Search

Odontogenic keratocysts are very well documented in the literature. Multiple odontogenic keratocysts (OKCs) are one of the most frequent features of nevoid basal cell carcinoma syndrome (NBCCS). It is linked with mutation in the PTCH gene (human homolog of the drosophila segment polarity gene, "patched",). Partial expression of the gene may result in occurrence of only multiple recurring OKC without any associated systemic findings. A rare case of multiple odontogenic keratocysts unassociated with any syndrome is reported, so as to add to the growing number of such cases in the literature. The possibility of this case being a partial expression of the Gorlin-Goltz syndrome is discussed.

Keratocystic odontogenic tumours (KOCTs) are common benign cystic tumours that arise sporadically or associated with nevoid basal cell carcinoma syndrome (NBCCS). PTCH mutation can be found in sporadically or NBCCS associated KOCTs. Few PTCH mutations in families with non-syndromic KOCTs have been reported. Through PCR and gene sequence analysis, the authors discovered one missense mutation c.3277G>C in exon 19 of PTCH gene in a Chinese family with non-syndromic KOCTs. This mutation causes one highly conserved glycine residue transit to arginine on the 10th transmembrane region of PTCH protein. This work revealed that the missense mutation of PTCH is the causative and dominant gene of KOCTs in this family.

The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.

Odontogenic keratocysts are relatively common lesions that may occur in isolation or in association with nevoid basal cell carcinoma syndrome (or Gorlin syndrome). The PTCH gene has been reported to be associated with Gorlin syndrome. We investigated 10 cases of non-syndromic keratocysts and two other cases associated with Gorlin syndrome, looking for PTCH mutations. Four novel and 1 known PTCH mutations were identified in five individual patients. Of the 5 mutations identified, 2 were germ-line mutations (2619C>A; 1338_1339insGCG) in 2 cysts associated with Gorlin syndrome, and 3 were somatic mutations (3124_3129dupGTGTGC; 1361_1364delGTCT; 3913G>T) in 3 non-syndromic cysts. This report describes PTCH mutations in both non-syndromic and Gorlin-syndrome-related odontogenic keratocysts in Chinese patients, and suggests that defects of PTCH are associated with the pathogenesis of syndromic as well as a subset of non-syndromic keratocysts.

In this study, we assessed the role of melanocortin 1 receptor ( MC1R ) variants and of two patched ( PTCH ) polymorphisms (c.3944C>T (P1315L), insertion 18bp IVS1-83) as risk factors for basal cell carcinoma (BCC) in the French population. The population investigated comprised 126 BCC patients who were enrolled on the basis of specific criteria (multiple and/or familial BCC and/or onset before the age of 40 years and/or association with another tumor) – and 151 controls matched for ethnicity, age, and sex. MC1R variants appeared as a moderate risk factor for BCC (odds ratio (OR) for one and two variants, 2.17 [1.28–3.68] and 7.72 [3.42–17.38], respectively), independently of pigmentation characteristics (OR=2.53 [1.34–4.8]). Interestingly, in addition to the predictable red hair color (RHC) alleles, two non-RHC alleles (V60L and V92M) were also closely associated with BCC risk (OR 3.21 [1.91–5.38] and 2.87 [1.5–5.48], respectively), which differs from the situation in the Celtic population. In addition, the PTCH c.3944C/C genotype was also associated with BCC risk (OR 1.94 [1.2–3.1]), especially in the subgroup of patients with multiple tumors (OR 2.16 [1.3–3.6]). Thus, our data show that MC1R and PTCH variants are associated with BCC risk in the French population. We further suggest that assessing MC1R and PTCH status could be useful, combined with the assessment of clinical risk factors, in identifying high-risk patients to be targeted for prevention or more rigorous surveillance.

Resume Introduction La naevomatose basocellulaire ou syndrome des hamartomes basocellulaires est une genodermatose de transmission autosomique dominante caracterisee par des anomalies du developpement et une predisposition aux cancers. Le gene PTCH 1, localise en 9q22.3 est le gene responsable de la naevomatose basocellulaire. L’objectif de ce travail etait de rapporter les caracteristiques cliniques et genetiques des malades suivis pour une naevomatose basocellulaire et de les comparer aux donnees de la litterature. Malades et methodes Une recherche de mutation du gene PTCH 1 a ete realisee chez 22 malades suivis entre 1981 et 2003 pour suspicion clinique de naevomatose basocellulaire. Les donnees cliniques et radiologiques etaient recueillies retrospectivement dans les dossiers. L’analyse genetique etait realisee sur un echantillon de sang apres signature d’un consentement eclaire par le malade. Si une anomalie du gene PTCH 1 etait identifiee, l’analyse etait egalement realisee pour les membres de la famille qui l’acceptaient. Resultats Tous les malades avaient des hamartomes basocellulaires, 45 p. 100 des puits palmo-plantaires, 62 p. 100 des kystes odontogeniques et 66 p. 100 une calcification de la faux du cerveau. Les medulloblastomes et les meningiomes etaient les tumeurs associees les plus frequentes. Treize malades avaient une mutation : 6 avaient une forme familiale, 3 une forme sporadique et pour 4 malades, il n’etait pas possible de conclure. Neuf nouvelles mutations germinales distinctes ont ete trouvees. Discussion L’analyse genetique apporte une confirmation moleculaire du diagnostic chez la moitie des malades environ. Il est souhaitable de depister les anomalies cliniques et radiologiques chez les sujets jeunes, afin d’apporter des conseils de prevention notamment en terme de photoprotection.

Background/Aims: Odontogenic keratocysts (OKC) are aggressive lesions in the jaws, which can occur as isolated cases or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations on PTCH gene have been identified in patients with NBCCS. It was hypothesized that PTCH mutations may be causative in isolated OKC. This study aims to investigate germline mutations of PTCH in families with OKC and NBCCS. Methods: Three Chinese families with OKC and NBCCS were enrolled in the study. The diagnosis was based on examination and medical history. Mutation analysis was performed by amplifying all exons of PTCH and sequencing the products. Results: One family with isolated OKC (family 1) and the other two families with NBCCS were diagnosed. Three novel germline mutations in PTCH were identified, including a missense mutation (p.S1089>P) in family 1, a nonsense mutation (p.Q160X) in family 2 and a de novo mutation (c.768_777delGACAAACTTC) in family 3. Conclusions: It is proposed that isolated OKC can be inherited in an autosomal dominant mode. The results suggest that germline mutations on PTCH can cause isolated OKC, and that the PTCH gene responsible for NBCCS plays an important role in the formation of OKCs even when they are not syndrome-related.

Summary PTCH gene is well-known to be responsible for the development of Gorlin syndrome. It is also believed that PTCH mutation is responsible for the developmental of odontogenic keratocysts both in the Gorlin syndrome related and the sporadic cases. There is a conflict opinion in the literature regarding its role in odontogenic cysts. Furthermore, it is not known whether PTCH expression has any relevant clinical role in the outcome of the odontogenic cysts. In this study 8 odontogenic keratocysts, 16 dentigerous cysts and 23 radicular cysts treated in the academic hospital of the Free University of Brussels were subjected to an immunohistochemistry study for their expression of PTCH. The data obtained were linked to the clinical behaviour of the cysts for a follow-up of up to 20 years. Eighty eight percent of the odontogenic keratocysts (OKC), 67% of dentigerous cysts, (DC) and only 25% of radicular cysts (RC) expressed PTCH. This difference was statistically significant. Seventeen patients could be called back for clinical evaluation, the follow-up ranged from 10 to 20 years. Four patients suffering from OKC had clinical complications, 3 in the DC group and 2 in the RC group. Complications ranged from (multiple) recurrence to one case of transformation into an ameloblastoma. Only one patient suffered from clinical complication of a RC without being PTCH positive. One patient who had a PTCH negative DC and seven patients with PTCH negative RC had no clinical complications. The results indicate that PTCH expression in odontogenic cysts is more likely to be the reason of clinical complication rather than a cause of pathogenesis.

The purpose of this report is to document the clinical, radiographic, pathological and molecular findings of the first case of multiple orthokeratinized odontogenic cysts (OOCs). Multiple odontogenic keratocysts are one of the major features of nevoid basal cell carcinoma syndrome (NBCCS), and loss of heterozygosity in the PTCH gene, the culprit gene for NBCCS, has recently been found in sporadic OOC cases. Therefore, in this presenting case, we also investigated the possibility that this patient might also have NBCCS, by comparing the available clinical information and the molecular findings of this case to the diagnostic criteria for NBCCS (as proposed by the First International Colloquium on NBCCS in 2011). However, this patient with multiple OOCs showed no evidence of having NBCCS. This conclusion supports the findings from previous case series based on sporadic cases that OOC does not appear to be associated with NBCCS.

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.

Brooke-Spiegler syndrome represents an autosomal dominant disease characterized by the occurrence of multiple cylindromas, trichoepitheliomas and (sporadically) spiroadenomas. Patients with Brooke-Spiegler syndrome are also at risk of developing tumors of the major and minor salivary glands. Patients with Brooke-Spiegler syndrome have various mutations in the CYLD gene, a tumor-suppressor gene located on chromosome 16q. To date, 68 unique CYLD mutations have been identified. We describe two families with Brooke-Spiegler syndrome, one with familial cylindromatosis and one with multiple familial trichoepithelioma, which showed wide inter-family phenotypic variability. Analysis of germline mutations of the CYLD and PTCH genes was performed using peripheral blood. In addition, formalin-fixed paraffin-embedded tumor samples were analyzed for PTCH somatic mutations and cylindroma cell cultures were obtained directly from patients for further growth and analysis. Clinically, the major features of Brooke-Spiegler syndrome include the presence of heterogeneous skin tumors and wide inter- and intra-familial phenotypic variability. Histopathologically, both cylindromas and trichoepitheliomas were found in affected individuals. Mutations or loss of heterozygosity was not found in CYLD and PTCH genes. In CYLD and PTCH mutation-negative patients, other genes may be affected and further studies are needed to clarify whether these patients may be affected by de novo germline mutations.

Purpose TO document the clinical, functional, and in vivo microanatomic characteristics of a patient with Gorlin-Goltz syndrome with a novel nonsense mutation in PTCH (patched). Methods Optical coherence tomography (OCT), fluorescein angiography, electrophysiologic testing, visual field, magnetic resonance imaging, and mutation screening of PTCH gene. Results Visual acuity was 20/20 in the right eye and 20/25 in the left. Fundus examination revealed myelinated nerve fibers in the left eye and bilateral epiretinal membranes with lamellar macular hole also documented with macular OCT. A reduction of the retinal nerve fiber layers in both eyes was found with fiber nervous OCT. Fluorescein angiography showed bilaterally foveal hyperfluorescence and the visual field revealed inferior hemianopia in the right eye. Pattern visual evoked potentials registered a reduction of amplitude in both eyes and latency was delayed in the left eye. Pattern electroretinogram showed a reduction in P50 and N95 peak time and a delay in P50 peak time in the left eye. Flash electroretinogram was reduced in rod response, maximal response, and oscillatory potentials in both eyes. Cone response was normal and 30-Hz flicker was slightly reduced in both eyes. Mutation screening identified a novel nonsense mutation in PTCH. Conclusions A novel nonsense mutation in the PTCH gene was found. We report the occurrence of epiretinal membranes and the persistence of myelinated nerve fibers. Electrophysiologic and visual field alterations, supporting a neuroretinal dysfunction, were also documented.

Caso clínico: Varón de 77 años con enfermedad de Parkinson y demencia senil. Presentaba múltiples carcinomas basocelulares faciales y ectropión en ojo izquierdo. Comenzó con insuficiencia respiratoria y fue diagnosticado de ameloblastoma en fosa nasal izquierda e intervenido quirúrgicamente. Discusión: El síndrome de Gorlin es una enfermedad autosómica dominante caracterizada por carcinomas basocelulares, anomalías esqueléticas y del sistema nervioso. Su pronóstico depende de la evolución de las lesiones malignas. Es importante sospechar un síndrome de Gorlin en pacientes jóvenes con múltiples carcinomas basocelulares o en pacientes que acuden al oftalmólogo con estas lesiones a nivel palpebral, ya que su seguimiento es fundamental. Clinical case: A 77 year-old male patient with Parkinson’s disease and senile dementia had many facial basal cell carcinomas and an ectropion of the left eye. When he experienced respiratory difficulty he was diagnosed to have an ameloblastoma in left nostril requiring surgery. Discussion: Gorlin syndrome is an autosomal dominant condition characterized by basal cell carcinomas, and skeletal and neurological anomalies. The presence of multiple basal cell carcinomas on the eyelids in a child or in a young patient should alert ophthalmologists to the possibility of this syndrome.

Neurologic involvement in nevoid basal-cell carcinoma syndrome includes intracranial calcification, congenital hydrocephalus, intracranial neoplasms, and mental retardation. A few cases of epilepsy with nevoid basal-cell carcinoma syndrome were reported. We report on a patient with nevoid basal-cell carcinoma syndrome and West syndrome. The patient had a heterozygous mutation (insertion of TGGC) in the PTCH gene. This mutation causes a shift of the reading frame, and creates a stop codon predicting the truncation of the PTCH protein. This mutation was not found in previously described patients with nevoid basal-cell carcinoma syndrome.

Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is a rare autosomal dominant disorder characterized by developmental abnormalities, cysts of the skin, jaws, and mesentery and cancer predisposition to basal cell carcinomas (BCC), medulloblastomas, meningiomas, fibromas of the ovaries and heart. The syndrome is caused by mutations in the human homolog of the Drosophila patched gene, PTCH. PTCH is a tumor supressor gene, located at 9q22.3, and encodes a 12 transmembrane glycoprotein that acts as an antagonist in the Hedgehog signaling pathway. We present a Gorlin syndrome patient with typical phenothypical features of widespread basal cell carcinomas, jaw malformations, strabismus and mental retardation, with family history that beside basal cell carcinomas includes lung cancer and gastrointestinal carcinomas. Since we found no mutations in exons of PTCH gene with conventional methods of SSCP, dHPLC screening and direct sequencing, we developed a new method of semi-quantitative fluorescent multiplex PCR with polymorphic markers surrounding PTCH gene. With this method we defined a deletion of 4.5 Mb in size between markers SHGC- 110746 and SHGC-132418 (9q22.3-9q31.1).Those results confirm previously reported findings that large deletions in PTCH region may also cause Gorlin syndrome through haploinsuficiency of PTCH gene.

Basal cell carcinoma (BCC) of the skin is the most common human cancer, and shows a conitnously increasing incidence. BCCs occur predominantly on sun-exposed skin of elderly fair-skinned people. Several tumor suppresor genes and oncogenes have been implicated in the pathogenesis of BCCs, and most of them are members of the Hedgehog signaling pathway. Hedgehog signaling pathway is one of the most fundamental signal transduction pathways in embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin and hair. Patched is a part of the Hedgehog-Gli signaling pathway. Patched is a 12-pass transmembrane protein which acts as a receptor for Hedgehog. When Hedgehog protein is not present, Patched represses the activity of Smoothened, another transmembrane protein. In case of Hedhegog binding to Patched, the repression is alleviated, and Smoothened is able to transmit the signal downwards toward transcription factors. When the signal is absent transcription factor Gli is located in the cytoplasm, where it is inactive. If Smoothened is activated, Gli transcription factor is ubiquitinated and transferred into nucleus. There it is responsible for target gene transcription, including Patched itself. Aberrant activation of the pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and also pancreatic, gastrointestinal and other cancers. We are investigating the role of pathway genes in sporadic BCCs underlining their importance in pathogenesis of the disease.

Clinical manifestations of an family case with Gorlin syndrome characterized by the usual phenotype features such as widespread basocellular tumors and craniofacial and bone malformations, but also including a less common appearance of craniopharyngioma might be associated with a novel constitutional mutation of PTCH gene. The novel PTCH mutation and clinical manifestations within Gorlin syndrome family links PTCH haploinsufficiency and aberrant activation of the Wnt pathway. Genetic analyses were performed on DNA samples extracted from blood leukocytes and tumor fresh or paraffin tissues including LOH (loss of heterozygosity) analysis, dHPLC and sequencing. Immunohistochemical analysis was performed on paraffin slides of tumor tissues. We found a novel constitutional mutation of PTCH gene, 1047insAGAA in exon 7 leading to termination of Ptch protein at exon 9. The family tumors we analyzed show extensive LOH in the PTCH region, both basocellular and in particular craniopharyngioma, and in the latter high expression of beta-catenin was detected. Our findings suggest involvement of the SHH/PTCH/SMO pathway in pathogenesis of the analyzed disorders, including its possible contribution to aberrant activation of the Wnt pathway in craniopharyngioma.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental and skeletal anomalies, palmo-plantar pits, odontogenic keratocysts, ectopic calcification, and occurrence of various types of tumors including basal cell carcinoma. Recent evidence has indicated that the human homologue of a Drosophila segment polarity gene, PTCH, is a NBCCS susceptibility gene. In the study presented here, we detected two novel mutations of the PTCH gene, I805X/2395delC and Y93X/C297A, in two unrelated Japanese patients. Early protection of the skin from the sunlight is important to the prevention of BCC development in NBCCS patients. Genetic analysis of the PTCH gene is essential for the early, definitive diagnosis of NBCCS, especially before the expression of clinical manifestations is complete.

We have been analyzing molecular genetic alterations of the Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome (NBCCS) region, chromosome 9q22.3 in ovarian fibromas, the third tumor by incidence in the syndrome. Gorlin sindrome or Nevoid Basal Cell carcinoma (NBCCS) syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin, medulloblastomas and ovarian fibromas, as wide spread developmental defects. Syndrome related disorders have been atributted to alterations of PTCH gene, a human homologue of the drosophila segment polarity gene patched, which maps to chromosome 9q22.3. Loss of heterozygosity (LOH) at this site in both sporadic and hereditary basal cell carcinomas and medulloblastomas suggestss that it functions as a tumor suppressor. The aim is to confirm the tumor suppressor role of the Ptch in genesis of ovarian fibromas even when they are not syndrome related. DNA was isolated from fresh tissues and blood leukocytes. The DNA samples were typed for several short tandem repeat polymorphisms spanning chromosome 9p21-q31 in tumors (ovarian fibroma) and matched constitutional tissues. Polymorphic markers D9S287, D9S127, D9S180 and D9S196 and 20 PTCH exons were used. We screened for allelic loss and by SSCP analysis we have been analyzing variability in PTCH exons. PCR reactions were performed and products were fractionated on 6-12% polyacrylamide gels. We found LOH in 30% of sporadic ovarian fibromas. In about 70% ovarian fibromas variability in SSCP pattern was detected. LOH for the ptch region and aberrant SSCP pattern confirmed the expectations that the gene patched has a decisive role in the genesis of ovarian fibromas when they are not syndrome related.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin syndrome is an autosomal dominant disorder characterized by cancer predisposition and multiple developmental defects. Syndrome related disorders have been attributed to alterations of PTCH gene, which plays an important role in Shh signalling pathway. Unresolved complexities of the pathway impede understanding of mechanisms through which PTCH alterations lead to variable phenotype expression in Gorlin syndrome patients, while the role of chromosomal instability is not yet clear. To increase our understanding of NBCCS, every manifestation of the syndrome and associated genetic damage should be seriously considered. Therefore, several atypical NBCCS cases are presented in this paper.

Constitutional hemizygous inactivation of PTCH, the Shh signaling pathway gene that moderates the signal, manifests itself as nevoid basal cell carcinoma syndrome or Gorlin syndrome, a condition variably characterized by a number of developmental disorders and malformations, and by predisposition to some malignancies, basal cell carcinoma in particular. Loss of heterozygosity for the PTCH region was found several years ago in the epithelial lining of odontogenic keratocysts, the cyst type with highly increased incidence in nevoid basal cell carcinoma syndrome. This finding confirmed the expectations that the gene responsible for the syndrome would have a decisive role in the genesis of these cysts even when they are not syndrome related. Suggestive temporal distribution of Shh signaling, recently observed during tooth development, lead us to investigate PTCH association with dentigerous cysts, the other major noninflammatory cyst of odontogenic origin. We report here that PTCH appears to be inactivated in dentigerous cysts, suggesting that it is responsible for their genesis as well. More generally, if our similar observations of incomplete heterozygosity in this region for dermoid cysts can be interpreted as loss of heterozygosity, PTCH alterations may prove to be a necessary, and perhaps the initiating event, in formation and growth of various noninflammatory cysts. This would be consistent with our view that local PTCH inactivation can, under favorable circumstances, lead to persistent though not by itself truly aggressive cell proliferation.

Louhelainen J, Lindstrom E, Hemminki K, Toftgard R. Dinucleotide repeat polymorphism within the tumor suppressor gene PTCH at 9q22.

The PTCH gene, a human homologue of the Drosophila segment polarity gene patched, is a tumor suppressor for Nevoid Basal cell Carcinoma Syndrome (NBCCS) and for sporadic Basocellular Carcinomas of the skin (BCCs). The aim is delineation of the biochemical pathway in which PTCH functions may lead to rational medical therapy for BCCs and possiblyy for other tumors associated with NBCCS. Tumor and blood samples were obtained from skin cancer patients and their family members. We collected NBCCS families, sporadic cases and BCC patients. PCR analysis was performed wwith polymorphic markers of NBCCS region. Allelic loss was scored when DNA from blood was heterozygous and one of the bands in tumor was absent or markedly reduced in intensity. In a clinically diverse series of 10 informative tumors, majority showedLOH for chromosome 9q22.3 markers, mostly D9S287. In cases where LOH for polymorphic markers was not detected it is necessary to search for mutations on PTCH.Inactivation of the gene on chromosome 9q22.3 may be necessary event for basocellular carcinoma. So far different germline mutations along the NBCCS region have been found in DNA samples from NBCCS individuals, but no significant correlation between mutation type and phenotype has been detected.

We investigated the molecular basis for developmental defects in Gorlin syndrome, an autosomal dominant disorder predisposing for neoplasia(basal cell carcinomas, medulloblastomas and ovarian fibromas) as well as wide variety of developmental defects including pits of palms and soles, bifid ribs, spina bifida occulta and keratocysts of the jaws.LOH at 9q22.3 in hereditary tumors as well in sporadic cases implies that the Gorlin syndrome gene is homozygously inactivated and normaly functions as a tumor suppressor.

The nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disease characterized by numerous basal cell carcinomas, odontogenic keratocysts of the jaws, palmar and plantal pits, skeletal abnormalities, and calcification of the falx cerebri. The gene responsible for this syndrome is the PTCH tumor suppressor gene encoding for the sonic hedgehog receptor. In this paper, we report thirteen novel mutations identified in the first screening of NBCCS patients in Italy. Except for p.T230P and p.F505_L506delinsLR, all the other mutations are predicted to determine a premature truncation of the protein. © 2004 Wiley-Liss, Inc.