Keywords

Introduction

Epidemiological analyses estimate the incidence of GGS to be 1 per 50,000–150,000 in the general population. The causative gene is the analogue to the patched (PTCH) gene of the fly.

Drosophila. PTCH1 maps to chromosome 9q22.3–31 [1]. In addition to the mutations of PTCH1, mutations in the genes PTCH2 [2] and suppressor of fused (SUFU) [3] were also detected in GGS patients. There are differences in the phenotype of the GGS patient in relation to the site of mutation [4]. Therapy is symptomatic.

History. In the late nineteenth century, Jarisch and White made the first descriptions of patients with findings corresponding to the current diagnostic criteria of GGS [5, 6]. Gorlin and Goltz coined their names to the condition in 1960 after presenting an accurate description of the hereditary nature of the disease, phenotype, and main clinical characteristics [7]. Soon after the description of the syndrome, Satinoff and Wells described two Egyptian skeletons of the Dynastic Period with skeletal anomalies compatible with findings recorded in GGS. The skeletons (Istituto di Antropologia, University of Turin) showed mandibular cysts and multiple bony cavities in maxilla, bifid ribs, os sacrum with incomplete fusion of the caudal laminae, and slightly enlarged sella turcica [8].

Terminology. GGS is mislabelled at times as “basal cell nevus syndrome” [9, 10]. The term “nevus”, however, is a misnomer in terms of describing the biological quality of the syndrome’s skin lesions because the cutaneous lesions frequently represent aggressive basal cell carcinoma (BCC) as seen in GGS, rather than a benign lesion as the term “nevus” implies. According to Gorlin, the general term “nevoid basal cell carcinoma syndrome” describes more precisely the potential risk of the affected patients from skin neoplasms [11]. GGS patients are at risk of more non-cutaneous neoplasms than the general population, so the medical assessment of the patient must include many functions and organs. Patients with this rare syndrome often have anomalies in multiple organs, many of which are subtle.

Clinical Characteristics

General characteristics. General characteristics in GGS are BCC, jaw keratocysts, and cerebral calcifications [12, 13] (Fig. 29.1a, b, c). However, general body characteristics are often of decisive importance for the first examination of patients in order to establish the diagnosis, in particular in young individuals [14,15,16,17,18]. The main visible facial feature frequently is a “coarse face” with an enlarged head, frontal bossing, hypertelorism, and broad nasal root [16, 19, 20]. About 70% of patients with this syndrome have some degree of craniofacial anomalies. GGS patients are often tall in relation to their next of kin. This finding is often noticed already in childhood.

Fig. 29.1
figure 1

(a) Left: Profile of a patient with GGS. Multiple scars and skin transplant resulting from uncounted surgical procedures for BCC excision. Note two scabbing ulcerations of pinna. Right: Frontal bossing and multiple nevi in a patient with GGS. (b) Orthopantomography of jaws of a young patient with GGS (cropped image, left body side). Note multiple cystic lesions in both jaws and retained permanent teeth. All cystic lesions proved to be odontogenic keratocysts (OKC). While the X-ray findings of solitary keratocysts are ambiguous, syndromic lesions mostly present as multiple OKC. (c) Posterior-anterior skull radiograph of a child with GGS. Note bilamellar ossification of falx cerebri (arrow). (d) Palmar pits in a GGS patient

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Skin

Whereas life expectancy in NBCCS is not significantly different from average, the neoplastic alterations can be a dominant burden in the patient’s life. The patients usually bear pronounced skin sensitivity to ionizing radiation, including ultraviolet light [21, 22]. They have an increased rate of BCC compared to the general population. BCCs may appear as early as 2 years of age, but the first manifestations usually appear between puberty and 35 years of age [23]. The majority (90%) of GGS patients develop BCC at age 30 years and older [24], which correspond strongly with increased exposure to the sun [25]. Bhattacharjee et al. [26] reported the first primary cutaneous carcinosarcoma associated with NBCCS. Reports on BCC in GGS are predominantly from Western countries. The early development of BCC in Caucasians with GGS is possibly facilitated due to their lower light protection of skin [15]. However, exposure of the skin to sunlight is not mandatory for the frequent development of BCC in GGS [25]. GGS was noted as a rare genetic disorder worldwide [27]. In addition to BCC, other skin findings like basal cell nevus, epidermal cysts [28], facial milia [29], and palmar and plantar pits are typical in GGS (65–80% of patients) (Fig. 29.1d).

Genetics

Epidemiological analyses estimate the GGS incidence to be 1 in 50,000–150,000 [30]. The disorder carries an autosomal dominant trait [14] and has been described equally in number in both sexes. Mutation of a candidate gene was identified on chromosome 9 [30] and finally characterized as the human homologue to the Drosophila patched gene (PTCH) [31]. Patched is part of the highly conserved hedgehog signalling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo [32,34,35,36]. The gene causing GGS in humans is located on chromosome 9q22.3–9q31 and termed “PTCH1” [11, 37,38,39,40,41,42].

However, recent studies have shown that, in addition to PTCH1, mutations in PTCH2 (chromosome 1) can also cause GGS, although the importance of PTCH2 mutations for the development of the GGS has so far been controversially discussed [43]. Mutations in a third gene, named suppressor of fused (SUFU; chromosome 10 [44]) are relevant in determining the genetic basis of neurogenic tumours in GGS [45]. Apparently, no OKC occurs with mutations of SUFU [45]. There are obviously differences in GGS phenotype depending on the particular mutation [46].

Radiology. Radiological findings in GGS are very numerous and variable [47]. Some findings are of diagnostic relevance; others are also of functional importance. Frequent clinical and radiological manifestations include (multiple) odontogenic keratocysts (OKC; up to 75%), macrocephaly, hydrocephalus, and agenesis of the corpus callosum, bridging of sella turcica, calcification of the falx cerebri (37–79%), skeletal abnormalities such as Sprengel deformity (elevation of the scapula with rotation of its lower angle towards the spine), marked pectus deformity (about 43%), bifid ribs (40%), short fourth metacarpal bone, and syndactyly of the digits. Cleft lip and/or palate occur in 3–8% of the cases [48, 49].

The first radiological indications for a GGS can often be seen on plain radiographs. On radiographs of the thorax and spine, spina bifida occulta, and congenital abnormalities of ribs and of the shoulder(s) were found in a large proportion of patients [50]. A variant of the first cervical vertebra, the ponticulus posticus, was demonstrated by lateral cephalograms to develop in many patients with GGS [51]. However, the diagnostically relevant sella turcica bridge is a much better known radiological sign on lateral cephalometry in patients with GGS [52].

Orbit and Eye

The most frequently reported orbital and ocular findings in GGS are hypertelorism (45.5%), congenital cataract (18%), nystagmus (9%), colobomas (9%) and strabismus (63%), epiretinal membranes (36%), and myelinated optic nerve fibre layers (36%), highlighting the value of ophthalmological investigation in this patient group [53].

Jaw Cysts

OKC can be the first finding of the syndrome, which is why the treating dentists are of particular importance when introducing the differential diagnosis of GGS in patients with OKC, especially when young patients are affected without further diagnostically relevant findings being evident. OKC is a locally aggressive osteolytic jaw lesion that occurs sporadically or in association with NBCCS. Indeed, only a few patients with OKC have GGS. Recurrence of OKC is a frequent finding both in sporadic and syndromic lesions. In contrast to cutaneous cysts, the morphological and immunohistochemical profiles of syndromic and sporadic jaw cysts show no significant differences [54, 55]. Sporadic OKC rarely appears in childhood. Careful examination of children and adolescents with OKC is therefore indicated in order to rule out GGS. In a retrospective study of 50 children up to 18 years of age presenting with first diagnosis of OKC and so far not diagnosed as GGS patients revealed a high frequency of new GGS cases. Hence, clinicians should have a low threshold for referral to complete examination or genetic testing in children with even a single OKC [56].

Other Findings

Reports of other findings, particularly dysplasias and tumours, are numerous, for example, ovarian calcification, fibromas of the ovaries (20%) or heart (2%), medulloblastoma (5%), and other tumours [57, 58]. The proportion of syndromic medulloblastomas in a larger case series (n = 129) is less than 10%. Both PTCH1 and SUFU germline mutations were detected in GGS cases (2/129) [59]. In an earlier evaluation of GGS-associated findings, the proportion of patients with medulloblastomas was 3.8% (4/105) and is currently estimated at around 5%. There are assessments of the genotype-phenotype ratio of the GGS that expect a significantly higher risk of medulloblastoma in cases with SUFU mutations (33%) in contrast to PTCH1 mutations (<2%) [60].

Diagnosis

Kimonis et al. [60, 61] have proposed that diagnosis of GGS can be made in an individual suspected of being affected by GGS if two major criteria, or one major and two minor criteria, are revealed.

The major criteria consist of two or more BCC in individuals younger than 20 years; OKC of the jaw (Fig. 29.1b); three or more palmar or plantar pits (Fig. 29.1d); bilamellar calcification of the falx cerebri (Fig. 29.1c), bifid, fused, or markedly splayed ribs; and a first-degree relative with GGS.

The minor criteria comprise macrocephaly, congenital craniofacial malformations (frontal bossing, coarse facies, cleft lip/palate, moderate or severe hypertelorism), Sprengel deformity and other skeletal abnormalities, syndactyly of the digits, ovarian or cardiac fibromas, and medulloblastoma. Genetic diagnostics plays an increasingly important role in differential diagnosis, especially in oligosymptomatic cases.

Imaging techniques may be necessary to establish the diagnosis and in-patient monitoring, such as MRI of the brain, echocardiography, abdominal ultrasonography, dental radiography, and skeletal survey, however, with the goal of minimizing the amount of ionizing radiation rendered at any given period. The rate of meningioma and medulloblastoma may increase post-irradiation in these patients. The combination of clinical, regular skin examinations, imaging, and histological findings is indispensable in identifying patients at risk and establishing diagnosis [61]. Patients suspected of having GGS should have biopsies obtained from several suspicious skin lesions. Obviously, if an infratentorial mass is detected by cranial MRI, it should be biopsied to rule out medulloblastoma.

Therapy and Prognosis

Patients with GGS may need to be treated by a wide range of specialists, including dermatologists, dentists, cardiologists, radiologists, oncologists, and orthopaedic surgeons [62,63,64]. Frequent clinical and dermatologic surveillance is necessary for individuals with established GGS, and sun protection is an important preventative measure. The colloquium group for NBCCS consists of individuals with research interest in this syndrome and additionally serves as the medical advisory board of the NBCCS Life Support Network [9, 19].

Skin

Surgical excision of neoplastic skin lesions is the therapy of choice [65]. In superficial and well-defined lesions, ablative surgery, cryosurgery, laser ablation, and electrocautery successfully may be applied [66]. However, the multiplicity of many lesions and difficult anatomical localizations of the lesions, especially in the face, place considerable demands on surgical therapy. In individual cases, the size and number of tumours may prompt the use of alternative therapies, e.g. cryotherapy or nonsurgical measures [65].

Topical therapies, such as 5% imiquimod or 5% fluorouracil, are recommended in patients with low-risk superficial BCC, in cases with nodular BCC possibly combined with phototherapy [65, 67]. In locally advanced and/or metastatic BCC, application of hedgehog inhibitors, e.g. vismodegib or sonidegib, should be considered. However, the rate of dropouts due to drug intolerance is very high in patients with BCC participating in clinical studies. After stopping the medication, further tumour development must be expected [29, 30]. New immunotherapies are currently being tested in clinical studies, e.g. medication with anti-programmed cell death 1 (PD-1) antibodies [65]. However, the study results have so far been unsuitable for developing general recommendations for PD-1 in BCC [68].

Odontogenic keratocyst (OKC)

Treatment of OKC is surgical [69]. The use of locally applied toxic agents such as Carnoy’s solution to prevent relapses is controversial [70]. In individual cases, conservative treatment strategies have been successful that have reduced the rate of loss of teeth and parts of the jaw [71]. Case reports detailed treatment results with vismodegib for BCC in GGS patients and showed remarkable shrinkage of osseous lesions in some patients with syndromic OKC [72].

Prevention

Adherence to effective measures to protect the skin from light and regular dermatological examinations is essential for patients with GGS. Siblings of GSS patients should be clinically and possibly genetically investigated for evidence of this syndrome. Early diagnosis and therapy may reduce the severity of the long-term sequelae of GGS, including malignancy and oromaxillofacial deformation and destruction. Annual screening for medulloblastoma (in patients younger than 8 years) and orthopantomography of the jaws for OKC (in patients older than 8 years) is recommended. The risk of developing neoplasm in the radiation area has been proven in patients with GGS, so radiation therapy should be avoided whenever possible [73].