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Characterizing Dermatologic Findings in PTEN Hamartoma Tumor Syndrome

Dr. Eng and colleagues conducted a multi-center analysis of skin findings in patients with PTEN hamartoma tumor syndrome.


A research team led by Charis Eng, MD, PhD, has conducted a multicenter cohort study to characterize dermatologic (skin) findings associated with PTEN hamartoma tumor syndrome (PHTS), according to new findings published in the Journal of the American Academy of Dermatology.

PHTS refers to a spectrum of rare genetic disorders defined by germline (heritable) mutations in the tumor suppressor gene PTEN. PHTS impacts multiple organ systems and can result in a wide range of clinical outcomes, such as certain cancers, autism spectrum disorder (ASD) and dermatologic features, including growths and lesions. In patients with PHTS, the development of dermatologic features is highly variable and poorly documented, indicating a need for a more extensive study of PHTS-related dermatologic findings.

In this study, the researchers analyzed demographic information (age, sex, race and ethnicity), dermatologic findings and PTEN mutation data collected from 201 PHTS patients (104 pediatric and 97 adult). The patients had either been previously enrolled in the Cleveland Clinic PTEN study or are part of an ongoing study conducted by the Developmental Synaptopathies Consortium, which is a national, multi-institution collaboration studying rare genetic syndromes, such as PHTS, that carry increased risk of ASD, developmental delay and/or intellectual disability.

Characterizing dermatologic findings in PHTS patients

The researchers revealed a wide variety of dermatologic findings, with the most common including cutaneous papillomatous papules (48%), penile freckling (47% of males), oral papillomas (46%) and lipomas (23%). Other findings were benign follicular neoplasms suspected to be trichilemmomas (18%), multiple lipomas (12%), café-au-lait macules (11%) and vascular malformations (2%). Vascular malformations included hemangiomas (10%), arteriovenous malformations (8%), lymphangiomas (6%) and capillary malformations (1%).

They found no gender differences in the average number of total dermatologic findings per patient, although females were more likely than males to have oral papillomas (57% versus 38%) and cutaneous papillomatous papules (57% versus 42%), and no differences in specific or total dermatologic findings between those with and without ASD. Compared to children, adults were shown to have a greater number of cutaneous findings, such as oral papillomas, vascular malformations, benign follicular neoplasms and acral keratosis. Among pediatric patients, café-au-lait macules (37%) and keratinocytic epidermal nevi (4%) were expressed more commonly than is expected in the general population.

Notably, no cases of skin cancer developed prior to adulthood in this cohort, and the rate of melanoma in adults (1%) was much lower than the 6% lifetime risk for melanoma that has been derived from larger, prospective studies of PHTS patients. In addition, the observed rates of adult basal cell carcinoma (5%) and cutaneous squamous cell carcinoma (2%) in this cohort were low, suggesting that patients with PHTS may not be at increased risk of nonmelanoma skin cancer compared to the general population.

“Potential explanations for our cohort’s low melanoma rate could include increased surveillance, more effective sun protective initiatives, missing records or younger average age,” said Dr. Eng. “Given that our study partly utilizes retrospective data, clinicians should continue to rely on the previously reported 6% risk of melanoma in PHTS until revised guidelines are formally established.”

Dr. Eng also noted that further investigation into nonmelanoma skin cancer risks in PHTS and pediatric melanoma risks are warranted before any adjustments are made to clinical guidelines. She recommends that children receive a baseline skin examination at PHTS diagnosis and another examination during puberty, in addition to family counseling regarding monthly skin checks, and that adults undergo annual skin surveillance and counseling regarding modification of risk factors, such as sun exposure.

Associations between PTEN mutation types and dermatologic findings

The researchers also identified associations between dermatologic findings and certain PTEN mutation types and sites.

For example, pathogenic (disease-causing) PTEN mutations were found to be predictors of higher number of skin findings, and mutations in the C2 and phosphatase domains of the PTEN protein were associated with increased odds of developing acral keratosis and vascular malformations, respectively. However, missense mutations (which occur when one of the base pairs in the DNA sequence is changed) were associated with a decreased likelihood of developing cutaneous papillomatous papules, oral papillomas and vascular malformations.

“While our results differ from a previous study that showed no significant associations between the PTEN genotype and dermatologic pathology in PHTS, our analysis, unlike the previous study, assessed additional variables and adjusted for confounders,” said Dr. Eng. “Replication of our observations and identifying the mechanism behind the potentially protective effects of a missense mutation in the skin context should be of interest for future studies.”

Altogether, the study findings describe rates of dermatologic pathology that clinicians can utilize to counsel PHTS patients on the development of skin findings and when to begin skin surveillance. 

Dr. Eng is the inaugural chair of the Genomic Medicine Institute and inaugural director of the Center for Personalized Genetic Healthcare, which includes the PTEN Multidisciplinary Clinic (designated as a PHTS Clinical Center of Excellence by the PTEN Hamartoma Tumor Syndrome Foundation) for children and adults with a confirmed or possible diagnosis within the PHTS spectrum. She was the first to link PTEN to Cowden syndrome, which is a PHTS disorder.

Frederick Morgan, BSPH, a medical student at the Cleveland Clinic Lerner College of Medicine, is first author on the study, which was supported in part by the National Institutes of Health Developmental Synaptopathies Consortium, the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health & Human Development, the National Institute of Mental Health (NIMH) and the National Center for Advancing Translational Sciences (all part of the National Institutes of Health).

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