Overlapping Phenotypic Features of PTEN Hamartoma Tumor Syndrome and Birt-Hogg-Dubé Syndrome

To the Editor:

PTEN hamartoma tumor syndrome (PHTS) encompasses a spectrum of disorders that most commonly are caused by autosomal-dominant germline mutations in the phosphatase and tensin homolog, PTEN, tumor suppressor gene on chromosome 10q23. We describe a patient who presented with clinical features of PHTS and Birt-Hogg-Dubé syndrome (BHDS). Because the genetic mutations associated with both PHTS and BHDS result in altered mammalian target of rapamycin (mTOR) signaling, patients may have overlapping phenotypic features.

A 51-year-old man with a history of multiple carcinomas presented for evaluation of flesh-colored papules on the cheeks, nose, tongue, and hands, in addition to numerous skin tags on the neck, axillae, and lower abdomen bilaterally. His medical history was notable for several nasal and gastrointestinal tract polyps, chromophobe renal cell carcinoma, cutaneous lipomas, atypical carcinoid syndrome of the right lung, and a multinodular thyroid. His family history was notable for small cell lung cancer in his father, breast cancer and pancreatic cancer in his maternal aunt, esophageal cancer in his maternal grandfather, and celiac disease in his daughter.

FIGURE 1. Flesh-colored papules on the right cheek with surrounding erythema.

Clinical examination revealed flesh-colored, dome-shaped papules measuring 1 to 2 mm in diameter on the nose and cheeks (Figure 1). He had hyperkeratotic papules on the dorsal fingers, consistent with acral keratoses. Additionally, multiple flesh-colored papules with a cobblestonelike appearance were noted on the oral mucosa (Figure 2). Other findings included pedunculated papules on the neck, axillae, and lower abdomen bilaterally, consistent with fibroepithelial polyps, as well as hyperpigmented velvety plaques on the axillae, characteristic of acanthosis nigricans (Figure 3). A shave biopsy of a papule on the right cheek revealed a proliferation of plump stellate fibroblasts, small blood vessels, and thick collagen bundles, characteristic of a fibrous papule (Figure 4).

FIGURE 2. Multiple flesh-colored papules with a cobblestonelike appearance on the tongue.

Differential diagnoses for our patient included BHDS and Cowden syndrome (CS). Due to the combination of extensive family history of multiorgan cancers as well as the clinical findings, he was referred to a geneticist for further evaluation. Genetic analysis was positive for a heterozygous mutation variant of uncertain significance in the PTEN gene.

FIGURE 3. Several pink pedunculated papules on the left axilla. Hyperpigmented velvety plaques also were present, indicative of acanthosis nigracans.

The PHTS disorders include CS, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, and Proteus-like syndrome (Table).^1-9 Our patient’s clinical findings were indicative of CS, a rare genodermatosis characterized by multiple hamartomas and neoplasms of ectodermal, mesodermal, and endodermal origin.¹ Most CS patients develop trichilemmomas of the central face, mucocutaneous papillomatous papules, and acral and plantar keratoses by the third decade of life.¹ Importantly, CS patients have an increased risk for breast, thyroid, renal, endometrial, and colorectal cancers, as well as melanoma, with estimated lifetime risks of 85%, 35%, 33%, 28%, 9%, and 6%, respectively.^2,10

Regarding the pathophysiology of PHTS disorders, PTEN encodes a phosphatase that inhibits phosphoinositide 3-kinase/Akt and mTOR signaling pathways, thereby controlling cell proliferation, cell-cycle progression, and apoptosis.^2,3 Loss of PTEN function, as seen in CS patients, results in an increased risk for cancer.² Other genetic diseases, including juvenile polyposis syndrome, Proteus syndrome, tuberous sclerosis, and Peutz-Jeghers syndrome, have phenotypic similarities to PHTS.³ Specifically, loss-of-function mutations of TSC1 and TSC2, tumor suppressor genes associated with tuberous sclerosis, similarly result in dysregulation of mTOR signaling.

FIGURE 4. A histologic section of a biopsy of a facial papule showed a proliferation of plump stellate fibroblasts, small blood vessels, and thick collagen bundles (H&E, original magnification ×20).

Our patient also had some clinical features characteristic of BHDS, such as flesh-colored facial papules, acrochordonlike lesions, and chromophobe renal cell carcinoma.¹¹ Birt-Hogg-Dubé syndrome most often is caused by an autosomal-dominant germline mutation in FLCN, a tumor suppressor gene.¹¹ Interestingly, FLCN interacts with AMP-activated protein kinase to help regulate mTOR signaling, which may explain phenotypic similarities seen in CS and BHDS.¹²

Because the PHTS disorders and BHDS result in similar functional consequences on the mTOR signaling pathway, patients can present with overlapping clinical features that may be diagnostically challenging. Management includes patient education regarding cancer risk, surveillance for early detection of malignancy, and genetic counseling for family members.² It is important for clinicians to appreciate phenotypic similarities between PHTS and other disorders affecting mTOR signaling to prevent delays in diagnosis.