Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Incomplete (Consensus scoring is Incomplete)
• Curation Status (Adult): Released 1.0.0
• GENE/GENE PANEL: PTCH1
• Condition: Basal Cell Nevus Syndrome (BCNS)
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity from odontogenic keratocysts / Panorex surveillance	1	3C	0D	3	7CD
Morbidity from basal cell carcinomas / Skin surveillance	2	3C	2E	3	10CE
Morbidity from basal cell carcinomas / Sun avoidance	2	3C	2C	3	10CC
Morbidity from basal cell carcinomas / Minimization of radiation	2	3C	2C	2	9CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Few studies have assessed the prevalence of basal cell nevus syndrome (BCNS; also known as Gorlin syndrome). The most quoted prevalence is 1/57,000, an estimate based on study of a UK population. This figure has been since updated to 1/30,827, though the true figure is likely higher as individuals with milder features may not be recognized. [1, 2, 3]

Clinical Features

BCNS is characterized by developmental anomalies and a predisposition of neoplasms. Multiple basal cell carcinomas (BCCs) are common and mostly occur on the face, back, and chest and may range in number from a few to several thousand. Other common clinical manifestations include multiple ondontogenic keratocysts (OKCs) of the jaws, palmar-plantar pits, skeletal anomalies (e.g., bifid ribs, wedgeshaped vertebrae), and ectopic calcification of the central nervous system (particularly in the falx cerebri). Head and facial features may also be present and include macrocephaly, frontal bossing, coarse facial features, eye abnormalities, and facial milia. Other features may include medulloblastoma (now often called primitive neuroectodermal tumor or PNET) and cardiac and ovarian fibromas. [4, 1, 2]

Natural History

Some features that present shortly after birth or during childhood include macrocephaly, facial features, and skeletal features. There is often some delay in motor milestones; however, most individuals catch up by about age five. The peak incidence of medulloblastoma is age 1-2 years, earlier compared to 7 years for the sporadic form. Medulloblastoma typically has a favorable prognosis and is more common in males. OKCs typically develop during the teenage years, though they can occur as early as 5 years, and rarely occur after age 30 years. Patients have, on average, 5 OKCs, but the number can range from 1 to 30. Ectopic calcification is present in most individuals by age 20 and usually does not result in clinical manifestations. Most individuals also develop BCCs with increasing frequency with age. These may occur in childhood, but in general do not present until the late teens or early adulthood with an average age of onset of 25 years. There is a relationship between skin pigmentation and BCCs, with fewer African American patients (40%) developing BCCs compared to Caucasians (90%). Individuals with type 1 skin (white skin that burns but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Evidence of metastatization of BCCs has been rarely reported. Life expectancy for BCNS is not significantly different from average. The major problem is with the cosmetic effect of treatment of multiple skin tumors and usually, to a lesser extent, treatment of OKCs. A poor cosmetic outcome can lead to social difficulties, including difficulty maintaining employment. [1, 2]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual diagnosed with BCNS, the following baseline evaluations are recommended:
• Tier 2 evaluations:
• MRI of brain with contrast and epilepsy protocol for comparison of symptoms develop in the future
• Pelvic ultrasound
• Tier 4 evaluations:
• X-rays to evaluate for rib and vertebral anomalies and falx calcification
• Ophthalmologic evaluation for evidence of strabismus, cataract, orbital cyst, microphthalmia, and pigmentary changes of the retinal epithelium
• Evaluation by a dentist or orthodontist familiar with NCBS; jaw x-ray (orthopantogram) in individuals age eight years or older to evaluate for OKCs and other anomalies
• Skin examination by a dermatologist familiar with NCBS
• Clinical genetics consultation. [4, 1]

Since individuals with NCBS have a large head circumference, a woman who is carrying an affected fetus should be assessed for the need for either early induction of labor or cesarean section delivery due to cephalopelvic disproportion. (Tier 4) [1]

During pregnancy an assessment of the fetus should be performed for cardiac fibromas, hydrocephalus, and macrocephaly. (Tier 2) [4]

Surveillance

The recommended management protocol for surveillance of adults with BCNS includes:
• Full skin examination by a dermatologist every 4 months
• Digital panorex of jaw annually
• Medical/clinical genetics evaluation annually
• Psychological evaluation as needed for support and counseling
• Neurology evaluation annually if prior medulloblastoma
• Obstetrics–gynecology evaluation annually for female patients
• Nutritional assessment to include Vitamin A, B, C, and D levels on an annual basis. (Tier 2) [4]

There is little evidence on effectiveness of skin exams in individuals with BCNS. In a recent US Preventative Services Task Force report, only limited evidence was identified for skin cancer screening in populations at general risk for skin cancer. However, this evidence was specific to melanoma mortality. The only evidence found related to non-melanoma skin cancer was related to the cosmetic appearance of shave biopsy. (Tier 5) [5]

Circumstances to Avoid

It is prudent to limit the amount of any type of radiation for these patients. It is advised that radiographs, including skull film or chest X-ray, to assess for major or minor criteria not be performed unless the diagnosis is in question or it is clinically indicated for management of the patient for valid medical issues. If necessary, modalities utilizing non-ionizing radiation, such as MRI, ultrasound, or digital technology, are preferred. (Tier 2) [4]

Use of radiotherapy can lead to the development of thousands of BCCs in the radiation field and therefore should be avoided if there are alternative treatments. Among children with medulloblastoma treated with radiotherapy, an increase of BCC’s in areas that correspond to treatment zones have manifested at an earlier age at onset and in a distribution unlike that of other family members with BCNS. In addition, these BCCs occur with 6 months to 3 years of radiotherapy while the median latent period for radiogenic BCCs in general is 21 years. (Tier 3) [1, 3]

Excessive sun exposure increases the likelihood of developing BCCs, which are most likely to appear in sun-exposed parts of the body, such as the face, back, and chest. Individuals should avoid direct sun exposure as much as possible, use complete sun block, and cover exposed skin with long sleeves, high collars, and hats.(Tier 4) There is little evidence on the effectiveness of avoidance of sun exposure on the development of BCCs in BCNS. One study of 55 individuals with BCNS did not detect a significant association between self-report history of sun exposure and number of BCCs. (Tier 5) In addition, a recent Cochrane review concluded that there is a lack of evidence regarding effectiveness of sun protection on the development of keratinocyte cancer, including BCCs, in the general population. Only one study was identified, which reported a lack of association between development of BCCs and daily application of sunscreen (n = 1621; RR=1.03, 95% CI: 0.74 to 1.43). No studies were identified that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors. (Tier 5) [1, 6, 3, 7]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

The prevalence of pathogenic variants associated with BCNS in the general population was not available. However, given the high penetrance of pathogenic variants (Tier 4), their prevalence should be similar to prevalence estimates of BCNS, estimated as roughly 1/31,000 (Tier 3). [1, 2, 3]

Penetrance

Experience clinically and from molecular testing is compatible with complete penetrance for BCNS. (Tier 4)
Reported prevalence of certain clinical features in individuals diagnosed with BCNS include:
• Tier 3 prevalence:
• OKC = 90%
• Ectopic calcification = >90%
• Palmar-plantar pits = 85%
• Ovarian cysts and fibromas = 20-50%
• Cardiac fibromas = 2%
• Medulloblastoma = 5%
• Tier 4 prevalence:
• BCC = 90%
• Facial features = 60%. [1, 2, 3]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

Information on variable expressivity was not available for the Adult context. [1, 2, 3]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified for BCNS include regular surveillance with multiple specialists and avoidance of sun exposure, x-rays, and radiotherapy which may be burdensome to the patient.

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Though many patients have had one or more early clinical signs suggestive of BCNS, some have not been diagnosed until adulthood. (Tier 4) [4]

Reference List

1. Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. GeneReviews®. (1993)

2. Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. (2008) 3:32.

3. Lo Muzio L, Pastorino L, Levanat S, Musani V, Situm M, Ponti G, Bianchi Scarra G. Clinical utility gene card for: Gorlin syndrome--update 2013. Eur J Hum Genet. (2013) 21(10).

4. Bree AF, Shah MR. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet A. (2011) 155A(9):2091-7.

5. Wernli KJ, Henrikson NB, Morrison CC, Nguyen M, Pocobelli G, Blasi PR. Screening for Skin Cancer in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. (2016) 316(4):436-47.

6. Goldstein AM, Bale SJ, Peck GL, DiGiovanna JJ. Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol. (1993) 29(1):34-41.

7. Sanchez G, Nova J, Rodriguez-Hernandez AE, Medina RD, Solorzano-Restrepo C, Gonzalez J, Olmos M, Godfrey K, Arevalo-Rodriguez I. Sun protection for preventing basal cell and squamous cell skin cancers. Cochrane Database Syst Rev. (2016) 7:CD011161.