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1.
Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. 总被引:16,自引:0,他引:16
M R Gailani S J Bale D J Leffell J J DiGiovanna G L Peck S Poliak M A Drum B Pastakia O W McBride R Kase 《Cell》1992,69(1):111-117
Gorlin syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, ovarian fibromas, and medulloblastomas. Unlike other hereditary disorders associated with cancer, it features widespread developmental defects. To investigate the possibility that the syndrome is caused by mutation in a tumor suppressor gene, we searched for loss of heterozygosity in 16 sporadic basal cell carcinomas, 2 hereditary basal cell carcinomas, and 1 hereditary ovarian fibroma and performed genetic linkage studies in five Gorlin syndrome kindreds. Eleven sporadic basal cell carcinomas and all 3 hereditary tumors had allelic loss of chromosome 9q31, and all informative kindreds showed tight linkage between the Gorlin syndrome gene and a genetic marker in this region. Loss of heterozygosity at this chromosomal location, particularly in hereditary tumors, implies that the gene is homozygously inactivated and normally functions as a tumor suppressor. In contrast, hemizygous germline mutations lead to multiple congenital anomalies. 相似文献
2.
Motivated by the diagnosis and treatment of two cases of nevoid or Goltz-Gorlin syndrome, we have taken a brief look at the literature and present these two cases, which display the four principal features defining this syndrome: multiple basal cell carcinomas, maxillary cysts, skeletal anomalies, and ectopic calcifications. Certain aspects are emphasized, including the association in one of them of basal cell carcinomas with a cystic adenoma or Brooke's tumor, which, although described by other authors, is infrequent. 相似文献
3.
Muthumula Daneswari Mutjumula Swamy Ranga Reddy 《Indian journal of human genetics》2013,19(3):369-372
Gorlin-Goltz syndrome is a rare multisystemic disease inherited in a dominant autosomal at a high level of penetrance and variable expressiveness. It is mainly characterized by basal cell carcinoma, odontogenic keratocyst and skeletal anomalies. Diagnosis is based upon established major and minor clinical and radiographic criteria and gene mutation analysis. This article presents a case of Gorlin-Goltz syndrome, its genetic predisposition, diagnosis and management. 相似文献
4.
Basal cell nevus syndrome 总被引:1,自引:0,他引:1
We report two patients with basal cell nevus syndrome. They had two previously unreported associated conditions--a myocardial fibroma and bilateral basal cell carcinomas of the soles of the feet. The syndrome is discussed, the literature is reviewed, and the management is outlined. 相似文献
5.
Martyn T. Cobourne Guilherme M. Xavier Louise Hagan Zoe Webster 《Developmental biology》2009,331(1):38-49
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant or spontaneous disorder characterized by multiple cutaneous basal cell carcinomas, odontogenic keratocysts, skeletal anomalies and facial dysmorphology, including cleft lip and palate. Causative mutations for NBCCS occur in the PTCH1 gene on chromosome 9q22.3-q31, which encodes the principle receptor for the Hedgehog signalling pathway. We have investigated the molecular basis of craniofacial defects seen in NBCCS using a transgenic mouse model expressing Shh in basal epithelium under a Keratin-14 promoter. These mice have an absence of flat bones within the skull vault, hypertelorism, open-bite malocclusion, cleft palate and arrested tooth development. Significantly, increased Hedgehog signal transduction in these mice can influence cell fate within the craniofacial region. In medial edge epithelium of the palate, Shh activity prevents apoptosis and subsequent palatal shelf fusion. In contrast, high levels of Shh in odontogenic epithelium arrests tooth development at the bud stage, secondary to a lack of cell proliferation in this region. These findings illustrate the importance of appropriately regulated Hedgehog signalling during early craniofacial development and demonstrate that oro-facial clefting and hypodontia seen in NBCCS can occur as a direct consequence of increased Shh signal activity within embryonic epithelial tissues. 相似文献
6.
C Grubben J P Fryns E Smeets H Van den Berghe 《Genetic counseling (Geneva, Switzerland)》1991,2(1):47-54
In this report we present a three-generation family in which five members present the basal cell nevus syndrome. In three of them a Noonan phenotype was present. The basal cell nervus syndrome is another example of a neural crest dysplasia associated with a Noonan-like phenotype. This observation supports the theory that the autosomal dominant mutation causing the neural crest dysplasia may lead to a Noonan-like phenotype. 相似文献
7.
Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: Linkage and loss of heterozygosity 总被引:3,自引:2,他引:1
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Georgia Chenevix-Trench Carol Wicking Jenny Berkman Helen Sharpe Athel Hockey Eric Haan Christine Oley David Ravine Anne Turner David Goldgar Jeffrey Searle Brandon Wainwright 《American journal of human genetics》1993,53(3):760-767
Nevoid basal cell carcinoma syndrome (NBCCS; basal cell nevus syndrome or Gorlin syndrome) is a cancer-predisposition syndrome characterized by multiple basal cell carcinomas (BCCs) and diverse developmental defects. The gene for NBCCS has been mapped to 9q23.1-q31 in North American and European families. In addition, loss of heterozygosity (LOH) for genetic markers in this region has been detected in sporadic BCCs, indicating that the NBCCS gene is probably a tumor-suppressor gene. In this study we have determined that the NBCCS gene is also linked to this region in Australasian pedigrees and that there is no significant evidence of heterogeneity. We have defined the localization of the gene by multipoint and haplotype analysis of 15 families, using four microsatellite markers. LOH at these loci was detected in 50% of sporadic BCCs, a rate that is significantly higher than that in other skin lesions used as controls. 相似文献
8.
Margherita Cirillo Silengo Gianfranco Davi Giorgio Crua Piergiorgio Franceschini 《Human genetics》1978,42(3):323-326
Summary An 8-year-old male with mental retardation, speech difficulties, and minor congenital anomalies is presented. The clinical findings suggest the trisomy-8 syndrome. The karyotype indicates trisomy-8 mosaicism with trisomic as well as normal cell lines in blood lymphocytes. 相似文献
9.
Molecular mapping and cloning of the breakpoints of a chromosome 11p14.1-p13 deletion associated with the AGR syndrome 总被引:1,自引:0,他引:1
Chromosome 11p13 is frequently rearranged in individuals with the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) or parts of this syndrome. To map the cytogenetic aberrations molecularly, we screened DNA from cell lines with known WAGR-related chromosome abnormalities for rearrangements with pulsed field gel (PFG) analysis using probes deleted from one chromosome 11 homolog of a WAGR patient. The first alteration was detected in a cell line from an individual with aniridia, genitourinary anomalies, mental retardation, and a deletion described as 11p14.1-p13. We have located one breakpoint close to probe HU11-164B and we have cloned both breakpoint sites as well as the junctional fragment. The breakpoints subdivide current intervals on the genetic map, and the probes for both sides will serve as important additional markers for a long-range restriction map of this region. Further characterization and sequencing of the breakpoints may yield insight into the mechanisms by which these deletions occur. 相似文献
10.
Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications 总被引:2,自引:0,他引:2
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Kumar S Deffenbacher K Marres HA Cremers CW Kimberling WJ 《American journal of human genetics》2000,66(5):1715-1720
Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome. 相似文献
11.
Mutations in CD96, a member of the immunoglobulin superfamily, cause a form of the C (Opitz trigonocephaly) syndrome
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Kaname T Yanagi K Chinen Y Makita Y Okamoto N Maehara H Owan I Kanaya F Kubota Y Oike Y Yamamoto T Kurosawa K Fukushima Y Bohring A Opitz JM Yoshiura K Niikawa N Naritomi K 《American journal of human genetics》2007,81(4):835-841
The C syndrome is characterized by trigonocephaly and associated anomalies, such as unusual facies, psychomotor retardation, redundant skin, joint and limb abnormalities, and visceral anomalies. In an individual with the C syndrome who harbors a balanced chromosomal translocation, t(3;18)(q13.13;q12.1), we discovered that the TACTILE gene for CD96, a member of the immunoglobulin superfamily, was disrupted at the 3q13.3 breakpoint. In mutation analysis of nine karyotypically normal patients given diagnoses of the C or C-like syndrome, we identified a missense mutation (839C-->T, T280M) in exon 6 of the CD96 gene in one patient with the C-like syndrome. The missense mutation was not found among 420 unaffected Japanese individuals. Cells with mutated CD96 protein (T280M) lost adhesion and growth activities in vitro. These findings indicate that CD96 mutations may cause a form of the C syndrome by interfering with cell adhesion and growth. 相似文献
12.
Guntram Borck Liat de Vries Hsin-Jung Wu Pola Smirin-Yosef Gudrun Nürnberg Irina Lagovsky Luis Henrique Ishida Patrick Thierry Dagmar Wieczorek Peter Nürnberg John Foley Christian Kubisch Lina Basel-Vanagaite 《Human genetics》2014,133(8):1041-1047
Athelia is a very rare entity that is defined by the absence of the nipple–areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp–ear–nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell–cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple–areola region. 相似文献
13.
The buccal micronucleus cytome assay was used to investigate biomarkers for DNA damage, cell death and basal cell frequency in buccal cells of healthy young, healthy old and young Down's syndrome cohorts. With normal ageing a significant increase in cells with micronuclei (P<0.05, average increase +366%), karyorrhectic cells (P<0.001, average increase +439%), condensed chromatin cells (P<0.01, average increase +45.8%) and basal cells (P<0.001, average increase +233%) is reported relative to young controls. In Down's syndrome we report a significant increase in cells with micronuclei (P<0.001, average increase +733%) and binucleated cells (P<0.001, average increase +84.5%) and a significant decrease in condensed chromatin cells (P<0.01, average decrease -52%), karyolytic cells (P<0.001, average decrease -51.8%) and pyknotic cells (P<0.001, average decrease -75.0%) relative to young controls. These changes show distinct differences between the cytome profile of normal ageing relative to that for a premature ageing syndrome, and highlight the diagnostic value of the cytome approach for measuring the profile of cells with DNA damage, cell death and proportion of cells with proliferative potential (i.e., basal cells). Significant correlations amongst cell death biomarkers observed in this study were used to propose a new model of the inter-relationship of cell types scored within the buccal micronucleus cytome assay. This study validates the use of a cytome approach to investigate DNA damage, cell death and cell proliferation in buccal cells with ageing. 相似文献
14.
Bertola DR Pereira AC Albano LM De Oliveira PS Kim CA Krieger JE 《Genetic testing》2006,10(3):186-191
Mutations in the PTPN11 gene are known to cause a large fraction of the cases of Noonan syndrome. The objective of this study was to determine the PTPN11 gene mutation rate in a cohort of clinically well-characterized Brazilian patients with Noonan or Noonan-like syndromes and to study the genotype-phenotype correlation. Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 5 with Noonan-like/multiple giant cell lesion syndrome, and 3 with neurofibromatosis/ Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography (DHPLC) followed by sequencing of amplicons with an aberrant elution profile. We detected missense mutations in the PTPN11 gene in 21 probands with Noonan syndrome (42%), in all 3 patients with LEOPARD syndrome, and in 1 case with Noonan-like/multiple giant cell lesion syndrome. One patient with neurofibromatosis-Noonan syndrome had a mutation in both the PTPN11 and NF1 genes. The only anomalies that reached statistical significance when comparing probands with and without mutations were the hematological abnormalities. Our data confirms that Noonan syndrome is a genetically heterogeneous disorder, with mutations in the PTPN11 gene responsible for roughly 50% of the cases. A definitive genotype-phenotype correlation has not been established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, mutation of the PTPN11 gene is the main causal factor in LEOPARD syndrome, and it also plays a role in neurofibromatosis-Noonan syndrome. Noonan- like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous. 相似文献
15.
Summary On account of genetic homologies, trisomy 16 in the mouse is generally regarded as a direct animal model of Down's syndrome. Mouse trisomy 19, on the other hand, can be seen as a general model of human trisomies. A detailed evaluation of the cardiovascular system and skeleton in 109 fetuses with trisomy 16 and 422 balanced siblings was carried out in order to systematize the cardiovascular anomalies and the pathogenetic mechanisms responsible for their formation according to (1) general retardation, (2) genetically determined impairment of neural-crest cell migration, and (3) direct gene action on organogenesis. Skeletal malformations in the form of a rib-vertebra syndrome encountered in Ts 16 are described here for the first time. In 108 fetuses and 219 neonates resulting from cross-breeding to induce trisomy 19, we found no significant increase in the frequency of the foregoing anomalies. These results are discussed with regard to a chromosome-specific genetic influence as opposed to a general effect of chromosome imbalance. The specificity of the Ts16 syndrome is compared with that of individual organ anomalies as can be induced by teratogenic agents. Our investigation shows that specific malformation patterns of a particular type can be produced by a variety of methods. However, the overall patterns of the two syndromes are highly chromosome-specific. On detailed examination, the malformation pattern of mouse trisomy 16 shows significant similarities with that of human trisomy 21. 相似文献
16.
Sofie Symoens Aileen?M. Barnes Charlotte Gistelinck Fransiska Malfait Brecht Guillemyn Wouter Steyaert Delfien Syx Sanne D’hondt Martine Biervliet Julie De?Backer Eckhard?P. Witten Sergey Leikin Elena Makareeva Gabriele Gillessen-Kaesbach Ann Huysseune Kris Vleminckx Andy Willaert Anne De?Paepe Joan?C. Marini Paul?J. Coucke 《American journal of human genetics》2015,97(4):521-534
The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells. 相似文献
17.
In vitro aldosterone, deoxycorticosterone, corticosterone and cortisol production of human adrenocortical cells derived from adenomas (Conn's syndrome, Cushing's syndrome), from hyperplastic adrenals (Cushing's syndrome) and from adrenals surrounding aldosteronoma are described. Cells from adenomas causing either Cushing's syndrome or Conn's syndrome harboured the highest basal and ACTH-stimulated corticosteroid production. Adrenocortical cells derived from micronodular hyperplasia causing Cushing's syndrome and cells from cortisol producing adenoma displayed predominantly cortisol and corticosterone secretion both under basal conditions and following stimulation with ACTH. Aldosteronoma cells showed highly variable aldosterone, deoxycorticosterone, corticosterone and cortisol response to ACTH. However, in aldosteronoma cell suspensions, the basal and ACTH-stimulated ratios of aldosterone to cortisol were increased when compared to ratios of steroids produced by cells from other adrenal tissues. Chronic treatment with spironolactone of patients with Conn's syndrome before surgery was associated with a decreased ratio of aldosterone to corticosterone, revealing that 18-hydroxylase in aldosteronoma cells may be inhibited during long-term therapy. Non-tumorous cells isolated from adrenals surrounding aldosteronoma displayed less aldosterone prior to and after stimulation with ACTH than aldosteronoma cells. 相似文献
18.
Utine GE Alanay Y Atkaş D Boduroğlu K Alikaşifoğlu M Tunçbilek E 《Genetic counseling (Geneva, Switzerland)》2008,19(3):291-300
Kabuki syndrome (KS) (MIM 147920) is a multiple congenital anomalies/mental retardation syndrome of unknown cause. There is multisystem involvement of anomalies, including 1) unique facial features, 2) postnatal growth retardation, 3) mild-to-moderate mental retardation, 4) skeletal anomalies and 5) dermatoglyphic abnormalities. Kabuki syndrome remains a clinical diagnosis despite significant research on detection of the genetic cause. We present 10 patients with Kabuki syndrome with a brief overview of the syndrome. An additional male patient and his affected aunt, both with trisomy 10p due to unbalanced segregation of a familial translocation, are also discussed for overlapping features and differential clinical diagnosis of the two conditions. Considering a significant overlap in clinical pictures of Kabuki syndrome and trisomy 10p in these two patients, as well as the previous patients with chromosomal abnormalities, we conclude that chromosome analysis is an important step in clinical work-up of patients with Kabuki syndrome. 相似文献
19.
Peters' plus syndrome is an infrequently described entity that combines anomalies in the anterior chamber of the eye with other multiple congenital anomalies, and a developmental delay. Major symptoms are extremely variable anterior chamber anomalies, cupid bow of the upper lip, cleft lip and palate, short stature, broad hands and feet, and variable mental delay. The syndrome follows an autosomal recessive pattern of inheritance. The etiology is unknown, but may involve abnormal neural crest development. A review of the pertinent literature is provided. 相似文献
20.
Congenital heart defects are known to be associated with facial dysmorphism and other congenital anomalies. Oculo-facio-cardio-dental (OFCD) syndrome is one such rare multiple congenital anomaly syndrome inherited as an X-linked dominant condition characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects and dental anomalies. It is unrecognized by many medical and dental professionals. Only 21 cases have been reported so far. This syndrome is often misrecognized as rubella embryopathy because of association of congenital cataract with cardiac anomalies. It is usually the orthodontists who diagnose the syndrome based on typical findings on dental panoramic radiographs. But we suspected our patient to be having OFCD syndrome based on typical facial dysmorphism, ocular and cardiac defects, and finally it was confirmed after noticing typical dental radiographic findings. 相似文献