Nevoid basal cell carcinoma syndrome (NBCCS, also known as basal cell carcinoma nevus syndrome, multiple basal cell carcinoma syndrome, Gorlin syndrome, and Gorlin–Goltz syndrome,and BCCNS), is an inherited medical condition involving defects within multiple body systems such as the skin, nervous system, eyes, endocrine system, and bones. People with this syndrome are particularly prone to developing a common and usually non-life-threatening form of non-melanoma skin cancer.
About 10% of people with the condition do not develop basal-cell carcinomas (BCCs). The name Gorlin syndrome refers to researcher Robert J. Gorlin (1923–2006).
First described in 1960, NBCCS is an autosomal dominant condition that can cause unusual facial appearances and a predisposition for basal-cell carcinoma, a type of skin cancer which rarely spreads to other parts of the body. The prevalence is reported to be 1 case per 56,000-164,000 population. Recent work in molecular genetics has shown NBCCS to be caused by mutations in the PTCH (Patched) gene found on chromosome arm 9q. If a child inherits the defective gene from either parent, he or she will have the disorder.
Many of the features of NBCCS present as signs rather than symptoms. Symptoms are most likely related to the major findings. Cutaneous symptoms: Local invasion of an aggressive BCC may lead to pain or symptoms (eg, neurologic) related to local invasion. Metastasis is extremely rare.
- Neurologic symptoms: Medulloblastoma, a cerebellar tumor of young childhood, may present with neurologic symptoms in a child who is affected.
- Genitourinary symptoms: Ovarian fibromas are usually asymptomatic, but they may present with pain secondary to torsion.
- Dental symptoms: Odontogenic keratocysts may be asymptomatic, or they may present with jaw pain or abnormal dentition. Physical Despite the recent understanding of the underlying genetic basis of NBCCS, the diagnosis remains clinical. Kimonis et al have suggested the following diagnostic criteria to help the clinician. Although not absolute, these criteria help guide the clinician in choosing laboratory evaluation for both diagnostic purposes and ongoing surveillance. Clinicians must remember that some of the findings listed may present at different ages; therefore, ongoing surveillance with respect to diagnosis may be needed. Diagnosis of NBCCS is made in the presence of 2 major criteria or 1 major and 2 minor criteria. The major criteria consist of the following: (1)more than 2 BCCs or 1 BCC in patients younger than 20 years; (2)odontogenic keratocysts of the jaw (proven by histologic analysis); (3) 3 or more palmar or plantar pits; (4) bilamellar calcification of the falx cerebri; (5) bifid, fused, or markedly splayed ribs; and (6) first-degree relative with NBCCS. The minor criteria include the following: (1) macrocephaly; (2) congenital malformations, such as cleft lip or palate, frontal bossing, coarse facies, and moderate or severe hypertelorism; (3) other skeletal abnormalities, such as Sprengel deformity, marked pectus deformity, and marked syndactyly of the digits; (4) radiologic abnormalities, such as bridging of the sella turcica, vertebral anomalies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands and the feet; and (5) ovarian fibroma or medulloblastoma. In several studies, Evans et al, Shanley et al, Kimonis et al, and Gorlin have documented the incidence of the various features found in the syndrome.
- Characteristic facies occur due to increased calvarial size. Other contributing features include a broadened nasal root, frontal and biparietal bossing, mild hypertelorism, and an exaggerated length of the mandible.
- Ocular findings include congenital blindness due to corneal opacity and cataract or glaucoma, occurring in as many as 10-15% of patients. Strabismus (exotropia) may be seen.
- Cleft lip or palate occurs in 3-5% of patients.
- BCCs are the most common finding in the syndrome (see Media file 1). Of whites older than 40 years, 97% had BCCs. Tumors are usually multiple. BCCs are most common on the face, the neck, and the upper part of the trunk, that is, in sun-exposed areas, but they are also increased in relatively sun-protected areas. Although some lesions may become aggressive, most are not. Tumors largely begin to appear between puberty and age 35 years, but they may appear at a younger age. In 1997, Kimonis et al found that 50% of whites had their first BCC by age 21.5 years, and 90% of them had it by age 35 years. Lesions may present as any kind of clinical or histologic BCC; however, some lesions may be small and resemble milia, small nevi, tags, or hemangiomas. Milia may be seen in as many as 30% of patients with NBCCS.
- Asymmetric palmar and/or plantar pits are seen in 65-87% of all people with NBCCS. When they do develop, they often do so early in life, being found in as many as 80% of patients younger than 10 years. Thus, they may be a helpful early criterion for the diagnosis of NBCCS. More than 3 pits should be noted because the relevance of 1 or 2 pits may not be diagnostic.
- Odontogenic keratocysts are seen in 74-80% of patients. They usually begin to develop in the first decade (after age 7 y), with the peak incidence in the second and third decades, which is younger than seen with isolated odontogenic cysts. They are more common in the mandible than in the maxilla. They are usually asymptomatic, but they may cause pathologic fracture, swelling, loose teeth, or displacement of developing permanent teeth.
- Medulloblastoma (malignant tumors of the cerebellum) occur in 1-4% of patients. They present in childhood, with the greatest risk from birth to 3 years, although cases have been reported as late as 7 years.
- Skeletal abnormalities include polydactyly of the hands or the feet, hallux valgus, pectus excavatum or pectus carinatum, and syndactyly of the second and third fingers. Kyphoscoliosis may also be more common or more severe in NBCCS. Sprengel deformity of the shoulder occurs in 5-10% of patients. A short fourth metacarpal may be seen with increased frequency, although as many as 10% of healthy persons also have this sign.
- Genitourinary system findings include bilateral calcified ovarian fibromas, which are found in 14-24% of women; these are often asymptomatic and rarely become malignant. Men may have associated cryptorchidism or gynecomastia and reduced body hair, although these findings have not been confirmed by recent studies.
- Cardiac findings are less common, but an increased risk of cardiac fibroma may be present. Cardiac fibroma usually presents in children or young adults.
- Other tumors, including fibrosarcoma, rhabdomyosarcoma, and meningioma, may be increased in frequency in persons with NBCCS.
NBCCS, also known as basal cell nevus syndrome (BCNS), is an autosomal dominant syndrome caused by mutations in the PTCH (patched) gene found on chromosome arm 9q. The disease has complete penetrance and variable expressivity. Although clinical features vary more among families than within families, no clear-cut link exists between specific mutations and phenotype. Approximately one third of cases are new mutations.
- Genetics of NBCCS
- First elucidated in fruit flies, the protein product of the patched gene is important in determining segment polarity of wings and limbs (anterior-posterior relationships in developing embryos). In mammals, the patched gene is an important step in a pathway that is required for correct patterning and development of many target tissues, such as the neural tube, the pharyngeal arches, the limb buds, and the somites.
- Its wide-reaching activity accounts for the myriad of findings in patients with NBCCS. The patched gene interacts closely with other important genes, such as the sonic hedgehog gene and the smoothened gene, abnormalities of which may influence the phenotypic outcome of a mutation in the patched gene.
- Other etiologic factors
- Ultraviolet (UV) light exposure appears to be an important cofactor. BCCs are much more common in sun-exposed areas and are much more common in whites with the syndrome. Nevertheless, molecular genetic studies looking for UV-related mutations in BCCs obtained from patients with NBCCS leave the possibility that agents other than UV-B may cause alterations to the gene.
- Patients are particularly sensitive to ionizing radiation (XRT), and reports of multiple BCCs in the radiation portal developing in patients treated with XRT for medulloblastoma exist. Reports of more aggressive BCCs occurring in sites of previous XRT for BCC also exist. Radiobiologic studies on fibroblasts suggest an abnormal response to radiation in fibroblasts obtained from patients with NBCCS.
Diagnosis of NBCCS is made by having 2 major criteria or 1 major and 2 minor criteria.
The major criteria consist of the following:
- more than 2 BCCs or 1 BCC in a person younger than 20 years;
- odontogenic keratocysts of the jaw
- 3 or more palmar or plantar pits
- ectopic calcification or early (<20 years) calcification of the falx cerebri
- bifid, fused, or splayed ribs
- first-degree relative with NBCCS.
The minor criteria include the following:
- congenital malformations, such as cleft lip or palate, frontal bossing, eye anomaly (cataract, coloboma, microphtalmia, nystagmus).
- other skeletal abnormalities, such as Sprengel deformity, pectus deformity, polydactyly, syndactyly or hypertelorism.
- radiologic abnormalities, such as bridging of the sella turcica, vertebral anomalies, modeling defects or flame-shaped lucencies of hands and feet.
- ovarian and cardio fibroma or medulloblastoma (the latter is generally found in children below the age of two).
People with NBCCS need education about the syndrome, and may need counseling and support, as coping with the multiple BCCs and multiple surgeries is often difficult. They should reduce UV light exposure, to minimize the risk of BCCs. They should also be advised that receiving Radiation therapy for their skin cancers may be contraindicated. They should look for symptoms referable to other potentially involved systems: the CNS, the genitourinary system, the cardiovascular system, and dentition.
Genetic counseling is advised for prospective parents, since one parent with NBCCS causes a 50% chance that their child will also be affected.
Treatment is usually supportive treatment, that is, treatment to reduce any symptoms rather than to cure the condition.
- Enucleation of the odontogenic cysts can help but new lesions, infections and jaw deformity are usually a result.
- The severity of the basal-cell carcinoma determines the prognosis for most patients. BCCs rarely cause gross disfigurement, disability or death.
- Genetic counseling