Basal Cell Nevus syndrome (BCNS)

What is Basal Cell Nevus syndrome (BCNS)?

Sometimes referred to as Gorlin syndrome, Basal Cell Nevus is a genetic condition that puts affected individuals at a possible greater risk of cancer.

Affected individuals are at higher risk of being diagnosed with basal cell carcinoma (the most common form of skin cancer) during puberty.

Defining features of the syndrome include issues with the skin, endocrine and nervous systems, eyes and bones.

This syndrome is also known as:
Basal cell nevus syndrome BCNS; Gorlin Syndrome; Gorlin-goltz Syndrome; Multiple Basal Cell Nevi, Odontogenic Keratocysts, And Skeletal Anomalies NBCCS Nevoid Basal Cell Carcinoma Syndrome; Nbccs

What gene changes cause Basal Cell Nevus syndrome (BCNS)?

Mutations in the PTCH, PTCH2, PTCH1 and SUFU gene are responsible for the syndrome.

Mutations in these genes affect the sonic hedgehog and SMO signaling which control cell growth. This disruption is believed to be responsible for causing the cancers associated with this condition.

The syndrome can be inherited in an autosomal dominant pattern but many cases are the result of a de novo or new mutation.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Basal Cell Nevus syndrome (BCNS)?

Basal cell carcinomas and cancers, as well as non dematological tumours.

Unique facial features of the syndrome include a large head and coarse face, high arched eyebrows, widely spaced eyes and a broad nasal bridge. A cleft lip or palate may also be present.

Other physical characteristics of the syndrome include skeletal abnormalities, such as fused ribs.

Possible clinical traits/features:
Autosomal dominant inheritance, Polycystic ovaries, Polydactyly, Hand polydactyly, Melanocytic nevus, Plantar pits, Orbital cyst, Osteolysis, Nystagmus, Parietal bossing, Palmar pits, Palmoplantar keratoderma, Ovarian fibroma, Ovarian neoplasm, Renal cyst, Seizure, Epicanthus, Cleft upper lip, Cleft palate, Coarse facial features, Sprengel anomaly, Conductive hearing impairment, Motor delay, Brachydactyly, Cryptorchidism, Finger syndactyly, Proptosis, Telecanthus, Frontal bossing, Skin tags, Sacrococcygeal pilonidal abnormality, Variable expressivity, Vertebral segmentation defect, Scoliosis, Spina bifida occulta, Spina bifida, Vertebral fusion, Hamartomatous stomach polyps, Supernumerary ribs, Vertebral wedging, Macrocephaly, Sarcoma, Strabismus, Down-sloping shoulders, Skin ulcer, Heterogeneous, Irregular ossification of hand bones, Kyphoscoliosis, Odontogenic keratocysts of the jaw, Iris coloboma, Intellectual disability, Mandibular prognathia, Neoplasm of the skin, Tall stature

How does someone get tested for Basal Cell Nevus syndrome (BCNS)?

The initial testing for Gorlin syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Basal Cell Nevus syndrome (BCNS)

The facial features can be characteristic with macrocephaly, frontal and temporo-parietal bossing, and prominent supraorbital ridges. The jaw is prognathic, the nasal root is broad and there might be telecanthus or even true hypertelorism. The multiple nevoid basal cell carcinomas appear after puberty, especially on the face and neck, but also on the trunk and elsewhere. Ulceration is common. Other skin lesions include pits (punctate lesions) on the palmar and plantar areas (rarely palmar basal cell carcinomas occur- Cabo et al., 2007) , cysts and comedones (Baselga et al., 1996). Pivnick et al., (1996) and Pilaete et al., (2012) reported cases with a midline nasal dermoid cyst. Bifid, fused, partially missing, or anteriorly splayed ribs occur in about 60% of cases. Kyphoscoliosis occurs in 30-40%. Spina bifida occulta occurs in about 60%. Short metacarpals, pre or postaxial polydactyly (Acharya et al., 2013), syndactyly of the 2nd and 3rd fingers, and Sprengel deformity are also seen less commonly. Thumb hypoplasia was reported by Kansal et al., 2007). Multiple cysts of the jaw develop during the first decade of life. These are odontogenic keratocysts. Eighty-five percent of cases will have developed these cysts by the age of 40 (Gorlin, 1987). Dural calcification, mild mental retardation, agenesis of the corpus callosum, medulloblastomas, ovarian fibromas, cardiac fibromas, lymphomesenteric cysts and hypogonadism (males have a female hair distribution) all occur (Evans et al., 1993). A case with a rhabdomyoma (they found five other cases in the literature) was reported by Watson et al., (2004). The empty sella syndrome occurred in four patients reported by Takanashi et al., (2000). Ophthalmological abnormalities such as squint or cataract also occur, with colobomata and microphthalmia being rarer associations (Manners et al., 1996). Ragge et al., (2005) found a mutation in a child with an orbital cyst, microphthalmos and a medulloblastoma. The tumour was detected by chance, when an MRI of the eye was performed. Hogge et al., (1994) reported a fetus detected with macrocephaly and ventriculomegaly by fetal ultrasound. Note the two cases of radiation-induced brain tumours after radiotherapy for medulloblastomas (Choudry et al., 2007). Ameloblastomas have also been reported (Eslami et al., 2008).
Farndon et al., (1992) and Reis et al., (1992) reported linkage to markers at 9q22-9q31. Gailani et al., (1992) and Bonifas et al., (1994) demonstrated loss of heterozygosity for 9q31 markers in basal cell carcinomas from individuals with this condition, and in isolated tumours. Levanat et al., (1996) reported a similar phenomenon in jaw cysts from patients. The radiological features of Gorlin syndrome are well reviewed by Kimonis et al., (2004).
Johnson et al., (1996) and Hahn et al., (1996) identified mutations in a gene coding for a transmembrane protein with homology to the Drosophila patched (ptc) gene product which acts in opposition to the Hedgehog signalling protein. Stone et al., (1996) presented evidence suggesting that patched is the receptor for sonic hedgehog. Gailani et al., (1996) found mutations in the ptc gene in a third of sporadic basal cell carcinomas by SSCP analysis. Petrikovsky et al., (1996) reported a case diagnosed prenatally both by DNA analysis and ultrasound. Wicking et al., (1997) found no genotype/phenotype correlation and showed that most mutations led to premature chain termination. Further mutations were reported by Lench et al., (1997) and by Veenstra-Knol et al., (2005). Chromosomal deletions of 9q21.33-q31 have been reported (Boonen et al., 2009, Yamamoto et al., 2009). Note that PTCH1 mutations are found in many sporadic tumours including breast cancer. The two patients reported by Yamamoto et al., (2009) both developed rare tumours.
Villavicencio et al., (2000) provide a good review of the Sonic hedgehog-patched-Gli pathway. Bale and Yu (2001) also review the Hedgehog pathway and the association with basal cell carcinomas. SUFU is a negative regulator of SHH signaling and mutations in this gene have also been found to result in Gorlin syndrome (Pastorino et al., 2009). The proband had in addition a medulloblastoma.
Note, Nagao et al., (2011) that mutations might not be found using PCR-based direct sequencing of the exons. In five families in which this was negative, entire PTCH1 deletions were found using high-resolution array-based comparative genomic hybridization technology. Heterozygous tandem duplication within the PTCH1 gene also results in Gorlin syndrome (Kosaki et al., 2012).
Evans et al. (2017) described clinical and genetic characteristics of 182 patients with basal cell nevus syndrome. PTCH1 pathogenic variants were found in 126 patients and SUFU mutations in nine; in 46 patients no mutations could be identified. Range of age of diagnosis was between 0.3 and 81 years. Clinical characteristics of 182 patients included jaw cysts (95 patients), more than ten basal cell nevi (86), palmar pits (132), meningioma (4), falx calcification (108), bifid ribs (72), skeletal anomalies (100), medulloblastoma (6), ovarian fibroma (11), cardiac fibroma (2) and cleft lip/palate (7). Patients with SUFU mutations were more likely to have medulloblastoma, meningioma or ovarian fibroma, but were less likely to develop a jaw cyst.
Shiohama et al. (2017) described nine patients (seven boys and two girls) from unrelated families with nevoid basal cell carcinoma syndrome and mutations in PTCH1 gene. Comparing patients' brain MRI to normal controls, individuals with Gorlin syndrome showed relative macrocephaly in 7/9 cases. The sizes of the cerebrum, cerebellum, and cerebral ventricles were larger in children with Gorlin syndrome than in control children. Anteroposterior deformation of the pons was observed in the brainstems of children with nevoid basal cell carcinoma syndrome.

* This information is courtesy of the L M D.
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