A novel splicing mutation of PTCH1 in a Chinese family with nevoid basal cell carcinoma syndrome
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PTCH1
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Nevoid basal cell carcinoma syndrome (NBCCS) manifests multiple defects involving the skin, endocrine and nervous systems, eyes and bones. Mutations in the patched homologue 1 (PTCH1) gene are the underlying causes of NBCCS, leading to aberrant cell proliferation through constitutive activation of the hedgehog signaling pathway. We identified a novel frameshift mutation (c.1207dupT) of PTCH1 in a NBCCS patient, which might explain multiple cystic lesions and neoplastic growth in the patient.
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Nevoid basal cell carcinoma syndrome (NBCCS), or Gorlin Syndrome, is a neurocutaneous disorder caused by mutations in the PTCH1 or, less commonly, SUFU genes. Mutations in these genes lead to malfunction of the sonic hedgehog pathway, causing unregulated cell proliferation and differentiation. As the sonic hedgehog pathway affects hair follicle growth and development, PTCH1 mutations could lead to unregulated hair follicle proliferation. We present the case of a patient whose discrete tufts of hair led to the diagnosis of NBCCS. This case demonstrates that NBCCS should be considered within the differential diagnosis of localized hypertrichosis, as this patient is the sixth case to demonstrate this finding as an early cutaneous sign of BCNS.
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Keratocystic odontogenic tumors (KCOTs, previously known as odontogenic keratocysts) are aggressive jaw lesions that may occur in isolation or in association with nevoid basal cell carcinoma syndrome (NBCCS). Mutations in the PTCH1 ( PTCH) gene are responsible for NBCCS and are related in tumors associated with this syndrome. Mutations in the SMO gene have been identified in basal cell carcinoma and in medulloblastoma, both of which are features of NBCCS. To clarify the role of PTCH1 and SMO in KCOTs, we undertook mutational analysis of PTCH1 and SMO in 20 sporadic and 10 NBCCS-associated KCOTs, and for SMO, 20 additional cases of KCOTs with known PTCH1 status were also included. Eleven novel (1 of which occurred twice) and 5 known PTCH1 mutations were identified. However, no pathogenic mutation was detected in SMO. Our findings suggest that mutations are rare in SMO, but frequent in PTCH1 in sporadic and NBCCS-associated KCOTs. Abbreviations: NBCCS, nevoid basal cell carcinoma syndrome; KCOTs, keratocystic odontogenic tumors; BCCs, basal cell carcinomas.
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Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin Syndrome, affects only 1 in 56 000 people. It is usually inherited from a parent with the condition and affects both males and females equally (autosomal dominant inheritance). People with NBCCS may show characteristic features such as extra fingers or toes, irregular ribs, an unusually shaped face and large head. Tumours sometimes develop, particularly jaw cysts and basal cell carcinomas (BCCs) of the skin from which the syndrome is named. NBCCS is caused by mistakes (mutations) in a gene called PTCH1 located on the long arm of chromosome 9. PTCH1 acts as a brake on a set of chemical processes in cells called the Hedgehog (HH)/GLI signalling pathway. In NBCCS, mutations inactivate PTCH1 allowing excessive Hedgehog signalling. This loss of control results in the abnormal bones and tumours. Within an affected family, people with the same genetic mutation can have very different abnormalities. This group from Spain studied 22 unrelated Spanish people with NBCCS to see if they could discern any relationship between specific clinical abnormalities and specific genetic mutations. BCCs were very common, occurring in 96% of patients with 43% having more than 50; 77% had jaw cysts. Two abnormalities had not previously been recognised in NBCCS: double uterus and a benign nerve tumour. They found 19 PTCH1 mutations that had not previously been reported. However, they could not find any pattern relating the type of mutation to the clinical abnormalities. Presumably other factors besides the PTCH1 mutation causes the clinical features.
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Mutations in the Patched homolog 1 (PTCH1) gene lead to an autosomal dominant disorder known as nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin syndrome (GS). Several PTCH1 mutations have been observed in NBCCS associated with keratocystic odontogenic tumors (KCOTs), including non-syndromic KCOTs. The missense mutation c.3277G>C (p.G1093R) in exon 19 of the PTCH1 gene has only been reported in non-syndromic KCOTs. The present study reports for the first time a familial case (father and daughter) of NBCCS and KCOTs, carrying the same c.3277G>C (p.G1093R) germline mutation. This observation suggests that this missense mutation is involved in the pathogenesis of NBCCS as well as in a subset of non-syndromic KCOTs. The identification of a missense mutation may lead to an earlier diagnosis of NBCCS.
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Abstract Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is inherited in an autosomal dominant manner and is characterized by a combination of developmental abnormalities and a predisposition to tumor formation. Hedgehog receptor Patched 1 ( PTCH1 ) has been identified as the mutated gene in NBCCS. We identified the PTCH1_c.3298_3299insAAG_p.1099_1100insE mutation in the transmembrane region, which comprises a sterol transporter whose abnormal function is reportedly related to pathogenicity.
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A familial case of nevoid basal cell carcinoma syndrome with a frameshift mutation in the PTCH1 gene
Nevoid basal cell carcinoma syndrome (NBCCS) is a condition characterized by findings such as a keratocystic odontogenic tumor (KCOT), basal cell carcinoma, and small pits on the palms or the soles of the feet. The responsible gene is PTCH1. In this paper, we report on a parent and child with NBCCS in whom we resected the KCOT and confirmed a PTCH1 genetic mutation. Case 1 developed in a 14-year-old boy, and case 2 was in a 32-year-old woman, the mother of the boy of case 1. Both patients underwent multiple maxillary tumorectomies, and a histopathological diagnosis of KCOT was obtained. Genetic analysis confirmed the presence of a frameshift mutation in the PTCH1 gene in both the parent and the child. Even with the diagnostic criteria of Kimonis et al, a diagnosis of NBCCS was reached. Many similar cases of NBCCS are encountered in dentistry and oral and maxillofacial surgery, and the dentist is considered to play an important role in diagnosis, treatment, and explanation of the condition. Moreover, because some symptoms emerge with advancing age, PTCH1 genetic analysis should be proactively performed to achieve an early diagnosis.
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