Review patients with Gorlin Syndrome (GS), documenting presentation, referrals, treatment patterns, and associated morbidity.

Methods:           

Cross-sectional review and retrospective data collection of 40 patients with Gorlin Syndrome. Patients from the GS support group were invited to be examined. Those that where unable to attend were questioned via either telephone or post. Demographics, presenting features, associated pathologies, and treatment modalities were recorded. Demographic data, age at presentation, age at diagnosis, spectrum of ophthalmic and peri-ocular disease, treatment modalities used, and peri-ocular deformities developed.

40 patients were included.
Age range = 8-72 years.
A wide range of presenting features were recorded:

The most common presenting feature was an odontogenic keratocyst; this being the initial feature in 16 patients. The age at which patients developed their first dental problem ranged from 5 to 30 years.

Basal cell carcinoma was the presenting feature in 13 patients, with the youngest histologically confirmed basal cell carcinoma at the age of 4 years. Of the 24 patients with a history of basal cell carcinoma, 16 had their initial basal cell carcinoma at less than 30 years of age. At the time of this report, 9 patients were aged less than 30 years, and of these, 4 had at least one basal cell carcinoma. One of these patients presented with a basal cell carcinoma at age 19, but also reported an intraocular tumour at age 1. 

Other presenting features were varied. Two patients presented before one year of age. One had congenital malformations (bifid ribs, cleft palate and enlarged lateral ventricle) in the absence of a family history, and the other presented with bifid ribs, spinal problems, developmental delay, in the presence of a positive family history. This child developed his first BCC at the age of four years. Two patients presented at ages 4 years and 6 years with skeletal malformations and a positive family history. One patient with strabismus at age 5 followed by an odontogenic keratocyst at age 10 and subsequent diagnosis at age 22. One patient was noted to have multiple eyelid cysts at age 9, followed by an odontogenic keratocyst at age 17.

Three patients with a positive parental history, but without morbidity from the disease, had the diagnosis made at time of genetic counselling on the basis of family history and clinical features. In two cases, it was not possible to identify the precise presentation.

As expected with the diversity of presentations, the diagnosis of BCNS was made by a variety of practitioners. Patients reported that the diagnosis had been confirmed by a clinical geneticist in 12 cases, by a dermatologist in 11 cases, maxillo-facial surgeon in 7 cases, plastic surgeons in 5 cases, and the ophthalmologist in 1 case, and general practitioner in 2 cases. Eight patients could not recall which practitioner made the diagnosis. In general, the geneticist acted as a tertiary referral, and presumably the referring practitioner had some index of suspicion of the diagnosis.

Thirty patients had undergone surgical excision of their BCC's. However, it must be remembered that the majority of these were carried out by other surgical specialties, thus it cannot be assumed that Mohs' micrographic techniques were used. Multiple recurrences were common, affecting 16 of these 30 patients, with several suffering more than twenty. Eleven patients
developed some degree of lid deformity from their recurrences and subsequent excisions. There was no significant difference in either the age the patient developed their first BCC or the number of different treatment modalities between those with lid deformity and those without. However, those with lid deformity had a longer delay from presentation to diagnosis (average 11 years compared to 8 years). 

Other treatment modalities experienced included photo-dynamic therapy, CO2 laser, cryotherapy, curettage, and topical chemotherapy (1 had 5-FU and 1 had imiquimod). Worryingly, 5 patients had undergone radiotherapy for their BCC's, albeit many years ago.

Associated ophthalmic features included multiple lid cysts (15 patients), strabismus (9 patients), myopia (6 patients), hyperopia (5 patients), cataracts (4 patients), myelinated nerve fibres and amblyopia (3 patients each), nystagmus and iris transillumination defects (2 patients each).

Sixteen of the 35 patients confirmed a parental diagnosis of BCNS, although the series does contain several patients from the same family.

Discussion:

1. About 40% of cases represent new genetic mutations with no family history,

2. As discussed above, despite being an autosomal dominant disorder, there is considerable variability in phenotypic  expression. Thus, patients may have affected family members who have very mild characteristics and who thus have not been previously diagnosed.

3. Many of the clinical features, especially the congenital malformations such as palmar pits and rib abnormalities, are asymptomatic signs, which may escape attention unless specifically looked for. Alternatively, they may only become symptomatic later in life, as is often the case with odontogenic keratocysts presenting in the second or third decade.

4. The most characteristic neoplasia, the basal cell carcinoma, presents later in life, albeit usually before the age of 30. Even in younger age group of patients with basal cell carcinoma, patients with BCNS make up minority 18.

5. The multisystem nature of this disorder results in patients presenting to a variety of practitioners. This may result in a delay in diagnosis if cared for by a practitioner less familiar with the clinical features.

If the major criteria can be highlighted amongst the relevant specialties, it may be possible to diagnose the syndrome at an earlier stage, when patients can be given advice regarding the use of sun screens and avoidance of UV exposure early on, as well as skin surveillance.

Following diagnosis, a structured referral plan to all the potentially relevant specialties would seem beneficial. At present it is apparent that patients are referred on an ad hoc basis following diagnosis, once problems come to light. Multi-disciplinary care is required for these patients from an early age. Early structured referral would allow individual management plans to be co-ordinated on a multi-disciplinary scale.

Several authors have suggested baseline panoramic x-rays of the jaw, MR scans of the brain, and pelvic ultrasonography in women with regular follow up investigations for patients with BCNS. This would seem sensible if skin lesions are to be picked up while small. In order for this strategy to work consistently, rigorous distribution of communication between the specialties is essential, so that each knows the current treatment being administered, and future plans may be co-ordinated.  In addition, a positive diagnosis clearly has genetic implications and a genetic counselling service is extremely helpful, not just for the patient, but for the family also. One patient in our series stated that she had made an informed decision to not have children following her diagnosis.

	Conclusion: Multi-disciplinary care is essential in the patient with GS. Early diagnosis of GS may allow for skin protection and surveillance at an earlier age. Early aggressive treatment may reduce peri-ocular morbidity. Co-ordination of a referral 'network' may improve the efficiency of referrals and management planning.   January 2006