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 23 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.

This syndrome existed during Dynastic Egyptian times as shown by a constellation of findings compatible with the syndrome in mummies dating back to 1,000 b.c. 7. In 1992, Farndon et al. estimated that the minimum prevalence is 1 per 57,000 89. An almost identical value was noted by Pratt and Jackson 10. A study in the North West of England showed that the disease affects 1 in 55,600 people 5. In Italy, the incidence (1/256,000) 11 of the disease appears to be lower than in Australia (1/164,000) 12 and in the United Kingdom 5 (Table 1). Rahbari and Mehregan noted that 2% of patients under 45 years of age with basal cell carcinomas have the syndrome 13. Recently two new studies reported the incidence of the syndrome in Korea 14, and in France15.

Many different signs and symptoms may be associated with NBCCS (Table 2). Clinical manifestations include basal cell carcinomas (BCCs), which may appear very early (2 years of age) 16; odontogenic keratocysts (OKCs) that generally develop in the first, second and third decades 611121718; palmar and/or plantar pits, and ectopic calcifications of the falx cerebri. These manifestations are considered as the major criteria for diagnosis 5. The disorder is also characterized by congenital skeletal abnormalities, macrocephaly with frontal bossing, cleft lip and/or palate, and eye anomalies. Various low-frequency neoplasms, such as medulloblastomas, meningiomas, and ovarian and cardiac fibromas have been also reported (Table 2).

Recurrent jaw cysts are the main oral sign, being present in 90% of patients 11. These cysts are known as keratocysts as they are characterized by a thin external fibrous capsule and an internal lining of keratinized stratified squamous epithelium. Keratocysts appear in the tooth-bearing areas of the jaws, and are believed to arise from the dental lamina 21. Cysts may appear in both jaws. In several cases, the first symptom is either an odontogenic keratocyst or an odontogenic cyst of the jaws 1118. Odontogenic keratocysts (OKCs) are the most consistent and representative signs of NBCCS in the first and the second decades of life. OKCs are detected in patients under 10 years of age 512: 13% of patients develop a jaw cyst by the age of 10 years and 51% by the age of 20 years. These data suggest that lesions may start to develop as early as at 7 or 8 years of age and underline the fact that keratocysts in patients affected by NBCCS arise earlier than those in healthy subjects 2829. In NBCC patients, there is continued development of new and recurring cysts until about age 30, when the rate of development tends to decrease 30. Most non-NBCCS keratocysts are isolated lesions, but in NBCCS the keratocysts are commonly multiple, from 1 to 30, and the average number is 5. The most common site in the mandible is the molar-ramus region (44%), followed by the incisor-canine region (18%) 18. In contrast, the majority of maxillary cysts occur in the incisor-canine (15%) and molar-tuberosity (13%) regions 18. Only a few cysts have been reported in the premolar region. There is no racial predilection. There may be remarkably few symptoms until cysts reach a large size, especially when the ascending ramus is involved. Presentations include swelling and/or displaced, impacted teeth. About one-half of patients present with swelling, a quarter with mild pain, and 15% with an unusual taste following rupture of a cyst. Despite these manifestations, jaw fractures almost never occur. Radiographically, the keratocyst may show a unilocular or multilocular pattern and the cystic spaces may have a smooth or scalloped border. One of the most problematic aspects is the 60% rate of recurrence following surgery. In part, this may be due to incomplete removal, i.e., from retention of epithelial islands and/or satellite microcysts, which occur with great frequency in the connective tissue capsule, or from proliferation of the basal layer of the epithelium 31. There have been a few reports of ameloblastoma arising in odontogenic keratocysts 32 or, rarely, of squamous cell carcinoma 33. Microscopically, the odontogenic keratocysts are multilocular with a parakeratinized (96%) or, rarely, orthokeratinized (4%) stratified squamous epithelium consisting of only a few layers of cells (about five to eight) with a well-defined basal epithelial cell layer, palisaded nuclei but no rete ridges 4. Budding of the epithelium into the connective tissue with suprabasilar splitting has been noted in at least 50% of cases 4.

Other defects of the stomatologic system are malocclusion, impacted teeth, mandibular prognathism, dental ectopy or heterotopy, and dental agenesis. Cleft palate and lip are rare (5%) 3435. Recently, a new sign has been described: bilateral hyperplasia of the mandibular coronoid processes 36, which may be a radiologic criterion for the syndrome, useful for establishing a diagnosis especially in pediatric patients 37.

Ectopic calcifications of the central nervous system have been reported: lamellar calcification of the falx cerebri (70–85%) 11, calcification of the tentorium cerebelli (20–40%) 11, the petroclinoid ligament (20%) and the diaphragma sellae (60–80%) 38, and complete or partial bony bridging of the sella turcica (25%) 11. Spotted meningeal calcifications are rare. These signs may not result in clinical manifestations, but can be useful in confirming the diagnosis. The calcification of the falx cerebri can appear very early in life, and is often strikingly apparent from late childhood. Other signs reported are cysts of the choroid plexus of the third and lateral ventricles of the brain, intraparenchymal brain cysts, arachnoid cysts, glial nodules projecting from the lateral ventricles, agenesis of the corpus callosum with or without lipoma 39, "empty" sella syndrome 39, communicating hydrocephalus 40414243, meningioma 4445, cysts of the septum pellucidum 46 and medulloblastoma 44474849505152535455 (see the paragraph "Other tumors"). Vermian dysgenesis has been noted in a mother and a daughter 5657. Seizures have occasionally been noted unassociated with brain tumors and possibly due to focal neuronal heterotopia 58. Mental retardation occurs in about 5% of cases.

Skeletal manifestations are also present in NBCCS 46. The signs in the bones found on X-ray may be helpful in making the diagnosis. The height (these patients can be much taller than expected for their family), the shape of the ribs, the shape of the bones in the vertebral column, and the shape of the skull are principally affected 4659. Mean height is increased (183 cm in males, 174 cm in females) and about 15% of patients are extremely tall 4. An abnormal skull configuration (characterized by frontal (25%), biparetial or temporal bossing, and large calvaria) is frequent (70%) 11. Relative macrocephaly with an occipital frontal circumference above the 95^th centile has been reported in 50% of cases 659. As a result of the abnormal growth of the skull (> 60 cm in adults), about 70% of patients affected by NBCCS have eyes which appear wider apart than usual. Other skeletal signs are scoliosis (40%), and abnormalities such as bifid, wide, fused, partially missing or underdeveloped ribs (30–60%) 11. Rib abnormalities may give rise to a prominent or depressed sternum in about 30% – 40% of patients. Spina bifida occulta of the cervical or thoracic vertebrae is found in 60% of cases 60. However, in a series studied by Kimonis et al., the spina bifida occulta occurred in only 20% of patients 6. Bifid wedges, fused vertebra and Sprengel anomaly (elevation of the scapula with rotation toward the spine with scoliosis) are observed in 10 to 40% of patients. Extra digits on the hands or feet can occur. In about 35% of individuals with Gorlin syndrome, an X-ray of the hands will show small cysts in the bones of the fingers. The numbers and site can be very variable. Bone cysts can also occur in the long bones of the arms and legs, the pelvis and the calvaria 61; usually, these do not cause problems, even if calvarial involvement may give the erroneous impression that medulloblastoma has spread to bone 62. Histologically, the flame-like lesions consist of fibrous connective tissue, nerves, and blood vessels, i.e., they are hamartomas 4.

NBCCS patients may have various ocular problems that occur with a frequency higher than that in the normal population (20%). These include hypertelorism (70%), exophthalmus, rotatory nystagmus, internal strabismus, congenital cataracts, orbital cysts, coloboma of the iris, choroid, and optic nerve, microphthalmia, and chalazions 5112163. Most striking are small very transient keratin-filled cysts (milia) found on the palpebral conjunctivae in about 40% of cases 4. This observation is a personal one, reported by a parental support group in Manchester, England 4. The author asked the assembled group if they had ever had one or more of these transient cysts 4, and this exercise was repeated for the American support group for NBCCS 4. Due to the transient nature of these cysts, most of the patients noted that they were not significantly disturbed by their presence, but they had been to ophthalmologists who confirmed the presence of milia of the palpebral mucosa 4.

Ovarian cysts and fibromas are present in 25–50% of affected women 5 and are often bilateral (75%). Ovarian calcifications are reported and may be mistaken for calcified uterine fibroids or calcified uterine leiomyomas. They do not seem to reduce fertility but may undergo torsion (twist). Some cases of ovarian fibrosarcoma 64 and primary ovarian leiomyosarcoma 65 have been reported. Males may exhibit hypogonadotrophic hypogonadism (5–10%), cryptorchidism, female pubic escutcheon, or gynecomastia. Other signs involving the kidneys (5%) may be: horseshoe kidney, L-shaped kidney, unilateral renal agenesis, renal cysts, or duplication of the renal pelvis and ureter.

Single or multiple chylous or lymphatic mesenteric cysts have been documented 4666768. The cysts are thin-walled and measure 2 to 14 cm in diameter, do not produce symptoms, and are often an occasional finding 21. The content is chylous but may contain hemorrhagic turbid fluid 4. Microscopically, the wall is composed of fibrous connective tissue and smooth muscle, and a layer of lymphatic cells is often located beneath the endothelial lining 4.

Fibroma of the heart has been described 52146697071727374. The syndrome is present in 3–5% of all patients with a cardiac fibroma 569. The cardiac fibroma is discrete, well-circumscribed, not encapsulated, firm, gray-white, 3 to 4 cm in diameter, and may, upon occasion, exhibit central calcification 4. The tumor is most often located in the left anterior ventricular wall. If the tumor projects into the chambers, hemodynamics is altered and/or impeded. Conduction defects (i.e., arrhythmias) may also be present due to involvement of the intraventricular septum 75. The tumors are composed of fibroblasts embedded in a dense matrix of collagen and elastic fibers.

Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS) 767778. RMSs are also present in 15% of mice haplodeficient for PTCH1 79. Medulloblastoma is frequent 44474849505152535455; Herzberg and Wiskemann first pointed out the association of NBCCS with medulloblastoma in 1963 80. The tumor characteristically presents during the first two years of life, while in the general population occurrence peaks at 7 to 8 years of age. The incidence of medulloblastoma in Evans' series was 1% to 2% 5. There is a sex predilection with a male-to-female ratio of 3:1. Early onset medulloblastoma may be the presenting sign of NBCCS; thus, in children in which this tumor is diagnosed, NBCCS should be suspected and a careful examination for other signs of the syndrome should be performed in order to rule it out 6. There is some evidence that medulloblastomas associated with NBCCS have a better clinical outcome than those found in isolation 478182, with the possibility of spontaneous recovery 82. Radiation therapy for medulloblastoma can induce invasive BCCs in the radiation field (i.e., from the nape to base of the spine) 83.

Other brain tumors, such as astrocystoma, craniopharyngioma, and oligodendroglioma, are infrequent, while meningioma is slightly more common. These tumors may well be secondary to radiation therapy.

In 1968, Schweisguth et al. reported fetal rhabdomyoma 84. This tumor has been described at various sites 21788586878889. Mature striated muscle within the tumor is indicative for diagnosis.

There are several reports that support an increased incidence of other neoplasms or hamartomas, such as leiomyomas of bowel and mesentery, leiomyosarcoma, adrenal cystic lymphangioma, thyroid adenoma, lymphangiomyoma, melanoma, ameloblastoma, craniopharyngioma, mesenchymoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, seminoma, paratesticular pseudotumor, schwannoma, pleiomorphic adenoma of parotid, adenoid cystic carcinoma of salivary gland, and adrenal tumors 909192.

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 9394. 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 896. 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 969899. 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 101102.

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 101102103104105106107108109110111112113114115116117118, and, in those with BCCs and medulloblastomas that are apparently not hereditary 119120.

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 123124, 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 115129, 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 621. 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 141142143144145, 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 149150151.

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 154155 or intracranial and sinonasal tumors 83156157158; 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 140160161162163164.

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

NBCCS: Nevoid basal cell carcinoma syndrome; MNBCCS: Multiple nevoid basal-cell carcinoma syndrome; BCNS: Basal cell nevus syndrome; BCCs: Basal cell carcinomas; OKCs: Odontogenic keratocysts; PBCC: Polypoid basal cell carcinomas; RMS: Rhabdomyosarcoma; SHH: Sonic Hedgehog; SNPs: Single nucleotide polymorphisms; MRI: Magnetic resonance imaging; PDT: Photodynamic therapy.

The author declares that they have no competing interests.