Patching Together the Genetics of Gorlin Syndrome

Background: Gorlin syndrome is an autosomal dominant disorder characterized by developmental defects and susceptibility to cancer, especially to basal cell carcinomas. The genetic basis of this disorder has recently been elucidated. Methods: In this article previous studies are reviewed in which loss of heterozygosity analysis of tumours and normal tissue pointed to a region on chromosome 9 as being involved in Gorlin syndrome. In this light, Knudson's two-hit model is discussed. The identification of the involvement of the patched gene in Gorlin syndrome is reviewed. New data on genotype-phenotype correlations in the syndrome are presented. Results: Loss-of-heterozygosity studies, together with standard family studies using linkage analysis, have proved useful in identifying the location of a gene with complex phenotypic expression. Conclusion: The application of the two-hit model, as utilized in loss-of-heterozygosity studies, has been very useful in elucidating the genetic basis of Gorlin syndrome. There may be a correlation between certain aspects of the mutations in patched and the clinical presentation of the disorder in families.

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Developmental defects in gorlin syndrome related to a putative tumor suppressor gene on chromosome 9

Cell ◽

10.1016/0092-8674(92)90122-s ◽

1992 ◽

Vol 69 (1) ◽

pp. 111-117 ◽

Cited By ~ 286

Author(s):

Mae R. Gailani ◽

Sherri J. Bale ◽

David J. Leffell ◽

John J. DiGiovanna ◽

Gary L. Peck ◽

...

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Suppressor Gene ◽

Chromosome 9 ◽

Gorlin Syndrome ◽

Developmental Defects ◽

Putative Tumor Suppressor Gene ◽

Putative Tumor Suppressor

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Basal Cell Carcinomas in Gorlin Syndrome: A Review of 202 Patients

Journal of Skin Cancer ◽

10.1155/2011/217378 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 54

Author(s):

Elizabeth A. Jones ◽

Mohammed Imran Sajid ◽

Andrew Shenton ◽

D. Gareth Evans

Keyword(s):

Basal Cell ◽

Early Life ◽

Disease Burden ◽

Autosomal Dominant ◽

Gorlin Syndrome ◽

Developmental Defects ◽

Basal Cell Carcinomas ◽

Males And Females ◽

Multiple Basal Cell Carcinomas ◽

Mutation Type

Gorlin syndrome (Naevoid Basal Cell Carcinoma Syndrome) is a rare autosomal dominant syndrome caused by mutations in thePTCHgene with a birth incidence of approximately 1 in 19,000. Patients develop multiple basal cell carcinomas of the skin frequently in early life and also have a predisposition to additional malignancies such as medulloblastoma. Gorlin Syndrome patients also have developmental defects such as bifid ribs and other complications such as jaw keratocysts. We studied the incidence and frequency of basal cell carcinomas in 202 Gorlin syndrome patients from 62 families and compared this to their gender and mutation type. Our data suggests that the incidence of basal cell carcinomas is equal between males and females and the mutation type cannot be used to predict disease burden.

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Allelic imbalance studies of chromosome 9 suggest major differences in chromosomal instability among nonmelanoma skin carcinomas

Sao Paulo Medical Journal ◽

10.1590/s1516-31802004000100005 ◽

2004 ◽

Vol 122 (1) ◽

pp. 18-21

Author(s):

Gabriela Pereira Gomes ◽

Aparecida Machado Moraes ◽

Hamilton Ometto Stoff ◽

Laura Sterian Ward

Keyword(s):

Microsatellite Instability ◽

Loss Of Heterozygosity ◽

Basal Cell ◽

Allelic Imbalance ◽

Sao Paulo ◽

Chromosome 9 ◽

São Paulo ◽

Wide Range ◽

Basal Cell Carcinomas ◽

Malignant Skin

CONTEXT: Loss of heterozygosity in the 9p21-p22 region, has been frequently described in a wide range of human malignancies, including familial melanomas. Also, losses and gains in other regions of chromosome 9 have frequently been observed and may indicate additional mechanisms for basal cell tumorigenesis. OBJECTIVE: To investigate allelic imbalance in the 9p21-p22 region, among basal cell carcinomas. TYPE OF STUDY: Microsatellite analysis. SETTING: Two dermatology services of public universities in São Paulo and the Laboratory of Cancer Molecular Genetics of Universidade Estadual de Campinas (Unicamp). PARTICIPANTS: 13 patients with benign skin lesions consecutively referred to the outpatient dermatology clinics of Unicamp and Universidade Estadual de São Paulo (Unesp) and 58 with malignant skin tumours. MEAN MEASUREMENTS: We examined 13 benign cases including four of solar keratosis, three keratoachanthomas, three melanocytic nevi, two of Bowen's disease and one of neurofibroma, and 58 malignant skin tumors: 14 of squamous cell, 40 basal cell carcinomas and four melanomas. Participating patients had the main tumor and a normal portion of non-adjacent skin surgically removed. DNA was extracted from the tumor and matching normal tissue. We used four sets of primers to amplify polymorphic microsatellite repeats on chromosome 9, two of them targeting the 9p21-p22 region. RESULTS: We identified eight cases (20%) of allelic imbalance among basal cell carcinomas, two cases of loss of heterozygosity and six cases of microsatellite instability in the 9p21-p22 region. Additional markers were also involved in three of these tumors. No events were detected among the benign or the other malignant cases. CONCLUSION: This phenotype dependency suggests that there is a major distinction between the two most important forms of nonmelanoma skin cancers in their tendency to present microsatellite instability in chromosome 9. Since the CDKN2a/p16INK4a, p19ARF and p15INK4b tumor suppressor genes do not appear to be responsible for the observed abnormalities, other genes at 9p21-p22 may be involved in the pathogenesis and progression pathway of basal cell carcinomas.

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Patched1 haploinsufficiency severely impacts intermediary metabolism in the skin of Ptch1+/−/ODC transgenic mice

Scientific Reports ◽

10.1038/s41598-019-49470-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Changzhao Li ◽

Bharat Mishra ◽

Mahendra Kashyap ◽

Zhiping Weng ◽

Shaida A. Andrabi ◽

...

Keyword(s):

Autosomal Dominant ◽

Tricarboxylic Acid Cycle ◽

Normal Skin ◽

Tumor Development ◽

Single Copy ◽

Tricarboxylic Acid ◽

Gorlin Syndrome ◽

Autosomal Dominant Disorder ◽

Basal Cell Carcinomas ◽

Multiple Basal Cell Carcinomas

Abstract The study of dominantly heritable cancers has provided insights about tumor development. Gorlin syndrome (GS) is an autosomal dominant disorder wherein affected individuals develop multiple basal cell carcinomas (BCCs) of the skin. We developed a murine model of Ptch1 haploinsufficiency on an ornithine decarboxylase (ODC) transgenic background (Ptch1+/−/ODCt/C57BL/6) that is more sensitive to BCCs growth as compared with Ptch1+/+/ODCt/C57BL/6 littermates. Ptch1+/−/ODCt/C57BL/6 mice show an altered metabolic landscape in the phenotypically normal skin, including restricted glucose availability, restricted ribose/deoxyribose flow and NADPH production, an accumulation of α-ketoglutarate, aconitate, and citrate that is associated with reversal of the tricarboxylic acid cycle, coupled with increased ketogenic/lipogenic activity via acetyl-CoA, 3-hydroybutyrate, and cholesterol metabolites. Also apparent was an increased content/acetylation of amino-acids, glutamine and glutamate, in particular. Accordingly, metabolic alterations due to a single copy loss of Ptch1 in Ptch1+/−/ODCt/C57BL/6 heterozygous mice may provide insights about the cancer prone phenotype of BCCs in GS patients, including biomarkers/targets for early intervention.

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Radiotherapy in Gorlin Syndrome

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475415612481 ◽

2015 ◽

Vol 20 (2) ◽

pp. 159-162 ◽

Cited By ~ 5

Author(s):

Sarah Baker ◽

Kurian Joseph ◽

Patricia Tai

Keyword(s):

Basal Cell Carcinoma ◽

Literature Review ◽

Basal Cell ◽

Autosomal Dominant ◽

Gorlin Syndrome ◽

Autosomal Dominant Disorder ◽

Comprehensive Literature Review ◽

Basal Cell Carcinomas ◽

Treatment Refractory

Gorlin syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare autosomal dominant disorder with multiple manifestations including early onset of cutaneous basal cell carcinomas (BCCs). Radiotherapy has traditionally been contraindicated due to reports of BCC induction. We describe here a patient treated successfully with radiotherapy with no tumour induction at 57 months of follow-up. A comprehensive literature review of radiotherapy outcomes in patients with Gorlin syndrome suggests radiotherapy may be a feasible treatment option for adult patients with treatment refractory lesions or surgical contraindication.

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To Be Or Not To Be? What Makes a Child Dyslexic: An Overview on Risk Factors and Correlated Clinical Aspects

Archives of Current Research International ◽

10.9734/acri/2020/v20i630198 ◽

2020 ◽

pp. 1-11

Author(s):

Claudio Rosa ◽

Carlo Aleci

Keyword(s):

Risk Factors ◽

Early Diagnosis ◽

Reading Disability ◽

Developmental Dyslexia ◽

Environmental Variables ◽

Developmental Disorders ◽

Genetic Basis ◽

Environmental Influence ◽

Phenotypic Expression ◽

Clinical Aspects

Developmental dyslexia, one of the most common neuro-developmental disorders, is frequently under-diagnosed or diagnosed late. Despite there is consensus on the neurobiological and genetic basis and on the environmental influence, the multi-faceted aspects of dyslexia and the complexity of its phenotypic expression hinder the identification of the risk factors. Indeed, determining risk factors and understanding how they predispose to the reading disability is important for an early diagnosis and a satisfactory rehabilitative outcome. The aim of this paper is therefore to provide an overview on the genetic, biochemical, anatomical and environmental variables involved in the pathogenesis of developmental dyslexia, and on the visual-perceptual aspects that characterize children who struggle to read.

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Progressive rod-cone degeneration (PRCD) in selected dog breeds and variability in its phenotypic expression

Veterinární Medicína ◽

10.17221/1564-vetmed ◽

2011 ◽

Vol 56 (No. 5) ◽

pp. 243-247 ◽

Cited By ~ 6

Author(s):

J. Dostal ◽

A. Hrdlicova ◽

P. Horak

Keyword(s):

Centromeric Region ◽

Late Onset ◽

Phenotypic Expression ◽

Modifier Gene ◽

Chromosome 9 ◽

Causative Mutation ◽

Photoreceptor Degeneration ◽

Cocker Spaniel ◽

Canine Chromosome ◽

Portuguese Water

Progressive rod-cone degeneration (PRCD) is a late onset autosomal photoreceptor degeneration found in canines. PRCD in canines is homologous to one form of retinitis pigmentosa (RP) found in humans and displays phenotypic similarity as well as having the identical causative mutation. The PRCD gene was mapped to the centromeric region of canine chromosome 9 (CFA9). We report here a population study of 699 dogs of the following breeds and the following frequencies of the disease-causing mutation: American Cocker Spaniel (0.09), English Cocker Spaniel (0.34), English Springer Spaniel (0.00), Welsh Springer Spaniel (0.00), Flat Coated Retriever (0.00), Golden Retriever (0.00), Chesapeake Bay Retriever (0.14), Nova Scotia Duck Tolling Retriever (0.44), Labrador Retriever (0.07), Poodle Toy (0.45), Poodle Miniature (0.20), Poodle Medium (0.05), Poodle Standard (0.00), Portuguese Water Dog (0.33), Chinese Crested Dog (0.02), Shipperke (0.06), and Australian Cattle Dog (0.00). The disease results in complete blindness in the affected individual in almost every case. The time of onset and disease progression varies between dog breeds as well as between individuals. A modifier gene is likely to segregate in genomic proximity to the PRCD gene and may influence phenotypic expression.

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