Version May 2024
INTRODUCTION — Nevoid basal cell carcinoma syndrome (NBCCS; MIM #109400) is a rare autosomal dominant, tumor-predisposing disorder caused by germline pathogenic variants in the human homolog of the patched (PTCH1) gene [1]. First described in 1894, the clinical manifestations of NBCCS were more clearly defined in 1960 by Gorlin and Goltz [2]. Affected patients have multiple developmental anomalies, multiple basal cell carcinomas and odontogenic keratocysts of the jaw at an early age, and an increased risk of developing a medulloblastoma in early childhood [3].
Synonyms for NBCCS include Gorlin or Gorlin-Goltz syndrome; basal cell nevus syndrome (BCNS); multiple basal cell nevi, odontogenic keratocysts, and skeletal anomalies; bifid-rib basal-cell nevus syndrome; basal cell cancer syndrome; and multiple basal cell nevi.
The pathogenesis, clinical manifestations, and management of NBCCS are reviewed here. Basal cell carcinoma is discussed separately. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence".)
EPIDEMIOLOGY — Nevoid basal cell carcinoma syndrome (NBCCS) is a rare disease. The prevalence is estimated between approximately 1 in 31,000 and 1 in 164,000 persons [4-7]. However, the true prevalence may be higher as individuals with mild clinical manifestations may be not recognized.
PATHOGENESIS — Nevoid basal cell carcinoma syndrome (NBCCS) is inherited as an autosomal dominant trait with a high degree of penetrance (approximately 97 percent) but variable expression [8]. Most cases of NBCCS are caused by a pathogenic variant of PTCH1 and, infrequently, by variants in the suppressor of fused (SUFU) gene and PTCH2 [9-11]. However, in some cases, no pathogenic variant is identified. In an analysis of 182 patients with NBCCS, 69 percent had PTCH1 variants, 5 percent had SUFU variants, and 26 percent had no pathogenic variant identified [12].
PTCH1 gene variants — In most cases, NBCCS is caused by germline inactivating variants involving PTCH1 on chromosome 9q22.3 [13-17]. Loss-of-function variants in PTCH1 result in premature termination of the PTCH protein [18-21]. (See 'PTCH protein function' below.)
Loss of heterozygosity at this site in both hereditary and sporadic basal cell carcinomas (BCCs) suggests that it functions as a tumor suppressor gene [22]. Acquired PTCH1 variants have been found in approximately one-third of sporadic BCCs [23,24], in a high proportion of xeroderma pigmentosum-associated BCCs, and in some sporadic medulloblastomas [25,26]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis" and "Histopathology, genetics, and molecular groups of medulloblastoma".)
A two-hit model in PTCH1, similar to that described for the RB1 gene in retinoblastoma, has been proposed to explain the pathogenesis of BCC, medulloblastoma, and other tumors in NBCCS [27]. According to this model, in individuals who carry a germline defect in the deoxyribonucleic acid (DNA) sequence in one of the two copies of a tumor suppressor gene, a second (somatic) DNA injury at the same locus or loss of heterozygosity (loss of the normal remaining allele) is necessary for the cell to undergo malignant transformation and clonal expansion [28,29]. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis", section on 'Pathogenesis'.)
PTCH protein function — The PTCH protein is a receptor for the hedgehog (HH) protein, a component of the sonic hedgehog (SHH) signaling pathway (figure 1). This pathway is important in determining tissue patterning and cell fate in multiple structures within the developing embryo [30,31]. SHH signaling is activated when HH binds to its receptor, a complex that is formed by PTCH and a second protein, Smoothened (SMO), a transmembrane protein (figure 2) [32-36]. PTCH functions as a regulatory molecule for SMO, with PTCH-induced repression of SMO limiting the effect of the SHH signal [33,36].
According to this model, SMO repression is relieved following mutational inactivation of PTCH1 in patients with NBCCS [37]. This results in constitutive overexpression of the SHH signal, which has been implicated in the development of BCC and other tumors, possibly via activation of the transcription factors Gli1 and/or Gli2 (figure 1) [31,33,38-42].
Evidence supporting a link between overexpression of the SHH pathway and tumorigenesis is provided by studies in animal models and in vitro studies using tumor tissues from patients with NBCCS:
●Transgenic mice overexpressing SMO or SHH in the skin spontaneously produce skin lesions resembling human BCCs [37,43].
●Owing to failure of negative feedback, the mutant PTCH1 transcript is overexpressed in affected tissues. Such transcripts are found at high levels in BCCs and odontogenic keratocysts from patients with NBCCS but not in skin or other types of tumors [44-46].
SUFU gene variants — Germline heterozygous loss-of-function variants in the SUFU gene on chromosome 10q24.32, encoding a component of the SHH/patched signaling pathway, have been found in individuals from families meeting the diagnostic criteria for Gorlin syndrome without variants in PTCH1 [3]. SUFU mutations appear to be associated with milder clinical features (lower number of BCCs and no odontogenic keratocysts) but with a greatly increased risk of developing a childhood medulloblastoma [12,47]. (See "Histopathology, genetics, and molecular groups of medulloblastoma".)
CLINICAL FEATURES
Overview — More than 100 clinical abnormalities have been reported in nevoid basal cell carcinoma syndrome (NBCCS). The major manifestations are [48]:
●Early development of multiple basal cell carcinomas (BCCs)
●Jaw odontogenic (bone) keratocysts
●Palmar and plantar pits (picture 1)
●Lamellar calcification of the falx cerebri
●Family history (first-degree relative with NBCCS)
Minor features include [6]:
●Craniofacial anomalies (macrocephaly, frontal bossing, hypertelorism)
●Vertebral/rib anomalies, such as bifid/splayed/extra ribs or bifid vertebrae
●Cleft lip/palate
●Polydactyly
●Childhood medulloblastomas
●Cardiac or ovarian fibromas, often bilateral
●Lymphomesenteric or pleural cysts
●Ocular anomalies (coloboma, cataract, glaucoma)
Although medulloblastomas that are characteristically of the desmoplastic subtype tend to develop at a young age, many of the classic features of NBCCS (ie, BCCs, palmar pits, calcified falx cerebri) may not be detected until the late teens or young adulthood [5]. (See "Histopathology, genetics, and molecular groups of medulloblastoma".)
The frequency of the major clinical findings may vary across different populations or ethnic groups. As an example, early-onset BCCs, jaw keratocysts, and a positive family history are detected in 71, 70, and 86 percent, respectively, of patients from populations of North European origin. In contrast, these same features are detected in 31, 90, and 43 percent, respectively, of those from East Asian populations [49].
Major features
Basal cell carcinomas — BCCs are found in approximately three-fourths of non-Hispanic White patients with NBCCS but are less frequent in affected African American and East Asian patients [49,50]. Age at first diagnosis ranges from 2 to 53 years old with an average age of 20 to 21 years. Common single nucleotide genetic polymorphisms in melanocortin-1 receptor gene (MC1R) and TERT-CLPTM1L may be associated with an earlier age of onset of BCC in these patients [51].
The number of BCCs can vary from only a few to thousands, and they range in size from 1 to 10 mm [52,53]. BCCs frequently occur on sun-exposed areas, such as the head, neck, back, chest, and upper limbs, but they can occur in any location [5,54]. BCCs arising in NBCCS are histologically indistinguishable from sporadic BCCs. The term "nevoid" does not refer to an association of the BCC with nevi but instead was coined because early lesions may be pigmented and have the appearance of nevi with a prominent vascular component. In some patients, the large tumor burden and the need for multiple surgical procedures result in significant disfigurement and poor quality of life [55].
BCCs tend to be more aggressive in patients with NBCCS. Despite this, only a small fraction become locally invasive, and they do so only after puberty [52].
Risk factors for basal cell carcinoma — Although sun exposure is the most important environmental cause of BCC in the general population, the relationship between sun exposure and the development of BCCs in patients with NBCCS is unclear. While ethnicity is a recognized factor affecting the number of BCCs developed by NBCCS patients, with patients with darker skin types developing fewer tumors, the reasons for the variability in the number of BCCs remain largely unknown.
The widespread anatomic site distribution of BCCs suggests that frequent sun exposure may not be essential for the development of BCCs in affected patients [53]. However, the observation that there are more tumors on sun-exposed areas suggests that exposure promotes the development of BCCs in patients with NBCCS [56]. A role of sun exposure in the pathogenesis of BCC in patients with NBCCS is supported by the finding that tumors from individuals with a low number of BCCs have fewer somatic ultraviolet (UV)-signature mutations compared with tumors from individuals with a high number of tumors [57].
Patients with NBCCS are particularly sensitive to the effects of ionizing radiation, and the development of multiple BCCs within irradiated fields in affected patients is well described [54,58-61]. DNA synthesis is abnormally induced in irradiated NBCCS cells, and this abnormality may supply the subsequent mutation necessary for tumor development in NBCCS patients who have been exposed to ionizing radiation [62,63]. Because of this, radiation therapy is generally avoided in patients with NBCCS.
Odontogenic (jaw) keratocysts — Odontogenic keratocysts (OKCs), also called keratocystic odontogenic tumors, are cystic lesions of the bone that are lined with keratinized epithelium and thought to originate from the dental lamina. Despite their bland histology, these lesions are locally destructive, possibly due to their heparanase expression, which is upregulated [64]. They are neoplastic rather than developmental in origin [65] and are characterized by aggressive clinical behavior, including involvement of the teeth and a high recurrence rate [66]
OKCs associated with NBCCS have a different immunophenotype from sporadic keratocysts [67]. In a study of sporadic and NBCCS-associated OKCs, the latter had an increased immunohistochemical expression of the sonic hedgehog proteins Shh, Gli1, and Smo [68].
The cysts usually develop after the age of seven and peak during the second or third decades [52,69], but they have been reported in children as young as four [50]. The number of jaw cysts averages six (reported range, 1 to 28), unlike sporadic cases, where they are typically solitary [5,50]. Unlike BCCs, there is no racial predilection [70].
Three-fourths of OKCs present in the mandible [50,71]. The most common locations in decreasing frequency are the mandibular third molar region, maxillary third molar region, and mandibular first and second molar region [72]. Approximately one-third are asymptomatic and are detected on routine dental examination, while 50 percent present with jaw swelling, 25 percent with mild pain, and 15 percent with altered taste [73].
Treatment is discussed below. (See 'Odontogenic keratocysts' below.)
Intracranial ectopic calcification — Approximately 65 percent of affected persons have calcification of the falx cerebri, but this increases to 80 to 90 percent of those over the age of 40 [50,74]. Other areas of ectopic calcification include the diaphragma sellae in 60 to 80 percent (with complete or partial bridging of the sella turcica), the tentorium cerebelli in 40 percent, and the petroclinoid ligament in 20 percent [75].
Palmar-plantar pits — Palmar and/or plantar pits are highly characteristic of NBCCS, occurring in approximately 80 percent of affected individuals [50,76]. They are asymptomatic, nonpalpable, shallow depressions (1 to 3 mm) in the skin of the palm and/or soles that are due to partial or complete absence of stratum corneum (picture 1). They may also be found on the sides, web spaces, and dorsum of the fingers and toes [77]. The differential diagnosis should consider punctate keratoderma, pitted keratolysis, and palmar pits of Darier's disease, but the clinical distinction is usually easy. (See "Pachyonychia congenita", section on 'Punctate palmoplantar keratoderma type 1' and "Darier disease".)
Pitting generally develops during the patient's 20s and later but has been reported in much younger patients [54]. In contrast to BCC, there is no racial difference in the frequency of pitting in affected patients with NBCCS [70]. The number of pits is variable but can reach more than 500 in number, particularly in older individuals [77]. They are permanent and do not wax and wane over time. Soaking the hands in water for 10 to 15 minutes can make their appearance more pronounced [5].
Minor features
Characteristic facies and macrocephaly — Many patients with NBCCS have a characteristic "coarse" facial appearance consisting of frontal bossing, macrocephaly (80 percent), hypertelorism (5 percent), high-arched eyebrows (40 percent) and palate, widened nasal bridge (60 percent), and mandibular prognathism (35 percent) [5,50,52,78,79]. In 50 to 60 percent of affected individuals, there are milia scattered on the face among the BCCs.
Brain tumors — Medulloblastomas develop in 2 to 5 percent of patients with NBCCS, with a male predominance of 3:1 [47,80,81]. Of note, patients with NBCCS due to SUFU mutations have a greatly increased risk of developing a childhood medulloblastoma [3,12,47]. In contrast to sporadic medulloblastomas, which most commonly present between the ages of 6 and 10, medulloblastomas characteristically present by age three in individuals with NBCCS [82]. This syndrome should be considered in any atypically young child with medulloblastoma and in those with tumors with nodular or desmoplastic histology [82,83]. (See "Histopathology, genetics, and molecular groups of medulloblastoma".)
Meningiomas are the next most common brain tumors developing in patients with NBCCS, although they are much less common than medulloblastoma [52,84]. Other tumors and cysts involving the brain have also been reported [52]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)
Myogenic tumors — Tumors with myogenic differentiation, including fetal rhabdomyoma and rhabdomyosarcoma (RMS), have been reported in a small number of patients with NBCCS [85]. Fetal rhabdomyomas typically arise in children and younger adults, predominantly in the head and neck region, do not metastasize, and are cured by surgical resection alone [86]. RMS is the most common soft tissue sarcoma of childhood and adolescence. It can occur anywhere in the body, but the most common primary sites are the head and neck region and the genitourinary tract [87]. The tumor is locally invasive with high propensity for distant metastasis to lung, bone marrow, and bone. (See "Rhabdomyosarcoma in childhood and adolescence: Clinical presentation, diagnostic evaluation, and staging".)
Skeletal abnormalities — Occult skeletal abnormalities are frequent in patients with NBCCS and may be associated with a more severe phenotype [88]. Between 38 to 60 percent have rib abnormalities, including bifid ribs, marked widening of the anterior rib ends, and fusion and modeling defects of the ribs [50,52,89]. Occult spina bifida may be seen as a component of NBCCS, although it has not been documented in all series [50,89].
Cardiac fibromas — Cardiac fibromas are increased in frequency in patients with NBCCS, developing in approximately 3 percent of affected individuals [6]. They typically present in infancy. However, late-onset cardiac tumors can develop in a minority of patients [90]. Cardiac fibromas are benign growths, and almost all develop within the ventricular myocardium. Although usually asymptomatic, they can result in impaired left ventricular function and conduction defects, necessitating resection [91,92]. (See "Cardiac tumors".)
Ovarian fibromas — Ovarian fibromas develop in 15 to 25 percent of girls with NBCCS and are often calcified and bilateral [5,6,50,93]. Other ovarian tumors, including fibrosarcomas, are rarely reported [94]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)
Lymphomesenteric cysts — Single or multiple lymphomesenteric cysts may be seen as a component of NBCCS [93]. They tend to calcify and are usually asymptomatic.
Ocular anomalies — Among the reported ocular anomalies in patients with NBCCS are congenital cataracts, colobomas (involving the choroids and optic nerve), nystagmus, strabismus, hypertelorism, and telecanthus (10 to 25 percent) [6,50,52]. Cleft palate is seen in approximately 5 percent of affected individuals.
Other anomalies — Both pectus deformities and Sprengel deformity (narrow sloping shoulders) are more common in individuals with NBCCS [5,50]. (See "Chest wall diseases and restrictive physiology".)
Approximately 10 percent of patients have anosmia, which may be a sign of hypogonadotropic hypogonadism. Other hypogonadal features include cryptorchidism, gynecomastia, and scanty facial or body hair [5,95]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
Minor kidney abnormalities, often diagnosed incidentally or at autopsy, are seen in approximately 5 percent of patients with NBCCS [52]. Scattered case reports indicate the occasional association of other neoplasms with NBCCS, including fetal rhabdomyoma [93,96], non-Hodgkin lymphoma [97], Hodgkin lymphoma, melanoma, chronic lymphoid leukemia, soft tissue leiomyosarcoma, breast and lung carcinoma, and sinonasal undifferentiated carcinoma (SNUC) [98].
DIAGNOSIS
Diagnostic criteria — The diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) can be established with [48,99-101]:
●One major criterion and genetic confirmation
●Two major criteria
●One major criterion and two minor criteria
Major criteria include:
●One basal cell carcinoma (BCC) under the age of 20 years or multiple BCCs
●Odontogenic keratocyst of the jaw proven by histology in an individual younger than 20 years
●Two or more palmar or plantar pits
●Lamellar (sheet-like) calcification of the falx cerebri or clear evidence of calcification in an individual younger than age of 20 years
●Childhood medulloblastoma
●First-degree relative with NBCCS
Minor criteria include:
●Rib anomalies (ie, bifid, fused, or markedly splayed ribs)
●Macrocephaly
●Cleft lip or palate
●Other specific skeletal abnormalities (ie, vertebral anomalies, kyphoscoliosis, short fourth metacarpals, postaxial polydactyly)
●Lymphomesenteric cysts
●Ovarian or cardiac fibroma
●Ocular anomalies (ie, strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma)
In infants with a family history of NBCCS, early diagnosis may be achieved with the use of screening radiography to look for calcification of the falx, rib anomalies, or calcified ovarian fibromas [5]. However, as individuals with NBCCS are susceptible to X-ray irradiation, the number of radiologic studies should be limited as much as possible, especially in children.
Diagnostic work-up — The following studies are indicated in patients suspected of having NBCCS to confirm the diagnosis and assess the disease extent:
●Skull radiograph or computed tomography (CT) can demonstrate a calcified falx cerebri, complete or partial bridging of the sella turcica, or a broadened nasal root.
●Panoramic films are recommended to identify odontogenic keratocysts; magnetic resonance imaging (MRI) may be superior in demonstrating the internal composition and structure of the cysts [102].
●Chest radiograph to document rib abnormalities (eg, bifid ribs).
●Hand and foot radiographs show flame-shaped lucencies (lytic bone lesions) in 30 percent of hand films and 17 percent of foot films [50].
●Skin biopsy of lesions suspicious for BCCs. Histopathologic features of BCC include nodules and/or strands of atypical basaloid cells that show nuclear palisading, cellular apoptosis, and scattered mitotic activity in the dermis (picture 2A-B). Artifactual cleft formation may be seen between the tumor lobules and the surrounding stroma, which may be mucinous. Solar elastosis is usually present in the dermis.
Molecular genetic testing — In patients fulfilling the criteria for clinical diagnosis, the identification of a heterozygous germline PTCH1 pathogenic variant in lymphocyte DNA confirms the diagnosis of NBCCS [1]. Molecular testing approaches include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
If the clinical suspicion is high but no pathogenic variant is found in PTCH1 or SUFU, DNA from two or more different BCCs can be isolated and genetically tested for PTCH1 and SMO using next-generation sequencing to evaluate for postzygotic mosaicism [100].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) includes a number of syndromes that share some of the NBCCS clinical features, including [103]:
●Sotos syndrome – Sotos syndrome 1 (MIM #117550), or 5q35 deletion syndrome, is an overgrowth syndrome characterized by macrocephaly, characteristic facial features (including bossed forehead and hypertelorism), and skeletal, brain, and cardiac anomalies [104]. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '5q35 deletion syndrome (Sotos syndrome)'.)
●Bazex syndrome – Bazex-Dupré-Christol syndrome (also called Bazex syndrome or follicular atrophoderma and basal cell carcinomas [BCCs]) is an X-linked dominant disorder characterized by congenital hypotrichosis, follicular atrophoderma, milia, and multiple BCCs [105].
●Rombo syndrome – Rombo syndrome is a genetic syndrome characterized by facial follicular atrophy, atrophoderma vermiculatum, multiple milia, hypotrichosis, peripheral vasodilation with cyanosis, trichoepitheliomas, and predisposition to develop BCCs [106,107].
●Brooke-Spiegler syndrome – Brooke-Spiegler syndrome is a rare autosomal dominant disorder characterized by multiple benign adnexal skin tumors (spiradenoma, cylindroma, and trichoepithelioma) [108]. Histopathologic examination will differentiate these tumors from "nevoid" skin tag-like BCCs in NBCCS. (See "Brooke-Spiegler syndrome (CYLD cutaneous syndrome)".)
MANAGEMENT — The management of individuals with nevoid basal cell carcinoma syndrome (NBCCS) requires a multidisciplinary approach. Important issues in the management of affected patients include surveillance for the development of cancers and syndrome-related complications and specific treatment for tumors and odontogenic keratocysts.
Surveillance — Individuals diagnosed with NBCCS are at risk for developing benign and malignant neoplasms and other syndrome-related complications at an early age. The following recommendations based on best available evidence have been proposed for surveillance of patients with NBCCS [100]:
●In carriers of PTCH1 variants (low risk of medulloblastoma):
•Screening for general growth and development at the time of diagnosis
•Regular visits to a dermatologist for total body examination annually by age 10, with increased frequency (every three to six months) after the first basal cell carcinoma (BCC) is diagnosed
•Dental examination and screening for odontogenic keratocyst (OKC) with orthopantogram or MRI starting at age 8 and every two years thereafter, if no abnormalities are detected, or annually after the detection of the first OKC
•Baseline cardiac ultrasound at the time of diagnosis, repeated if indicated
•Baseline ophthalmologic examination, including an ocular pressure, repeated if indicated beginning at age 8
•No brain MRI screening for medulloblastoma unless concerning neurologic examination, head circumference change, or other unusual signs or symptoms
●In carriers of SUFU variants (high risk of medulloblastoma):
•Same as PTCH1 mutation carriers, with the exception of no jaw radiographs, as OKCs have not been described
•Baseline brain MRI for medulloblastoma screening every four months until the age of 3 years and then every six months until age 5
Treatment of basal cell carcinomas — Because of the large number of lesions, treatment of basal cell carcinomas (BCCs) in patients with NBCCS may be extremely difficult.
There is no evidence-based approach to the management of multiple lesions in patients with NBCCS, and the treatment options are the same as for sporadic BCC. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment of basal cell carcinomas at high risk for recurrence".)
Surgical excision is the first-line therapy for lesions that are limited in number and for fast-growing lesions. For locally aggressive tumors and for those located in high-risk areas, Mohs micrographic surgery is preferable to conventional excision. (See "Treatment of basal cell carcinomas at high risk for recurrence".)
As multiple surgical excisions are often a source of discomfort, pain, and disfigurement for patients with NBCCS, alternative surgical and nonsurgical approaches can be valuable options in patients with numerous small, nodular tumors or superficial tumors. These include curettage and electrodesiccation (C&E), laser therapy, topical therapies, and photodynamic therapy (PDT) (see "Treatment and prognosis of basal cell carcinoma at low risk of recurrence"):
●C&E is most appropriate for low-risk, superficial or nodular BCCs on the trunk or extremities but is not recommended for BCCs with clinical and histologic features that suggest an elevated risk for tumor recurrence [109].
●Carbon dioxide laser therapy can be a useful modality in selected patients for tumors in low-risk areas and has shown efficacy in combination with microscopically controlled excision (Mohs micrographic surgery) [110-114].
●Superficial lesions can be treated with 5% topical fluorouracil or imiquimod 5% cream. In several reports, imiquimod 5% cream applied three days per week has shown considerable efficacy for superficial BCCs in affected patients [115-120]. Imiquimod is less effective for nodular BCCs [115].
●There is increasing experience with PDT in patients with NBCCS [121,122]. As with sporadic BCCs, PDT appears most effective for superficial lesions [114]. One of the advantages of PDT is that multiple contiguous BCCs can be treated in one session. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence", section on 'Photodynamic therapy'.)
●Radiation therapy is not recommended for the treatment of BCC in patients with NBCCS, given their sensitivity to ionizing radiations and the risk of induction of new BCCs.
Locally advanced and metastatic basal cell carcinomas — Vismodegib and sonidegib, oral small-molecule inhibitors of Smoothened (SMO) that block the activation of the sonic hedgehog (SHH) pathway, offer a new approach for patients with metastatic disease or for patients who are no longer amenable to local therapy [123,124].
A randomized trial including 41 patients with NBCCS found that vismodegib was more effective than placebo in slowing the rate of BCC development and reducing tumor burden [125]. In this trial, patients were treated with either 150 mg per day of vismodegib (n = 26) or placebo (n = 15) for 1 to 15 months (mean, 8 months). At three months, a significantly lower mean per-patient incidence of new, surgically eligible BCCs was detected in the active treatment group than in the placebo group (2 versus 29 BCCs per year). In addition, tumor size decreased to a greater extent in patients who received vismodegib than in those who received placebo, with a few patients achieving complete remission. Adverse effects of vismodegib included loss of taste, muscle cramps, hair loss, and weight loss and led to treatment discontinuation in 14 of 26 patients (54 percent). In addition, tumors regrew following drug discontinuation. In the subsequent, open-label phase, 37 patients continued vismodegib for up to 36 months [126]. In the 11 patients initially assigned to placebo, vismodegib reduced the development of new surgically eligible BCCs compared with placebo (0.4 versus 30 BCCs per year). However, only a few patients tolerated vismodegib continuously for the full 36 months.
Regrowth of tumors despite continued therapy has also been reported in patients with tumors that had initially responded to vismodegib [127,128]. In a series of 28 patients (including 5 patients with NBCCS) with a total of 230 advanced and nonadvanced BCCs, tumor regrowth during treatment was detected in 6 patients (21 percent) and affected 5 percent of all tumors [127]. The mean time to tumor regrowth was 56 weeks. The reason for this occurrence is unknown. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Vismodegib'.)
Oral sonidegib at a daily dose of 200 mg has shown a similar efficacy as vismodegib in the treatment of locally advanced or metastatic BCC [124,129-131]. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Sonidegib'.)
Topical sonidegib was evaluated in a randomized trial in which 27 BCCs in eight patients with NBCCS were treated with topical sonidegib or vehicle twice daily for four weeks [132]. Complete or partial responses were observed in 12 out of 13 lesions treated with sonidegib compared with 1 out of 14 lesions treated with placebo.
Prevention of basal cell carcinomas — Patients with NBCCS should be counseled to minimize exposure to ultraviolet light and avoid therapeutic and diagnostic ionizing irradiation (eg, MRI is preferred over computed tomography [CT]), if at all possible [58].
Oral nicotinamide (vitamin B3), a dietary supplement available over the counter, at the dose of 500 mg twice daily was evaluated for the prevention of nonmelanoma skin cancer in a phase III randomized trial including 386 participants who had had at least two skin cancers in the previous five years [133]. At 12 months, the rate of new BCCs was 20 percent lower in the nicotinamide group compared with the placebo group.
Oral retinoids (isotretinoin and acitretin) have shown some efficacy for the chemoprevention of nonmelanoma skin cancers in high-risk populations [134,135]. However, there are no studies evaluating the efficacy of systemic retinoids as chemopreventive agents for patients with NBCCS. At least one report suggests that low-dose isotretinoin (10 mg daily) is ineffective in preventing additional BCCs in patients who have had two or more sporadic BCCs [136]. Because of the need for moderate to high doses, the limited degree of benefit, and their adverse effects, oral retinoids are seldom used. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Acitretin'.)
Odontogenic keratocysts
Surgery — The treatment of choice is wide surgical excision and curettage with extraction of associated teeth by an experienced oral-maxillofacial surgeon or otolaryngologist [5,52]. Bone and alveolar nerve grafting may be required in some instances. A 10-year retrospective review of 83 cases of odontogenic keratocysts suggests that marsupialization followed by enucleation results in the lowest recurrence rate [137]. Histopathologic examination of tissue is important because several cases of malignant transformation to squamous cell carcinoma have been reported [138-140].
Recurrence can result from incomplete removal, remnants of dental lamina within the jaw, or the presence of satellite cysts. In a review of over 6000 sporadic and syndromic keratocysts treated with various surgical techniques, the recurrence rate for those associated with NBCCS was 35 percent [66].
Vismodegib — Reduction in size or resolution of odontogenic keratocysts has been reported in some patients with NBCCS treated with vismodegib, an oral inhibitor of the HH pathway approved for the treatment of advanced BCC [141]. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Vismodegib'.)
A series of six patients with nine odontogenic keratocysts for whom baseline MRI was available were treated with vismodegib 150 mg per day for 11 to 24 months [142]. Post-treatment MRI showed a 50 percent reduction of the longest diameter of keratocysts in four of six patients. In one patient with complete resolution of one lesion, there was no recurrence nine months after drug cessation. All patients experienced mild to moderate adverse effects of taste loss, muscle cramps, and hair loss; three patients required a brief drug break.
However, additional studies are necessary to determine the role, long-term efficacy, and maintenance regimen of vismodegib for the treatment of odontogenic keratocysts.
Medulloblastomas — In patients with NBCCS, radiation therapy for medulloblastomas induces hundreds of difficult to manage BCCs and should be avoided [59,143]. The management of medulloblastoma is discussed in detail separately. (See "Treatment and prognosis of medulloblastoma".)
Vitamin D deficiency — Patients with NBCCS who adopt strict sun protection measures have an increased risk for vitamin D deficiency and may require vitamin D supplementation. In a retrospective cohort study of 41 patients with NBCCS, the prevalence of vitamin D deficiency (25[OH]D level ≤20 ng/mL) was significantly greater than that reported in the general population (56 versus 18 percent) [144]. Thus, clinicians should be aware of the potential for vitamin D deficiency in patients with NBCCS. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
GENETIC COUNSELING — Referral to a geneticist for counseling is advised for patients and families with nevoid basal cell carcinoma syndrome (NBCCS). Approximately 70 to 80 percent of individuals diagnosed with NBCCS have an affected parent [1]. Since NBCCS is an autosomal dominant disorder, the offspring have a 50 percent risk of inheriting the PTCH1 or SUFU pathogenic variant.
An updated genetic consultation is recommended prior to childbearing years, so that the affected individual can better understand their own reproductive risks and options. Early referral for genetics consultation prior to pregnancy and planning of pregnancies is recommended for couples interested in prenatal diagnosis.
PROGNOSIS — Nevoid basal cell carcinoma syndrome (NBCCS) is generally not associated with increased mortality. However, the prognosis is guarded for those with metastatic basal cell carcinoma (BCC) or medulloblastoma.
ONLINE RESOURCES AND SUPPORT GROUPS — Several online resources and patient organizations can provide information and support for patients and families with nevoid basal cell carcinoma syndrome (NBCCS):
●The Australian Gorlin Syndrome Mutual Support Group
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant, multisystem, tumor-predisposing disorder caused by germline pathogenic variants in the PTCH1 or SUFU tumor suppressor genes. (See 'Pathogenesis' above.)
●Clinical manifestations – The primary manifestation of NBCCS is the development of multiple basal cell carcinomas (BCCs), which are histologically identical to sporadic BCCs. NBCCS is also associated with a variety of other benign and malignant tumors, including odontogenic keratocysts, cardiac and ovarian fibromas, and medulloblastomas. Other features include palmar and plantar pits, craniofacial and skeletal abnormalities, ocular abnormalities, and ectopic intracranial calcifications. (See 'Clinical features' above.)
●Diagnosis – The diagnosis of NBCCS is established in patients who fulfill two major clinical criteria or one major and two minor clinical criteria. The identification of germline pathogenic variants in PTCH1 or SUFU by molecular genetic testing confirms the diagnosis. (See 'Diagnosis' above.)
●Management – The management of individuals with NBCCS requires a multidisciplinary approach. Important issues in the management of affected patients include surveillance for the development of cancers and syndrome-related complications starting in early childhood and specific treatment for tumors and odontogenic keratocysts. (See 'Management' above and 'Surveillance' above.)
●Basal cell carcinoma treatment – The management of BCCs can be particularly difficult, due to the multiplicity of lesions and the need for multiple procedures. Vismodegib and sonidegib, oral small-molecule inhibitors of the sonic hedgehog pathway, are a therapeutic option for patients with locally advanced and metastatic BCCs. (See 'Treatment of basal cell carcinomas' above and "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies", section on 'Initial therapy (hedgehog pathway inhibitors)'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gary Goldenberg, MD, who contributed to an earlier version of this topic review.
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