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Genetic Conditions With High Malignancy Risk 

Jonathan Dyer, MD, discussed several rare skin diseases that are associated with malignancy or increased risk of malignancy at the 2019 Society of Dermatology Physician Assistants Conference in Scottsdale, AZ. Dr Dyer is a professor of dermatology, director of pediatric dermatology, and interim chair of the department of dermatology with the University of Missouri in Columbia, MO.

According to Dr Dyer, the skin diseases he discussed in his presentation are rare but not many providers in other areas of medicine are aware of them. “These patients are out there,” he said, adding that he does not expect providers to remember everything but hopes that if they encounter a patient who they suspect has one of these conditions, they will be able to figure it out and help that patient. I am astounded by the number of patients with rare skin diseases who I treat in my clinic, he added.

Dr Dyer discussed Marie, the first indexed patient with Gorlin syndrome diagnosed by Robert J. Gorlin, MD. Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is one of the most common inherited dermatologic conditions. It is autosomal dominant and only needs 1 mutation in the PTCH1 gene to manifest, said Dr Dyer. About 20% to 30% of patients are the first in their family to have this disease, he added.

Major criteria for Gorlin syndrome includes basal cell carcinoma, cysts in the jaw, pitting in the palms and soles. Some patients with SUFU mutations have a higher risk of developing medulloblastoma. Basal Cell nevi appear before puberty and are predominately benign behavior, said Dr Dyer. In these patients, providers do not need to treat every nevi, he said, because they will require a lifetime of intervention and not every lesion will activate and become aggressive.

A treatment option for patients with Gorlin syndrome is vismodegib, which can reduce the growth and size of tumors, but does have some serious adverse effects, said Dr Dyer. Early stage data is starting to show treating with intermittent doses still suppress the growth of basal cell nevi while reducing the rate of adverse effects, he added. Dr Dyer also recommended counseling these patients about sun protection because sun exposure is related to basal cell carcinoma development.

Muir-Torre syndrome is not necessarily its own condition but thought to be a subtype of hereditary nonpolyposis colorectal cancer or Lynch syndrome, said Dr Dyer. It is also autosomal dominate and associated with sebaceous neoplasms that can be benign or malignant. They tend to grow on the sun-exposed face, he said. One clue is noticeable Fordyce spots on the lips, he added. Consider this diagnosis if a patient has an atypical presentation, even if they only have one neoplasm, Dr Dyer recommended. He also suggested taking a good family history and having these patients undergo cancer screenings as the disease is associated with cancers of the colon and genitourinary tract.

Gardner syndrome is considered to have an incidence of 1 out of 8000 to 16,000 in the dermatology textbooks, said Dr Dyer. However, he believes it is not as common as the textbooks estimate. Patient with this syndrome develop polyps in the colon, almost 100% of which are or can become malignant, he said. Some patients will develop epidermoid cysts, which show up early in life, can even be congenital, and appear in odd locations, such as the lower leg, he noted. These have pilomatricoma-like features and can increase in number as well as in size. Other abnormalities in these patients include osteomas, thyroid cancer, and desmoid tumors, as well as hamartomas in the eyes. Patients with Gardner syndrome will need to see a gastrointestinal specialist early to remove the polyps before they become malignant, stated Dr Dyer.

Peutz-Jeghers syndrome has a higher rate of mutations, and about 40% of patients will be the first in their family to develop this disorder, he said. The characteristic skin finding is the presence of pigmented macules or lentigines on the lips. These can present in the first few years of life and are also visible on the digits, nails, palms, and soles. Aside from lesions present on the buccal mucosa, the macules can fade over time. Dr Dyer said he often examined the parents of children he suspects have this condition. In addition, these patients can develop benign hamaromatous polyps in the gastrointestinal tract. He will ask if the patient has ever had problems with their gut, such as cramping or intussusception.

While it was originally thought Peutz-Jeghers syndrome did not increase the risk of malignancy, new findings suggest these patients can develop various tumors, said Dr Dyer. Specifically, patients have a higher risk for cancers of the gastrointestinal tract, breasts, lungs, ovaries, and testicles, with some instances of cervical cancer, although this is rare, he said. Patients may need more detailed work up if they have this condition. He recommended providers have genetic testing performed immediately for patients they suspect have this syndrome in order to screen for cancers.

Dr Dyer also discussed Cowden syndrome, which is more common in female patients. It is caused by mutations in the PTEN gene and presents primary in the second and third decade of life. Common skin findings for this syndrome include trichilemmomas and papillomas, said Dr Dyer, as well as acral keratotic papules on the ankles and wrists. Other findings include lipoma, angioma, and sclerotic fibroma. Patients with Cowden syndrome have a higher risk for gastrointestinal, thyroid, and breast cancers. A variant that is more common in male patients is Bannayan, which is associated with genital lentigines and large head size.

Reed syndrome is one of those sneaky rare diseases, said Dr Dyer, who believes it is more common than previously thought. Dermatologists are the ones who diagnosis this disorder, he said. There are variable skin phenotypes, but growth of leiomyomas is typical, he noted. These are bothersome and sensitive to touch. Using 5% lidocaine patches can help with leiomyomas, he added. This syndrome is associated with aggressive renal cell carcinoma and requires close monitoring, he stated.

Patients with Birt-Hogg-Dube syndrome have an increased risk of renal cell carcinoma as well, but it is less aggressive compared with Reed syndrome, said Dr Dyer. Fibrofolliculomas are the major skin finding, which does not present until middle age, he added. Papules are another common presentation. These patients can also develop lung cysts and pneumothorax.

Facial angiofibroma, collagenomas, and café au lait macules are some of the common skin findings for patients with multiple endocrine neoplasia type 1, said Dr Dyer. This is caused by mutations in the menin gene. In type 2b, patients have more striking skin findings, he added. These patients tend to be tall and thin, have blubber lips that look like bad lip filler, he said. Patients have a higher incidence of thyroid cancer.

Patients with Carney complex have a lot of skin findings, said Dr Dyer. Usually, these patients present with lentigines all over the body and many of them have red hair and fair complexion. They can also develop myxomas. He recommended performing a thorough skin exam for these patients.

Dr Dyer concluded his presentation with a review of BAP1 tumor predisposition syndrome. This condition is not rare and everyone who practices in dermatology will have a patient with this condition or is already treating one, he said. These patients are being diagnosed early because of increased recognition of this condition and dermatopathologists now know what these lesions look like, he added. However, there are still a lot of questions regarding how to intervene, said Dr Dyer.

These patients can have a variety of different tumors and atypical nevi, and have an increased risk for uveal melanoma, melanoma atypical spitz, basal cell carcinoma, renal cell carcinoma, and mesothelioma. Tumors appear when patients are young and cancers behave aggressively, aside from mesothelioma, said Dr Dyer. He also recommended screening the patient’s family if he suspects a patient has this syndrome.

Current recommendations, which are controversial, said Dr Dyer, include yearly eye screening starting at 16 years of age, with some suggesting starting as early as 11 years of age. At 30 years of age, the patient should receive this screening every 6 months. A full skin exam is recommended every 6 months, along with annual kidney screening with imaging performed every 2 years. After 55 years of age, it is recommended these patients have abdominal CT scans.


Dyer J. Genodermatoses that matter. Presented at: 2019 Fall Society of Dermatology Physician Assistants Conference; November 22, 2019; Scottsdale, AZ.


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