Clinical Diagnosis

Nevoid basal cell carcinoma syndrome (NBCCS) is diagnosed in individuals with two major diagnostic criteria and one minor diagnostic criterion or one major and three minor diagnostic criteria [Evans et al 1993]. A similar series of diagnostic criteria was proposed by Kimonis et al [1997]. No study has been able to assess which combination of diagnostic criteria represents the best trade-off between sensitivity and specificity.

Although a typical facial gestalt is present in most individuals with NBCCS, measurement of head circumference and examination of the skin for basal cell carcinomas (BCCs), nevi, milia, and plantar/palmar pits is necessary for clinical diagnosis.

The availability of molecular genetic testing has broadened the phenotypic spectrum of NBCCS and, thus, individuals who do not fulfill all diagnostic criteria may be found to have pathogenic PTCH1 mutations. (An individual who is the first in the family to be affected may have milder signs because of somatic mosaicism.)

Major criteria

• Lamellar (sheet-like) calcification of the falx or clear evidence of calcification in an individual younger than age 20 years. Falx calcification is nearly always present and is visible on anteroposterior (AP) x-rays* of the skull after age 20 years. (Sella calcification, when present, is visible on lateral x-rays of the skull.)

• Jaw keratocyst (odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency)

• Palmar/plantar pits (two or more); particularly useful in diagnosis and more pronounced when the hands and feet are soaked in warm water for up to ten minutes. Pits may appear as white "punched-out" or pink "pin-prick" lesions.

• Multiple BCCs (>5 in a lifetime) or a BCC before age 30 years. Provision needs to be made for decreased risk of BCC in dark-skinned races and increased risk for Caucasians living in hot sunny climates.

• First-degree relative with NBCCS

Minor criteria

• Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET])

• Lympho-mesenteric or pleural cysts

• Macrocephaly (OFC >97th centile)

• Cleft lip/palate

• Vertebral/rib anomalies observed on chest x-ray and/or spinal x-ray*: bifid/splayed/extra ribs; bifid vertebrae

• Preaxial or postaxial polydactyly

• Ovarian/cardiac fibromas

• Ocular anomalies (cataract, developmental defects, and pigmentary changes of the retinal epithelium)

* Note re radiographs. To verify a clinical diagnosis of NBCCS, AP and lateral x-rays of the skull, an orthopantogram, chest x-ray, and spinal x-ray are usually necessary.

Note: (1) If radiographs have already been taken (i.e., before the diagnosis of NBCCS is being considered) it is preferable to obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (2) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings as these can also be normal variations in the general population. (3) X-ray findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly [Debeer & Devriendt 2005, Veenstra-Knol et al 2005].

Testing

Cytogenetic analysis. Although chromosomal translocations or large cytogenetically detectable deletions on chromosome 9 have been reported in a small number of individuals with NBCCS, chromosome analysis is rarely likely to be helpful in diagnosis.

A 9q deletion (see 9q22.3 microdeletion) should be considered when both of the following are present:

• Clinical features consistent with NBCCS

• Additional features, including severe developmental delay or short stature

Presence of the latter features suggests that additional chromosomal material has been lost.

Molecular Genetic Testing

Gene. PTCH1 is the only gene in which mutations are known to cause NBCCS.

Clinical testing

• Sequence analysis of exons 2-23 with intron-exon junctions and one of the splice forms of exon 1 detects mutations in 50%-85% of individuals with typical clinical findings of NBCCS. Individuals and families with no other features apart from multiple BCCs have a very small probability of having a PTCH1 mutation [Klein et al 2005, Marsh et al 2005].

• Deletion/duplication analysis using any one of a variety of methods detects exonic, multiexonic, and whole-gene deletions in 6% of individuals with NBCCS.

• Linkage analysis. If the family pedigree structure is sufficient and family members are cooperative to the testing process, linkage analysis may be performed to confirm cosegregation of a potential pathogenic mutation with disease in individual families. Linkage testing cannot be used to confirm the diagnosis of NBCCS.

Table 1. Summary of Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PTCH1	Sequence analysis	Sequence variants 2	50%-85%	Clinical
	Deletion / duplication analysis 3	Exonic, multiexonic, and whole-gene deletions	6%
	Linkage analysis	Not applicable	Not applicable

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Missense mutations are relatively common and may be difficult to interpret in an individual who has no family history of NBCCS and does not fulfill diagnostic criteria.

• The identification of a pathologic allelic variant (nonsense, frameshift deletion/insertion, splice site mutation) confirms a clinical diagnosis of NBCCS. Because some individuals with a clinical presentation consistent with NBCCS do not have PTCH1 mutations detectable by routine techniques, failure to detect a PTCH1 mutation does not exclude the diagnosis of NBCCS.

• The sensitivity of the testing depends on both the test methods and the diagnostic criteria used. Low mutation detection rate in some studies may reflect the clinical diagnostic criteria rather than the molecular testing strategy [Boutet et al 2003].

• The likelihood of detecting a mutation may be lower in an individual who is known to be the first affected in the family, possibly because a de novo mutation has resulted in somatic mosaicism in that individual. In such cases, the likelihood of detecting a mutation is increased if the person tested is an affected child of an individual who has mild features of NBCCS.

• The same PTCH1 mutation present in two or more tumors but not present (or present at a lower-than-normal ratio) in lymphocyte DNA strongly suggests somatic mosaicism.

Testing Strategy

To confirm/establish the diagnosis in a proband. Molecular genetic testing can be used to confirm the diagnosis in individuals with atypical clinical findings. Testing of lymphocyte DNA with direct sequencing of all exons and then deletion analysis (e.g., MLPA) can be instituted.

In individuals suspected of having mosaic NBCCS it is probably better to start with a tumor such as an accessible BCC. Identification of an identical mutation in two separate tumors, even if not found in lymphocytes, confirms the presence of mosaicism [Evans et al 2007].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Ming et al [2002] reported PTCH1 missense mutations in five of 100 unrelated probands with holoprosencephaly. The authors hypothesized that the missense mutations would lead to enhanced repressive activity of PTCH1 on the hedgehog signaling pathway, unlike the mechanism in NBCCS in which the pathway is activated, usually by haploinsufficiency for PTCH1. Four further PTCH1 missense mutations were reported to be associated with holoprosencephaly in Ribeiro et al [2006].

9q22.3 microdeletion, which includes deletion of PTCH1, is characterized by the clinical findings of NBCCS as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, pre- and postnatal macrosomia, long philtrum and seizures

Somatic mutations in PTCH1 are involved in a range of sporadically occurring tumors including those observed in NBCCS: keratocysts, BCC, skin trichoepithelioma, medulloblastoma, and ovarian fibroma.

Natural History

More than 100 features that are variable within and among families have been associated with nevoid basal cell carcinoma syndrome (NBCCS) [Farndon 2004].

Findings in their usual order of manifestation:

• Appearance. Approximately 60% of individuals with a PTCH1 mutation have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. The shoulders slope downward.

• Macrocephaly. The first feature likely to be observed is relative macrocephaly. A large proportion of babies with NBCCS require delivery by caesarean section because of large head size. After birth, the head growth pattern often resembles that of arrested hydrocephalus, but hydrocephaly requiring treatment is rare. Head circumference increases above the 97th centile until age ten to 18 months and then maintains its centile.
  
  There is often some delay in motor milestones; most individuals catch up by about age five years. No published psychometric evidence for global delay exists.

• Birth defects. Most individuals have skeletal anomalies identified on radiographs (e.g., bifid ribs, wedge-shaped vertebrae). Severe skeletal defects resulting from multiple rib/vertebral anomalies have been reported but are uncommon, as is open spina bifida.
  
  Ectopic calcification, particularly in the falx, is present in more than 90% of individuals by age 20 years [Ratcliffe et al 1995, Kimonis et al 2004].
  
  Congenital malformations, found in approximately 5%, include cleft lip/palate (5%), polydactyly, and severe eye anomalies. Eye findings include strabismus, cataract, orbital cyst, microphthalmia, and pigmentary changes of the retinal epithelium [Black et al 2003, Ragge et al 2005].

• Medulloblastoma. Approximately 5% of individuals with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuroectodermal tumor [PNET]) [Cowan et al 1997]. The tumor tends to be of desmoplastic histology [Amlashi et al 2003] and to have a favorable prognosis. Peak incidence of medulloblastoma in NBCCS is at approximately age two years, compared to seven years in its sporadic form [Cowan et al 1997, Amlashi et al 2003].

• Jaw keratocysts. Approximately 90% of affected individuals develop multiple jaw keratocysts. They can occur as early as age five years, but the peak occurrence is in the teenage years. Jaw keratocysts usually present as painless swellings. Untreated, they can lead to major tooth disruption and fracture of the jaw. Jaw cysts rarely occur after age 30 years.

• BCCs. Brownish/pink/orange basal cell nevi may occur in early childhood and may lie quiescent without evidence of aggressive behavior. The histologic appearance is that of a typical BCC which, when excised, can be the first, unexpected finding of NBCCS in simplex cases (i.e., affected individuals with no known family history of NBCCS), especially children. Active BCCs may grow from existing basal cell nevi that may be numerous, or typical BCCs may appear from virtually blemish-free skin. BCCs may also crust, bleed, and ulcerate, or may present as a localized infection.
  
  BCCs can occur in early childhood, but in general do not present until the late teens or early adulthood. They occur more frequently with age, although 10% of individuals with NBCCS never develop a BCC. Individuals with type 1 skin (white skin that burns, but never tans, e.g., Celtic skin) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Clinically, some affected individuals seem to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy.

Other skin manifestations include facial milia, which can be numerous, and meibomian cysts in the eyelids. Sebaceous cysts and dermoid cysts are also common. Skin tags (especially around the neck) often have the histologic appearance of BCCs but do not act aggressively.

Other tumors. Cardiac and ovarian fibromas occur, respectively, in approximately 2% and 20% of females [Evans et al 1993, Gorlin 2004]. Cardiac fibromas are usually present at birth or soon after. They can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow. Rhabdomyomas may occur at other sites as well as in the heart [Watson et al 2004].

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 is uncommon.

The risk of other malignant tumors is not clearly increased, although lymphoma and meningioma have been reported.

Morbidity/mortality. Life expectancy in NBCCS 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 jaw keratocysts. A poor cosmetic outcome can lead to social difficulties, including difficulty maintaining employment.

Genotype-Phenotype Correlations

Early reports did not find a genotype-phenotype correlation [Wicking et al 1997]. Predictions about clinical severity are not yet possible for specific PTCH1 mutations, which are likely to be modified by the effects of other genes.

A large deletion has been identified in a family with an array of ophthalmic features, including a retinal pigmentary abnormality [Black et al 2003].

Penetrance

Although NBCCS shows intra- and interfamilial variation in expression, experience clinically and from molecular testing is compatible with complete penetrance [Author, personal observation].

Anticipation

No evidence of anticipation has been reported. Variable expressivity explains the instances in which children appear more severely affected than a parent.

Prevalence

Few studies of disease prevalence exist. The most quoted prevalence figure, 1:57,000, comes from a study of a UK population of four million in northwest England [Evans et al 1991b]. Since publication of the study, an increased awareness of NBCCS and consequent increased diagnosis has led to a revision of that figure to nearer to 1:30,827 [Evans et al 2010]. The true figure may be even higher, as milder cases may not be recognized.

A study in Australia gave a minimum prevalence of 1:164,000 [Shanley et al 1994].

Birth incidence has recently been confirmed to be as high as 1:18,976 [Evans et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with nevoid basal cell carcinoma syndrome (NBCCS), the following evaluations are recommended:

• Baseline measurement of head circumference, preferably with plotting on a chart that accounts for height. Evidence of rapid increase in centiles should prompt further investigation to exclude hydrocephalus.

• Physical examination for birth defects of clinical significance (e.g., orofacial clefting, polydactyly)

• X-rays to evaluate for rib and vertebral anomalies and falx calcification

• Evaluation by a dentist or orthodontist familiar with NBCCS; jaw x-ray (orthopantogram) in individuals age eight years or older to evaluate for jaw keratocysts and other anomalies

• Skin examination by a dermatologist familiar with NBCCS

• Ophthalmologic evaluation for evidence of cataract, developmental defects, and pigmentary changes of the retinal epithelium

• Ultrasound examination of the ovaries to evaluate for ovarian fibromas prior to pregnancy

• Echocardiography in the first year of life to evaluate for cardiac fibromas

Because mesenteric and pleural cysts are rare, evaluation is not necessary in the absence of symptoms.

Treatment of Manifestations

Manifestations should be treated by specialists (e.g., oral surgeon, dermatologist, plastic surgeon, pediatrician, medical geneticist) experienced with the condition.

Keratocysts usually require surgical excision.

Early treatment of BCCs is essential to prevent long-term cosmetic problems, particularly on the face. The priorities are to ensure complete eradication of aggressive BCCs, and to preserve normal tissue to prevent disfigurement. Surgical excision is supplemented by a number of other possible treatments including cryotherapy and laser treatment for early lesions and photodynamic therapy. Surgical treatment using Mohs' microsurgery [Mohs et al 1980] appears particularly effective.

Systemic treatment with retinoids (e.g., etretinate) is possible but often not well tolerated.

Cardiac fibromas may be asymptomatic and can be monitored by a pediatric cardiologist.

If ovarian fibromas require surgical treatment, preservation of ovarian tissue is recommended, although it involves a risk of recurrence [Seracchioli et al 2001].

Prevention of Primary Manifestations

Sun exposure and x-irradiation should be avoided.

Surveillance

Head circumference should be followed throughout childhood and plotted on appropriate growth charts. Rapid enlargement should prompt evaluation for possible hydrocephalus.

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. No evidence for the efficacy of regular neuroimaging exists; frequent computer tomography (CT) should be avoided because of risks associated with radiation sensitivity.

No other tumors occur at a frequency that warrants surveillance above that offered to members of the general population.

Orthopantogram is indicated every 12-18 months in individuals older than age eight years to identify jaw keratocysts.

Skin should be examined at least annually; some physicians recommend skin examination by a professional every three to four months.

Agents/Circumstances to Avoid

Excessive sun exposure increases the likelihood of developing BCCs. Affected individuals should use complete sunblock and cover the skin by wearing long sleeves, high collars, and hats.

Use of radiotherapy can lead to the development of thousands of BCCs in the radiation field [Strong 1977, Evans et al 1991a] and is not recommended. If the treating team believes that no other treatment modality is possible, radiotherapy should be used through as few skin ports as possible.

Evaluation of Relatives at Risk

Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma in children and jaw cysts and BCCs in adults) and the need for sun screening, clarification of the genetic status of at-risk relatives, including children, is appropriate.

• Molecular genetic testing is possible if a pathologic mutation has been identified in an affected family member.

• Clinical examination and x-rays of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Photodynamic therapy (with infra-red light) showed early promise and appears safe [Haylett et al 2003]. A recent study showed outcomes in 33 individuals with NBCCS treated with PDT with a close to 60% control rate [Loncaster et al 2009].

Aminolevulinic acid has been investigated [Itkin & Gilchrest 2004, Oseroff et al 2005]. It is usually used in conjunction with PDT [Loncaster et al 2009].

Topical treatment with 5 fluorouracil (Efudex^®) or imiquimod (5%) has been investigated [Kagy & Amonette 2000, Marks et al 2001, Stockfleth et al 2002]. A recent review suggested control rates approaching 90% for superficial BCCs and 50% for aggressive or nodular BCCs with imiquimod [Alessi et al 2009].

Topical 5-fluorouracil appears effective for superficial multicentric BCCs without follicular involvement but should not be used for deeply invasive BCCs.

Recently topical use of sonic hedgehog antagonists has entered clinical trials and is showing promise [Saran 2010].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Nevoid basal cell carcinoma syndrome (NBCCS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent.

• Approximately 20%-30% of probands have a de novo mutation.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a detailed skin examination, AP and lateral x-rays of the skull, chest x-ray, and spine x-ray. Molecular genetic testing can be used to clarify the genetic status of a parent when a PTCH1 mutation has been identified in the proband or other affected family member.

Note: (1) Although 70%-80% of individuals diagnosed with NBCCS have an affected parent, the family history may appear to be negative as a result of failure to recognize the disorder in family members because of variable expressivity. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation, and may be mildly/minimally affected.

Sibs of a proband

• The risk to a sib depends on the genetic status of the parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If the disease-causing mutation cannot be detected in the DNA of the parent, the risk to sibs is low, but greater than that of the general population because of the possibility of somatic mosaicism or germline mosaicism. Although this has not been proven in NBCCS, low risks have been confirmed in the analogous situation in individuals with neurofibromatosis type 2 (NF2) [Evans et al 2007].

Offspring of a proband

• Each child of an affected individual has a 50% risk of inheriting the mutation.

• The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the disease-causing mutation.

Other family members

• The risk to other family members depends on the genetic status of the proband's parents.

• If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ^®, National Cancer Institute).

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Predictive testing of individuals during childhood. Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Clinical examination and x-rays of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS. Molecular genetic testing may be considered if a pathologic mutation has been identified in an affected family member.

Predictive testing of adults. Clinical examination and x-rays frequently act as a "genetic test" in an apparently unaffected individual. Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of PTCH1.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like NBCCS) do not affect intellect, have variable expression, and have some treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

The comparatively young mean age at onset of medulloblastoma in individuals with nevoid basal cell carcinoma syndrome (NBCCS) (age 2 years, vs 7 years in the general population) and the loss of the normal copy of the gene in tumors [Cowan et al 1997] confirm PTCH1 as a tumor suppressor in medulloblastoma as well as in BCC. Inactivation of the normal gene also appears to be the mechanism responsible for jaw cysts, whereas the congenital malformations are likely to result from alterations in the concentration of the protein patched homolog 1 in the extremely dosage-sensitive hedgehog signaling pathway [Villavicencio et al 2000].

PTCH2, highly homologous to PTCH1, was mapped to chromosome 1p32.1-p32.3 [Smyth et al 1999]. Mutations were found in one simplex case (i.e., a single occurrence of the disease in a family) of medulloblastoma and one simplex case of BCC. No PTCH2 mutations were found in 11 simplex cases of NBCCS or 11 individuals with familial cases of NBCCS who did not have identifiable PTCH1 mutations.

Normal allelic variants. PTCH1 consists of 23 exons. Normal allelic variants in PTCH1 have been identified.

Pathologic allelic variants. See Table 2.

Normal gene product. Protein patched homolog 1 is an integral membrane protein with 12 transmembrane regions, two extracellular loops, and a putative sterol-sensing domain. Protein patched homolog 1 binds the secreted factor sonic hedgehog (SHH) and functions as the SHH receptor. The protein represses the signaling activity of the co-receptor smoothened (SMOH). When in complex with SHH, protein patched homolog 1 is not a repressor, and signaling ensues. At least three forms of the protein patched homolog 1 are present in human cells [Hahn et al 1996].

Abnormal gene product. Pathologic variants found in individuals with NBCCS and non-familial BCC include those predicted to result in a truncated protein and missense mutations.

Published Guidelines/Consensus Statements

1. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available at jco.ascopubs.org. 2003. Accessed 10-21-11.

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Suggested Reading

1. Huret JL. Naevoid basal cell carcinoma syndrome (NBCS). Atlas of Genetics and Cytogenetics Oncology and Haematology. 1997. Available at atlasgeneticsoncology.org. Accessed 10-28-11.
2. Rees JL. Skin cancer (including nevoid basal cell carcinoma syndrome). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 46. Available at www.ommbid.com. Accessed 10-28-11.
3. Zurada J, Ratner D. Diagnosis and treatment of basal cell nevus syndrome. Skinmed. 2005;4:107–10. [PubMed: 15788894]

Revision History

• 3 November 2011 (cd) Revision: 9q22.3 microdeletion (Genetically Related Disorders)

• 22 July 2010 (me) Comprehensive update posted live

• 25 January 2008 (me) Comprehensive update posted to live Web site

• 6 October 2004 (me) Comprehensive update posted to live Web site

• 20 June 2002 (me) Review posted to live Web site

• 21 November 2001 (pf) Original submission