Basal cell nevus syndrome (Gorlin-Goltz syndrome): genetic predisposition, clinical picture and treatment.
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SUBMITTER: Witmanowski H
PROVIDER: S-EPMC5560190 | biostudies-literature | 2017 Aug
REPOSITORIES: biostudies-literature
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Basal cell nevus syndrome (Gorlin-Goltz syndrome): genetic predisposition, clinical picture and treatment.
Witmanowski Henryk H Szychta Paweł P Błochowiak Katarzyna K Jundziłł Arkadiusz A Czajkowski Rafał R
Postepy dermatologii i alergologii 20170802 4
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Project description:PurposeTo answer the following clinical research question: "Among patients with multiple basal cell carcinomas (mBCCs), can panoramic radiograph (PaR) facilitate the diagnosis of Gorlin-Goltz syndrome (GGS)?"MethodsThis retrospective study enrolled mBCCs subjects who presented to a German tertiary care center between 1 January 2015 and 31 December 2021. The primary predictor was presence of syndromic mBCCs, and the main outcomes were jaw cysts and odontogenic keratocysts (OKCs). Descriptive, bi- and multivariate statistics, diagnostic test evaluation, and number needed to screen (NNS) were computed at α = 95%.ResultsThe sample comprised 527 mBCCs patients (36.1% females; 6.8% GGS; 5.5% OKCs; mean age, 74.5 ± 15.8 years [range, 15-102]). There was a significant association between syndromic mBCCs and jaw cysts (P < .0001; NNS = 2 [95% CI, CI, 1.1 to 1.4]). In the adjusted logistic model, PaR identified GGS via radiographic diagnosis of jaw cysts in case of 1) age ≤ 35 years, 2) ≥ 5 BCCs, and 3) ≥ 1 high-risk BCCs. Nearly every jaw cyst identified by PaR was OKCs (P = .01; 95% CI, 3.1 to 3,101.4; NNS = 1.3 [95% CI, .9 to 2]). The post hoc power was 100%.ConclusionsDental screening with the use of PaR for mBCCs patients, especially those aged ≤35 years, or with ≥5 BCCs, or ≥1 high-risk BCCs, may be helpful in detection and identification of GGS through recognition of OKCs.
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Project description:BackgroundGorlin syndrome, also known as Gorlin-Goltz syndrome (GGS) or basal cell nevus syndrome (BCNS) or nevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant familial cancer syndrome. It is characterized by the presence of numerous basal cell carcinomas (BCCs), along with skeletal, ophthalmic, and neurological abnormalities. It is essential to anticipate the diagnosis by identifying the pathology through the available diagnostic tests, clinical signs, and radiological manifestations, setting up an adequate treatment plan.Main bodyIn the first part, we searched recent databases including MEDLINE (PubMed), Embase, and the Cochrane Library by analyzing the etiopathogenesis of the disease, identifying the genetic alterations underlying them. Subsequently, we defined what are, to date, the major and minor clinical diagnostic criteria, the possible genetic tests to be performed, and the pathologies with which to perform differential diagnosis. The radiological investigations were reviewed based on the most recent literature, and in the second part, we performed a review regarding the existing jawbone protocols, treating simple enucleation, enucleation with bone curettage in association or not with topical use of cytotoxic chemicals, and "en bloc" resection followed by possible bone reconstruction, marsupialization, decompression, and cryotherapy.ConclusionTo promote the most efficient and accurate management of GGS, this article summarizes the clinical features of the disease, pathogenesis, diagnostic criteria, differential diagnosis, and surgical protocols. To arrive at an early diagnosis of the syndrome, it would be advisable to perform radiographic and clinical examinations from the young age of the patient. The management of the patient with GGS requires a multidisciplinary approach ensuring an adequate quality of life and effective treatment of symptoms.
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Project description:BackgroundGorlin-Goltz syndrome (GS) is an inherited disease characterized by predisposition to basal cell carcinomas (BCCs) and various developmental defects, whose numerous disease-causing PTCH1 mutations have been identified in the hedgehog (Hh) signaling pathway.MethodsIn this study, whole exome sequencing was used to screen for both somatic and germline deleterious mutations in three sisters with a lethal GS. The mutations we found were confirmed by subcloning and Sanger sequencing of the genomic DNA. RNA-seq was performed to profile gene expression in paired BCCs samples and the expression levels for selected genes were validated by quantitative PCR.ResultsThe clinical and histopathologic features were analyzed for the proband in the three-generation GS family. We identified the insertion mutation PTCH1 c.1341dupA (p. L448Tfs*49), which segregated with BCC phenotype and contributed to the death of two in four patients from a Chinese family with GS. Compared with adjacent non-cancerous tissues (ANCT), four second-hit mutations were found in four of the six pairs of BCC from three patients. Of note, somatic genomic alterations in all six BCC samples were mainly clustered into non-clock-like Signature 7 (ultraviolet mutagenesis) and 11 (related to certain alkylating agents). Both RNA-seq and quantitative RT-PCR confirmed that the mRNA levels of PTCH1 and its effector GLI1 were markedly upregulated in six pairs of BCC samples versus ANCT.ConclusionsThe distinct non-clock-like signatures of BCCs indicated that GS was not a life-threatening illness. The main reasons for untimely death of GS patients were PTCH1 mutation, exposure to intense ultraviolet radiationand the poor economic conditions.
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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.
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Project description:Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.
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Project description: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.
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Project description:PDT is widely applied for the treatment of non-melanoma skin cancer pre-malignant and malignant lesions (actinic keratosis, basal cell carcinoma and in situ squamous cell carcinoma). In photodynamic therapy (PDT) the interaction of a photosensitizer (PS), light and oxygen leads to the formation of reactive oxygen species (ROS) and thus the selective tumor cells eradication. Xeroderma pigmentosum (XP) and Gorlin-Goltz Syndrome (GS) patients are at high risk of developing skin cancer in sun-exposed areas. Therefore, the use of PDT as a preventive treatment may constitute a very promising therapeutic modality for these syndromes. Given the demonstrated role of cancer associated fibroblasts (CAFs) in tumor progression and the putative CAFs features of some cancer-prone genodermatoses fibroblasts, in this study, we have further characterized the phenotype of XP and GS dermal fibroblasts and evaluated their response to methyl-δ-aminolevulinic acid (MAL)-PDT compared to that of dermal fibroblasts obtained from healthy donors. We show here that XP/GS fibroblasts display clear features of CAFs and present a significantly higher response to PDT, even after being stimulated with UV light, underscoring the value of this therapeutic approach for these rare skin conditions and likely to other forms of skin cancer were CAFs play a major role.
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