Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Basal cell carcinomas may arise in various stages of the syndrome: most often they appear between puberty and 35 years of age [16], but cases have been reported in 3 or 4 year-old patients [5, 12]; in general, the mean age of onset is about 25 years of age. The incidence varies widely among ethnic groups: only about 40% of black patients affected by NBCCS manifest BCCs, while in whites they are reported in up to 90% of cases. However, the incidence in whites is also variable with some studies showing a lower prevalence (30%), probably due to protective skin pigmentation [11], as already established for African-American patients [6, 19]. BCCs may vary in number (from a few to literally thousands) and range in size from 1 to 10 mm in diameter. Clinically, they may vary from flesh-colored papules to ulcerating plaques and may be mistaken for skin tags, nevi, or hemangiomas. There appears to be a relationship with increased sun exposure, and therefore BCCs are most likely to appear on the sun-exposed parts of the body, but non-exposed areas may also be involved. The most common locations are the face, the back, and the chest; the waist and extremities are rarely involved; BCCs have also been described on genitalia [20]. BCCs in this syndrome behave in the same manner as sporadic BCCs. In general, it is after puberty that the basal cell cancers become aggressive and invade locally [5]. If a lesion increases in size or begins to bleed or crust, invasion should be suspected and excluded. Radiation therapy must be avoided [6, 21], since tumors may appear in the radiation fields even after many years [16]. Evidence of metastatization has been rarely reported [22, 23]. If left untreated, BCCs can lead to disfigurment, especially on the face. Wang and Goldberg reported a patient with NBCCS who developed multiple polypoid basal cell carcinomas (PBCC) in the perineum, leading to the recommendation that the perineum, perianal, and genital areas should be included in the routine examination of patients with NBCCS [24]. The histopathology of nevoid BCC cannot be differentiated from that of ordinary sporadic BCC [4]. The tumors are composed of nests and islands or sheets of large, deeply-stained nuclei with indistinct cell membranes [4]. At the periphery of each lesion, the epithelial cells are well-polarized, suggestive of cutaneous basal cells. About 30% of NBCCS patients have two or more types of BCC patterns (morphea-like, solid, superficial, cystic, adenoid, fibroepithelial) [4]. Commonly (30–50% of cases), there are milia intermixed with the basal cell islands and calcified foci may be noted, not only within the tumor but also in normal skin [4]. Perhaps this reflects the "turning on" of the bone morphogenetic protein (BMP) gene [4].

Between 30% and 65% of patients with the syndrome have small asymmetric palmar-plantar pits by the age of 10 years, this percentage rising to 80% by the age of 15 [21, 25]. Pits occur in 85% of patients over the age of 20 years [25]. These lesions are 2–3 mm in diameter and 1–3 mm in depth [26], with the color of the base being red in caucasians and black in africans. They increase in number with age, are permanent, and are a strong diagnostic indicator whenever found in a child. They are found more commonly on the palms (77%) than on the soles (50%). The pits may be easier to see if the hands are soaked in warm water for about 10 minutes. No BCC has been found to arise from these pits [21].

Other skin signs are nodular or patch lesions, and benign dermal cysts. Small keratin-filled cysts (milia) can be found on the face in 30% of cases, most commonly in the area below the eyes, but they can also occur on the forehead.

Recently, Wilson et al. reported the occurrence of hairy skin patches (discrete patches of unusually long pigmented hair) on the skin of three patients affected by Gorlin syndrome from two unrelated families with confirmed heterozygous mutations in the PTCH1 gene, suggesting that the patches may represent a sign associated with the syndrome [27].

Recurrent jaw cysts are the main oral sign, being present in 90% of patients [11]. These cysts are known as keratocysts as they are characterized by a thin external fibrous capsule and an internal lining of keratinized stratified squamous epithelium. Keratocysts appear in the tooth-bearing areas of the jaws, and are believed to arise from the dental lamina [21]. Cysts may appear in both jaws. In several cases, the first symptom is either an odontogenic keratocyst or an odontogenic cyst of the jaws [11, 18]. Odontogenic keratocysts (OKCs) are the most consistent and representative signs of NBCCS in the first and the second decades of life. OKCs are detected in patients under 10 years of age [5, 12]: 13% of patients develop a jaw cyst by the age of 10 years and 51% by the age of 20 years. These data suggest that lesions may start to develop as early as at 7 or 8 years of age and underline the fact that keratocysts in patients affected by NBCCS arise earlier than those in healthy subjects [28, 29]. In NBCC patients, there is continued development of new and recurring cysts until about age 30, when the rate of development tends to decrease [30]. Most non-NBCCS keratocysts are isolated lesions, but in NBCCS the keratocysts are commonly multiple, from 1 to 30, and the average number is 5. The most common site in the mandible is the molar-ramus region (44%), followed by the incisor-canine region (18%) [18]. In contrast, the majority of maxillary cysts occur in the incisor-canine (15%) and molar-tuberosity (13%) regions [18]. Only a few cysts have been reported in the premolar region. There is no racial predilection. There may be remarkably few symptoms until cysts reach a large size, especially when the ascending ramus is involved. Presentations include swelling and/or displaced, impacted teeth. About one-half of patients present with swelling, a quarter with mild pain, and 15% with an unusual taste following rupture of a cyst. Despite these manifestations, jaw fractures almost never occur. Radiographically, the keratocyst may show a unilocular or multilocular pattern and the cystic spaces may have a smooth or scalloped border. One of the most problematic aspects is the 60% rate of recurrence following surgery. In part, this may be due to incomplete removal, i.e., from retention of epithelial islands and/or satellite microcysts, which occur with great frequency in the connective tissue capsule, or from proliferation of the basal layer of the epithelium [31]. There have been a few reports of ameloblastoma arising in odontogenic keratocysts [32] or, rarely, of squamous cell carcinoma [33]. Microscopically, the odontogenic keratocysts are multilocular with a parakeratinized (96%) or, rarely, orthokeratinized (4%) stratified squamous epithelium consisting of only a few layers of cells (about five to eight) with a well-defined basal epithelial cell layer, palisaded nuclei but no rete ridges [4]. Budding of the epithelium into the connective tissue with suprabasilar splitting has been noted in at least 50% of cases [4].

Other defects of the stomatologic system are malocclusion, impacted teeth, mandibular prognathism, dental ectopy or heterotopy, and dental agenesis. Cleft palate and lip are rare (5%) [34, 35]. Recently, a new sign has been described: bilateral hyperplasia of the mandibular coronoid processes [36], which may be a radiologic criterion for the syndrome, useful for establishing a diagnosis especially in pediatric patients [37].

Ectopic calcifications of the central nervous system have been reported: lamellar calcification of the falx cerebri (70–85%) [11], calcification of the tentorium cerebelli (20–40%) [11], the petroclinoid ligament (20%) and the diaphragma sellae (60–80%) [38], and complete or partial bony bridging of the sella turcica (25%) [11]. Spotted meningeal calcifications are rare. These signs may not result in clinical manifestations, but can be useful in confirming the diagnosis. The calcification of the falx cerebri can appear very early in life, and is often strikingly apparent from late childhood. Other signs reported are cysts of the choroid plexus of the third and lateral ventricles of the brain, intraparenchymal brain cysts, arachnoid cysts, glial nodules projecting from the lateral ventricles, agenesis of the corpus callosum with or without lipoma [39], "empty" sella syndrome [39], communicating hydrocephalus [40‐43], meningioma [44, 45], cysts of the septum pellucidum [46] and medulloblastoma [44, 47‐55] (see the paragraph "Other tumors"). Vermian dysgenesis has been noted in a mother and a daughter [56, 57]. Seizures have occasionally been noted unassociated with brain tumors and possibly due to focal neuronal heterotopia [58]. Mental retardation occurs in about 5% of cases.

Skeletal manifestations are also present in NBCCS [46]. The signs in the bones found on X-ray may be helpful in making the diagnosis. The height (these patients can be much taller than expected for their family), the shape of the ribs, the shape of the bones in the vertebral column, and the shape of the skull are principally affected [46, 59]. Mean height is increased (183 cm in males, 174 cm in females) and about 15% of patients are extremely tall [4]. An abnormal skull configuration (characterized by frontal (25%), biparetial or temporal bossing, and large calvaria) is frequent (70%) [11]. Relative macrocephaly with an occipital frontal circumference above the 95^th centile has been reported in 50% of cases [6, 59]. As a result of the abnormal growth of the skull (> 60 cm in adults), about 70% of patients affected by NBCCS have eyes which appear wider apart than usual. Other skeletal signs are scoliosis (40%), and abnormalities such as bifid, wide, fused, partially missing or underdeveloped ribs (30–60%) [11]. Rib abnormalities may give rise to a prominent or depressed sternum in about 30% – 40% of patients. Spina bifida occulta of the cervical or thoracic vertebrae is found in 60% of cases [60]. However, in a series studied by Kimonis et al., the spina bifida occulta occurred in only 20% of patients [6]. Bifid wedges, fused vertebra and Sprengel anomaly (elevation of the scapula with rotation toward the spine with scoliosis) are observed in 10 to 40% of patients. Extra digits on the hands or feet can occur. In about 35% of individuals with Gorlin syndrome, an X-ray of the hands will show small cysts in the bones of the fingers. The numbers and site can be very variable. Bone cysts can also occur in the long bones of the arms and legs, the pelvis and the calvaria [61]; usually, these do not cause problems, even if calvarial involvement may give the erroneous impression that medulloblastoma has spread to bone [62]. Histologically, the flame-like lesions consist of fibrous connective tissue, nerves, and blood vessels, i.e., they are hamartomas [4].

NBCCS patients may have various ocular problems that occur with a frequency higher than that in the normal population (20%). These include hypertelorism (70%), exophthalmus, rotatory nystagmus, internal strabismus, congenital cataracts, orbital cysts, coloboma of the iris, choroid, and optic nerve, microphthalmia, and chalazions [5, 11, 21, 63]. Most striking are small very transient keratin-filled cysts (milia) found on the palpebral conjunctivae in about 40% of cases [4]. This observation is a personal one, reported by a parental support group in Manchester, England [4]. The author asked the assembled group if they had ever had one or more of these transient cysts [4], and this exercise was repeated for the American support group for NBCCS [4]. Due to the transient nature of these cysts, most of the patients noted that they were not significantly disturbed by their presence, but they had been to ophthalmologists who confirmed the presence of milia of the palpebral mucosa [4].

Ovarian cysts and fibromas are present in 25–50% of affected women [5] and are often bilateral (75%). Ovarian calcifications are reported and may be mistaken for calcified uterine fibroids or calcified uterine leiomyomas. They do not seem to reduce fertility but may undergo torsion (twist). Some cases of ovarian fibrosarcoma [64] and primary ovarian leiomyosarcoma [65] have been reported. Males may exhibit hypogonadotrophic hypogonadism (5–10%), cryptorchidism, female pubic escutcheon, or gynecomastia. Other signs involving the kidneys (5%) may be: horseshoe kidney, L-shaped kidney, unilateral renal agenesis, renal cysts, or duplication of the renal pelvis and ureter.

Single or multiple chylous or lymphatic mesenteric cysts have been documented [4, 66‐68]. The cysts are thin-walled and measure 2 to 14 cm in diameter, do not produce symptoms, and are often an occasional finding [21]. The content is chylous but may contain hemorrhagic turbid fluid [4]. Microscopically, the wall is composed of fibrous connective tissue and smooth muscle, and a layer of lymphatic cells is often located beneath the endothelial lining [4].

Fibroma of the heart has been described [5, 21, 46, 69‐74]. The syndrome is present in 3–5% of all patients with a cardiac fibroma [5, 69]. The cardiac fibroma is discrete, well-circumscribed, not encapsulated, firm, gray-white, 3 to 4 cm in diameter, and may, upon occasion, exhibit central calcification [4]. The tumor is most often located in the left anterior ventricular wall. If the tumor projects into the chambers, hemodynamics is altered and/or impeded. Conduction defects (i.e., arrhythmias) may also be present due to involvement of the intraventricular septum [75]. The tumors are composed of fibroblasts embedded in a dense matrix of collagen and elastic fibers.

Tumors in patients with NBCCS include basal cell carcinoma, medulloblastoma, fibroma and rhabdomyosarcoma (RMS) [76‐78]. RMSs are also present in 15% of mice haplodeficient for PTCH1 [79]. Medulloblastoma is frequent [44, 47‐55]; Herzberg and Wiskemann first pointed out the association of NBCCS with medulloblastoma in 1963 [80]. The tumor characteristically presents during the first two years of life, while in the general population occurrence peaks at 7 to 8 years of age. The incidence of medulloblastoma in Evans' series was 1% to 2% [5]. There is a sex predilection with a male-to-female ratio of 3:1. Early onset medulloblastoma may be the presenting sign of NBCCS; thus, in children in which this tumor is diagnosed, NBCCS should be suspected and a careful examination for other signs of the syndrome should be performed in order to rule it out [6]. There is some evidence that medulloblastomas associated with NBCCS have a better clinical outcome than those found in isolation [47, 81, 82], with the possibility of spontaneous recovery [82]. Radiation therapy for medulloblastoma can induce invasive BCCs in the radiation field (i.e., from the nape to base of the spine) [83].

Other brain tumors, such as astrocystoma, craniopharyngioma, and oligodendroglioma, are infrequent, while meningioma is slightly more common. These tumors may well be secondary to radiation therapy.

In 1968, Schweisguth et al. reported fetal rhabdomyoma [84]. This tumor has been described at various sites [21, 78, 85‐89]. Mature striated muscle within the tumor is indicative for diagnosis.

There are several reports that support an increased incidence of other neoplasms or hamartomas, such as leiomyomas of bowel and mesentery, leiomyosarcoma, adrenal cystic lymphangioma, thyroid adenoma, lymphangiomyoma, melanoma, ameloblastoma, craniopharyngioma, mesenchymoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, seminoma, paratesticular pseudotumor, schwannoma, pleiomorphic adenoma of parotid, adenoid cystic carcinoma of salivary gland, and adrenal tumors [90‐92].

1. Multiple (>2) BCCs or one under 20 years

2. Odontogenic keratocysts of the jaws proven by histopathology

3. Palmar or plantar pits (3 or more)

4. Bilamellar calcification of the falx cerebri

5. Bifid, fused or markedly splayed ribs

6. First degree relatives with NBCCS

1. Macrocephaly determined after adjustment for height

2. Congenital malformation: cleft lip or palate, frontal bossing, "coarse face", moderate of severe hypertelorism

3. Other skeletal abnormalities: sprengel deformity, marked pectus deformity, marked syndactyly of the digits

4. Radiological abnormalities: bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet

5. Ovarian fibroma

6. Medulloblastoma.

The presence of the most frequent and/or specific features of the syndrome make the diagnosis easier; however, diagnosis in a child with a 50% risk of having inherited the condition may not be so easy because of the extreme variation in expression, both within and between families. Some children may have only rib anomalies, whilst others have the "typical face" without other signs. Gene tracking and mutation analysis may be helpful for pre-symptomatic diagnosis.

For apparently isolated cases, detailed examination and X-ray investigation of the relatives should be undertaken before concluding that a child's condition is the result of a new mutation. If an adult has no sign, no pertinent history and normal radiology, it is unlikely that he or she has Gorlin syndrome. Direct mutation analysis of the gene may be helpful. It is particularly helpful to follow a specific clinical protocol in the examination of these subjects (Table 3).

In case of a family history of the disease, at birth or immediately after, a detailed examination should look for the presence of a large head, frontal and temporal bossing, cleft palate [35], eye anomalies and bifid ribs [16, 19], or vertebral anomalies. In order to detect a deficit related to a medulloblastoma, a neurological examination is recommended every six months [5]. At 3 years, the frequency of examinations could be reduced to once a year until 7 years of age, after which a medulloblastoma is very unlikely.

A panoramic radiograph of the jaws once a year from the age of 8 years onward is also suggested [18]. The appearance of two or more recidivant OKCs, or an early OKC in a young subject, is suggestive of NBCCS syndrome. An at least annual examination of the skin from puberty is recommended but as a lesion may suddenly become aggressive, the patient needs open access to the specialist taking responsibility for treatment of the skin.

In children at risk, diagnosis can often be achieved by radiographic means (calcification of falx, rib anomalies, calcification of ovarian fibromas). Depending on the situation, imaging studies may include magnetic resonance imaging (MRI) of the brain, echocardiography, abdominal ultrasonography, dental radiography, and skeletal survey. Kimonis et al. described the radiologic findings that are most helpful in diagnosing NBCCS [46]. As patients with NBCCS are especially sensitive to ionizing radiation, the use of irradiation should be minimized when possible. Nevertheless, definitive presymptomatic diagnosis can be achieved by molecular genetic linkage. Rarely, babies can have fibromas in the heart: at least two cases have presented before 3 months of age with fibromas [71, 136].

No specific laboratory studies are indicated; however, several laboratories offer commercial testing for Gorlin syndrome and testing is certainly indicated in children with desmoplastic medulloblastoma, where radiation is contemplated. Patients with suspected Gorlin syndrome should undergo biopsy with samples obtained from several suspicious skin lesions. The histologic features of BCCs in Gorlin syndrome are usually identical to those observed in sporadic BCCs. Medulloblastomas in Gorlin syndrome usually have the desmoplastic phenotype, which has been linked, in some studies, with an improved prognosis [47]. If an infratentorial mass is detected during brain MRI, it should be sampled during biopsy as well. The Chang staging system is used to stage medulloblastoma in Gorlin syndrome.