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A rare hereditary disorder due to autosomal dominant transmission with hamartosis characterized by multiple early-onset basal cell carcinoma (BCC), multiple jaw keratocysts and skeletal abnormalities.
ORPHA:377Classification level: Disorder
The prevalence of Gorlin syndrome (GS) is estimated to be 1/30,827-1/164,000. Males and females are equally affected. Birth incidence is reported to be 1/18,976.
GS is characterized by the early onset of mandibular odontogenic keratocysts (2nd decade of life) and/or multiple BCCs (most commonly seen on the face, back and chest - 3rd decade of life). Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. 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, wedge-shaped vertebrae, bifid or fused ribs, hemivertebra, kyphoscoliosis, pectus deformity, sprengel deformity, syndactyly, polydactylia) are also reported. Additional features include facial dysmorphism (cleft lip/palate, macrocephaly), eye anomalies (cataract, coloboma, microphthalmos) and lymphomesenteric cysts. A predisposition to malignant or benign tumors such as medulloblastoma, meningioma, papillary fibroelastoma of the heart, ovarian fibroma (commonly bilateral and calcified), fibrosarcoma, nephroblastoma is observed.
GS is caused by loss of functions due to mutations in the tumor suppressor gene PTCH1 (9q22.1-q31), which encodes the receptor of the sonic hedgehog ligand. Environmental exposure and other modifier genes (SUFU; PTCH2) may contribute to the variable expressivity observed in the clinical presentation. Mutations in PTCH1 also account for the majority of features in monosomy 9q22.3.
Diagnosis is based upon presence of two major criteria and one minor criterion or one major and three minor criteria. Physical examination, radiography, ophthalmologic evaluation, dentist or orthodontist examination, skin examination, ultrasound test and echocardiography are essential to identify the criteria leading the diagnosis. Identification of a heterozygous germline PTCH1 or SUFU pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.
Differential diagnosis includes: Sotos syndrome, Brooke-Spiegler syndrome, Bazex syndrome, Rombo syndrome, Muir-Torre syndrome, Beckwith-Wiedemann syndrome, isolated hydrocephaly or megalencephaly, an autosomal dominant or X-linked syndrome of hypotrichosis.
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 counselling, including testing family members to distinguish familial mutations from de novo pathogenic variants, and assessment of genetic cancer risk should be offered. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
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. Use of oral retinoids is also suggested. Oral vismodegib may reduce development of BCC but adverse events are common. Sonic hedgehog inhibitors may be particularly helpful with lesions around the eyes. Radiation therapy must be avoided as it can cause invasion of BCC years later. Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. Surgical treatment using Mohs' microsurgery appears particularly effective. 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.