| Diagnosis: | ||||||
| This man demosntrates many of the features of Gorlin syndrome also known as basal cell nevus syndrome. Binkley and Johnson in 1951 and Howell and Caro in 1959 suggested a relationship between multiple basal cell cancers and developmental defects. In 1960 Gorlin and Goltz were the first to describe a distinct syndrome consisting of the presence of multiple nevoid basal cell epitheliomas, jaw cysts and bifid ribs. This genodermatosis, also known also as Gorlin syndrome exhibits an autosomal dominant inheritance with variable penetrance and has a prevalence of one in 56,000. The Gorlin syndrome phenotype displays two major features: (1) developmental malformations including palmar pits, cleft palate, strabismus, polydactyly and rib and central nervous system abnormalities and (2) multiple neoplasms including basal cell carcinomas, medulloblastoma, odontogenic keratocysts, as well as other benign and malignant tumors. This combination of birth defects and neoplasms in unusual. Chromosomal mapping and genetic studies suggested that the underlying basis for this disease is an abnormality in the Hedgehog(Hh) signaling pathway. The role of this pathway in embryogenesis of the brain, craniofacial structures, ribs, vertebrae and limbs has been well-studied. More recent investigations have begun to reveal the role of the Hh pathway in cell cycle regulation in adults. In the Drosphila model, the primary receptor for the Hh signaling pathway has two transmembrane protein companents--Patched and Smoothened (fig. Hedgehog-1). In the absence of Hh protein, the Patched protein inhibits Smoothened (fig. Hedgehog-2). Under normal conditions, Hh, when present, binds Patched, releasing Smoothened to effect downstream events such as cell growth and differentiation (Hedgehog Pathway-2). Based on this model, inactivation of Patched or constituitive activity of Smoothened or Hh could lead to overactivity of Smoothened, resulting in neoplasm formation. Additional studies identified the Gorlin syndrome gene as the human homolog of Drosophila Patched and mapped this gene to chromosome 9. It is believed that Gorlin's syndrome is caused by inactivating mutations of Patched; this inactivation occurs in two steps--the first "hit" occurs in the germline, the second occurs post-natally. Haploinsufficiency for Patched due to the inherited germline mutation is likely to give rise to the development abnormalities seen in Gorlin's syndrome. Subsequent post-natal loss of the normal Patched allele leads to multiple basal cell carcinomas and other neoplasms. Smoothened overactivity due to either inactivation of Patched or oncogenic activation of Smoothened has also been implicated in sporadic cases of basal cell carcinoma, the most common human cancer, suggesting the importance of delineating the Hh signaling pathway. | ||||||
| Differential: | ||||||
| Other tumors such as trichoepitheliomas can mimic the cutaneous lesions found in basal cell nevus syndrome. However, the constellation of cutaneous findings, dysmorphic facies, jaw cysts, central nervous system findings, and associated benign and malignant tumors is distinctive. The clinical presentation, especially in childhood, can be variable and subtle. Basal cell nevi can be mistaken for pigmented nevi, epidermal nevi. skin tags, flat warts, molluscum contagiosum, flat warts and other epidermal lesions. | ||||||
| Treatment: | ||||||
| Currently there are many treatment options for the basal cell tumors that occur in Gorlin syndrome. However, the multiplicity and recurrent nature of these tumors often represents a challenge to traditional treatments including surgical excision, topical chemotherapies, and laser ablation. Based on the understanding of the Hh signaling pathway and the premise that tumors arise due to overactivity of this pathway, therapies involving inhibition of this pathway might be expected to suppress tumor growth. A new treatment strategy is evolving from the correlation of epidemiologic and developmental findings. Teratologists noted a high rate of holoprosencephaly in sheep offspring whose mothers were known to graze on a particular lily plant, called Veratrum Californicum. Investigators recently found that holoprosencephaly can be caused by inactivating mutations of Hedgehog. This information suggests that a compound in the lily plant can function in the same way as an inactivating mutation of Hh and that this compound could repress the Hh signaling pathway. This comound has been purified and is called Cyclopamine. It has recently been found to reverse Smoothened overactivity due to either inactivation of Patched as in Gorlin syndrome or oncogenic activation of Smoothened. The mechanism by which it blocks the overactivity of Smoothened is being investigated. In the future, this minimally toxic compound or a synthetic derivative of it might be used in the treatment of tumors occuring in Gorlin syndrome or in sporadic cases arising due to mutations in the Hh signaling pathway. From a management standpoint,patients with Gorlin syndrome require a multidisciplinary approach. Jaw cysts should be evaluated and treated by oral surgery as necessary. Periodic visits and full skin examinations are required for early diagnosis and removal of malignant tumors. Benign cysts and tumors which cause symptoms will also require surgical management. A good primary care physician may also need input from dentistry, neurology, orthopedics and plastic surgery. Patients should receive counseling regarding sun protection and genetic risks. | ||||||
| Summary: | ||||||
| In summary, Gorlin syndrome is an autosomal dominant condition with variable penetrance characterized by both developmental abnormalities and neoplasms, especially basal cell carcinomas. Identification of the defect in the Hedgehog signaling pathway in Gorlin syndrome has resulted in a new understanding of the molecular basis of this genodermatosis as well as sporadic basal cell carcinomas | ||||||
| References | ||||||
| 1. Binkley GW and Johnson HH Jr.: Epithelioma adenoids cysticum: Basal cell nevi, agenesis of the corpus callosum and dental cysts. Archives of Dermatology and Syphilology 1950;63:73-84. | ||||||
| 2. Howell JB and Caro MR: The basal cell nevus: Its relationship to multiple cutaneous cancers and associated anomalies of development. Archives of Dermatology and Syphilology 1958;79:67-80. | ||||||
| 3. Gorlin RJ and Goltz RW: Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: A syndrome. The New England Journal of Medicine 1960;62:908-912. | ||||||
| 4. Bale AE and Yu K: The hedgehog pathway and basal cell carcinomas. Human Molecular Genetics 2001;10:757-762. | ||||||
| 5. Bale AE: Cancer: Sheep, lilies and human genetics. Nature 2000;406:944-945. | ||||||
| 6. Johnson RL, Rothman AL, Xie J, et al.: Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668-1671. | ||||||
| 7. Hahn H, Wicking C, Zaphiropoulos PG, et al.: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85:841-851. | ||||||
| 8. Keeler RF and Binns W: Teratogenic compounds of Veratrum californicum. Teratology 1968;1:5-10. | ||||||
| 9. Roessler E, et al.: Mutations in the human sonic hedgehog gene cause holoprosencephaly. Nature Genetics 1996;14:357-360. | ||||||
| 10. Taipale J, Chen JK, Cooper MK, et al.: Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000;406:1005-1009. | ||||||
