Gorlin-Goltz syndrome – a medical condition requiring a multidisciplinary approach

Background

Gorlin-Goltz syndrome (GGS), also referred to as the nevoid basal cell carcinoma syndrome (NBCCS), is an infrequent inherited disease with a broad range of clinical symptoms, thus this multidisciplinary disorder constitutes a true challenge for medical specialists and, in particular, to dermatologists and dentists who often become primary care physicians for GGS patients.

The characteristic symptoms of the syndrome were first recorded by Jarish in 1894. In the 1960s, Gorlin and Goltz described them as a triad of disorders including multiple basal cell carcinoma, numerous keratocysts in the jaws and skeletal abnormalities, which gave rise to the Gorlin-Goltz syndrome designation [1–3]. Further research revealed a whole range of its clinical manifestations, consequences, and genetic background.

We searched 2 scientific databases – Medline (EBSCO) and Science Direct – for the years 1996 to 2011. In our search of titles and/abstracts, we used such key words as nevoid basal cell carcinoma syndrome and Gorlin-Goltz syndrome to select adequate scientific materials among clinical cases and literature reviews published in English.

Our search revealed 287 studies from Medline and 80 from Science Direct. We tried to choose the newest and, in our opinion, the most interesting papers, which presented the issue most extensively and precisely. Apart from earlier recalled articles, we decided to use slightly older sources, including articles by R. Gorlin (due to their educational value) and a few Polish-language articles. Moreover, we used information included on the website www.gorlingroup.co.uk and www.emedicine.com/PED/topic890.htm. Finally, we used 60 papers to prepare this article. The text below has been structured in a number of sections referring to: etiology and occurrence, symptoms and complications, treatment of a BCC, treatment of a KCOT, treatment of a medulloblastoma, discussion and conclusions.

Etiology and occurrence

Disregarding the most popular designation of the disease suggested by professor Gorlin (nevoid basal cell carcinoma syndrome), in 10% of patients no basal cell carcinoma develops in the skin [4,5].

In the scientific papers published in English there are many designations of the syndrome, which often stem from its symptoms (Table 1) [6].

NBCCS is a genetic disorder inherited in a dominant autosomal way [1,4,7,8]. Although its occurrence among family members an important diagnosing criteria, it has been found that between 20% and 40% of cases result from a de novo mutation of the PTCH1 [9q22.3] gene [4,9–13]. According to the current state of knowledge, mutations of other genes such as Patched2 [PTCH2], Smoothened [SMO] and Sonic Hedgehog [SHH], observed also in relation to basal cell carcinoma and medulloblastoma [7,13,14], may exert a certain influence on the occurrence of the syndrome.

The assumed prevalence of the disease is 1:60,000; however, in various studies its values range from 1:57,000 (in England) to 1:164,000, and even 1:256,000 (in Italy). The syndrome occurs with an equal frequency in men and women and in almost all ethnic groups except for the Caucasian race, which is most often affected by it [1,2,4–6,9]. NBCCS is sometimes diagnosed in very young patients, but in most cases it occurs in people aged between 17 and 35 years [1,15]. The condition is very difficult to diagnose in early childhood because its symptoms appear gradually as the child grows [3,16].

Symptoms and Complications

Skin anomalies

BASAL CELL CARCINOMA (BCC): Multiple basal cell carcinoma of the skin constitutes the most characteristic feature of the syndrome. The highest incidence rate is observed in people between puberty and age 35, although it was also observed in children ages 3 to 4 years. It is diagnosed in 90% of Caucasians age 40 or older [4,17] and in 40% of the Negroid population [10,18,19]. The number of BCC lesions varies from several to thousands [10], their diameter ranges from 1 mm to 10 mm, and they may have various forms from skin-coloured nodules or papules to ulcerating plaques. They are usually located on the face, back and chest, but they may also be found on skin not exposed to the sun [10]. Aggressive forms of basal cell carcinomas, which infiltrate the facial bones, hardly ever occur [20]. The above-mentioned lesions are extremely challenging for therapists but, thanks to the combined efforts of various medical specialists such as maxillofacial surgeons, plastic surgeons, laryngologists, oncologists, radiation oncologists, restorative dental specialists and psychologists, the patients have a chance to recover and regain their regular social functions [8,15,21].

MILIA: In 30% of patients, milia (small cysts filled with keratin) appear on the face, just below the eyes, and less frequently on the forehead [4,5,10].

PALMAR AND PLANTAR PITS: The presence of palmar (70%) and/or plantar (50%) pits is a very important diagnostic factor. They are small, with a diameter ranging from 2 to 3 mm and depth from 1 to 3 mm. They are red at the bottom in Caucasians and black in Negroids. From 30% to 65% of cases involve children under 10, but the prevalence in the age group above 20 years is 85%. The number of pits increases with age. They become more visible after the palms have been held in warm water for about 10 minutes [4,5,10].

KERATOCYSTIC ODONTOGENIC TUMOUR (KCOT):

The most important manifestations of Gorlin-Goltz syndrome within the oral cavity are recurrent multiple jaw tumours called keratocysts. The lesions occur in as many as 90% of patients above age 40 [10,22]. They are most frequently located in the mandible − 44% are found in the mandibular angles and 18% in the zones adjacent to incisor and canine teeth [10,23]. In the maxilla, they accompany canines and incisors (15%), as well as molars (14%) (Figure 1). In spite of their less frequent occurrence as compared to in the mandible, they are more aggressive than those in the lower jaw area.

The KCOTs are divided into parakeratotic, orthokeratotic, and (rarely) mixed and solid lesions, and they are differentiated based on a histological image of the cells lining them. The tumour consists of a thin fibrous external pouch, whose interior is lined with a stratified squamous epithelium of a parakeratotic (96%) type [23,24]. The orthokeratotic form of tumour seldom (in 4% of cases) occurs, has a milder course and considerably fewer recurrences. That is why, according to the WHO regulations, the orthokeratotic form of the lesion is classified as an odontogenic cyst and the parakeratotic form is considered a benign neoplasm [23]. The cavity of the tumour is filled with thick keratinous material or a straw-coloured fluid [24]. The tumours are usually diagnosed accidentally during routine X-ray examinations performed in the course of a regular dental treatment [25]. Inflammatory symptoms occurring within the tumour sometimes force the patient to consult a medical practitioner, and this enables a faster diagnosis of KCOT [26].

An X-ray image of a KCOT in its early stage shows a spherical or oval unilocular lytic bone lesion often involving a wisdom tooth (Figure 2). It is well circumscribed and has a well-defined osteosclerotic rim, which may become less visible while the lesion grows and transforms into a multilocular form [25,27]. The latter form of the tumour needs to be differentiated from ameloblastoma [24,28]. In the course of its growth, the tumour causes bony expansion that may result in deformation or asymmetry of the facial structures. In spite of a considerable size of the tumours, pathological bone fractures hardly ever occur. Other rare anomalies in the oral cavity include occlusal problems related to the adjustment, shape and number of teeth, as well as mild mandibular prognathism manifested in soft tissues by protrusion of the lower lip [29]. In many cases, a high palatal arch or a close relationship between the canal and the lower border of the mandible [30] were observed. Less frequent symptoms included cleft lip, cleft palate [31] and alveolar process [27,29], as well as other deformities of alveolar processes caused by tumours. Tumours developing within the nasal sinuses may lead to a deteriorated patency of nasal passages [32]. It has been recently noted that patients with GGS have a bilateral hyperplasia of the coronoid process of the temporomandibular joint, which constitutes a useful diagnostic criterion, especially in the assessment of pediatric patients [10,33].

Apart from the earlier mentioned symptoms of NBCCS, patients may have numerous disorders affecting various systems and organs (Table 2) [2,4,5,10,17,22,25,27,29,30,34–39].

Treatment of a BCC

Owing to the possible occurrence of a varied number of neoplastic lesions, the patients must be provided with optimized treatment adjusted to the clinical conditions. The best method should result in a high percentage of successfully treated patients and a short period of healing. It should also save the biggest area of healthy skin possible, leave no scars and cause no adverse effects [40]. In spite of continually developing new and enhancing traditional treatment procedures (Table 3) [4,5,10,41–48], we should not forget prophylaxis. Prevention consists in following certain principles – patient self-control, avoiding sun, using UV sun block or wearing sun glasses and sun-protective clothing [4,5].

Treatment of a KCOT

Keratocystic odontogenic tumour therapy depends on several important factors, including: the age of the patient; size, extent and location of the lesion; and possible perforation of the cortical bone lamellae or soft tissue infiltration. The methods may be divided into conservative, aggressive and radical. Conservative treatment consists of a regular enucleation of tumours from their bony beds in the course of a 1- or 2-stage procedure, which is used in the cases of ordinary intraosseous cysts [49]. Unfortunately, due to the presence of satellite micro-tumours in the surrounding bone, this method has the highest recurrence rate [7,49]. Much better results can be obtained if enucleation is followed by a chemical or mechanical curettage of the surrounding bone. For that purpose, either liquid nitrogen (−70°C) or Carnoy’s solution – a mixture of 6 ml of absolute alcohol, 3 ml of chloroform, 1 ml of glacial acetic acid and 1 g of ferric chloride [50] – may be applied to the bone cavity. In the case of Carnoy’s solution, the recurrence rate does not exceed 2%. Cryotherapy, however, has an 11% recurrence rate. Carnoy’s solution is most often used in the mandible, as in the maxilla the method involves the risk of necrosis of the mucosa lining the maxillary sinus or nasal cavity. Disregarding the above-mentioned facts and taking into account his clinical experience, Stoelinga considers the application of this method to be equally successful within the maxilla, as well as effective and relatively safe [51]. Radical treatment methods involve partial resection of the tumour-invaded bone together with a 5-millimetre margin of healthy bone tissue and are, undoubtedly, associated with the lowest recurrence rate. Nevertheless, in children whose tooth eruption or bone forming processes have not finished, the radical procedures should be replaced by conservative ones [7,52,53]. Whenever dental practitioners encounter cases of multiple or recurrent cysts (Figure 3), they are obliged to provide such patients with comprehensive dental care and carry out diagnostic tests or refer them for such tests, because the cysts might be the first noticeable symptoms of the nevoid basal cell carcinoma syndrome (GGS) [1,7,24].

Treatment of a Medulloblastoma

Medulloblastoma is a malignant tumour of the posterior cranial fossa, typically occurring in children between 7 to 8 years of age, whereas in people with Gorlin syndrome it occurs during the first 3 years of life [5,10]. Estimated prevalence of this disorder is 2%, and it is 3 times higher in boys than in girls [22]. It is assumed that about 10% of the patients in whom medulloblastoma was diagnosed at an early age have Gorlin syndrome. Early diagnosis of medulloblastoma should always lead to a suspicion of NBCCS. The best results of treatment are obtained when the treatment procedure combines aggressive tumour resection with both chemo- and radiotherapy [54]. The latter form is controversial because it induces invasive/multiple squamous cell carcinomas in the skin area submitted to radiation, as well as numerous neoplastic lesions in adjacent tissues [55–57]. Therefore, it should be avoided if possible or replaced with non-conformal radiation techniques conserving the skin, although their adverse effects include ototoxicity or radiation injury of the temporal lobes. Most of the GGS-associated medulloblastoma are desmoplastic lesions with a milder course and better prognoses [according to the clinical reports, the patient may even have a spontaneous recovery [54]], which is an important reason for why radiation therapy should not be used in such cases [4,5,10,56]. GGS rarely results in premature death (10%) but, if it does, the death is usually caused by medulloblastoma [4,5] or an X-ray therapy of invasive basal cell carcinomas that leads to secondary dissemination and re-initiates carcinogenesis of skin lesions, which in effect also causes death of the patient [4].

Discussion

Gorlin-Goltz syndrome (GGS) is a condition whose management requires the involvement of many different health professions. It may seem that the numerous symptoms of this disease make diagnosis a very simple task, but, in fact, it is quite difficult. Its variable expressiveness is proportional to the age of patients. Therefore, genetic tests are a matter of key importance for formulating adequate diagnosis, in particular during the first years of lives of the youngest patients. In most cases, however, GGS is detected using clinical criteria such as the presence of 2 symptoms of high importance or 1 of high and 2 or 3 symptoms of little importance (Table 4) [4,5,16,21,58,59].

If there is a suspicion that the disease found in a child results from a de novo mutation, detailed radiological examinations of relatives need to be carried out. In the case where no abnormalities are detected, genetic tests should be the most helpful tool, and can provide definitive information [60].

In pregnant women at a high risk for GGS, ultrasonographic examination may reveal fetal anomalies such as increased head circumference or cardiac fibroma; however, they are extremely rare at that stage of development. In such cases, prenatal diagnosis may be formulated based on the genetic material collected in the course of amniocentesis performed between the 15th and 18th week of pregnancy or chorionic villus sampling (CVS) done between the 10th and 12th week of pregnancy [10]. Nevertheless, prenatal diagnosis is very rare and the necessary condition of its performance is a confirmed presence of a disease-causing allele in a patient’s relative [12].

After birth, the child needs to have a careful clinical examination. If GGS is suspected, X-ray imaging is needed to show deformities of the rib or vertebrae. An echocardiogram is also recommended in order to exclude or confirm the presence of cardiac fibromas [25].

When the result of family medical history is positive, a newborn child should undergo a detailed assessment aimed at finding significant symptoms of GGS. If there is a suspicion of NBCCS in an adult patient, they too need to be carefully examined (Table 5) [1,4,5,10,16,21,35,59].

Conclusions

A patient with Gorlin-Goltz syndrome needs particular multidisciplinary medical care and what’s more he should understand nature of the problem. In the case of adults, self-control is crucial for maintaining good health, as it allows the noticing of even very subtle changes. Awareness of the risk related to radiation enables them to avoid its harmful influence by using UV filters and other available protective agents.

Medical specialists’ knowledge of the multiple and difficult to diagnose symptoms of the syndrome is a matter of key importance. The consequences of the disease pose a threat to both the health and life of a patient. Therefore, an early diagnosis creates an opportunity for effective prevention and treatment. Prevention is better than cure.