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

Gorlin-Goltz syndrome is a rare genetic condition showing a variable expressiveness. It is inherited in a dominant autosomal way. The strongest characteristic of the disease includes multiple basal cell carcinomas, jaw cysts, palmar and plantar pits, skeletal abnormalities and other developmental defects. Owing to the fact that the condition tends to be a multisystemic disorder, familiarity of various medical specialists with its manifestations may reduce the time necessary for providing a diagnosis. It will also enable them to apply adequate methods of treatment and secondary prevention. In this study, we present symptoms of the disease, its diagnostic methods and currently used treatments. We searched 2 scientific databases: Medline (EBSCO) and Science Direct, for the years 1996 to 2011. In our search of abstracts, key words included nevoid basal cell carcinoma syndrome and Gorlin-Goltz syndrome. We examined 287 studies from Medline and 80 from Science Direct, all published in English. Finally, we decided to use 60 papers, including clinical cases and literature reviews. Patients with Gorlin-Goltz syndrome need particular multidisciplinary medical care. Knowledge of multiple and difficult to diagnose symptoms of the syndrome among professionals of various medical specialties is crucial. The consequences of the disease pose a threat to the health and life of patients. Therefore, an early diagnosis creates an opportunity for effective prevention and treatment of the disorder. Prevention is better than cure.

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 and . 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].

Table 1

Synonims of Gorlin-Goltz syndrome.

Designations of the Gorlin-Goltz syndrome used in the scientific papers
Basal cell naevus (carcinoma) syndrome	Multiple hereditary cutaneomandibular polyoncosis
Epithelioma naevique multiple	Multiple naevoid basal-cell carcinoma syndrome
Fifth phakomatosis	Naevous epitheliomatodes multiplex
Gorlin syndrome12	Nevoid basal cell carcinoma syndrome
Hereditary cutaneo-mandibular polyoncosis	Nevoid basal cell carcinoma epithelioma – jaw cysts
Hermans-Grosfeld-Spaas-Valk syndrome	Multiple bifid rib syndrome
Multiple basal-cell carcinoma syndrome	Ward syndrome II
Multiple basal-cell naevi syndrome

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.

Figure 1

Panoramic view reveals multiple KCOT’s in patient with inherited GGS (daughter of T.S.)

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].

Figure 2

Panoramic view of the patient W.J. with GGS de novo, revealing multiple KCOT’s in both jaws involving and replacing germs of the molars.

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].

Table 2

Other manifestations of NBCCS.

Calcifications of the central nervous system and other lesions

Calcification of: – falx cerebri – tentorium cerebelli – sella turcica – petrosphenoidal ligament [2,4,5]

Cysts of the choroid plexus, third and lateral cerebral ventricles

Agenesis of corpus callosum

Meningioma

Medulloblastoma

Multiform glioblastoma

Astrocytoma

Foetal rhabdomyosarcoma

Grand mal

Congenital hydrocephalus

Mental retardation ~5% patients with NBCCS [10]

Ophtalmic and otologic anomalies

20% patients with GGS

Hypertelorism 70%

Microcysts on eyelids

Congenital cataract,

Strabismus,

Nystagmus,

Orbital cysts

Congenital blindness.

Otosclerosis,

Conductive hearing loss

Posteriorly angulated ears

Skeletal anomalies

Significant height – average for females is 174 cm and for males 183 cm [30]

Increased pneumatisation of the paranasal sinuses (in particular frontal sinuses)

Increased head circumference [30,34] 50%

Strongly marked superciliary arches

Retracted and a wide base of the nose typical for pseudohypertelorism (in 5–40% cases true hypertelorism were reported) [22,25,35]

Wide eyes 70%

Congenital skeletal anomalies: – bifid, fused, splayed or missing ribs 30-60% (27) – bifid wedges fused vertebra – scoliosis 40% – frontal, temporal, parietal bossing – polydactyly, sindactyly [36] – short fourth metacarpal – sprengel shoulder [elevation of the scapula characterised by medial rotation of the distal pole of the scapula ~10–40% patients with GGS]

Spina bifida occulta 40–60% [5,10]

Sternal protrusion or depression 30–40% of patients [5]

Cysts within the phalanxes, long bones, pelvis and even calvaria – the symptoms may create an impression that the bone is occupied by medulloblastoma cells [10]

Urogenital anomalies

25–50% of affected ♀ reveal ovarian cysts and fibromas: – bilateral in a 3/4 of cases [37,38] – do not impair women’s fertility – risk of ovarian torsion [17] In ♂: – hypogonadism – cryptorchidism – gynecomastia Urinary system [29,35,39]: – U- (horseshoe) and L-shaped kidneys – unilateral renal agenesis – double kidneys – double ureters

Gastro-enteric system

Limphomesenteric cysts Ø 2–14 cm, asymptomatic

Gastric polyps

Cardio-vascular system

Cardiac fibroma [22,36]: – 3–5% of patients with cardiac fibromas reveal GGS – Ø 3–4 cm – usually located in the anterior wall of the left atrium – if they involve also the ventricles, impair hemodynamics of the heart [22,36] Absent internal carotid artery

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].

Table 3

presents review of methods of BCCs treatment [4,5,10,41–48].

Curettage and electrodessication	– simple, fast and effective, success rate is 92–93% – for small and located in the areas where the recurrence risk is low (such as the neck, body or limbs), not recommended for treatment of large lesions or the ones located on the face (4, 5) – carried out under infiltration anaesthesia, the lesions are scraped off using a curette and then desiccated with an RF knife; healing period ranges from 10 to 21 days; repeated 3 or 4 times approximately; side effects as damage to the nerves or numbness within the operated area – curettage is also used in combination with imiquimod, photodynamic therapy or cryosurgery
Cryosurgery	– destruction of neoplastic tissue during one or several cycles of freezing with liquid nitrogen
Laser ablation (CO2 laser vaporization)	– used as an independent treatment method or in association with the curettage – for multiple superficial lesions – still in clinical trials
Surgical excision	– in the case of a limited number of lesions – 2–8-millimetre margin of clinically normal surrounding tissues (41) – allows histopathological examination (inform about final diagnosis and treatment efficacy-completeness) – cosmetic effects depend mainly on the sizes and location of carcinomas (42)
Mohs micrographic surgery	– surgical removal of the neoplasms with a precise microscopic marginal control – allows radical excision of the lesions while minimizing the damage of healthy tissue – the highest success rate but it is long lasting and costly at the same time, therefore, it is used only in special cases (5, 10) – preserved for recurrent BCC, in high risk site, infiltrating lesions, previous radiation therapy in the area, lesions in Gorlin syndrome
Photodynamic therapy (PDT)	– a photosensitizing agent is applied intravenously or locally, becomes accumulated by neoplastic cells and then activated by means of radiation whose wavelength corresponds to its absorbance spectrum, in result cells of the carcinoma infused with the above-mentioned agent are killed – brings excellent cosmetic effects – best effect in superficial small/large lesions in low risk site – very promising method but not suitable for children [10,42–44]
Ionizing radiation	– rarely used for treatment of the lesions accompanying Gorlin syndrome – applied only in special cases [45] – induces sudden dissemination of new lesions with the same characteristics as basal cell carcinomas
Chemotherapy of bcc:
5% imiquimod cream	– used for treatment of the nodular basal cell carcinomas alone or in association with curettage; the therapy involves 5 applications of the cream in a week and lasts 6 weeks [10,43,46]
0.1% tretinoin cream	– application involves a dermatological follow-up during three subsequent months
5-fluorouracil cream	– _local application; usually applied twice a day for a period of 6–12 weeks; the cure rate ranging from 80% to 95%; effective only in the case of superficial BCCs (4)
SHH (sonic hedgehog) antagonist,	– in the form of a cream (cyclopamine) together with oral medications (GDC-0449); the most recently tested treatment modality; it seems to be promising in inoperative bcc, more clinical observations should be conducted [47,48]
Oral retinoid (isotretinoin)	– are used for chemoprevention or delaying the development of bcc; patients have to take the medications in large doses for a long period; it leads to intensification of side effects affecting the organs of vision, liver, bones, nervous system or muscles; the lesions may reoccur after the end of the therapy [4,5]
Interferon	– in the experimental stage; injected directly into the neoplastic lesions 3 times a week for the period of 3 weeks; the method needs to be confirmed; side effects include: fever, shivering, drop in leukocyte level and pain at the site of injection [42]

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].

Figure 3

Panoramic view reveals KCOT’s in patient (T.S. father) with GGS.

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].

Table 4

Symptoms of GGS.

The symptoms of high importance include:

The symptoms of little importance include:

Occurrence of two or more basal cell carcinomas of skin in patients below 20 Histologically confirmed 2≥ KCOT Palmar or plantar pits 3≥ Calcification of the cerebellar falx Rib deformations (fused or bifid ribs) Presence of GGS in first-degree relatives

Increased circumference of the head Inborn developmental malformations such as: cleft lip or palate, hypertelorism or frontal bossing Other skeletal abnormalities such as: Sprengel scapular deformity, deformity of the rib cage or syndactyly Anomalies visible during the x-ray evaluation such as: bridging sella turcica, elongated or fused bodies of vertebrae, hemivertebrae or malformations of hands and feet Ovarian and cardiac fibromas Medulloblastoma

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].

Table 5

The algorithm for diagnosis and prevention of GGS [1,4,5,10,16,21,35,59].

a.i.1. A detailed medical and, in particular, dental history;

a.i.2. A number of clinical examinations including: Dental assessment, Dermatological evaluation performed: – at least once a year from puberty on; – adult persons every 2 or 3 months and regular themselves-control Neurological evaluation; owing to the fact that medulloblastoma of the brain develops at a very young age, MRI (magnetic resonance imaging) should be carried out: – every half a year in children under three – and once a year in those aged from 3 to 8, Measurement of the circumference of the head, distance between the irises and height of the patient, Ophthalmologic, Cardiologic, Orthopaedic, Gynaecologic and urologic;

a.i.3. Genetic tests: PTCH (Patched) SMO (Smmothened), SHH (Sonic hedgehog);

a.i.4. Radiological examinations: Panoramic radiographs taken annually in patients aged from 8 to 40 CT (computed tomography) scans of the facial bones may be very helpful in planning the surgical removal of lesions (in particular the CBCT-cone bean computed tomography ones owing to a low dose of radiation); the frequency of such examinations in older patients depends on the precedent set by the course of the disease, because in 10% of the patients the keratocysts never appear; it is assumed that in people older than 30 the occurrence rate is much lower; Of the chest Of the skull including anteroposterior and lateral views Of the cervical and thoracic spine including anteroposterior and lateral views, Of the hands, Of the pelvis in female patients;

a.i.5. USG (ultrasonography) of the abdominal cavity and pelvis minor (focused on finding ovarian and mesentery fibromas and cysts);

a.i.6. USG (ultrasonography), ECG (electrocardiogram) of the heart (in search of fibromas)

a.i.7. Patients education: raising the awareness of the patient about one’s illness and the promotion pro-healthy behaviours and the self-control

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.