Two male patients with bifid rib-basal cell nevus-jaw cyst syndrome (BCNS) were admitted to Department of Stomatology, the First Affiliated Hospital of Bengbu Medical College due to radiological findings of multiple low density shadows in the jaw. Clinical and imaging findings showed thoracic malformation, calcification of the tentorium cerebellum and falx cerebrum as well as widening of the orbital distance. Whole exon high-throughput sequencing was performed in two patients and their family members. The heterozygous mutations of c.C2541C>A(p.Y847X) and c.C1501C>T(p.Q501X) in PTCH1 gene were detected in both patients. Diagnosis of BCNS was confirmed. The heterozygous mutations of PTCH1 gene locus were also found in the mothers of the two probands. Proband 1 showed clinical manifestations of low intelligence, and heterozygous mutations of c.C2141T(p.P714L) and c.G3343A(p.V1115I) were detected in FANCD2 gene. Proband 2 had normal intelligence and no FANCD2 mutation. The fenestration decompression and curettage of jaw cyst were performed in both patients. Regular follow-up showed good bone growth at the original lesion, and no recurrence has been observed so far.
Humans ; Male ; Basal Cell Nevus Syndrome/diagnosis* ; Mutation ; Nevus ; Patched-1 Receptor/genetics* ; Pedigree ; Ribs/abnormalities*

BACKGROUNDNevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disease characterized by a combination of development anomalies and a predisposition to tumour formation. Mutation of patched gene (PTCH), considered the molecular defect of NBCCS, in a Chinese NBCCS family was investigated in this study.

METHODSGenomic DNA was isolated from blood samples of all 12 members of this family. The mutated PTCH gene was screened by polymerase chain reaction amplification and direct sequencing.

RESULTSA new mutation of 3 bp (GAT deletion) was found in all seven affected members of this family. This mutation caused one aspartate deletion in the fourth transmembrane domain of the PTCH protein located within the sterol sensing domain (SSD). This deletion was not found in any unaffected members of this family nor in 200 control samples.

CONCLUSIONSOur findings suggest that one 3-bp deletion in PTCH gene was the cause of nevoid basal cell carcinoma in a Chinese family through affecting the conformation and function of PTCH protein.

Basal Cell Nevus Syndrome ; genetics ; Humans ; Mutation ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface ; genetics

The first three disorders discussed are abnormalities of bone: too little bone in cleidocranial dysplasia caused by mutations in RUNX2; too much bone in fibrodysplasia ossificans progressiva with overexpression of BMP4; and abnormal bone in McCune-Albright syndrome and fibrous dysplasia caused by mutations in GNAS1. Disorders of the sonic hedgehog signaling network are discussed next, including holoprosencephaly and the nevoid basal cell carcinoma syndrome, the former being caused by sonic hedgehog (SHH) mutations and the latter being caused by patched mutations (PTCH).
Basal Cell Nevus Syndrome ; genetics ; Craniofacial Abnormalities ; genetics ; Gene Expression Regulation, Developmental ; Holoprosencephaly ; genetics ; Humans ; Mutation

Objective: To detect the SMO mutations in odontogenic keratocyst (OKC) and to explore the mechanism behind. Methods: Patients with OKC who received treatment in the Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology,Peking University, from September 2012 to June 2017 were enrolled. OKC samples from 10 patients diagnosed as naevoid basal cell carcinoma syndrome (NBCCS)-related OKC (4 females and 6 males) and 20 patients diagnosed as sporadic OKC (7 females and 13 males) were collected. Genomic DNAs were extracted from fibrous capsules and epithelial lining respectively. SMO mutations were detected and analyzed by Sanger sequencing. Results: Three SMO mutations were found in one NBCCS-associated OKC who carrying c.2081C>G (p.P694R) mutation) and two sporadic OKC who carrying c.907C>T (p.L303F) mutation and c.1247_1248delinsAA (p.G416E), respectively), among which the first two mutations were novel mutations that had not been reported before. Besides, two mutations in sporadic OKC were not paired with PTCH1 mutations. Conclusions: In addition to PTCH1 gene mutations, SMO gene mutations also exist in OKC which might be related to the development of OKC.
Basal Cell Nevus Syndrome/genetics* ; Female ; Humans ; Male ; Mutation ; Odontogenic Cysts/genetics* ; Odontogenic Tumors/genetics* ; Smoothened Receptor/genetics*

OBJECTIVETo study the molecular genetic etiology of a Chinese pedigree with basal cell nevus syndrome.

METHODSThe proband and his affected mother and a unaffected individual in the pedigree were chosen and peripheral blood was collected from them for DNA. Direct sequencing was performed to detect the mutations of PTCH gene. In order to further confirm the results of sequence analysis, all available family members were analyzed with genetic linkage analysis using 3 highly polymorphic microsatellite DNA markers in the region of 9q22.3-q31.

RESULTSNo mutations of PTCH gene was detected in the proband's mother, one synonymous mutation was detected in the proband. Linkage analysis showed that the Lod scores of the 3 markers were: D9S283, Z = -2.11 (theta = 0.00); D9S1690, Z = -2.95 (theta = 0.00); D9S1677, Z = -5.94 (theta = 0.00).

CONCLUSIONSIn this pedigree, mutation of PTCH gene is not related to the underlying pathogenesis of the syndrome.

Asian Continental Ancestry Group ; genetics ; Basal Cell Nevus Syndrome ; genetics ; Female ; Genetic Linkage ; Humans ; Male ; Mutation ; Patched Receptors ; Patched-1 Receptor ; Pedigree ; Receptors, Cell Surface ; genetics

Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1 cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
Anilides ; pharmacology ; Basal Cell Nevus Syndrome ; Hedgehog Proteins ; genetics ; pharmacology ; Humans ; Molecular Targeted Therapy ; Odontogenic Cysts ; genetics ; physiopathology ; therapy ; Odontogenic Tumors ; genetics ; physiopathology ; therapy ; Pyridines ; pharmacology

OBJECTIVETo investigate the frequency, type and distribution of PTCH mutations in odontogenic keratocysts (OKC) and to analyze the molecular pathological relationship between sporadic OKC and OKC associated with nevoid basal cell carcinoma syndrome (NBCCS).

METHODSGenomic DNA was extracted from 8 cases of OKC lesions (4 sporadic OKCs and 4 NBCCS-related OKCs). PTCH gene mutations were detected by PCR-direct sequencing.

RESULTSSix novel PTCH mutations were identified in 6 out of 8 cases (2 sporadic and 4 NBCCS-related OKCs). Two of these were missense mutations leading to substitution of an amino acid residue respectively. The other 4 mutations were identified as insertion or deletion ranging from one single base to 7 bases, three of which caused frame-shift leading to premature truncation of PTCH protein and one resulted in an insertion of 2 amino acid residues. All these identified mutations were novel and have not been previously described.

CONCLUSIONSPTCH gene mutation is a common event in NBCCS-related OKCs and could also be detected in some sporadic OKCs. Abnormalities of PTCH gene may be involved in the pathogenesis of OKC.

Adolescent ; Adult ; Aged ; Basal Cell Nevus Syndrome ; complications ; genetics ; DNA Mutational Analysis ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Odontogenic Cysts ; complications ; genetics ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface ; genetics ; Young Adult

Hedgehog was first described in Drosophila melanogaster by the Nobel laureates Eric Wieschaus and Christiane Nüsslein-Volhard. The hedgehog (Hh) pathway is a major regulator of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of a rare familial disease, Gorlin syndrome, in 1996. Follow-up studies revealed activation of this pathway in basal cell carcinoma, medulloblastoma and, leukemia as well as in gastrointestinal, lung, ovarian, breast, and prostate cancer. Targeted inhibition of Hh signaling is now believed to be effective in the treatment and prevention of human cancer. The discovery and synthesis of specific inhibitors for this pathway are even more exciting. In this review, we summarize major advances in the understanding of Hh signaling pathway activation in human cancer, mouse models for studying Hh-mediated carcinogenesis, the roles of Hh signaling in tumor development and metastasis, antagonists for Hh signaling and their clinical implications.
Animals ; Antineoplastic Agents ; therapeutic use ; Basal Cell Nevus Syndrome ; drug therapy ; metabolism ; Carcinoma, Basal Cell ; drug therapy ; metabolism ; Cell Differentiation ; Cerebellar Neoplasms ; drug therapy ; metabolism ; Hedgehog Proteins ; antagonists & inhibitors ; metabolism ; Humans ; Medulloblastoma ; drug therapy ; metabolism ; Models, Animal ; Neoplasms ; drug therapy ; metabolism ; Patched Receptors ; Receptors, Cell Surface ; genetics ; metabolism ; Signal Transduction ; drug effects ; Skin Neoplasms ; drug therapy ; metabolism

AIMTo clarify the role of PTCH in patients with NBCCS-related and non-sydromic keratocystic odontogenic tumors.

METHODOLOGYMutation analysis was undertaken in 8 sporadic and 4 NBCCS-associated KCOTs.

RESULTSFour novel and two known mutations were identified in 2 sporadic and 3 syndromic cases, two of which being germline mutations (c.2179delT, c.2824delC) and 4 somatic mutations (c.3162dupG, c.1362-1374dup, c.1012 C>T, c.403C>T).

CONCLUSIONOur findings suggest that defects of PTCH are associated with the pathogenesis of syndromic as well as a subset of non-syndromic KCOTs.

Adolescent ; Adult ; Amino Acid Sequence ; Basal Cell Nevus Syndrome ; genetics ; Chromatography, High Pressure Liquid ; Codon, Nonsense ; genetics ; Codon, Terminator ; genetics ; Conserved Sequence ; genetics ; Cytosine ; Exons ; genetics ; Female ; Frameshift Mutation ; genetics ; Gene Duplication ; Germ-Line Mutation ; genetics ; Guanine ; Humans ; Male ; Middle Aged ; Mutation ; genetics ; Mutation, Missense ; genetics ; Odontogenic Tumors ; genetics ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Deletion ; genetics ; Syndrome ; Threonine ; genetics ; Thymine