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Clinical aspects of Cowden syndrome. A Patient with a “narrow bird-like” face and occipitofrontal macrocephaly. B Nodule of fibrous consistency in the helix of the left ear. C Acral keratosis lesions (black arrows) with the aspect of warty papules covering the dorsum of the hands
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Middle-aged and old adults (≥ 50 years) diagnosed with Cowden syndrome (CS) with orofacial manifestations are uncommon. We describe a case of CS in a 53-year-old female showing “narrow bird-like” face, macrocephaly, acral keratoses, oral candidiasis, burning in the mouth, and multiple asymptomatic papillomatous lesions with a cobblestone pattern di...
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PURPOSE
PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk confer...
Citations
... The median age of cancer diagnosis in patients diagnosed with CS is around 36 years, with cumulative lifetime risks of 85-90% in females and 81-88% in males [1]. Also, the mean age of patients diagnosed with CS varies in the literature, being reported between 36 and 50.5 years [11,[16][17][18][19]. ...
... According to existing literature, approximately 99% of CS patients exhibit dermatological lesions by the age of 30 [21]. However, the accuracy of this percentage remains uncertain due to discrepancies in the literature, with prevalence rates varying between 90% and 100% before the age of 30 [16,39]. Nonetheless, what remains evident is that most CS patients do develop dermatological disorders by the conclusion of their third decade of life. ...
... It is noteworthy that certain authors have reported a skewed distribution among CS patients in middle age or older with orofacial manifestations, noting that a ratio of 2.3 to 1 favours women over men in this subgroup. However, older studies did not explicitly highlight any discernible disparities between the sexes in terms of dermatological features in CS [16]. ...
PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.
... 24,25 The criteria proposed by Eng and Yehia are shown in Table 2. 24 Mucocutaneous manifestations of CS are important because these symptoms tend to be the first signs of CS. 22 Therefore, dermatologists have to understand the mucocutaneous findings of CS including trichilemmoma, acral keratosis, oral papilloma, and mucocutaneous neuroma. 22 Oral and perioral regions are also frequently affected in patients with CS, and the role of oral healthcare providers is also important for an early diagnosis of CS. 26 Recent genetic tests, such as comprehensive genomic profiling, also enable detection of the PTEN mutation and its variants. 27 Given that some patients with CS do not meet the clinical criteria, genomic profiling is also important for making a diagnosis of CS and PTEN hamartoma tumor syndrome. ...
Gorlin syndrome and Cowden syndrome are hereditary diseases that are characterized by multiple malignancies, cutaneous symptoms, and various other abnormalities. Both disorders are caused by a mutation of the gene that regulates cell proliferation and growth, resulting in tumorigenesis. Representative mutations are mutation in the patched 1 gene (PTCH1) in Gorlin syndrome and mutation in the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene in Cowden syndrome. Making a diagnosis of these diseases in the early years of life is important because detection of malignancies at an early stage is linked to improved prognosis. Both Gorlin syndrome and Cowden syndrome have cutaneous findings in the early phase in childhood, and the role of dermatologists is therefore important. These diseases are generally diagnosed by clinical criteria, but some patients who do not meet the criteria need genetic examinations including a genetic diagnostic panel and next-generation sequencing. The most important treatment and management are detection and resection of malignancies in the early stage, and targeted therapies have recently been used for treatment of tumors and other symptoms in these diseases. Although evidence of the effectiveness of targeted therapies has been limited, they are promising therapeutic options and further clinical trials are needed in the future.
... Current literature on oral manifestations of PHTS usually describe small case series or case reports, more often including patients with CS. Moreover, the differential diagnosis with other conditions, including genetic syndromes, that can express themselves with gingival overgrowth is often discussed [12][13][14][15][16]. ...
... Commonly, macrocephaly is observed (84%), due to an abnormally enlarged brain (megalencephaly). Such signs are easily detectable at physical examination, but not always enough to meet the CS/PHTS diagnostic criteria [12]. ...
PTEN hamartoma tumor syndrome (PHTS), is a spectrum of disorders caused by mutations of PTEN, in which non-cancerous growths, called hamartomas, develop in different areas of the body, often including the oral mucosa. PHTS also implies a recognized increased risk of malignancies, as PTEN is a tumor suppressor gene capable of inhibiting progression of several cancers. One of the main and most common clinical manifestation of PHTS are gingival overgrowths presenting as warty lumps. The current study describes patients with gingival or mucosal enlargements leading to the diagnosis of PHTS associated to novel PTEN pathogenic variants. Patients referred to us for gingival lumps suggestive of PHTS associated overgrowths were submitted to genetic analysis in the PTEN gene. Two related and two unrelated patients were investigated. PTEN novel pathogenic variant was found in all of them. Two patients also fulfilled diagnostic criteria of Cowden syndrome (CS). Mucocutaneous lesions, and particularly diffuse gingival overgrowths, are both early and major clinical signs revealing a potential diagnosis of PHTS. Further genetic and clinical assessments are needed in order to confirm and clarify the diagnosis within the PHTS spectrum, including, among others, the CS. A correct interpretation of oral clinical features potentially associated to PHTS is mandatory for diagnosis and a surgical approach can be useful just in case of impairment of periodontal health or for aesthetic needs. The increased risk of malignancies associated to PHTS makes a correct diagnosis pivotal to set up an appropriate lifelong surveillance, aiming at secondary cancer prevention.
A 56-year-old Brazilian woman sought dental care, presenting with multiple asymptomatic papillomatous lesions with a coalescent pattern and intermingled cobblestone-like clefts along the alveolar ridge and marginal and attached gingivae. Multiple whitish papules were also observed on the face, neck, and limbs. Incisional biopsies of these lesions were performed. Microscopically, the skin lesion revealed epithelial clear cells and intraepithelial keratinization with areas of orthokeratosis, while the gingival lesions showed a parakeratinized stratified squamous epithelium with collagenous connective tissue. These features were consistent with those of a trichilemmoma and fibroepithelial hyperplasia, respectively. This article illustrates a case of Cowden syndrome (CS), a rare multisystem genetic condition in which both cutaneous and mucosal tissues were affected. Fewer than 40 cases of CS with oral involvement affecting middle-aged adults have been documented hitherto.
