Nevoid basal cell carcinoma syndrome (NBCCS)

Gorlin syndrome

Gorlin-Goltz syndrome

Basal cell nevus syndrome, BCNS (OMIM 109400)

Fifth phacomatosis

The syndrome, delineated by Gorlin and Goltz in 1960 [1], was first reported in 1894 [2, 3] and has been given several different names:

• Gorlin syndrome

• Gorlin-Goltz syndrome

• Nevoid basal cell carcinoma syndrome (NBCCS)

• Multiple nevoid basal-cell carcinoma syndrome (MNBCCS)

• Multiple basal-cell carcinoma syndrome

• Basal cell nevus syndrome (BCNS)

• Multiple basalioma syndrome

• Fifth phacomatosis

• Jaw cysts-basal cell tumors-skeletal anomalies syndrome

• Odontogenic keratocytosis-skeletal anomalies syndrome

• Multiple nevoid basal-cell epithelioma-jaw cysts-bifid rib syndrome

• Hereditary cutaneomandibular polyoncosis

• Epitheliomatose multiple generalisee

Currently, this disorder, resulting from mutations in the PTCH1 gene, is called the nevoid basal cell carcinoma syndrome (NBCCS), as Professor Gorlin suggested. However, patients and their relatives prefer to use the name "Gorlin syndrome", since it does not contain the word "carcinoma", even if about 50% of white patients will develop a significant number of skin cancers. Skin cancers do not generally occur in black patients [4].

Diagnostic criteria, based on the most frequent and/or specific features of the syndrome, were defined by Evans et al. in the Journal of Medical Genetics in 1993 [5], and modified by Kimonis et al. in 1997 [6].

NBCCS is a hereditary condition caused by mutations in the PTCH1 gene and is transmitted in an autosomal dominant manner with high penetrance and variable expressivity [93, 94]. There is no sexual predilection. Individuals with no known affected family members may comprise up to 60% of all affected individuals [95].

The PTCH1 gene has recently been mapped to the long arm of chromosome 9 (q22.3-q31) with no apparent heterogeneity [8, 96]. Approximately 50% of NBCCS patients have allelic losses including this site [97]. Data suggest that the product of this gene acts as a tumor suppressor [96, 98, 99]. Furthermore, the typical malformative pattern of NBCCS suggests that the gene has a fundamental function in controlling growth and development of normal tissues [100]. This gene was isolated in 1996 as the human homolog of the Drosophila PTCH1 gene, simultaneously in Australia and in the USA [101, 102].

The PTCH1 gene in the fruit fly is important for body segmentation. If the gene is faulty, abnormal segmentation occurs. Several mutations of the PTCH1 gene have been identified in patients with NBCCS [101–118], and, in those with BCCs and medulloblastomas that are apparently not hereditary [119, 120].

The gene consists of 23 exons, which span 34 kb. It encodes a transmembrane glycoprotein composed of 1447 amino acids, with 12 transmembrane domains and two large hydrophilic extracellular loops where Sonic Hedgehog (SHH) ligand binding occurs. If a mutation occurs in PTCH1 and the second loop is not formed, SHH cannot bind.

Thus, the PTCH1 gene product acts as membrane receptor [121] for the SHH signal and represses transcription (in certain cells) of genes encoding signaling proteins belonging to the transforming growth factor (TGF)-beta and Wnt families. The Hedgehog (Hh) family comprises several regulation factors described in several species. SHH is a true signaling switch used in differentiating subpopulations of cells throughout the embryo; in fact, SHH patterning is involved in several embryonal processes, such as the formation of the ventral neural tube (basal plate, motor columns), the limb bud, parts of the brain, hair follicle development, and tooth development. PTCH1 in the absence of its ligand, SHH, acts a cell-cycle regulator, normally inhibiting expression of downstream genes that control cell fate, patterning, and growth [122]. In the case of a C-terminal truncation caused by a mutation in PTCH1, these genes are no longer repressed.

The molecular biology of cancers in NBCCS is similar to that of retinoblastoma, the prototypical pediatric cancer syndrome, which is characterized by mutations in a recessive oncogene. Data from patients with retinoblastoma support the Knudson two-hit hypothesis; this theory of oncogenesis states that normal cells require two mutagenic hits (two distinct episodes of DNA damage) to produce a cancer. Patients with retinoblastoma, NBCCS, and other similar syndromes have a constitutional (germline) defect in the DNA sequence in one of the two copies of a tumor suppressor gene. A defect in one of the two copies is insufficient to cause a cancer. If a second DNA injury or if loss of the normal remaining allele occurs at the same locus (the second hit), the cell may become malignant. In NBCCS, various tumors and hamartomas (BCC, OKCs, meningiomas, ovarian fibromas) exhibit loss of heterozygosity [123, 124], but other lesions do not, for example, palmar pits [125]. Loss of heterozygosity at the PTCH1 locus has been observed in almost 90% of hereditary BCCs. Various physical anomalies (bifid rib, macrocephaly) apparently need only one hit. An interesting aspect of this syndrome is that some of the developmental defects (e.g. jaw cysts) appear to have two genetic hits but without developing into a true malignancy. In some patients, the lining of these odontogenic keratocysts has lost the normal gene for NBCCS, while retaining the mutant allele. Agaram et al. found that 70% of jaw cysts showed loss of heterozygosity of one or more of the several common tumor suppressor genes [126]. This finding may explain the behavior of jaw cysts, which may be more similar to low-grade neoplasms than congenital malformations.

Analysis of gene mutations in the syndrome has identified deletions, insertions, splice site alterations, nonsense and missense mutations, with no hot spots identified for mutations. About 70% of germ-line PTCH1 mutations are rearrangements. Over 80% of these mutations seem to result in a truncation of the coded protein [115], which suggests that developmental anomalies seen in NBCC syndrome may be due to haplo-insufficiency [127]; recently, PTCH1 mutations have been reported as a result of errors in the recombinational repair process [109].

In 2006 Lindström et al. analyzed 284 mutations and 48 single nucleotide polymorphisms (SNPs) located in the PTCH1 gene, compiled from a PTCH1 mutation database [110]. They found that the PTCH1 mutations were mainly clustered into the two large extracellular loops of the corresponding protein and its large intracellular loop [110]. The SNPs appeared to be clustered around the sterol-sensing domain and the second half of the protein [110]. NBCCS cases and each class of tumor analyzed revealed a different distribution of the mutations in the various PTCH1 domains [110]. Moreover, the types of mutations were also unique for the different groups [110]. Finally, the PTCH1 gene harbors mutational hot spot residues and regions, including a slippage-sensitive sequence in the N-terminus [110].

Several studies reported polymorphisms for the PTCH1 gene in North American [128], European [115, 129], Chinese [130], and Japanese [131] populations. Some of these polymorphic variants (i.e., 1686C>T, 2199A>G, 3944T>C, IVS10-51G>C, IVS10-8T>C) occur with a high frequency. A recent study has reported that certain haplotypes of PTCH1 polymorphisms may mediate the susceptibility to basal cell carcinomas [132]. Pedigrees with multiple features of NBCCS were most likely to test positive for PTCH1 mutations [133]. Pedigrees with multiple or early-onset basal cell carcinomas without other features of the disease did not test positive for PTCH1 mutations [133].

PTCH2, highly homologous to PTCH1, has been mapped to chromosome 1p32.1-p32.3 [134]. PTCH2 comprises 22 coding exons and spans approximately 15 kb [134]. It encodes a 1203 amino acid putative transmembrane protein that is highly homologous to the PTCH1 product. Mutations have been found in one simplex case (i.e., a single occurrence of the disease in a family) of medulloblastoma and one simplex case of BCC [134]. No PTCH2 mutations were found in 11 simplex cases of NBCCS or in 11 individuals with familial cases of NBCCS who did not have identifiable PTCH1 mutations. In many cases, medulloblastoma arising from perturbations of PTCH1 function leads to a concomitant up-regulation of the highly similar gene PTCH2. Lee et al. investigated the role of PTCH2 in tumor suppression by generating PTCH2-deficient mice [135]. In striking contrast to PTCH1-/- mice, PTCH2-/- animals were born alive and showed no obvious defects and were not cancer prone [135]. However, loss of PTCH2 markedly affected tumor formation in combination with PTCH1 haploinsufficiency. PTCH1+/-PTCH2-/- and PTCH1+/-PTCH2+/- animals showed a higher incidence of tumors and a broader spectrum of tumor types compared with PTCH1+/- animals [135]. Therefore, PTCH2 modulates tumorigenesis associated with PTCH1 haploinsufficiency [135].

Diagnosis of NBCCS can be made in the presence of two major criteria or one major and two minor criteria [6]:

Precise differential diagnosis needs exclusion of some rare dermatological syndromes, such as Bazex syndrome (characterized by basal-cell carcinoma associated with hypotrichosis, hypohidrosis, milia and folliculare atrophodermia), trichoepithelioma papulosum multiplex (named also epithelioma adenoides cysticum), or Torre's syndrome (Muir-Torre's syndrome).

The syndrome is a hereditary condition, thus referral to a geneticist for counseling is mandatory. NBCC syndrome is caused when one copy of the PTCH1 gene pair contains a fault; this means that every child of a person with the syndrome has a 1 in 2 (50:50) chance of inheriting the faulty gene. The risk to family members is various, about 70–80% of individuals diagnosed with NBCCS have an affected parent and about 20–30% of probands have a de novo mutation. The risk to a sib of a proband depends on the genetic status of the parents: if a parent of the proband is affected, the risk to the sibs is 50%; when the parents are clinically unaffected, the risk to the sibs of a proband appears to be low; if the disease-causing mutation cannot be detected in the DNA of the parent, the risk to sibs is low, but greater than that of the general population because of the possibility of somatic mosaicism or germline mosaicism exists. The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a risk of less than 50% of inheriting the disease-causing mutation. The risk to other family members depends upon the genetic status of the proband's parents; if a parent is affected, his or her family members are at risk.

DNA tests, by looking directly at the mutation in the gene, may confirm that the patient is affected by this syndrome. In clinical situations suggesting genetic predisposition to BCC, germline mutations of PTCH1 are not common [107]. Genetic variants might contribute to the variation in numbers of BCCs and jaw cysts observed in NBCCS families [137].

It is recommended to involve families in regular screening. It may be possible to prove whether someone in a family has inherited the condition or not by DNA tests, either by tracking the chromosome 9 containing the faulty gene, or by direct analysis of the mutation causing the disease in a particular family.

In some families, only one person appears to be affected. This event is the result of two conditions: 1) the mother or the father have the syndrome, but the effects are so mild that it has never been diagnosed; 2) the fault in the PTCH1 gene has occurred for the first time in that family. It is a "new mutation" [16]. If a family member has not inherited the gene, the surveillance program is not necessary.

The definitive diagnostic test is to demonstrate a mutation in the PTCH1 gene, although this is labor-intensive as there are 24 exons. Recently Fujii et al. used newly designed high-resolution oligonucleotide microarrays with a median distance between the probes of 776 bp (average probe interval 2,271 bp) to detect gene deletions in NBCCS patients. This probe interval was chosen because small submicroscopic genomic deletions and duplications constitute up to 15% of all mutations underlying human monogenic diseases. Two out of three deletions could not be detected by conventional chromosomal analysis. A submicroscopic deletion as small as 165 kb was detected affecting only PTCH1, whereas the other two deletions were much larger (5 and 11 Mb) [138].

Antenatal diagnosis may be useful to prevent complications. Ultrasound scans during pregnancy may be helpful in detecting serious developmental malformations, even if they are rare. Some fetuses with NBCCS have large heads and so may need assistance in delivery either by forceps or by Cesarian section. Very rarely, fibroma of the heart may be detected. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at about 15–18 weeks of gestation) or by chorionic villus sampling (CVS) at about 10–12 weeks of gestation. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed. Requests for prenatal testing for conditions such as NBCCS that do not affect intellect, have variable expression and for which some treatments are available, are not common.

Patients affected by Gorlin syndrome must be treated by several specialists. Keratocysts can be treated by surgical removal. This requires exposure of the lesion by making an osteotomy in the jawbone under local or general anesthesia, finding the wall of the cyst and removing this completely. Cysts that recur after such a treatment are removed with a bone box including a layer of bone at the margin of the cyst. This is intended to ablate any daughter cysts; only in extreme cases it is necessary to remove an entire section of the affected jawbone.

As regards BCC, only a small fraction of these tumors become invasive and the very rare cases of death result from spread to the brain or lung. Results from several epidemiologic studies have indicated that the risks of BCCs show a strong positive correlation with exposure to UV radiation. Thus, these patients need to avoid excess sun exposure. They must use 100% UV protective sunglasses as the skin surrounding the eyes (similar to that of the nose/ears) is vulnerable to BCCs. Sunshine during the mid-day hours should be avoided if possible. High factor sunscreens (SPF30+) should be applied before going outside and re-applied every 2–3 hours, or more frequently, if perspiring or swimming.

Radiotherapy should be avoided if possible [6, 21]. Tumors on the scalp can be particularly aggressive and need early intervention [5].

Management of superficial BCCs without follicular involvement can be accomplished by total body application of topical 0.1% tretinoin cream [16]. Patients should be examined every 3 months, and lesions manifesting growth must be excised [16]. More debatable is the use of oral retinoids or combined oral etretinate and surgical treatment [16]. Some authors indicated that doses of 0.5–1.0 mg/kg/day cause regression of lesions of less than 1.0 cm and prevent new lesions [139]. Nevertheless, a study of high-dose oral isotretinoin (mean daily dose: 3 mg/kg/day) found that only 8% of BCCs underwent complete clinical and histological regression, while all patients developed moderate-to-severe acute toxicity [140]. In addition, oral etretinate should not be taken by women of child-bearing age [16], a negative pregnancy test should be obtained prior to therapy and adequate contraception should be used by women during and for at least two months after stopping isotretinoin therapy.

Recent studies indicated that imiquimod 5% cream appears to be an effective treatment for nodular basal cell carcinoma alone [141–145], or if combined with curettage prior to its application [146]. In fact, 17 nodular BCCs on 15 patients were treated by curettage without electrodesiccation followed by once-daily application of imiquimod 5% cream, 5 times per week for 6 weeks; the area was excised and examined histologically 6 weeks after cessation of imiquimod cream and all 17 lesions (100%) showed no histological evidence of residual tumor on the post-treatment excision [146].

Surgical excision is the typical approach for a patient with BCC if the number of lesions is limited. Other treatments that may be effective and more efficient than surgical excision in patients with multiple lesions include laser ablation, photodynamic therapy, and topical chemotherapy [147].

Electrodessication and curettage is a very common procedure used as an alternative to topical chemotherapy in the treatment of small BCCs located in low recurrence areas of the body (neck, trunk, extremities) [148]. The area is first numbed with a local anesthetic injection and then scraped out from surrounding normal skin with a curette. An electrosurgical needle is then used to desiccate (heat and dry up) the remaining cancerous tissue. This is repeated for a total of three or four times in succession in order to achieve maximal cure rates. This form of treatment is quick, efficient and cost effective, but it is of limited value for large lesions and cancers of the mid face due to higher recurrence rates. Pain during treatment is minimal and post-operatively the patient feels nuisance comparable to a small burn. The cosmetic result will appear as a lighter hypopigmented flat spot that is of similar size as the cancer was prior to treatment. The chance of a definitive cure with this procedure is 92–93%. Another possibility is cryosurgery; it is quick, efficient and cost effective. However, this method should be avoided when treating lesions in high recurrence areas. The post-operative cosmetic result, follow-up care, and healing time is very similar to electrodessication and curettage. The overall chance of a cure with this procedure is 92.5%. Cryosurgery, in a few cases, was complicated by nerve damage and numbness, but in general has no side effects, except for scarring. Recently, laser vaporization with the carbon dioxide laser has been used alone or combined with curettage in cases of multiple/superficial tumors [149–151].

Surgical excision by scalpel allows removal of the cancerous tissue plus surrounding normal skin, with minimal discomfort during treatment and in the post-operative period. The cosmetic result is good, but it depends on the size and location of the tumor. The overall chance of a cure with surgical excision may range from 94–98%. Long term side effects include scarring, and rarely, nerve damage. The scalpel excision gives the advantage of being able to check the margins of the specimen microscopically by a pathologist.

Another therapeutic possibility is photodynamic therapy (PDT), a cancer treatment involving use of a photosensitizing dye (given intravenously or topically) that preferentially accumulates within malignant cells [16]. BCCs are then treated with red light (usually produced by a laser) that leads to dye activation and, definitively, to death of these cells [16]. Scabs form over the basal cell carcinomas; the scabs usually fall off by the end of the first month following PDT [16]. The management of patients with NBCCS consists of regular visits (every 2–3 months) to a dermatologist, especially during adolescence [16]. Recently, nodular BCCs resistant to multiple forms of treatment in two patients with NBCCS were treated with systemic porfimer sodium-based photodynamic therapy with a good response to treatment on clinical evaluation and on measurement by a 20-MHz high-resolution ultrasound [152].

Interferon has also been proposed in experimental studies for the treatment of BCCs. This substance is injected directly into the cancer three times each week, for three weeks. Some reports have shown complete resolution of treated tumors, but other studies demonstrated that this treatment was less effective [153]. Side effects include fever, chills, decreased white blood cell count, and pain at the site of injection. This procedure needs to be investigated further.

Patients with Gorlin syndrome can present with medulloblastoma, a malignant tumor of the posterior fossa [52]. Intensive multimodality therapy is typically required to treat medulloblastoma. The best outcomes are obtained in patients who are treated with aggressive resection, chemotherapy, and radiation therapy. Radiotherapy for medulloblastoma causes multiple BCCs in these patients [154, 155] or intracranial and sinonasal tumors [83, 156–158]; thus, post-operative radiotherapy should be used judiciously. This is particularly important in patients with the desmoplastic NBCCS subtype [47]. As a general rule, if possible, patients should be treated without radiation therapy or using a treatment field that only includes the posterior fossa [159], with a skin-sparing nonconformal technique [159]. In fact, the risk of multiple radiation-induced BCC is decreased with this technique that allows the exposition of skin to ionizing radiation to be reduced. On the contrary, this approach may increase the risk of other well-established toxicities, such as ototoxicity and irradiation of the temporal lobes.

The most common lesions accounting for NBCCS are usually not life-threatening. Medulloblastoma may be a potential cause of early death, even if NBCCS patients may have better outcome than patients with sporadic medulloblastoma (as the desmoplastic subtype of medulloblastoma is associated with an improved survival compared to the classic form of medulloblastoma). Therefore, this could be one argument to limit therapy to young children with Gorlin syndrome and desmoplastic medulloblastoma. Problems can derive from some techniques used for the therapy of specific lesions: i.e. radiation therapy for medulloblastoma that may cause multiple BCCs. For this reason, nonstandard treatments should be considered in children with Gorlin syndrome and medulloblastoma. Chemoprevention may also be used to avoid skin lesions. Vitamin A analogs, such as retinoids, including isotretinoin, may play an important role in preventing or slowing the development of new BCCs [140, 160–164].

A list of groups that support patients, families, and clinicians caring for patients with NBCCS is supplied in Additional file 1.