PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

Abstract

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.

Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis

“…The authors suggested that the presence of these features should prompt physicians and dentists to consider a further assessment for PHTS in adults [74]. These findings were supported by an Italian study of 20 patients with PTHS (16 adults and 4 children) wherein all patients had the typical mucocutaneous features of papules on the trunk or extremities (74%), papules in the oral mucosa (68%), facial papules (58%), and acral/palmoplantar keratosis (58%) [75,76].…”

New Insights into Melanoma Tumor Syndromes

“…More recently, Innella and colleagues identified an atypical mole/melanoma syndrome phenotype in patients with pathogenic PTEN variants containing a rare truncating mutation (c.495G>A) in the CDH13 gene (Innella et al 2021). Lifetime risk for acquiring melanoma is estimated at 6% (Tan et al 2012), which is substantially less than the estimated risk for breast, thyroid, endometrial, colorectal, and kidney carcinomas.…”

“…PTEN loss manifests as a complex spectrum of disorders called PTEN hamartoma tumor syndrome (PHTS) ( Innella et al., 2021 ). Patients with PHTS will primarily exhibit numerous hamartomas and a high risk of multisystem tumor development, although they may suffer from rarer genetic disorders such as Cowden syndrome (CS), Lhermitte‒Duclos disease, Bannayan‒Riley‒Ruvalcaba syndrome, and autism spectrum disorders ( Pilarski, 2019 ) ( Table 1 ).…”

“…Some early case reports suggest an increased risk for melanomas in individuals with PTEN variants ( Greene et al., 1984 ; Reifenberger et al., 2003 ), although melanoma is not part of the diagnostic criteria for PHTS. More recently, Innella et al. (2021) identified an atypical mole/melanoma syndrome phenotype in patients with pathogenic PTEN variants containing a rare truncating sequence alteration (c.495G>A) in the CDH13 gene.…”

Benign goiters requiring thyroidectomy as the signal for PTEN hamartoma tumor syndrome diagnosis

“…Despite the recommendations by genetic professionals, the pathways leading to PHTS diagnosis are difficult and highly variable (National Comprehensive Cancer Network [NCCN], http://www.nccn.org). Multiple unique pathognomonic features in PHTS have been reported, such as adult LDD, various mucocutaneous features, such as trichilemmomas, acral keratoses, papillomatous papules, multiple palmoplantar keratoses, macular pigmentation of glans penis (freckling on the glans penis), and esophageal glycogenic acanthosis (Innella et al, 2021; McGarrity et al, 2003; Morgan et al, 2022; Tan et al, 2011). Most of these unique pathologies are indolent, the appearance becomes more obvious after young adulthood, and cannot be easily recognized by health‐care providers (D'Ermo & Genuardi, 2022; Macken et al, 2019).…”