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Gorlin syndrome (GS) is a genodermatosis characterized by multiple early-onset basal cell carcinoma (BCC), odontogenic keratocysts and skeletal abnormalities.
The prevalence of GS is estimated to be 1/57,000-1/256,000. Males and females are equally affected.
GS is characterized by the early onset of multiple BCC (most commonly seen on the face, back and chest), usually between the 1st and 2nd decade of life, benign mandibular odontogenic keratocysts (2nd-3rd decade of life), palmar or plantar pits (asymmetrical, 2-3 mm in diameter, 1-3 mm in depth and developing in the 2nd decade) and skeletal anomalies (fusion of vertebrae, bifid or fused ribs, hemivertebra, kyphoscoliosis, pectus deformity, sprengel deformity, syndactyly, polydactylia). Additional features include facial dysmorphism (cleft lip/palate, macrocephaly), eye anomalies (cataract, coloboma, microphthalmos) and lymphomesenteric cysts. A predisposition to other malignancies such as medulloblastoma, meningioma, papillary fibroelastoma of the heart, ovarian fibroma (commonly bilateral and calcified), fibrosarcoma, nephroblastoma (see these terms) is observed.
GS is caused by loss of function mutations in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor of the sonic hedgehog ligand. It represses transcription of genes encoding proteins belonging to the transforming growth factor (TGF)-beta, hence controlling growth and development of normal tissue. Environmental exposure and other modifier genes may contribute to the variable expressivity observed in the clinical presentation. Mutations in PTCH1also account for the majority of features in monosomy 9q22.3 (see this term).
Diagnosis is based upon presence of two major criteria (>2BCC or 1 in patient <20 years; odontogenic keratocyst of the jaw; ≥3 palmar or plantar pits; bilamellar calcifications of falx cerebri; bifid or fused ribs; positive family history) and one minor criterion (facial dysmorphism, skeletal/radiologic anomalies (bridging of the sella turcica, hemivertebrae, fusion or elongation of the vertebral bodies, flame-shaped lucencies of the hands and feet); ovarian/cardiac fibroma, medulloblastoma, and eye anomalies) or one major and three minor criteria. Diagnosis is confirmed by genetic screening of PTCH1.
Differential diagnosis includes Brooke-Spiegler syndrome, Bazex syndrome, Rombo syndrome, Muir-Torre syndrome, Beckwith-Wiedemann syndrome (see these terms), and acquired causes of multiple BCCs (e.g. arsenic exposure).
Antenatal diagnosis is possible with ultrasound scans and DNA analysis extracted from fetal cells after amniocentesis or chronic villus sampling. Preimplantation genetic diagnosis may be proposed to families in which the pathogenic variant has been identified.
Transmission is autosomal dominant, with high penetrance and variable expressivity. Genetic counseling may be proposed. The recurrence risk is 50%.
Management and treatment
The treatment of choice for multiple BCC consists of a combined approach including surgery supplemented by cryotherapy, laser, photodynamic therapy or topical treatments (0.1% tretinoin cream and 5% fluorouracil). Use of oral retinoids (isotretinoin, etretinate) is also suggested. Oral vismodegib (inhibitor of the Hedgehog signaling pathway) may reduce development of BCC but adverse events are common. Radiation therapy must be avoided as it can cause invasion of BCC years later. Offspring should be screened for BCC on a regular basis and should avoid excessive exposure to ultraviolet radiation. Jaw keratocysts are often recurrent and demand repeated surgical excisions. Ovarian fibroma is usually managed with conservative surgery to preserve normal ovarian tissue.
Life expectancy in GS is not affected. Early diagnosis is important due to susceptibility to multiple neoplasms in early age. Ovarian tumors are usually benign with risk of recurrence. In young patients, mandibular odontogenic keratocysts can cause displacement of developing teeth and may be associated with unerupted teeth and cause root resorption.