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Nevoid basal cell carcinoma syndrome

Authors
Benjamin Barankin, MD, FRCPC
Gary Goldenberg, MD
Section Editors
Robert S Stern, MD
June K Robinson, MD
Deputy Editor
Rosamaria Corona, MD, DSc

INTRODUCTION

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare inherited multisystem disorder that is due to germline mutations in the human homolog of the patched (PTCH) gene. The estimated prevalence is between 1 in 57,000 and 1 in 164,000 persons [1-3].

First reported in 1894, the clinical manifestations of NBCCS were more clearly defined in 1960 by Gorlin and Goltz [4]. Affected patients have multiple developmental anomalies and the early onset of multiple nevoid basal cell carcinomas (BCCs) and medulloblastomas, usually by age 35 [5]. Other synonyms for NBCCS include the Gorlin or Gorlin-Goltz syndrome, basal cell nevus syndrome, bifid-rib basal-cell nevus syndrome, basal cell cancer syndrome, and multiple basal cell nevi.

MOLECULAR GENETICS

PTCH1 mutations — Nevoid basal cell carcinoma syndrome (NBCCS) is inherited as an autosomal dominant trait with a high degree of penetrance (approximately 97 percent), but variably expressed [6]. The cause is a germline inactivating mutation involving the human homolog of the Drosophila PTCH1 (patched) gene, which is located on chromosome 9q22.3 [2,7-10]. In most cases, loss of function mutations in PTCH1 result in premature termination of the PTCH protein [11-14]. Loss of heterozygosity at this site in both hereditary and sporadic basal cell carcinomas (BCCs) suggests that it functions as a tumor suppressor gene (see 'PTCH1 in sporadic basal cell carcinomas' below) [15]. In a manner similar to the retinoblastoma gene, two somatic "hits" in the same cell appear to be required for sporadic cases, while one somatic "hit" plus the inheritance of one defective allele underlies familial cases [16]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Pathogenesis'.)

SUFU mutations — Germline heterozygous loss-of-function mutations in the suppressor of fused gene (SUFU) on chromosome 10q24.32, encoding a component of the sonic hedgehog/patched signaling pathway, have been found in individuals from families meeting the diagnostic criteria for Gorlin syndrome without mutations in PTCH1 [17]. SUFU mutations appear to be associated with a greatly increased risk of developing a childhood medulloblastoma.

MOLECULAR PATHOGENESIS

The only known function of the PTCH protein is as a receptor for the hedgehog (HH) protein, a component of the sonic hedgehog (SHH) signaling pathway (figure 1).

                                  

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