Multidisciplinary approach to Gorlin-Goltz syndrome: from diagnosis to surgical treatment of jawbones

Gorlin syndrome is caused by a mutation in PTCH1, a tumor suppressor gene located on chromosome 9q22.32.

As shown in Fig. 1, when SHH reaches its target cell, it binds to the patched-1 receptor (PTCH1) [9]. In the absence of such a ligand, PTCH1 inhibits Smoothened (SMO), a downstream protein in the pathway. It has been suggested that SMO is regulated by a small protein, whose intracellular localization is controlled by PTCH. PTCH1 has a sterol binding domain called sterol-sensing domain (SSD), which has proved essential for the suppression of SMO activity. A new theory claims that PTCH regulates SMO by acting as a sterol pump, removing the oxysterols created by 7-dehydrocholesterol reductase. Following the link between SHH and PTCH1 or in the presence of a mutation in the SSD domain of PTCH1, this pump is deactivated allowing the oxysterols to accumulate around SMO. This accumulation allows SMO to activate or remain on the membrane for a long time, leading to the activation of the nuclear transcription factors glioma-associated oncogene homolog GLI1 and GLI2, activators, and GLI3, repressor. The activated GLI accumulates in the nucleus controlling the transcription of target genes [10‐13].

In addition to PTCH1, mammals have another hedgehog receptor namely PTCH2, whose gene sequence is in common with PTCH1 at 54% and binds SHH. However, PTCH2 is the most expressed in the testis and mediates DHH signaling. In the absence of binding to the ligand, PTCH2 has a reduced ability to inhibit SMO and furthermore its overexpression does not replace PTCH1 mutated in BCC [14‐16].

This pathway plays a fundamental role in cell growth and differentiation, in the regulation of organogenesis in vertebrates, in the differentiation of the fingers, and in the development of the brain and spinal cord, eyes, and teeth. Indeed, the SHH protein is necessary for the development of the anterior part of the brain (forebrain), participating in establishing the midline for the lower part (ventral surface) of the forebrain; moreover, together with other signaling proteins, it is necessary to form the cerebral hemispheres. SHH also plays an important role in eye formation: During early development, the eye cells form a single structure called ocular field. This structure is in the center of the primary face. The sonic hedgehog signaling pathway leads the ocular field to separate into two distinct eyes [17‐24].

Homozygous inactivation of the PTCH gene leads to cancerogenesis and the formation of multiple BCCs and other neoplasms. Patients with Gorlin syndrome inherit a defective copy of the tumor suppressor gene (first stroke) and may acquire a mutation in the second healthy tumor suppressor, caused for example, by ultraviolet light or ionizing radiation (second stroke).

Recently, gene alterations have been identified in the suppressor of fused homolog (SUFU) gene, present on chromosome 10q24.32, and in the PTCH2 gene, located on chromosome 1p34.1, in patients with Gorlin syndrome. Gene alterations in the PTCH2 gene may not be conclusive [25].

Gene alterations in the SUFU gene cause functional deficits in the cytoplasmic protein SUFU. This is an important inhibitor of the GLI1 protein, also known as glioma-associated oncogene, encoded by the GLI1 gene. The SUFU protein binds to the GLI1 protein sequestrating it in the cytoplasm, thus preventing its endonuclear translocation and, consequently, its activity as a transcriptional inducer. Mutations in the SUFU gene lead to the formation of a non-functional protein leading to the loss of one of the most important mechanisms that limit Hedgehog signaling. Patients with SUFU mutations have a 20-fold higher risk of developing medulloblastoma (33%) than patients with PTCH1 mutations in Gorlin syndrome (<2%) [26‐28].

Diagnosis of BCNS requires the presence of two major or one major and two minor clinical criteria [5, 7, 29‐32]. Major criteria include:

Minor criteria include:

Genetic testing for PTCH1 is suggested for the following situations:

Approaches to molecular testing may include serial testing of a single gene, the use of a multigene panel, and more comprehensive genomic testing [33‐39].

The suggested order for performing a serial test of a single gene is:

SUFU molecular testing should be performed first in families with medulloblastoma and without maxillary keratocysts [39].

The execution of a multigene panel that includes PTCH1, SUFU, and other genes of interest may be considered (Table 1) [32].

When considering NBCCS, a tailor-made panel of PTCH1 and SUFU only should be considered optimal as large multigene panels may have reduced sensitivity and may not include gene targeted deletion/duplication analysis or gene analysis. PTCH1 RNA required to identify large rearrangements [33, 39].

More comprehensive genomic testing (if available), including exome sequencing, the portion of the genome capable of encoding a protein, and genome sequencing, may be considered. These tests may provide or suggest a previously not considered diagnosis (for example, mutation of one or more different genes resulting in a similar clinical presentation).

A recent review of 182 genotyped individuals having NBCCS found that individuals with PTCH1 gene mutations were more likely to be diagnosed early (p = 0.02), had mandibular keratocysts (p = 0.002), and had bifid ribs (p = 0.003) or any skeletal abnormality (p = 0.003) compared to individuals with no pathogenic variant identified [35]. Approximately 90% of individuals with PTCH1-related NBCCS develop multiple keratocysts of the jaw, and approximately 60% of individuals with a pathogenic variant of PTCH1 have a recognizable appearance with domed forehead, coarse facial features, and milia facial features [32, 35]. The risk of medulloblastoma in PTCH1-related NBCCS was less than 2% [40].

SUFU-related NBCCS is associated with a high risk of medulloblastoma up to 33% (3/9) and a high risk of post-radiation meningioma. Overall, clinical features are milder in individuals with SUFU-related NBCCS, in whom BCCs are less present and no odontogenic keratocysts have been reported [32, 35].

One study reported heterozygous pathogenic missense variants of PTCH1 in five out of 100 unrelated probands with holoprosencephaly. The authors hypothesized that pathogenic missense variants would lead to greater inhibition of PTCH1 on the sonic hedgehog signaling pathway, unlike the mechanism in NBCCS where the pathway is usually activated by haploinsufficiency for the patched-1 protein encoded by the PTCH1 gene [32, 41].

A non-recurrent deletion on chromosome 9q22.3 comprising a region of 352 Kb, in which the PTCH1 gene is present, has been shown to cause NBCCS and developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, pre- and postnatal macrosomia, and convulsions. Affected individuals are also at increased risk for Wilms’ tumor. The clinical spectrum of the 9q22.3 deletion is variable, and the clinical results are somewhat dependent on the size of the microdeletion. 9q22.3 microdeletion cannot be identified by routine genetic analysis, except with extremely large deletions [32, 40].

If macrocephaly and other neonatal defects are present, the presence of Sotos syndrome, Beckwith-Wiedemann syndrome (BWS), and isolated hydrocephalus or megalencephaly should be considered:

If the initial clinical signs are multiple BCCs, clinical examination and radiographs should diagnose NBCCS. However, there are other inherited disorders with similar skin signs:

If there is an exposure to arsenic, this can also be a differentiation point [52].

Gorlin-Goltz syndrome is characterized by a triad of typical manifestations: multiple basal cell nevi, odontogenic keratocysts, and skeletal deformities.

Radiological investigations play a fundamental role in the diagnosis of GGS. About 60% of patients have characteristic dysmorphisms such as macrocephaly, bulging forehead, and facial milia. Skeletal anomalies such as fused or cuneiform vertebrae, hemivertebrae, and kyphoscoliosis may be present, and there is a presence of facial dysmorphisms such as cleft lip/palate, macrocephaly, and ocular anomalies. The maxilla may appear hypoplastic and mandibular hyperplasia with variable prognathism may be present. Other less frequent skeletal anomalies are malocclusion and dental crowding, caused by the presence of keratocysts that can cause dislocation of the dental elements, non-eruption, and root resorption.

In a case report published by Nilesh et al. in 2017 [53], the usefulness of the radiographic investigation using orthopantomography was highlighted, as there were multiple radiolucent lesions present in both maxillary bones, some of which associated with the dental apexes of the third molars. Furthermore, the lesions present at the alveolar process caused thinning of the bone thickness.

The typical radiographic findings in the jaws are in fact multilocular radiolucent lesions, with well-defined sclerotic edges. Keratocysts are asymptomatic and often occasional findings, a factor that can explain the late diagnosis in some cases, but can become symptomatic in the event of infection, nerve compression, tooth mobility, or edema. They are more localized in the area of the mandibular branch, while the mandibular body and the upper jaw are less frequently affected areas. Keratocysts are usually surrounded by a few satellite cysts. This feature associated with high mitosis of the epithelium in the presence of a thicker fibrous capsule favors a high recurrence of the lesion after surgical removal; therefore, follow-up with radiographic examination is indicated. Other typical lesions can be found in radiographic images of the skull, where bilamellar calcification of the falx cerebri and alterations of the sella turcica are often highlighted.

It consists in the complete removal of the cyst in a single operating session. The bone cavity residual typically undergoes spontaneous healing, with bone regeneration thanks to a mechanism of organization of the primitive blood clot that forms in the postoperative period. This method is advantageous in terms of timing, as it allows the resolution of the pathology in a single session and with faster healing times.

In the case of larger keratotic tumors that have already reached the periosteal plane and created dislocation or erosion of the bone cortices, complete excision is difficult due to the adhesions of its epithelium to the periosteal or mucous tissue. The attempt to preserve the adjacent dental elements or neurovascular structures and the difficulty of access in some sites can add up to the attempt to limit the extension of the surgical field and lead to incomplete removal, for example in the posterior sectors of the maxillaries and at the mandibular branch level. In cases of encroachment outside the periosteal capsule, the overlying mucosa, which merges with the cystic wall, must be carefully removed because it is one of the main sources of recurrence; in case of contiguity with dental elements, the most suitable treatment modality must be evaluated in order not to leave residues in their proximity (for example, extraction or root canal therapy and apicoectomy).

There are different types of enucleation:

Surgical resection or “en bloc” resection consists in the surgical removal of an entire section of the maxillary or mandibular bone without maintaining continuity. This demolition technique is the only approach that does not show recurrence of keratocysts in surgical follow-ups but, despite the high long-term success rate, it also produces a very high cost in terms of morbidity, such as the loss of bone continuity and mandibular and facial deformation. The resection can also be only marginal, which is an advantageous technique because it allows the lesions to be surgically removed, while maintaining an intact bone margin to ensure continuity. Resective treatment does not appear justified for asymptomatic lesions, even large ones, involving only the spongy part of the bone, without expansion, erosion, or perforation of the cortical bone. Resection should be reserved only for tumors that have perforated the cortical layer, especially those that are recurrent. The lesions limited to the medullary part, on the other hand, should generally be approached in a more conservative way. In the case of “en bloc” resection at the mandibular level, it is indicated, if possible, to proceed with the immediate reconstruction of the mandible with autologous bone grafts or free flaps of the fibula or iliac wing. In the case of extensive, multilocular lesions, in sites at risk or relapsing, in the phase of malignant degeneration or trespassing in the deep planes, the use of a more radical therapy, such as “en-bloc” resection, would seem more suitable for the purpose of avoid a recurrence of the lesion and its further expansion.

Marsupialization is the most conservative method of treating keratocystic lesion: the principle on which it is based is to make the cyst communicate widely with the oral cavity with consequent elimination of endocystic pressure. The drop-in blood pressure will cause a block osteoclastic activity and stimulation of repair with activation of osteoblasts, with a progressive reduction in the size of the lesion.

It has two main indications:

The advantages are represented by the simplicity of execution (possibility of treatment under anesthesia also of large lesions), by the reduced risk of iatrogenic fractures and of neurovascular lesions, and by the elimination of the risk of loss of vitality of dental elements plunging into the lesion.

The progressive decrease of the cystic size over time allows to safeguard the surrounding anatomical structures (maxillary sinus, dental elements, neurovascular bundles), to minimize the risk of fracture and to carry out the subsequent enucleation in the presence of a lesion that is technically easier to remove.

The disadvantages of marsupialization are represented by a resolution of the pathology very slow with discomfort for patients, as an accessory cavity is created in the oral cavity difficult to cleanse.

Furthermore, this method requires a great collaboration on the part of the patient who must undergo irrigations of the residual surgical communication and frequent follow-up.

It has been observed at histological level that, in the biopsy material taken from the healed surface of the surgical access after the resolution of the lesion, there are no signs of epithelial residues of the cyst or daughter cysts. In the studies that have been conducted, in the biopsies prior to surgery, the presence of the expression of B-cell lymphoma 2 (bcl-2) in the cystic epithelium, but not in the material taken after the procedure, is noted. Furthermore, there is also a reduced expression of interleukin-1 alpha (IL-1α). These two factors have been associated with the expansion of the lesion [69‐71].

Decompression is a technique very often confused with marsupialization, but with a different approach. In fact, this method involves the opening of the cystic lesion through a small incision and the insertion of a catheter to maintain the opening and drainage. Decompression is often followed by cystectomy a few months later, when the size of the lesion has reduced. In this way, the second step of the surgical technique can be performed without damaging important anatomical structures, such as the teeth or the inferior alveolar nerve, also reducing the possibility of spontaneous fracture.

The reason for decompression is to reduce the pressure inside the cystic lesion, an objective also achieved through marsupialization, to expose the capsule of the lesion to the oral environment for a definitive resolution. Both methods, decompression and marsupialization, are particularly effective in pediatric treatments and in patients with severe pathologies and extensive lesions. The advantage of these techniques is that they are minimally invasive, can be performed under local anesthesia, and avoid the risk of resection and consequent deformity of the face.

Both decompression and marsupialization, although considered effective techniques, have cases of relapse in long-term follow-up [69, 70].

Cryotherapy consists in the use of a nitric oxide cryoprobe at a temperature of about −20 ° C or lower on the bone walls after enucleation or on the soft tissues if the lesion has perforated the bone plane and encroaches beyond the periosteal capsule. The application lasts 1 min and is repeated twice with an interval of 5 min. Cryotherapy appears to be able to produce cellular necrosis at the bone level, but to keep the inorganic component intact, maintain the extracellular architecture, and facilitate new bone formation; cell death occurs due to direct damage caused by the formation of intra- and extracellular ice crystals, osmotic and electrolytic disturbances. This method allows a relative absence of bleeding and scarring; however, due to the difficulty in controlling the amount of liquid nitrogen applied to the cavity, the resulting necrosis and swelling can be unpredictable. In addition, an increased risk of subsequent spontaneous fracture was also observed [66].