Macrocephaly, not secondary to hydrocephalus, may
be present in up to 39% of patients and usually becomes evident only
after the first year of life. It is often accompanied by frontal bossing,
adenoid facies, hypoplastic maxilla and mandible, and high arched palate.
Mild mental retardation with seizures and cerebellar signs (tremor) is
present in 12% of patients. Kyphosis, kyphoscoliosis, and anomalies of
the thyroid gland are reported in approximately two thirds of patients and
may include multinodular goiter, adenomas, and follicular adenocarcinoma.
Patients should undergo regular checkups for signs of thyroid cancer
(especially men). The most serious malignancy in females is (early-onset)
breast cancer, which may affect up to one third of female patients and often
occurs bilaterally. Gastrointestinal adenomas, hamartomatous and
hyperplastic polyps, lymphangiomas, and ganglioneurofibromas may occur in
almost three fourths of patients and can be localized anywhere between the
esophagus and the anus (including gallbladder) but are most common in the
colon. Malignant transformation is a possible risk. Urogenital lesions
include carcinomas of the kidneys, urethra, and uterine cervix, ovarian
cysts, leiomyomas, and teratomas, vaginal and vulvar cysts, and testicular
hamartomas. Mucocutaneous lesions are present in more than 90% of
patients and may appear in different forms. In more than three fourths of
patients, small, white, oral papules representing fibromas with a diameter
up to 3 mm can be detected on the lips, palate, gingiva, and tonsillar
fossae. Involvement of the tongue can result in scrotal tongue (lingua
scrotalis), with thickening and deep furrowing giving it the appearance of
scrotal skin. Verruciform, flesh-colored papules (most often trichilemmomas)
with a diameter of up to 5 mm are often located in periorificial areas and
exhibit a keratin-plugged center. About two thirds of patients manifest
acral keratosis characterized by verruciform papules on the dorsum of the
hands and the feet, while approximately one third of patients have signs of
keratosis palmoplantaris. Additional skin lesions may include subcutaneous
lipomas, hemangiomas, and neuromas.