# Handbook of Genetic Counseling/Gorlin - Nevoid Basal Cell Carcinoma Syndrome

Gorlin - Nevoid Basal Cell Carcinoma Syndrome

## Contracting

* Introductions
* How did you first learn about Gorlin syndrome? (Tell us about that experience), What were you told at the time? How did you feel, what did you think? How have you coped with the diagnosis? Did you think about contacting genetics then? What motivated you to contact genetics now?
* Assess main concerns of patient
** Are there any specific questions or concerns we can address?
** What issues would they like to discuss?
** What do they hope to gain from the session?
* Overview of today's session
** Restate patient's concerns
** Medical history, family history, physical exam

## Gather Medical and Family History

* State that we are going to get some information about your family history and medical history to help give us clues to whether or not the syndrome you have may have been passed down through the family
* Jaw keratocysts
* Skin findings (cysts, bumps, tags)
* Cancers: skin cancer (basal cell carcinoma), medullablastoma, other cancers
* Birth defects: cleft lip/palate, eye problems, polydactyly
* Other
** major health concerns
** others with cancer
** benign conditions, required biopsies, had polyps
** thyroid problems
** female problems
** mental retardation or learning disabilities
** anything you think may be inherited
* Ethnic background

## Risk Assessment

* About 70-80% of probands have inherited the condition from a parent and about 20-30% of probands have a de novo mutation
* Offspring will have a 50% chance of inheriting the deletion

## Inheritance

* Hereditary cancers are caused by a change in a specific gene
* Have you ever taken a biology class, do you know about genes and chromosomes, review of genes so we are on the same page:
* Explain genes and chromosomes (use recipe analogy)
* Explain autosomal dominant inheritance
** Autosomal - The changed gene can be inherited either from a mother or father, because the gene is carried on an autosome
** Dominant - Only one copy of the changed gene is needed to be at an increased risk for cancer
** Show diagram of autosomal inheritance
** Carrier has a ½ or 50% risk of passing changed to gene to children, if it is not inherited they would not be at increased risk for cancer and could not pass it on.

## Clinical Diagnosis

* diagnosed in individuals with two major and one minor criteria or one major and three minor criteria
Major criteria
* Lamellar (sheet-like) calcification of the falx or clear evidence of calcification in an individual <20 years of age. Falx calcification is nearly always present and observed on AP and lateral X-rays* of the skull after age 20 years.
* Jaw keratocyst (odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency)
* Palmar/plantar pits (two or more). Plantar/palmar pits are particularly useful in diagnosis and are more pronounced when the hands and feet are soaked in warm water for up to ten minutes. They may appear as white "punched out" or pink "pin prick" lesions.
* Multiple basal cell carcinomas (BCCs) (more than five in a lifetime) or a basal cell carcinoma before the age of 30 years.
* First degree relative with NBCCS
Minor criteria
* Childhood medulloblastoma (also called primitive neuro-ectodermal tumor [PNET])
* Lympho-mesenteric or pleural cysts
* Macrocephaly (OFC >97th centile)
* Cleft lip/palate
* Vertebral anomalies observed on chest x-ray and/or spinal x-ray: bifid/splayed/extra ribs; bifid vertebrae.
* Polydactyly that is either pre-axial or post-axial
* Ovarian/cardiac fibroma
* Ocular anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium)

## Testing

* NBCCS is caused by germline mutations of the gene PTCH (chromosomal locus 9q22.3)
* In about 60-85% of individuals fulfilling diagnostic criteria, it is possible to identify the underlying gene mutation.
* Uses of testing: confirmatory diagnostic testing, predictive testing, prenatal testing
* Cost is $1700.00 (from GeneDx)
* Testing Methods:
** Sequence analysis. Sequence analysis of the PTCH coding region is available on a clinical basis and detects mutations in up to 85% of patients with typical clinical findings of NBCCS.
** Southern analysis for large deletions. In patients with typical clinical findings of NBCCS who test negative for a mutation by sequence analysis, Southern analysis may be performed to detect large deletions.
** Linkage analysis. When a known disease causing PTCH mutation is not identified in a family, linkage analysis can be considered in families with more than one affected family member. It is 98-99% accurate. Linkage testing is not available to families with only a single affected individual.

## Incidence and Carrier Frequency

* Incidence is 1 / 40 000, but may be underestimated due to missed milder cases

## Clinical Features

* NBCCS is characterized in 90% of patients by the development of multiple jaw keratocysts typically observed in the second decade of life and/or basal cell carcinomas usually seen from the third decade onwards.
* About 60% of individuals with a PTCH mutation have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia
* Findings in their usual order of appearance are:
** Macrocephaly. The first feature likely to be observed is relative macrocephaly. A large proportion of babies with NBCCS require delivery by Caesarian section due to large head size. Head circumference increases above the 97th centile until 10-18 months and then maintains its centile. Large head size may also contribute to some delay in motor milestones, although as yet there is no psychometric evidence for more global delay.
** Birth defects. Congenital malformations, found in about 5%, include cleft lip/palate (5%), polydactyly, and severe eye anomalies. Severe skeletal defects due to multiple rib/vertebral anomalies have been reported. Open spina bifida is uncommon.
** Medulloblastoma. About 5% of individuals with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuro-ectodermal tumor [PNET]) The tumor tends to be of desmoplastic histology and to have a favorable prognosis. Peak incidence of medulloblastoma in NBCCS is about two years of age compared to seven years in its sporadic form.
** Jaw keratocysts. Although these can start at about five years of age, the peak occurrence of jaw keratocysts is in the teenage years. They usually present as painless swellings. Untreated, they can lead to major tooth disruption and fracture of the jaw. Jaw cysts become less frequent after age 30 years, after which it is unusual for de novo keratocysts to occur.
** Basal cell carcinomas. Browny/pink/orange basal cell nevi may occur in early childhood and may lie quiescent without evidence of aggressive behavior. A 75% risk of developing BCCs by age 20, a 90% risk by age 40. They can occur in early childhood, but in general do not present until late teenage/early adulthood. 10% of individuals with NBCCS never develop a BCC. 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. Clinically, some patients seem to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy.
** Other skin manifestations. Other skin manifestations include facial milia, which can be numerous, and meibomian cysts in the eye lids. Sebaceous cysts and dermoid cysts are also common. Skin tags (especially around the neck) often have the histological appearance of basal cell carcinomas but do not act aggressively.
** Other. Cardiac and ovarian fibromas occur in about two and 20% of individuals respectively. Cardiac fibromas are usually present at birth or soon after. They can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow. Ovarian fibromas are usually an incidental finding on ultrasound examination or at Caesarian section. They may cause torsion of the ovary, but are not thought to affect fertility. They can become large and calcified; however, malignant transformation rarely occurs.
** Morbidity/mortality. Life expectancy in NBCCS is not significantly different from average. The risk of other malignant tumors is not clearly increased, although lymphoma and meningioma have been reported. No other tumors occur at a frequency that warrants surveillance above that offered to members of the general population. The major problem is with the cosmetic effect of treatment of multiple skin tumors and usually, to a lesser extent, treatment of jaw keratocysts. A poor cosmetic outcome can lead to social difficulties such as holding employment.

## Management and Treatment

* Medulloblastoma. Awareness of the risk of medulloblastoma in the first years of life is important and may justify developmental assessment and physical examination every six months
* Jaw keratocysts. There is probably justification for regular (every 12-18 months) jaw x-rays (orthopantograms) from around eight years of age. Keratocysts identified early in life usually need surgical excision. Any symptomatic or expanding keratocysts should be excised.
* Skin. Strong advice about avoiding excessive sun exposure is important. Patients are advised to use complete sunblock and cover the skin by using long sleeves, high collars and hats. Radiotherapy should be avoided in the treatment of tumors in NBCCS unless absolutely necessary. The skin should be checked at least annually and patients should have close follow up if they have skin problems in the meantime. Some physicians recommend examinations of the skin by a professional every three to four months. The sheer number of lesions means that early treatment is essential to prevent long-term cosmetic problems particularly on the face.
* Other features. Surveillance is probably not necessary for the other disease features.

## Psychosocial Issues

* Contracting - coping with diagnosis, sense of well being (how have you been doing, how have you been coping); motivations for making the appointment, why didn't she come when she was first diagnosed.
* Family History - support, assess closeness with family, do they live in the area, do they know about the diagnosis, has she shared with the family that she is here?
* Other:
* Concern over what issues to anticipate with NBCCS
* Feelings of guilt over passing gene, or risk of passing gene, to the children
* Social stigma and self consciousness due to multiple skin tumors.

## Support Groups and Resources

* BCCNS Life Support Network
    P.O. Box 321
    Burton, Ohio 44021
    email: info@bccns.org
    http://www.bccns.org
    http://www.gorlinsyndrome.org
    Phone: 440-834-0011
    Toll-free: 866-834-1895
    Fax: 440-834-0132
* Basal Cell Carcinoma Nevus Syndrome/Gorlin Syndrome Homepage
    3044 Peoria
    Steger, IL 60475
    Phone: 708-756-3410
    Email: gorlinadvocate@aol.com
* Gorlin Syndrome Support Group (UK)
    Phone: UK: 01772 517624; International: (+44) 1772 517624
    Contact: http://www.gorlingroup.org/index.php?option=com_contact&view=category&catid=0&Itemid=8
    http://www.gorlingroup.org

## References

* www.geneclinics.org
* Counseling About Cancer: Strategies for Genetic Counseling. Schneider, 2002.

## Notes

The information in this outline was last updated in April 2003.