Nevoid basal cell carcinoma syndrome
Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a genetic condition characterized by a range of manifestations including multiple basal cell carcinomas (BCCs), jaw keratocysts, palmar and plantar pits, and intracranial calcifications. It is inherited in an autosomal dominant manner, primarily due to mutations in the PTCH1 gene, which plays a crucial role in cell signaling involved in embryonic development. Individuals with NBCCS may exhibit distinct facial features and various skeletal anomalies, with many affected developing jaw cysts and skin cancer from a young age.
The syndrome poses a heightened risk for certain tumors, notably medulloblastoma, particularly in those with specific genetic variations. Diagnosis typically involves meeting criteria based on clinical manifestations, supported by imaging and genetic testing. While treatment often includes surgical interventions for cysts and cancers, preventative measures such as avoiding sun exposure are strongly advised to mitigate risks. Despite the associated health challenges, individuals with NBCCS generally have a life expectancy comparable to the broader population. Regular monitoring and surveillance are essential for managing the condition and its potential complications.
Nevoid basal cell carcinoma syndrome
ALSO KNOWN AS: NBCCS; Gorlin syndrome; Basal cell nevus syndrome; Gorlin-Goltz syndrome
DEFINITION Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by such major manifestations as jaw keratocysts, multiple basal cell carcinomas (BCC) of the skin, intracranial calcification of the falx, and palmar/plantar pits. In addition, most affected individuals have skeletal abnormalities and a classic facial appearance. NBCCS is an autosomal dominant condition with high/complete penetrance; approximately 30 to 50 percent of cases result from de novo (spontaneous) mutations.
Risk Factors
All individuals who harbor a mutation in the PTCH1 gene are expected to develop manifestations of NBCCS, however intra- and interfamilial variability in clinical expression is observed. Relatives of an individual with a PTCH1 gene mutation also are at risk for carrying the familial mutation and developing some or all of the syndrome’s clinical features.
Etiology and Genetics
NBCCS results from a mutation in the PTCH1 gene located on chromosome 9q22.3. PTCH1, a tumor-suppressor gene, contains twenty-three exons with five alternative first exons. The PTCH protein is involved in the well-defined Sonic hedgehog-Patched-Gli (Shh-Ptch-Gli) pathway, a highly conserved signaling cascade essential to normal embryogenesis. It appears that while inactivation of the normal PTCH1 gene represents the mechanism resulting in BCC and jaw cysts, changes in the concentration of the PTCH protein in the dosage-sensitive Shh-Ptch-Gli pathway cause the congenital malformations observed in this syndrome.
Symptoms
Development of multiple jaw keratocysts typically begins in the second decade of life and may number in the hundreds to thousands during an individual’s lifetime. BCC usually present in the third decade of life onward, placing individuals at very high risk for skin cancer. Calcification of the falx, visible on anteroposterior (AP) X rays of the skull, is present in the majority of individuals by age twenty. Also included as a major criterion for diagnosis of NBCCS are palmar/plantar pits. The remaining clinical features discussed are considered minor diagnostic criteria. Multiple skeletal anomalies are observed, notably of the vertebrae (bifid and/or splayed) and ribs (bifid and/or wedge-shaped). Additional congenital malformations present in approximately 5 percent of individuals, most frequently cleft lip and/or palate, polydactyly, and eye abnormalities. Approximately 60 percent of patients have a characteristic facial appearance with frontal bossing, macrocephaly, coarse features, and milia (benign, keratin-filled cysts). Sebaceous and dermoid cysts also are common. About 5 percent of children with NBCCS will develop medulloblastoma (also called primitive neuroectodermal tumor), with peak incidence at two years of age. Affected individuals also are at increased risk for cardiac fibromas (2 percent) and ovarian fibromas (20 percent of women). Individuals with an SUFU pathogenic variant are at much greater risk of developing medulloblastoma than those with a PTCH1 pathogenic variant, at a rate of 33 percent v. less than 2 percent, respectively.
Screening and Diagnosis
According to clinical diagnostic guidelines published in 1993, NBCCS is diagnosed in individuals with two major diagnostic criteria and one minor diagnostic criterion, or one major and three minor diagnostic criteria. Verification of a clinical diagnosis often relies on AP and lateral X rays of the skull, orthopantogram (panoramic X ray of the mouth), and chest and spinal X rays. Additional evaluations recommended for initial diagnosis include physical examination for congenital anomalies, dermatologic examination, measurement of head circumference, ophthalmologic examination, echocardiography, and ultrasound examination of the ovaries. Genetic testing is available to identify disease-causing mutations in the PTCH1 gene for molecular diagnosis of NBCCS. At least 60 percent of patients harbor PTCH1 mutations detectable by gene sequence analysis. The majority of these changes cause premature termination of protein translation and include nonsense, frame-shift, and splice-site mutations. Large exonic and whole gene deletions account for the syndrome in a smaller number of patients.
Treatment and Therapy
Surgical excision is performed on jaw keratocysts, especially for those diagnosed early in life. Surgical excision, supplemented by cryotherapy and laser treatment, is used for treatment of BCC. Systemic treatment using retinoids can be tried but is often not well tolerated. Cardiac fibromas, present in a minority of patients and frequently asymptomatic, can be monitored by a pediatric cardiologist. Management of ovarian fibromas typically consists of surgical removal with the option of preservation of the normal ovarian tissue.
Prevention and Outcomes
Avoidance of sun exposure and radiotherapy as well as frequent skin examination are strongly recommended for patients with NBCCS. No other NBCCS-associated tumors necessitate surveillance above that recommended for individuals in the general population. Regarding medulloblastoma, there is no evidence for the efficacy of regular neuroimaging, and it is recommended that frequent computed tomography (CT) be avoided due to risks associated with radiation sensitivity.
Despite the risks for malignancy, lifetime expectancy for individuals with NBCCS is not significantly shortened as compared to that of people in the general population. Additional surveillance recommendations include regular monitoring of head circumference and an orthopantogram every twelve to eighteen months in individuals older than age eight years for detection of jaw cysts. Individuals with SUFU-related NBCCS should have a brain MRI every three to four months until three years of age; every six months until age five; annually until age eight for medulloblastoma; and every three to five years starting at age thirty for meningioma; women should have ovarian ultrasounds at age eighteen years.
A number of therapies are under investigation, including photodynamic therapy with infrared light and topical treatments.
Bibliography
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