Review of Ocular Manifestations of Nevoid Basal Cell Carcinoma Syndrome: What an Ophthalmologist Needs to Know.

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare, autosomal dominant disorder characterized by multiple basal cell carcinomas (BCCs), odontogenic keratocysts, palmar and/or plantar pits, and ectopic calcifications of the falx cerebri. Myriad ophthalmologic findings are associated with NBCCS, including periocular BCCs, hypertelorism, strabismus, myelinated nerve fibers, and disorders of the retina and retinal pigment epithelium. We performed a literature search in PubMed for articles on the ophthalmologic manifestations of Gorlin syndrome, published between 1984 and 2014. Of 33 papers, 31 were included. Although Gorlin syndrome is due to mutations in a single gene, it displays variable phenotypic expressivity. Therefore, familiarity with this disorder across clinical specialties is necessary to avoid misdiagnosis. The ophthalmologist should be included in the multidisciplinary team for the management of Gorlin syndrome in order to prevent visual loss and improve the quality of life of these patients.

INTRODUCTION

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare, autosomal dominant condition1 characterized by basal cell carcinoma (BCC), odontogenic keratocysts (OKCs), palmar and/or plantar pits, and ectopic calcifications of the falx cerebri. Jarisch and White originally reported the clinical manifestations in 1894.23 However, Gorlin and Goltz were the first to classify the constellation of findings as a syndrome, initially as a triad,1 but eventually as a pentad.4 Although originally called the “multiple nevoid basal cell epithelioma, jaw cysts, and bifid rib syndrome,” this condition has had many names over the years [Table 1].56

Table 1

Scientific titles referring to Gorlin syndrome

CASE REPORT

A 31-year-old Hispanic male was referred to the oculoplastics service complaining of large growths on the lower eyelids. He first noticed the lesions at age 14, but in the previous 3 years, he has noted a significant growth and spreading of the lesions and increasing ocular irritation. No biopsies had been performed, and no family members have a history of similar symptoms. His past surgical history was significant for removal of gingival cysts several years prior to the presentation.

On clinical examination, unaided visual acuity was 20/50 in the right eye and 20/25 in the left eye. External examination revealed multiple large, purple, ulcerating lesions on the lower eyelids, obliterating the eyelid margins and lateral canthi, and causing ectropion bilaterally [Figure 1]. Many smaller nevi were scattered on the face. Hypertelorism and a wide nasal bridge were noted. Anterior segment exam showed well-healed laser in situ keratomileusis flaps bilaterally, a foreshortened lower fornix in the right eye and multiple iris nevi bilaterally. Dilated fundus examination was significant for a thick epiretinal membrane and a lamellar macular hole in the right eye. Inspection of the patient's hands revealed palmar pits [Figure 2]. Keratocystic odontogenic tumors of the maxillary sinuses and calcification of the dura were evident on maxillofacial and head computed tomography, respectively [Figure 3].

Figure 1

Photograph of the patient's eyes displaying innumerable basal cell carcinomas on lower eyelid bilaterally, obscuring the eyelid margin

Figure 2

Photograph of the patient's hand depicting palmar pitting. Though only one hand is shown, the other had similar findings

Figure 3

Computed tomography maxillofacial and head of the case report patient, showing: (a) Large odontogenic keratocytes obscuring the maxillary sinuses and (b) calcification of the falx cerebri

The anterior and posterior lamellae of the lower eyelids of both eyes were biopsied and revealed nodular type BCCs. The clinical diagnosis was Gorlin syndrome based on these findings, and the patient is currently undergoing genetic testing. Due to the extensive nature of the lesions, the patient was referred to the oncology clinic and began systemic treatment with vismodegib.

EPIDEMIOLOGY

NBCCS is a rare condition, with a prevalence of approximately 1 in 60,0000, which varies based on geographic region and ethnicity.6 For example, the prevalence in North America is approximately 1/57,000 people,789 while lower prevalence rates of 1/256,000,10 1/164,000,11 1/235,800,12 and 1/13,939,39313 have been noted in Italy, Australia, Japan, and Korea, respectively. This difference may partially be explained by ethnicity, as it has been shown that the disease is more common in Caucasians, but essentially equal in all others.6 Males and females also appear to be equally affected.

Though the disease is rare in the general population, young patients presenting with characteristic findings should be carefully screened for this syndrome, even without a significant family history. Twenty-three percent (3/13 patients) of young adults aged 21–35 years presenting with periocular BCCs had NBCCS in one series.14 Another series of six pediatric patients diagnosed with NBCCS found palmoplantar pitting in 100% and multiple BCCs in 83%, but only 33% had a positive family history in a first-degree relative.15

METHODS

A PubMed search was performed for articles written in English published on NBCCS between 1984 and 2014. The search combined keywords “NBCCS” or “Gorlin syndrome” with any of the following: “Ophthalmology,” “eye,” and “ocular manifestations.”

Our literature search indicated 87 published articles. After excluding unrelated articles, 33 articles were reviewed. Emphasis was placed on recently published papers as well as those that focused on ophthalmologic manifestations. Thirty-one articles were ultimately used at final review. Previously published review articles, large case series, and other pivotal publications on Gorlin syndrome were also referenced.

OPHTHALMOLOGIC FINDINGS

Basal cell carcinoma

The most iconic feature of NBCCS is multiple BCCs. The average age of onset is 25 years, but they have been reported in children as young as 3–4 years old.48 Patients with NBCCS will display BCCs that vary in number from 2 to 1000, vary in size from 1 to 10 mm in diameter, and vary in appearance from flesh-colored papules to ulcerating plaques. They can often be mistaken as skin tags, nevi, or hemangiomas.

Population studies have noted differing frequencies of BCCs in patients with NBCCS, with the highest rates in western countries such as the United States (91%),4 Australia (85%),11 and the United Kingdom (73%).8 The difference in incidence is thought to be due to the ultraviolet radiation exposure, a theory supported by the fact that BCCs are most commonly found on sun exposed areas such as the face, back, and chest.6 Non-Caucasian and African and American population studies have lower incidences.10121316 The protective effects of skin pigmentation are thought to be the likely reason for these observations.

While most patients with NBCCS will have periocular BCCs, most patients with periocular BCCs will not have NBCCS.1417 Additionally, BCCs in Gorlin syndrome are most commonly of the infundibulocystic variety, which is less aggressive and rarely undergoes metastasis.18 Though rarely malignant, periocular BCC can still be a source of morbidity from the high burden of disease or alteration of eyelid architecture.19

Hypertelorism

Hypertelorism is an abnormal increase in the distance between the medial canthi and the interpupillary distance secondary to enlargement of the sphenoid bone causing a greater separation between the two orbits. This condition should not be confused with telecanthus, which is an increased distance between the medial canthi, but with a normal interpupillary distance. Hypertelorism is one of the most common ocular findings in NBCCS, classically reported to occur in 70% of patients, but it also varies by region.101213 While usually nonprogressive, its identification often aids in diagnosis.

Strabismus

The prevalence of strabismus in population studies of NBCCS is between 10% and 20%, with the highest prevalence noted in an English study at 23%17 and the lowest in a Korean study at 3%.81013 Though inconsistent, scattered case reports indicate a higher frequency of esotropia and esophoria compared to exotropia and exophoria. Patients with strabismus should be referred to a pediatric ophthalmologist for further evaluation, especially children within the amblyogenic period who are at risk of irreversible visual loss without timely treatment.

Myelinated nerve fibers

Gorlin syndrome can be a cause of myelinated retinal nerve fibers, which result from propagation of the myelin sheath anterior to the lamina cribosa, and are seen as a fluffy white sheet following the nerve fiber layer on retinal examination. Though infrequently found in normal individuals,20 Gorlin syndrome patients are affected at higher rates, are more frequently bilaterally affected, and the myelination tends to cover a larger area.1721 Though benign and nonprogressive, identification is important because patients can have visual field deficits or even poor visual acuity if a large area of the retina is involved.

Retina

Episodic case reports have also been made linking NBCCS with retinal anomalies. Bilateral retinal detachments due to multiple retinal fibrotic falciform folds22 and a limited retinal detachment associated with two peripheral retinal holes, a tear, and retinoschisis all in the same eye have been reported.23 Though there is no definitive proof that Gorlin syndrome is the cause of these findings, the vitreous may be selectively affected in NBCCS due to the mesodermal origin and large proportion of collagen.23 More recently, cases of bilateral epiretinal membranes,24 bilateral macular holes,25 and a combined hamartoma of the retina and retinal pigment epithelium (RPE)26 in patients with NBCCS have been published. Mouse models of patched gene (PTCH) knockouts show photoreceptor dysplasia and secondary Muller cell-derived gliosis,27 possibly explaining the link between the pathogenesis of Gorlin syndrome and these aberrant retinal findings.

Other ocular findings

Several other ophthalmologic manifestations are intermittently present in Gorlin syndrome. Eyelid cysts are usually only found in 5–10% of patients, but an incidence as high as 38% has been reported.17 Microphthalmia is also well described but only affects 1–2% of patients.8 One recently published case reported simultaneous presentation of microphthalmia with cyst.28

Congenital cataracts can also occur, with rates averaging 3–8%.81317 Less frequently, the cataracts may be associated with dysgenesis of the anterior segment and Peters’ anomaly. Nystagmus, colobomas of the iris, choroid, and optic nerve, congenital glaucoma, iris transillumination defects, and subconjunctival epidermoid cysts are even rarer (usually in the 1–5% range), but well documented.13172930

SYSTEMIC FINDINGS

Table 2 shows a full list of clinical manifestations of Gorlin syndrome.

Table 2

Systemic manifestations of Nevoid basal cell carcinoma syndrome

Palmar and plantar pits

Palmar and plantar pits are a characteristic dermatologic finding of NBCCS, consisting of small reddish to dark brown/black papules measuring 2–3 mm in diameter and 1–3 mm in depth,31 located on the palms and soles, respectively. Similar to BCCs, the incidence increases with age, affecting 30–65% of patients at 10, 80% of patients at 15,32 and over 85% of patients over 20 years of age.31

Odontogenic keratocytes

OKCs are one of the most common findings in NBCCS and one of the major criteria for diagnosis. OKCs are cysts of the jaw that exhibit a characteristic external fibrous capsule along with an internal stratified squamous epithelium lined by keratin and are often detected on X-ray. The prevalence is high, usually in the 85–90% range,1012 and they are often numerous. Data suggest that OKCs develop earlier in life, as early as 10 years old,1112 and have a higher rate of recurrence in NBCCS patients.13 As one of the first and more persistent manifestations of the disease, the discovery of an OKC in a young patient or the development of two or more recurrent OKCs should prompt investigation for NBCCS.101333

Calcification of the falx cerebri

The most frequently described radiologic sign of NBCCS is calcification of the falx cerebri, which often increases in frequency with age. The incidence varies from 21% in a Korean cohort to 92% in an Australian study, with the United States reporting 65%.4111213 Although symptoms are rare, it can be useful in conjunction with other findings for diagnosing NBCCS.

Skeletal abnormalities

Many skeletal abnormalities have been associated with NBCCS. The most common, which is also a major criterion for diagnosis, is bifid, fused, or markedly splayed ribs. This clinical manifestation does not vary by region or ethnicity, with a uniform prevalence of about 35%.41012 The third, fourth, and fifth ribs were most commonly involved, but other ribs are also occasionally involved.4 Kyphoscoliosis, which occurs in 10–40% of NBCCS patients,34 is another prominent skeletal manifestation of NBCCS. These skeletal abnormalities are most commonly asymptomatic, incidental radiographic findings, but in severe cases can cause musculoskeletal pain, intercostal nerve entrapment, shortness of breath, or even chest pain.

Medulloblastoma

Medulloblastoma is a well-documented and potentially devastating complication of NBCCS. It occurs sporadically in approximately 5% of NBCCS cases8 and is found at the earlier age of 2 rather than the age of 7–8 years in the general population.68 Therefore, diagnosis of medulloblastoma at an early age should raise suspicion for Gorlin syndrome.6

Treatment for patients with concurrent medulloblastoma is especially challenging because of sensitivity to radiation therapy, which makes NBCCS patients prone to the development of aggressive secondary cancers in the radiation field.145834 Most often, patients develop multiple BCCs within the field, but intracranial meningiomas after undergoing craniospinal radiation have also been described.35 Therefore, treatment of medulloblastoma should be coordinated by specialists, familiar with its management within the context of the syndrome.

DIAGNOSIS

Diagnosis of NBCCS is based on clinical manifestations.4 The presence of two major criteria or one major and two minor criteria is required,4 as detailed in Table 3.

Table 3

Major and minor diagnostic criteria for NBCCS

The challenge of diagnosing Gorlin syndrome lies in its phenotypic variety. Because the syndrome has over 100 clinical manifestations and affects many major organ systems, patients will present to physicians in many different specialties who may be unfamiliar with the condition, thereby leading to misdiagnosis and/or a delay in diagnosis. In one case series of 39 patients,17 the diagnosis was made by a geneticist in 31%, a dermatologist in 28%, an oral surgeon in 23%, a plastic surgeon in 8%, a family medicine practitioner in 5%, and unknown in the remaining 5%. Fifty-six percent of the patients had no family history, representing new spontaneous mutations, while 40% experienced no diagnostic delay, the average delay was 12 years (range 1–32 years). These findings exhibit the importance of improving the awareness of NBCCS as well as maintaining a high index of suspicion in patients with suspicious features, even in those with no family history of the condition.

GENETICS

The gene responsible for NBCCS has been mapped to chromosome 9q23.3-q31.17 It encodes the patched gene (PTCH), which translates into the transmembrane receptor protein for the secreted molecule Sonic Hedgehog in the Hedgehog signaling pathway, responsible for both developmental regulation and tumor suppression.36 Mutations in the PTCH gene cause premature termination of the PTCH protein translation36 and have been found in nearly half of all families with NBCCS.17 It is hypothesized that patients in NBCCS families inherit an initial germline mutation and then acquire a second “hit” to the second allele in a classic two-hit tumor suppressor gene model.17

MANAGEMENT AND PROGNOSIS OF OPHTHALMOLOGIC CONDITIONS

Surgical excision remains the mainstay of treatment for BCCs, with an overall rate of remission of 94–98%.537 Adjunctive therapies, such as cryosurgery and electrocauterization, are often utilized due to the aggressive behavior of BCC in the setting of NBCCS.38 Excision by a Mohs surgeon gives the highest rate of success, especially in complex cases.6

Alternative therapies are of great interest in this disorder because Gorlin syndrome patients often present with numerous lesions in challenging locations to reconstruct. Photodynamic therapy (PDT) was the first alternative therapy to be attempted, utilizing a laser-activated photosensitizing dye that accumulates in malignant cells. Methyl aminolevulinate-PDT was recently approved by a panel of experts, but mainly for superficial and nodular BCCs <2 mm in thickness.39 Vismodegib, a small-molecule inhibitor of the Hedgehog pathway, is approved by the United States of Food and Drug Administration for the treatment of metastatic and locally advanced BCC. Several case series describing the use of Vismodegib in NBCCS have shown a significant promise, even in recurrent, inoperable cases, demonstrating an appreciable decrease in the thickness of the lesions as early as 4 weeks, and >80% regression in 49% of cases.3740 Once the control of existing lesions has been achieved, chemoprevention with isotretinoin has been shown to effectively prevent the growth of new BCC lesions.41

Unfortunately, many of the other ophthalmologic manifestations of Gorlin syndrome do not have effective treatments. Congenital cataracts, glaucoma, or strabismus should be referred to a pediatric ophthalmologist, especially for children within the amblyogenic period to prevent further vision loss. Retinal pathology such as holes, tears, detachments, or epiretinal membranes should be referred to a vitreoretinal specialist, as surgical intervention may improve the visual outcome in some cases.24 Eyelid cysts can be referred to oculoplastics specialists for evaluation and possible surgical removal.

With appropriate medical monitoring, patients with Gorlin syndrome can enjoy a normal life span. The most common reasons for early mortality are medulloblastoma or invasion and metastasis of BCC.5 Fortunately, both are relatively rare, particularly if inciting radiotherapy is avoided. A multidisciplinary approach toward treatment and monitoring should be undertaken, involving specialists from genetics, dermatology, maxillofacial surgery, otolaryngology, neurology, urology, cardiology, gynecology, and ophthalmology to optimize care.

CONCLUSION

Although rare, Gorlin syndrome is a complex, autosomal dominant inherited disease with multiple clinical manifestations, originating from mutations in the tumor suppressor gene PTCH. The ophthalmologic manifestations include but are not limited to multiple periocular BCCs, hypertelorism, strabismus, myelinated nerve fibers, and disorders of the retina and RPE. Awareness among the ophthalmology community is important because periocular symptoms, such as BCC, are often the presenting feature. Familiarity with the diagnostic criteria [Table 3] and maintaining an appropriate index of suspicion can be crucial to the successful management of these patients. Coordination with a multidisciplinary team is important in the care of patients with Gorlin syndrome.

Financial support and sponsorship

The National Eye Institute Core Grant EY001792 for Vision Research. An unrestricted grant from Research to Prevent Blindness, Inc., New York, NY. CAPES Foundation – Brazilian Federal Agency for Support and Evaluation of Graduate Education. Vinay Aakalu is supported by The National Eye Institute (K08EY024339), a research grant from Midwest Eye Banks and a grant in aid from Fight for Sight.

Conflicts of interest

There are no conflicts of interest.