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Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome.

ABSTRACT: Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU)SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62-e67. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

SUBMITTER: Foulkes WD

PROVIDER: S-EPMC7309678 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome.

Foulkes William D WD Kamihara Junne J Evans D Gareth R DGR Brugières Laurence L Bourdeaut Franck F Molenaar Jan J JJ Walsh Michael F MF Brodeur Garrett M GM Diller Lisa L

Clinical cancer research : an official journal of the American Association for Cancer Research 20170601 12

Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (<i>PTCH1)</i> and S ...[more]

PMID: 28620006

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Project description:BACKGROUND:The clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co-occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported. METHODS:We investigated a family with members harboring a germline SMARCB1 deletion by means of whole-body MRI as well as high-resolution microstructural magnetic resonance neurography (MRN). Breakpoint-spanning PCRs were performed to characterize the SMARCB1 deletion and its segregation in the family. RESULTS:The index patient of this family was in complete continuous remission for an atypical teratoid/rhabdoid tumor (AT/RT) treated at the age of 2 years. However, at the age of 21 years, she exhibited paraparesis of her legs and MRI investigations revealed multiple intrathoracic and spinal schwannomas. Breakpoint-spanning PCRs indicated that the germline deletion segregating in the family encompasses 6.4-kb and includes parts of SMARCB1 intron 7, exons 8-9 and 3.3-kb located telomeric to exon 9 including the SMARCB1 3' UTR. The analysis of sequences at the deletion breakpoints showed that the deletion has been caused by replication errors including template-switching. The patient had inherited the deletion from her 56-year-old healthy mother who did not exhibit schwannomas or other tumors as determined by whole-body MRI. However, MRN of the peripheral nerves of the mother's extremities revealed multiple fascicular microlesions which have been previously identified as indicative of schwannomatosis-associated subclinical peripheral nerve pathology. CONCLUSION:The occurrence of schwannomatosis-associated clinical symptoms independent of the AT/RT as the primary disease should be considered in long-term survivors of AT/RT. Furthermore, our investigations indicate that germline SMARCB1 mutation carriers not presenting RTs or schwannomatosis-associated clinical symptoms may nevertheless exhibit peripheral nerve pathology as revealed by MRN.

Project description:Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature. Associated clinical features encompass feeding problems, congenital pulmonary emphysema, mammary hypoplasia in females and urogenital anomalies, such as cryptorchidism and hypoplastic labia minora and majora. Typical facial characteristics during childhood comprise a small mouth with full lips and micro-retrognathia. During ageing, a narrow, convex nose becomes more prominent. The diagnosis MGS should be considered in patients with at least two of the three features of the clinical triad of microtia, patellar anomalies, and pre- and postnatal growth retardation. In patients with short stature and/or microtia, the patellae should be assessed with care by ultrasonography before age 6 or radiography thereafter. Mutations in one of five genes (ORC1, ORC4, ORC6, CDT1, and CDC6) of the pre-replication complex, involved in DNA-replication, are detected in approximately 67-78% of patients with MGS. Patients with ORC1 and ORC4 mutations appear to have the most severe short stature and microcephaly. Management should be directed towards in-depth investigation, treatment and prevention of associated problems, such as growth retardation, feeding problems, hearing loss, luxating patellae, knee pain, gonarthrosis, and possible pulmonary complications due to congenital pulmonary emphysema with or without broncho- or laryngomalacia. Growth hormone treatment is ineffective in most patients with MGS, but may be effective in patients in whom growth continues to decrease after the first year of life (usually growth velocity normalizes after the first year) and with low levels of IGF1. At present, few data is available about reproduction of females with MGS, but the risk of premature labor might be increased. Here, we propose experience-based guidelines for the regular care and treatment of MGS patients.

Project description:Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. The estimated prevalence varies from 1/57,000 to 1/256,000, with a male-to-female ratio of 1:1. Main clinical manifestations include multiple basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles, skeletal abnormalities, intracranial ectopic calcifications, and facial dysmorphism (macrocephaly, cleft lip/palate and severe eye anomalies). Intellectual deficit is present in up to 5% of cases. BCCs (varying clinically from flesh-colored papules to ulcerating plaques and in diameter from 1 to 10 mm) are most commonly located on the face, back and chest. The number of BBCs varies from a few to several thousand. Recurrent jaw cysts occur in 90% of patients. Skeletal abnormalities (affecting the shape of the ribs, vertebral column bones, and the skull) are frequent. Ocular, genitourinary and cardiovascular disorders may occur. About 5-10% of NBCCS patients develop the brain malignancy medulloblastoma, which may be a potential cause of early death. NBCCS is caused by mutations in the PTCH1 gene and is transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. Clinical diagnosis relies on specific criteria. Gene mutation analysis confirms the diagnosis. Genetic counseling is mandatory. Antenatal diagnosis is feasible by means of ultrasound scans and analysis of DNA extracted from fetal cells (obtained by amniocentesis or chorionic villus sampling). Main differential diagnoses include Bazex syndrome, trichoepithelioma papulosum multiplex and Torre's syndrome (Muir-Torre's syndrome). Management requires a multidisciplinary approach. Keratocysts are treated by surgical removal. Surgery for BBCs is indicated when the number of lesions is limited; other treatments include laser ablation, photodynamic therapy and topical chemotherapy. Radiotherapy should be avoided. Vitamin A analogs may play a preventive role against development of new BCCs. Life expectancy in NBCCS is not significantly altered but morbidity from complications can be substantial. Regular follow-up by a multi-specialist team (dermatologist, neurologist and odontologist) should be offered. Patients with NBCCS should strictly avoid an excessive sun exposure.

Dataset Information

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome.

Publications

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome.

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