Neurofibroma is the hallmark finding of neurofibromatosis type 1 (NF1). NF1 is inherited in an autosomal-dominant fashion with a nearly even split between spontaneous and inherited mutations [3]. The disease is due to mutations in the NF1 gene, which is located on chromosome 17q11.2 and encodes for the protein neurofibromin [3]. Neurofibromas tend to be multiple and develop towards the end of the first decade of life, with penetrance approaching 100 % by the second decade of life [3]. Expressivity is highly variable, even among family members [3]. The neurofibromas appear as discrete soft tumors on the face (including eyelids), hands, and trunk. Based on their appearance and extent of tissue involvement, neurofibromas can be classified as cutaneous, subcutaneous, nodular plexiform, and diffuse plexiform. Often, neurofibromas of the eyelids can lead to ptosis and sometimes detachment of the lateral canthal ligament. Neurofibromas in the upper eyelid can also lead to an “S”-shape deformity because the tumor infiltrates more the lateral side of the lid [4].

In general, only about 10 % of all patients with nevus flammeus or port-wine stain of the eyelid are associated with Sturge-Weber syndrome (SWS) (Fig. 12.1) [5]. Sturge-Weber syndrome only occurs in patients who have hemangiomas in the V1 or V2 areas of distribution of the trigeminal nerve. Bilateral port-wine stains of the eyelids have a higher likelihood of being associated with Sturge-Weber syndrome than unilateral lesions [5]. In a study of 55 patients with Sturge-Weber syndrome, glaucoma was the main ocular disease and was related to the extension of the nevus flammeus in the palpebral area [6]. Patients in the study who did not develop a nevus flammeus in the palpebral area did not develop glaucoma or choroidal hemangioma [6]. In the absence of leptomeningeal involvement, patients should only be given a diagnosis of nevus flammeus, port-wine stain, or facial angioma to avoid the stigmata associated with a diagnosis of Sturge-Weber syndrome.

Gardner syndrome was first described by Eldon J. Gardner in 1951 as a autosomal-dominant disorder characterized by the triad of multiple osteomas, colonic polyposis, and benign tumors of the skin and soft tissues [7]. Gardner syndrome is a variant of familial adenomatous polyposis caused by a mutation in the APC gene on chromosome 5q21 [7]. Extracolonic manifestations of Gardner syndrome include radiologic jaw anomalies, pigmented ocular fundus lesions that resemble congenital hypertrophy of the retina pigment epithelium, soft tissue tumors, desmoid tumors, and other cancers [8, 9]. Orbital osteoma, soft tissue tumors of the brows or eyelids, and epidermoid cysts of the eyelid may also occur [10–12].

Nevoid basal cell carcinoma syndrome (NBCCS) is also referred to as basal cell nevus syndrome, Gorlin syndrome, or Gorlin-Goltz syndrome [13, 14]. Although basal cell nevi may occur in early childhood, it is the risk for multiple basal cell carcinoma and developmental anomalies that characterizes NBCCS [15]. Other features include development of multiple jaw keratocysts and characteristic facial features.

Cowden syndrome was first described in 1963 and is named after the surname of the patient on whom the initial observations were made [29]. As the majority of tumors in this syndrome are hamartomatous malformations, it has also been referred to as multiple hamartoma syndrome [30]. Other features include benign and malignant tumors of the thyroid, breast, and endometrium [30].