YES NO UNKNOWN. Stage I: Rule-Out Dashboard Secondary Findings in Adults ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS

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1 Stage I: Rule-Out Dashboard HGNC ID: 9585 OMIM ID: ACTIONABILITY PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? UNKWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? Family Management Circumstances to Avoid ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? 3. Is the result actionable in an undiagnosed adult with the genetic condition? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition Stage II: Summary Report Topic Narrative Description of Evidence Ref 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) 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. 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. 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. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. 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 Patient Tier 4 evaluations: Management 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. (1-3) (1, 2, 4) (1, 2) 2

3 Surveillance Family Management Circumstances to Avoid During pregnancy an assessment of the fetus should be performed for cardiac fibromas, hydrocephalus, and macrocephaly. (Tier 2) 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) The recommended management protocol for surveillance of adults with BCNS includes (Tier 2): 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. 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) Due to the need for surveillance for complications of NCBS and to avoid sun exposure and x-rays, clarification of the genetic status of at-risk relatives, including children, is appropriate. (Tier 4) Clinical examination and x-rays of the skull for calcification may be performed if the pathogenic variant in the family is not known. (Tier 4) 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) 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) 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) (5) (1, 3) (1, 3) (6) (7) 3

4 Description of sources of evidence: Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources Tier 5: Evidence from a non-systematically identified source Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Autosomal dominant 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). (1-3) Experience clinically and from molecular testing is compatible with complete penetrance for BCNS. (Tier 4) (1-3) 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%. Information on relative risk was not available. Expressivity Clinical features of BCNS are variable within and among families with BCNS. (Tier 4) (1-3) 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) (1, 2) 4

5 Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score Morbidity from odontogenic keratocysts + 1 3C 0D 3 7CD Panorex surveillance Morbidity from basal cell carcinomas + 2 3C 2E 3 10 CE PTCH1 Skin surveillance Morbidity from basal cell carcinomas + 2 3C 2C 3 10CC Sun avoidance Morbidity from basal cell carcinomas + Minimization of radiation 2 3C 2C 2 9CC To see the scoring key, please go to: Date of Search (MM.DD.YYYY): References 1. Evans DG, Farndon PA. Nevoid Basal Cell Carcinoma Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA) Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. 2008;3: Lo Muzio L, Pastorino L, Levanat S, Musani V, Situm M, Ponti G, et al. Clinical utility gene card for: Gorlin syndrome--update 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): 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: 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: Sanchez G, Nova J, Rodriguez-Hernandez AE, Medina RD, Solorzano-Restrepo C, Gonzalez J, et al. Sun protection for preventing basal cell and squamous cell skin cancers. Cochrane Database Syst Rev. 2016;7:CD