homolog gene) mapped to gene locus 10q23.3, with consecutive suppression of protein tyrosine phosphatase (PTEN), a protein that physiologically supports the onset of cell death. Suppression of PTEN protein thus stimulates cell proliferation and hamartoid growth.

Related syndromes in which PTEN germline mutations have also been found are Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome.

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.

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).

1. Bruce H et al. (2009) Cutaneous manifestations of internal malignancy. Cancer J Clin 59: 73-98

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
5. Fritsch P et al (1981) The multiple hamartoma syndrome (Cowden syndrome). Dermatologist 32: 285-291
6. Happle R et al. (2002) Radiation-induced cutaneous hamartoma in a patient with Cowden syndrome. Clinical evidence for heterozygosity. Dermatology 53: 47-49
7. Lloyd KM, Dennis M (1963) Cowden's disease: A possible new symptom complex with multiple systemic involvement. Ann Intern Med 58: l36-142

8. Murata J et al. (1999) Dysplastic gangliocytoma (Lhermitte-Duclos disease) associated with Cowden disease: report of a case and review of the literature for the genetic relationship between the two diseases. J Neurooncol 41:129-136.

9. Plana-Pla A det al. (2023) Verrucous epidermal nevus as a manifestation of a type 2 mosaic PTEN mutation in Cowden syndrome. Pediatr Dermatol 40:179-181.

10. Schaller J et al. (2003) Identification of human papillomavirus DNA in cutaneous lesions of Cowden syndrome. Dermatology 207: 134-140

11. Suzuki H et al. (2017) A Case of Cowden Syndrome Associated with Lhermitte-Duclos Disease. Brain Nerve 69:1442-1446
12. 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