GORLIN SYNDROME (NEVOID BASAL CELL CARCINOMA SYNDROME)
This is an autosomal dominant condition with a minimal prevalence of 1 in 70,000 of the population. The main features of this syndrome are multiple basal cell carcinomas (BCC) of the skin (most common in sun-exposed areas) and palmar and plantar pits (occurring in 65 % of cases) (see Fig. 1a). The basal cell skin lesions arise as pink or brown papules from the age of puberty onwards. Only 15 % manifest before puberty, and 10 % or more of patients have no skin lesions at the age of 30 years. They mainly affect the thorax, neck, and face. UV light increases the incidence of the BCC; they are more common in white-skinned patients, and therapeutic radiation is often associated with progression of BCC that is present within the radiation field. Only a small proportion of carcinomas become locally invasive, but they can cause severe destruction, particularly around the eyes and orifices. Metastasis is very rare. There are many associated non-dermatological features, including hypertelorism with a broad nasal bridge and frontal and parietal bossing and a prominent chin. Odontogenic keratocysts of the jaw are common (see Fig. 1b). These are multiple, usually bilateral, recurrent, and slow growing and occur in 85 % of mutation carriers by the age of 40 years.
Squamous cell carcinomas have been reported within keratocysts in patients with Gorlin syndrome who have been treated by radiotherapy for facial BCC (Moos and Rennie 1987). Variable skeletal abnormalities are associated, including “bridging” of the sella with calcification of the falx cerebri (see Fig. 1c); bifid (usually third, fourth, or fifth), absent, or rudimentary ribs fusion defects of the cervical spine; polydactyly or syndactyly, short fourth
metacarpals, flame-shaped lucencies of the metacarpals and/or phalanges, and Sprengel deformity. Ocular abnormalities have been reported, including exotropia, chalazia and coloboma, and congenital blindness. All except the skeletal features increase with age, but there is considerable variability of expression of these features in different affected people (Gorlin 1987, 1995). The condition is inherited as an autosomal dominant trait with almost complete penetrance but highly variable expression. Diagnostic features are described in Table 1.
Fig. 6 Gorlin syndrome: (a) palmar pits, (b) odontogenic keratocyles and (c) calcified falx cerebri (courtesy of Robert Gorlin). Reproduced with permission from Cambridge University Press
Table 1 Diagnostic criteria for Gorlin syndrome (Evans et al. 1993)
A variety of other, less common, abnormalities have been noted in affected people, including milia, epidermoid cysts, chalazia and comedones of the skin, cleft lip and palate, pectus carinatum, and hypogonadotropic hypogonadism in males. Hamartomatous upper GI polyposis has also been reported (Schwartz 1978). There is a definite increase in incidence of non- dermatological malignancies, including squamous cell carcinoma and fibrosarcoma in the jaw cysts, and nasopharyngeal carcinomas. Mental
retardation has been reported in about 3 % of cases, but its true incidence is unclear. Detailed CT and MRI have revealed a high incidence of asymmetric or dilated ventricles in 24 %, and one in ten individuals has dysgenesis or agenesis of the corpus callosum (Kimonis et al. 2004). Childhood medulloblastoma may occur in the first 2 years of life, and meningioma and craniopharyngioma have been described. Bilateral ovarian fibromas (which can be hormonally active) are common in affected women, and there is a risk of ovarian fibrosarcoma or other malignancy developing in these lesions (Ismail and Walker 1990).
Seminoma has been reported in males. Cardiac fibromas may occur from early childhood; these may remain static or possibly regress or enlarge with age. Other Tumours that have been described in association with Gorlin syndrome include renal fibroma, melanoma, neurofibroma, leiomyoma, and rhabdomyoma/sarcoma. Mesenteric lymphatic or chylous cysts may occur.
Surveillance of affected people should consist of yearly dermatological examinations and 6-monthly evaluation of the jaw cysts by means of an oropantogram, since odontogenic cysts can erode locally and be very destructive, and early enucleation of these cysts can prevent this. Infants should be kept under surveillance for signs of medulloblastoma, and some have recommended 6-monthly MRI until the age of 7 years (after which the risk declines significantly) (Kimonis et al. 2004). Cranial ultrasound may also be a useful investigation because care should be taken to restrict exposure to radiation to a minimum in view of the extreme radiation sensitivity in this condition. Pelvic ultrasound scanning may detect ovarian Tumours, but in view of the low incidence of this complication, regular scanning is generally not advised.
Reproduced from X with permission from X – author to insert credit line at proof stage
Genetic counseling should be facilitated by molecular genetic analysis. Affected children may show few features. However, if at the age of 5 years an at-risk child has no abnormality on X-ray of spine or skull and has no osteomas or dermatological lesions, the risk of the child being a gene carrier is very small (Farndon et al. 1992).
Gorlin syndrome is caused by mutations in the human homologue (PTCH) of the Drosophila segment polarity gene patched which maps to chromosome 9q (Hahn et al. 1996; Johnson et al. 1996). There is no evidence of locus heterogeneity in Gorlin syndrome, and most reported mutations are predicted to cause protein truncation. No genotype–phenotype relationships have been identified (Wicking et al. 1997). PTCH encodes a transmembrane glycoprotein that acts as an antagonist in the Hedgehog signaling pathway.
PTCH inhibits smoothened (SMO), which in turn activates transcription factors in the Wnt and decapentaplegic pathways. It appears likely that some manifestations of Gorlin syndrome (e.g., symmetrical developmental defects, such as macrocephaly) result from haploinsufficiency but that basal cell carcinomas and other Tumours require inactivation of both alleles in a two-step mechanism of Tumoursigenesis (Levanat et al. 1996). Interestingly, too much activity in the Hedgehog pathway leads to Gorlin syndrome with the associated cancer risk, whereas underactivity causes holoprosencephaly (Roessler et al. 1997; Odent et al. 1999).