Basal Cell Nevus Syndrome (BCNS)

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: PTCH1 (HGNC:9585)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 11/07/2022
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
PTCH1	nevoid basal cell carcinoma syndrome (0007187)	109400	Moderate Actionability

Actionability Assertion Rationale

• A majority of experts agreed with the assertion computed according to the rubric. The data are limited as to the effectiveness of the interventions, especially for basal cell carcinomas which are considered a cardinal feature of this condition.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity from basal cell carcinomas / Avoidance of sun exposure and radiation	1	2C	0D	3	6CD
Morbidity from neoplasia / Evaluation and surveillance by specialists to detect neoplasia and guide treatment	1	3D	2B	3	9DB

Severity of Outcome

Prevalence of the Genetic Condition

Few studies have assessed the prevalence of nevoid basal cell carcinoma syndrome (NBCCS; also known as basal cell nevus syndrome, Gorlin-Goltz syndrome, or Gorlin syndrome). Prevalence is estimated at 1/31,000 to 1/57,000, though the true figure may be higher as individuals with milder features may not be recognized. The estimated birth incidence of clinical NBCCS is 1/15,000 to 1/19,000, suggesting that most of those with germline PTCH1 pathogenic variants may never reach a clinical diagnosis. It is estimated that basal cell carcinomas (BCCs) occur in 2 million Americans annually. Case series suggest that up to 1 in 200 (0.5%) individuals with BCCs and 6% of individuals with odontogenic keratocysts (OKCs) demonstrate findings supportive of a diagnosis of NBCCS.

Clinical Features (Signs / symptoms)

NBCCS is characterized by diverse congenital malformations and a broad spectrum of benign and malignant tumors. BCCs and OKCs are the main tumor types, but others have been reported including medulloblastomas, ovarian or cardiac fibromas, meningiomas, and sarcomas. BCCs mostly occur on the face, back, neck, and chest and may range in number from a few to several thousand. BCCs can be nonpigmented or pigmented and involve all histological subtypes and occur on both sun-exposed and nonsun-exposed parts of the body. Patients have, on average, five OKCs, but the number can range from 1 to 30. Other common clinical manifestations include palmar-plantar pits, skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae, preaxial or postaxial polydactyly), and ectopic calcification of the central nervous system (particularly in the falx cerebri). Head and facial features may also be present and include macrocephaly, hypertelorism, frontal bossing, coarse facial features, cleft lip/palate, eye abnormalities, and facial milia. Children with NBCCS may have an increased risk of developmental delay.

Natural History (Important subgroups & survival / recovery)

Most individuals with NBCCS develop BCCs with increasing frequency with age. BCCs have been reported in children as young as 2 years old, but in general do not present until the late teens or early adulthood with reported mean and median age-at-onset of the first BCC of 21 and 33 years, respectively. 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. BCCs generally have a good prognosis, with a metastatic rate of <0.1%, but can produce substantial local destruction along with disfigurement. OKCs typically develop during the teenage years, though jaw cysts have been diagnosed in young children during the first years of life and rarely occur after age 30 years. OKCs are benign and initially asymptomatic, but the typically slow progression may result in major tooth dislocation and even fractures of the jaw. The peak incidence of medulloblastoma is age 1-2 years and typically has a favorable prognosis. Cardiac fibromas may develop with a mean age of onset of 0-1 month, but diagnoses later in life up to 60 years have been reported. If a cardiac fibroma results in ventricular outflow obstructions or chamber abolition, it may lead to conduction delays, arrhythmia, or heart failure. Ovarian fibromas typically develop between the ages of 16 and 45 years. Ovarian fibromas are usually asymptomatic, do not affect fertility, and rarely cause ovarian torsion, though they may cause physiologic compromise of normal function, especially when calcified. Palmar or plantar pits typically develop in the 2nd decade. Life expectancy for NBCCS is not significantly different from average. The major problem is with the cosmetic effect of treatment of multiple BCCs and usually, to a lesser extent, treatment of OKCs.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

1-2 in 50000

PTCH1 pathogenic variants are found in 60-85% of patients who meet NBCCS clinical criteria. Approximately 20-30% of pathogenic variants are de novo.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Experience clinically and from molecular testing is compatible with almost complete penetrance for NBCCS.

Tier 4

>= 40 %

In a series of 202 patients (from 62 families) with a clinical diagnosis of NBCCS or a PTCH1 pathogenic variant, the cumulative incidence of BCC was 13% in males and 12% in females by age 20, 76.5% in females and 80% in males by age 50. The penetrance of BCC seems to be lower in African Americans and other racial and ethnic groups with darker skin pigmentation.

Tier 3

>= 40 %

Reported prevalence of certain clinical features in individuals diagnosed with NBCCS include:

• OKC = 44-100%

• Lamellar calcification of the falx cerebri = 65-95%

• Palmar-plantar pits = 70-87%

• Ovarian fibromas = 6%-60%

• Cardiac fibromas = 1-5%

• Medulloblastoma = <2% (for individuals known to have PTCH1 pathogenic variants)

Tier 3

Expressivity

NBCCS has high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes. More than 100 features that are variable within and among families have been associated with NBCCS. The clinical features of NBCCS differ more among families than within families.

Tier 3

Individuals with PTCH1 missense variants were diagnosed later and were less likely to develop ten or more BCCs and OKCs than those with other PTCH1 pathogenic variants.

Tier 4

Intervention Effectiveness

Patient Management

All individuals with NBCCS should be followed annually by a medical geneticist or pediatric/adult oncologist familiar with NBCCS to check for non-tumoral manifestations of the syndrome, educate on alarming symptoms, and to ensure that all screening procedures have been performed. In addition, patients/parents should be informed of the tumor risks associated with the syndrome, so that adequate investigation can be performed urgently in case of symptoms. To provide optimal care, a multidisciplinary approach is recommended.

Tier 2

Adequate sun-protective measures are very important and should be discussed during every visit.

Tier 2

A Cochrane review concluded that there is a lack of evidence regarding effectiveness of sun protection on the development of 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).

Tier 1

A study of 47 individuals with NBCCS assessed self-reported sunscreen use and occurrence of BCCs. Neither childhood sunscreen use nor current sunscreen use was associated with a statistically significant decrease in the number of BCCs, although both of these outcomes trended toward statistical significance and linear regression analysis of the data for both outcomes demonstrated clear trends supporting the efficacy of sunscreen in BCC prevention.

Tier 5

Physicians should identify bone deformities via physical examination at diagnosis to make early intervention possible when needed. One guideline recommends a baseline spine film (digital if possible) at age 1 or at time of diagnosis.

Tier 2

Baseline measurement of head circumference should be performed, preferably plotted on a chart that accounts for height; evidence of rapid increase in centiles should prompt further investigation to exclude hydrocephalus.

Tier 4

A baseline ophthalmological examination including an ocular pressure measurement (if possible) is recommended.

Tier 2

To screen for cardiac fibromas a baseline cardiac ultrasound should be performed at the time of diagnosis, ideally within the first 6 months of life. If cardiac symptoms occur, a cardiac ultrasound should be repeated to exclude a late-onset cardiac tumor.

Tier 2

Patients and parents should be informed of the symptoms of ovarian fibromas and especially of risk of torsion so that in case of abdominal pain, imaging evaluation can be performed urgently.

Tier 2

Psychological evaluation for support and counseling after the diagnosis is recommended for all patients.

Tier 2

Surveillance

Surveillance recommendations are based on current data and expert opinion, but this is not yet fully evidence based.

To screen for BCC a full skin examination by a dermatologist every 12 months starting at age 10 years is recommended, starting earlier in people who have had previous radiotherapy. The interval between dermatological examinations should be shortened to every 3 to 6 months after the occurrence of the first BCC and for adults. The primary goal of treatment of BCC is the complete removal of the tumor and the maximal preservation of function and cosmesis.

Tier 2

There is little evidence on effectiveness of skin exams in individuals with NBCCS. A systematic review addressing physician visual screening for skin cancer identified limited evidence for the effectiveness of skin cancer screening on morbidity and mortality 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 1

Guidelines vary on recommendations for OKC screening. Two guidelines recommend yearly dental examination starting around age 2 years and orthopantomogram (OPG) using digital imaging starting at age 8, or sooner in cases of late dental eruption. OPG can be reduced to every 2 years when no cysts are observed and every 3 years from age 30. Another guideline recommends OPG every 2 years and increasing to annual OPG after the first OKC. Then after the age of 22 years, additional OPGs can be performed in case of pain/unexplained positional change of the teeth. A fourth guideline recommends yearly OPG starting at age 3 or as soon as tolerated, increasing to every 6 months after first OKC until no jaw cysts for 2 years or until age 21. Early detection enables adequate treatment, which may be crucial for maintaining jaw function.

Tier 2

Due to the low risk for medulloblastomas, children with PTCH1 pathogenic variants should be followed clinically with neurological examinations and with a high index of suspicion during the first years of life, leading to prompt brain MRI if symptoms or neurological signs appear. Routine MRI is not indicated. The impact of early detection of medulloblastoma on the outcome of these tumors has not been demonstrated thus far. However, theoretically, early detection should allow diagnosis of small tumors before the occurrence of metastases and easier resection of these tumors.

Tier 2

Guidelines vary on recommendations for ovarian fibroma screening. Two guidelines recommend that individuals assigned as female at birth have a pelvic ultrasound at age 18 years. Pelvic ultrasound every 3 years is recommended if the first was normal. Monitoring should be more frequent in case of detection of a suspicious lesion. One guideline recommends a pelvic ultrasound at menarche or age 18 years with repeat ultrasound if the first was abnormal or if symptoms develop. A fourth guideline does not recommend ultrasound surveillance in nonsymptomatic patients, but only if patients have abdominal pain or menstrual irregularities.

Tier 2

During follow-up, physicians should pay attention to psychological distress and address the possibility of a psychological consultation.

Tier 2

One guideline recommends annual nutritional assessment for adults to include Vitamin A, B, C, and D levels.

Tier 2

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. Radiation therapy is contraindicated.

Tier 2

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 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 NBCCS. One study of 55 individuals with NBCCS did not detect a significant association between self-report history of sun exposure and number of BCCs.

Tier 5

Nature of Intervention

Nature of Intervention

Surveillance interventions include the use of imaging and exams by multiple specialists to screen for neoplasia. Some of the interventions in this report involve lifelong surveillance. Regular use of sunscreen and avoidance of sun exposure, x-rays, and radiotherapy are recommended which may be burdensome to the patient. Removal of BCCs and OKCs can result in a poor cosmetic outcome which can lead to social difficulties, reduced quality of life, and difficulties maintaining employment.

Context: Adult Pediatric

Chance to Escape Clinical Detection

Due to the rarity of NBCCS and the variability of clinical signs, diagnosis of NBCCS may be difficult.

Context: Adult Pediatric

Tier 3

Though many patients have had one or more early clinical signs suggestive of NBCCS, some have not been diagnosed until adulthood. Delayed diagnosis due to variability in presentation can lead to treatments that greatly increase the associated morbidity and even mortality.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			PTCH1			109400	0007187

References List

BASAL CELL NEVUS SYNDROME; BCNS. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 109400, (2020) World Wide Web URL: http://omim.org/

Basal Cell Skin Cancer. NCCN (2022) URL: https://www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf

Bree AF, Shah MR. (2011) Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). American journal of medical genetics. Part A. 155A(9):2091-7.

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

Foulkes WD, Kamihara J, Evans DGR, Brugières L, Bourdeaut F, Molenaar JJ, Walsh MF, Brodeur GM, Diller L. (2017) Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(1557-3265):e62-e67.

Goldstein AM, Bale SJ, Peck GL, DiGiovanna JJ. (1993) Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome. Journal of the American Academy of Dermatology. 29(1):34-41.

Gorlin syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=377

Guerrini-Rousseau L, Smith MJ, Kratz CP, Doergeloh B, Hirsch S, Hopman SMJ, Jorgensen M, Kuhlen M, Michaeli O, Milde T, Ridola V, Russo A, Salvador H, Waespe N, Claret B, Brugieres L, Evans DG. (2021) Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG). Familial cancer. 20(1573-7292):317-325.

Lo Muzio L, Pastorino L, Levanat S, Musani V, Situm M, Ponti G, Bianchi Scarra G. (2013) Clinical utility gene card for: Gorlin syndrome--update 2013. European journal of human genetics : EJHG. 21(10).

PDQ Cancer Genetics Editorial Board. (2002) Genetics of Skin Cancer (PDQ®): Health Professional Version. PDQ Cancer Information Summaries.

Sanchez G, Nova J, Rodriguez-Hernandez AE, Medina RD, Solorzano-Restrepo C, Gonzalez J, Olmos M, Godfrey K, Arevalo-Rodriguez I. (2016) Sun protection for preventing basal cell and squamous cell skin cancers. The Cochrane database of systematic reviews. 7(1469-493X):CD011161.

Verkouteren BJA, Cosgun B, Reinders MGHC, Kessler PAWK, Vermeulen RJ, Klaassens M, Lambrechts S, van Rheenen JR, van Geel M, Vreeburg M, Mosterd K. (2022) A guideline for the clinical management of basal cell naevus syndrome (Gorlin-Goltz syndrome). The British journal of dermatology. 186(1365-2133):215-226.

Waldman RA, Grant-Kels JM. (2019) Sunscreen may prevent the development of basal cell carcinoma in individuals with basal cell carcinoma nevus syndrome: A retrospective survey study. Journal of the American Academy of Dermatology. 81(1097-6787):1028-1030.

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