Cowden syndrome (CS), or multiple hamartoma syndrome, is a rare genodermatosis of autosomal dominant inheritance with variable penetrance and incomplete expressivity.[4
] Mutations in the PTEN gene (phosphatase and tensin homologue deleted from chromosome 10) are responsible of CS and other diseases hamartomatous tumor syndromes (PHTS).[1
] Cowden syndrome is a disease of the young adult (second and third decade)[1
] but it can be observed at a variable age between 4 and 75 years[5
] with an average of 39 years at the time of diagnosis.[8
] CS involves both sexes with a slight female predominance (sex-ratio M/F=0,6).[4
The CS is characterised essentially by its pathognomic mucocutaneous signs  that are sometimes isolated or accompanied by the visceral manifestations.
Summary of various manifestations of Cowden syndrome discovered in our patients.
The cutaneous signs, observed in 100 per cent of cases, are usually the first presenting lesions of the disease.[6
] The typical cutaneous lesions consist of small, multiple and coloured facial papules of 1 to 4 mm in diameter with smooth or keratotic surfaces. Theses lesions are mainly found on eyelids, forehead, nose, clustered around the mouth and sometimes on ear pavilions.[4
] The second most common lesions are papillomas that have the same topography but are larger in size.[10
] Acral keratoses are also characteristic and consist of beaded keratotic papules with often rough surface of 1 to 4 mm in diameter existing on dorsal site of forearms, hands and feet.[5
] Translucent keratotic papules are another prominent finding. They consist of small indurated papules sometimes centred by a depression found over palms and soles.[4
] Non typical cutaneous lesions can be observed such as benign tumours: angiomas (Case 1), dermal fibromas, lipomas, neurinomas, neurofibromas, nævocytic nævi, xanthomas and xanthelasmas,[6
] or malignant tumours: melanomas, basal cell carcinoma, squamous cell carcinomas and carcinomas of Merkel[13
] and as dyschromic lesions: "café au lait spots" and vitiligo.[9
The histological features of cutaneous lesions are characteristic showing multiple trichilemmomas, associating epithelial hyperplasia, papillomatosis, parakeratosis and acanthosis[4
] but histological features of trichilemmomas were not found in all cutaneous lesions.[16
] The majority of trichilemmomas contain HPV DNA.[16
The characteristic mucous manifestations consist essentially of papules which are pink or white smooth lesions of 1 to 3 mm in diameter found essentially over the palate, gums, more rarely on the labial mucosa, the ano-genital region and the nasal mucosa.[4
] By coalescence, papules constitute the papillomatous lesions. These papillomas are diffuse and attain the totality of the upper aero-digestive mucosa.[4
] Scrotal tongue[5
] and gingival hypertrophy[11
] are also frequent mucous lesions of CS. Other lesions can be seen as macrocheilitis,[10
] polyps of hypopharynx, larynx and vocal fold, uvula hypoplasia,[7
] dental caries, periodontitis, gingivitis and squamous cell carcinomas of tongue and lips.[11
CS (multiple hamartoma syndrome) often presents various visceral manifestations seen after or before reminiscent mucocutaneous pictures. Thyroid, breast, genitourinary, gastrointestinal and skeletal abnormalities are the most frequent.[9
] These clinical manifestations are summarized in .
Visceral manifestations of Cowden syndrome.
The big variability of the expression of CS make the diagnosis difficult. In all our patients, the diagnosis of CS was based on International Cowden Consortium operational criteria for the diagnosis of CS, Version 2000.[8
No etiological treatment is available for this genodermatosis with high potential for visceral malignancy. However, some therapeutics can be proposed. Oral retinoids, mainly acitretine at the dose of 0,75 mg/kg/day, had been proposed for the treatment of mucocutaneous lesions.[12
] Their role in the prevention of cancers may be hypothesized. However, it has been indicated that digestive polyps do not respond to retinoid therapy.[12
] Two of our patients were treated with oral retinoids with transient improvement and relapse after withdrawal of therapy. Other treatments, such as bleomycin chemotherapy, radiotherapy with Iridium 192, surgery and CO2-laser for the multiple mucous lesions,[4
] local tretinoin for face lesions and salicylic acid for acral kerotoses[9
] were proposed. Thyroid manifestations must prompt to a regular endocrinology check-ups.[15
] Breast lesions require a monthly self examination, yearly ultrasonography and mammography, repeated biopsies of the suspected lesions and the avoidance of oestrogen therapy.[10
] The prophylactic bilateral mastectomy has been proposed by some authors because the high risk of breast cancer,[15
] however, this idea was not shared by other authors. Early and repeated gynaecological examinations are recommended for early diagnosis of endometrial or cervical cancers.[15
] Because of the low malignant potential of the gastrointestinal polyps, an endoscopic control every two years seems sufficient. Prompt intervention is indicated in any case of suspicion of malignant transformation.[15
] Lhermitte-Duclos syndrome should be suspected and MRI of the brain is indicated in patients who develop persistent headache.[15
] Sirolimus is currently undergoing a phase II study, coordinated by the National Institute of Healh (NIH) in United States to evaluate its possible efficacy in Cowden syndrome.
The prognosis of the CS is poor because of the frequent risk to develop neoplasia. No predictive factors exist to estimate the risk in the individual patient. Thyroid and breast cancers are the most frequent determinants of poor prognosis.[5
] Germline KILLIN methylation witch is common among patients with Cowden syndrome seems to be associated with increased risks of breast and renal cancer over PTEN mutation-positive individuals.[16
The diagnosis and the management of CS is multidisciplinary. Tracking of members of the patient's family for possible other cases of CS is essential. They should undergo a meticulous clinical examination followed possibly by a genetic test in order to early diagnose and cure avoidable consequences of malignancies.