Kimonis et al. (1997) tabulated major and minor criteria that could be used in making the diagnosis of Gorlin syndrome by the presence of 2 major or 1 major and 2 minor criteria. They suggested that a child ... Kimonis et al. (1997) tabulated major and minor criteria that could be used in making the diagnosis of Gorlin syndrome by the presence of 2 major or 1 major and 2 minor criteria. They suggested that a child who is at risk for having inherited the gene should have careful physical examination at birth for pits and other minor features and radiologic evaluation with rib, skull, and spine films to look for skeletal abnormalities. In their study, the risk of developing a medulloblastoma was greatest between 2 and 3 years; however, such had been reported up to age 7 years (Evans et al., 1991). Kimonis et al. (1997) suggested that advising patients to reduce exposure to UV radiation may lessen their risk of developing BCCs. Radiation therapy should also be avoided, but this is understandably difficult when there is a need to make the diagnosis and provide for proper surveillance. - Prenatal Diagnosis Bialer et al. (1994) made the prenatal diagnosis of Gorlin syndrome in a pregnancy sired by a man with Gorlin syndrome. There were 2 other affected members in the family. Polymorphic DNA markers on chromosome 9 were used and the fetal diagnosis was confirmed by ultrasound scan which showed unilateral cleft lip, probable cleft palate, and hydrocephalus. The parents elected to terminate the pregnancy and examination of the fetus revealed aqueductal stenosis, cleft lip, and cleft palate with a prominent forehead and macrocephaly.
Gorlin and Goltz (1960) described a familial syndrome comprising multiple nevoid basal-cell epitheliomas, jaw cysts, and bifid rib. Inheritance was autosomal dominant.
Herzberg and Wiskemann (1963) described what they termed the 'fifth phakomatosis,' basal cell nevus ... Gorlin and Goltz (1960) described a familial syndrome comprising multiple nevoid basal-cell epitheliomas, jaw cysts, and bifid rib. Inheritance was autosomal dominant. Herzberg and Wiskemann (1963) described what they termed the 'fifth phakomatosis,' basal cell nevus syndrome with medulloblastoma. They reported a family in which both father and son had basal cell nevi, with the son also having medulloblastoma and congenital thoracic scoliosis. Cawson and Kerr (1964) described a syndrome of jaw cysts, basal cell tumors, and skeletal abnormalities. One of the patients had astrocytoma with severe hydrocephalus. Other features included pits of the palms and soles. Lile et al. (1968) observed 4 cases in 3 generations of a family. Two of the patients had a short terminal phalanx of the thumb. Berlin et al. (1966) observed ovarian carcinoma in association with this syndrome. Huge calcified ovarian fibromas were present in a clinicopathologic conference (CPC) case discussed by Holmes (1976) at the Massachusetts General Hospital. The occurrence of lymphomesenteric cysts, described by Clendenning et al. (1963), was emphasized in another CPC case by Ottinger and Vickery (1986). Holubar et al. (1970) found basal cell epitheliomas in multiple palmar pits in an 8-year-old girl with BCNS. Schwartz (1978) noted hamartomatous polyps of the stomach and mesenteric cysts as features of the basal cell nevus syndrome. Totten (1980) observed a large congenital lung cyst occupying the left thoracic cavity in an affected patient. Cramer and Niederdellmann (1983) described 9 subjects from 3 families with cerebral gigantism syndrome (117550); 7 of the patients also had signs of the basal cell nevus syndrome. In 1 family, a father was 193 cm tall at age 45 and his son was 197 cm tall at age 18; both had jaw cysts and other signs of basal cell nevus syndrome. Another son was 198 cm tall at age 17 years. Macrocephaly, mild hydrocephalus, intracranial calcification, and EEG abnormalities were also described. McKusick (1985) observed unilateral coloboma of the iris and glaucoma in a patient with BCNS. Levine et al. (1987) described subconjunctival epithelial cysts presenting a dramatic appearance of everted upper eyelids in patients with this condition. Jones et al. (1986) reported a woman with Gorlin syndrome who underwent cardiac transplantation for an unresectable fibrous histiocytoma of the left ventricle at age 19 years (Jamieson et al., 1981). She had a marfanoid habitus, frontal bossing with large occipitofrontal circumference, ocular hypertelorism, broad nasal root, enlarged jaw, glaucoma, long fingers, multiple odontogenic keratocysts, postaxial polydactyly of right foot, and bony bridging of right metatarsals 4 and 5. Evans et al. (1991) found abnormal ribs in 2 infants delivered preterm at 29 and 25 weeks. The finding at first was thought unimportant but subsequently was shown to indicate that some members of their families had Gorlin syndrome. In the first case, early routine chest radiographs showed an incidental finding of bifid ribs. The 25-year-old father had a dislocated shoulder from birth due to Sprengel deformity (184400), pronounced frontal bossing with enlarged head, hypertelorism, calcification of the falx cerebri, pituitary fossa totally bridged by bone, and bilateral bifid ribs. A 5-year-old brother had calcifications within the falx cerebri. A 4-year-old brother had been diagnosed as having arrested congenital hydrocephalus, and chest radiograph showed 2 bifid ribs. The second index patient had possible Sprengel deformity in addition to bifid ribs. This patient's mother had had 5 jaw cysts removed between ages 11 and 31. She also had an enlarged head with pronounced frontal bossing, pits in the palms of her hands and feet, multiple milia on her forehead, and hypertelorism. Radiographs showed scoliosis, calcified ovarian fibroma, calcification of the falx cerebri, and minor rib anomalies. Evans et al. (1993) reported the clinical complications of this disorder in 84 patients. Basal cell carcinomas and jaw cysts occurred in more than 90% of patients by 40 years of age, but both sometimes occurred before 10 years of age. Less well-described complications included ovarian calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma (3%), cleft palate (5%), and ophthalmic abnormalities such as squint or cataract (26%). Shanley et al. (1994) identified 118 cases in Australia. The frequency of most manifestations were similar to those reported by Evans et al. (1993). A major difference, however, was that the multiple basal cell carcinomas were manifest from an earlier age in the Australian population, which was considered to reflect greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented sporadic cases, and accordingly the new mutation rate appeared to be high. Multiple BCCs occurred before age 20 years in 90 (75%) of 118 cases. Goldstein et al. (1994) examined 11 African Americans from 2 families with Gorlin syndrome, which they abbreviated 'NBCC' for nevoid basal cell carcinoma syndrome. They also reviewed the literature on this condition in African Americans. African Americans tended to have reduced expression of the basal cell carcinomas but full expression of other syndrome components. The 3 most common findings in their 11 cases were jaw cysts, palmar and/or plantar pits, and calcification of the falx cerebri. Only 4 of the 11 had 1 or more confirmed basal cell carcinomas, whereas the frequency of basal cell carcinomas in whites had been estimated at 90%. Kimonis et al. (1997) reviewed the findings in 105 individuals with Gorlin syndrome examined at the NIH since 1985. The data derived from 48 males and 57 females ranging in age from 4 months to 87 years. They found that 80% of whites (71 of 90) and 38% of African Americans (5 of 13) had at least 1 basal cell carcinoma, with the first tumor occurring at a mean age of 23 and 21 years, respectively. Excluding individuals exposed to radiation therapy, the number of BCCs ranged from 1 to more than 1,000, and 1 to 3, respectively, in the 2 ethnic groups. Other features included jaw cysts (74%), palmar pits and plantar pits (87%), and ovarian fibromas (17%). Medulloblastoma occurred in 4 patients at a mean age of 2.3 years. Three patients had cleft lip or palate. Physical findings included coarse facies (54%), relative macrocephaly (50%), hypertelorism (42%), frontal bossing (27%), pectus deformity (13%), and Sprengel deformity (11%). Important radiologic signs included calcification of the falx cerebri (65%), of the tentorium cerebelli (20%), bridged sella (68%), bifid ribs (26%), hemivertebrae (15%), fusion of the vertebral bodies (10%), and flame-shaped lucencies of the phalanges, metacarpal, and carpal bones of the hands (30%). Several traits previously considered components of the syndrome, such as short fourth metacarpal, scoliosis, cervical ribs, and spina bifida occulta, were not found to be significantly increased in the affected individuals. Korczak et al. (1997) reported an African American boy who developed medulloblastoma at age 2 years. He was treated with surgery, chemotherapy, and craniospinal irradiation. He was diagnosed with Gorlin syndrome at age 6 following identification of a large odontogenic keratocyst of the mandible, pits of the palms and soles, and numerous BCCs in the area of the back and neck that had been irradiated previously. Examination of other relatives showed that the mother also had Gorlin syndrome but was more mildly affected; in particular, she had no BCCs. This family illustrated a complex gene-environment interaction. Increased skin pigmentation in African Americans was presumably protective against UV, but not ionizing, radiation. Similar cases in the literature illustrated the importance of considering Gorlin syndrome in the differential diagnosis of any patient who presents with a medulloblastoma, especially before the age of 5 years. Korczak et al. (1997) also concluded that for individuals who are radiosensitive, protocols that utilize chemotherapy in lieu of radiotherapy should be considered. Hall et al. (1998) reported an 11-year-old African American boy with NBCCS who presented with exotropia and a painful, expanding, cystic mass in the left posterior alveolar ridge. An impacted molar was displaced into the orbit by an odontogenic keratocyst. Further examination revealed palmar and plantar pitting. Lo Muzio et al. (1999) described the clinical features of Gorlin syndrome in northern Italy. Aside from the many features previously reported, other manifestations included benign dermal cysts, impacted teeth, dental ectopy, exophthalmos, ovarian cysts, and calcification of tentorium cerebelli. The relatively lower percentage of patients with basal cell carcinomas (30%) may have been related to the protective skin pigmentation in the Italian population, as has already been established in African Americans. Honavar et al. (2001) reviewed 105 consecutive patients with eyelid basal cell carcinoma and found 4 patients with Gorlin-Goltz syndrome, all of whom had a family history of this disorder. Common systemic manifestations included multiple basal cell carcinomas, frontal bossing or increased occipitofrontal circumference, palmar pits, odontogenic keratocyst, ectopic calcification, and bifid ribs. The mean age at detection of the first basal cell carcinoma was 30 years (range, 16-38 years). The eyelid basal cell carcinomas were advanced with orbital infiltration in 3 patients, 1 of whom opted for palliative radiotherapy and 2 of whom underwent orbital exenteration. The fourth patient underwent local reexcision of recurrent basal cell carcinoma with upper eyelid reconstruction. After 41 months' mean follow-up, 3 patients were cured of eyelid basal cell carcinoma and 1 was stable. No patient had life-threatening sequelae of Gorlin-Goltz syndrome. The authors concluded that lifelong monitoring is essential for patient management in Gorlin-Goltz syndrome. Acrochordons are distinctly uncommon in childhood. Chiritescu and Maloney (2001) evaluated 7 children who presented with pedunculated papules (acrochordon-like growths). Histopathologic examination of these papules showed basal cell carcinomas in each biopsy specimen. Further physical examination of the subjects and family members confirmed a diagnosis of NBCCS in all 7 children. Chiritescu and Maloney (2001) considered that 'skin tag'-like basal cell carcinomas in childhood may represent a marker for NBCCS and that early diagnosis of this syndrome and early sun protection of the affected children could help decrease the number of lifetime tumors. Leonardi et al. (2001) reported a patient with NBCCS who had bilateral mandibular coronoid process hyperplasia, a condition that causes a progressive and painless limitation of jaw movements, especially in opening. Leonardi et al. (2002) examined 10 patients with NBCCS for mandibular coronoid process hyperplasia and found that 4 were affected. They suggested that coronoid hyperplasia may be a radiologic criterion for NBCCS and may help in establishing a diagnosis, especially in pediatric patients. Koch et al. (2002) described a 13-year-old boy with NBCCS who presented with right-sided abdominal pain and was found to have a mesenchymal hepatic tumor. At the age of 3 years he had had treatment of a medulloblastoma by resection and irradiation. The diagnosis of NBCCS was made at the age of 9 on the basis of palmar pits and odontogenic keratocysts of the mandible and maxilla. Multiple basal cell carcinomas developed on his forehead and occipital scalp the following year. The hepatic mass, removed at the age of 13 years, was found to be a mesenchymal tumor of low cellularity, composed of elongated cells embedded in a myxoid matrix. Nuclei were small and elongated, with no nuclear pleomorphism or mitoses. These findings were considered consistent with a benign mesenchymal tumor in the liver. The patient remained asymptomatic without evidence of recurrence at the 18-month follow-up. The mother and older brother were thought to have NBCCS; the paternal grandmother had surgical resection for medulloblastoma, but apparently had no other features of NBCCS. With studies of markers that mapped to the PTCH gene locus at 9q23, loss of heterozygosity in that region was evident in DNA samples from basal cell carcinoma, medulloblastoma, and a mesenchymal hepatic tumor. On the basis of Knudson's 2-hit hypothesis, Koch et al. (2002) concluded that mesenchymal tumors, such as the hepatic fibromyxoid tumor in their patient, may be another complication of NBCCS. They referred to the report by Darling et al. (1997) as another example of benign mesenchymal tumors occurring in another hereditary neoplastic disorder, multiple endocrine neoplasia type I (MEN1; 131100). Ozturk et al. (2003) reported a mother and daughter with Gorlin syndrome who had calcification of the falx cerebri and tentorium cerebelli and dysgenesis of the corpus callosum and vermis. Vermian dysgenesis was detected in both mother and daughter, suggesting a previously unrecognized finding associated with the disorder. Fujii et al. (2003) reported a 14-year-old Japanese girl with Gorlin syndrome and ulcerative colitis (see 266600). She had complained of blood stools for 6 months and had exhibited severe scoliosis since infancy. Physical examination revealed multiple nevi, palmar and plantar pits, jaw cysts, and calcification of the falx cerebri, consistent with the diagnosis of Gorlin syndrome. Total colonoscopy revealed an edematous and spotty bleeding mucosa extending from the anus to the transverse colon, and histologic examination was compatible with ulcerative colitis. Fujii et al. (2003) noted that Katz et al. (1968) and Sawyer and Braverman (1969) had also reported Gorlin syndrome associated with inflammatory bowel disease. Wilson et al. (2006) reported on the occurrence of discrete patches of unusually long pigmented hair on the skin of 3 patients with Gorlin syndrome from 2 unrelated families with confirmed heterozygous PTCH1 mutation. The SHH (600725)-PTCH1 pathway is known to play an important role in the formation and cycling of hair follicles. Wilson et al. (2006) suggested that these discrete patches of hair represented genuine physical signs associated with Gorlin syndrome and discussed molecular mechanisms by which they might arise. Kimonis et al. (2013) studied minor and major clinical features in 30 children and teenagers and compared the findings with 75 adults from 26 families with nevoid basal cell carcinoma syndrome. Fifty percent of children/teenagers and 82% of adults had at least one basal cell carcinoma. Jaw cysts occurred in 60% of children/teenagers and 81% of adults. Palmar/plantar pits were the most frequent feature seen in affected individuals at all ages. Macrocephaly was seen in 50% of affected and 8% of unaffected children/teenagers. Frontal bossing, hypertelorism, Sprengel deformity, pectus deformity, and cleft lip/palate were seen among affected children/teenagers but not among their unaffected sibs. Falx calcification was seen in 37% of individuals under 20 and 79% of those over 20 years of age. Kimonis et al. (2013) suggested evaluation for palmar/plantar pits, craniofacial features, and radiologic manifestations to permit early diagnosis and optimum surveillance of nevoid basal cell carcinoma syndrome.
Wicking et al. (1997) screened 71 unrelated individuals with NBCCS for mutations in the PTCH exons. They identified 28 mutations that were distributed throughout the entire gene and predicted that 86% would cause protein truncation. Wicking et al. ... Wicking et al. (1997) screened 71 unrelated individuals with NBCCS for mutations in the PTCH exons. They identified 28 mutations that were distributed throughout the entire gene and predicted that 86% would cause protein truncation. Wicking et al. (1997) identified 3 families bearing identical genotypes with variable phenotypes. From this they concluded that phenotypic variability in NBCCS is a complex genetic event. No phenotype/genotype correlation between the position of the truncation mutations and major clinical features was evident. Wicking et al. (1997) concluded that the preponderance of truncation mutations in the germline of NBCCS patients suggests that the developmental defects associated with NBCCS are likely due to haploinsufficiency. Bale (1997) reviewed factors contributing to the variable expressivity of PTCH mutations in NBCCS. He reported that clinical features of NBCCS syndrome differ more among families than within families. Shimkets et al. (1996) reported 2 patients with small interstitial deletions on chromosome 9q which involved the PTCH gene. Phenotypes of the 2 patients differed with respect to several key findings (e.g., occurrence of jaw cysts, palmar pits, and skeletal abnormalities). Bale (1997) noted that developmental defects may also arise through a 2-hit mechanism and he reviewed evidence for loss of the normal allele in epithelial cells lining jaw cysts. Bale (1997) noted the absence of genotype/phenotype correlations in NBCCS and concluded that modifying genes and germline variants resulting in hypomorphic or hypermorphic alleles may play an important role in determining the phenotype.
In 2 unrelated patients with Gorlin syndrome, Johnson et al. (1996) identified 2 different heterozygous mutations in the PTCH1 gene (601309.0001 and 601309.0002, respectively). Johnson et al. (1996) stated that PTCH1 is expressed ... - PTCH1 Gene In 2 unrelated patients with Gorlin syndrome, Johnson et al. (1996) identified 2 different heterozygous mutations in the PTCH1 gene (601309.0001 and 601309.0002, respectively). Johnson et al. (1996) stated that PTCH1 is expressed in developing sclerotome, branchial arches, limbs, and spinal cord and in vertebrate skin and noted that the pattern of vertebrate gene expression was consistent with the abnormalities found in BCNS. Simultaneously and independently, Hahn et al. (1996) isolated a identified PTCH1 mutations in unrelated patients with BCNS (see, e.g., 601309.0003-601309.0005). The authors proposed that a reduction in the expression of the PTCH1 gene can lead to the developmental abnormalities observed in this syndrome and that complete loss of PTCH1 function contributes to the transformation of certain cell types. Two sporadic basal-cell carcinomas with allelic loss of the NBCCS region had inactivating PTCH1 mutations in the remaining allele. Fujii et al. (2003) identified a mutation in exon 9 of the PTCH1 gene (601309.0016) in a 14-year-old Japanese girl with Gorlin syndrome and ulcerative colitis. Takahashi et al. (2009) identified 6 different heterozygous truncating germline mutations in the PTCH1 gene in 6 Japanese families with BCNS. There was no evidence of a founder effect. - PTCH2 Gene Using combined single-strand conformation polymorphism (SSCP) and heteroduplex analysis, Smyth et al. (1999) identified somatic mutations in the PTCH2 gene (603673.0001 and 603673.0002) in a medulloblastoma and basal cell carcinoma, respectively. In affected members of a Chinese Han family with BCNS, Fan et al. (2008) identified a heterozygous germline mutation in the PTCH2 gene (603673.0003). - SUFU Gene In a family exhibiting atypical signs and symptoms of Gorlin syndrome, in which the 4.5-year-old proband had palmar and plantar pits, macrocrania, and medulloblastoma, and his 37-year-old father had plantar pits, calcification of the falx and macrocrania, Pastorino et al. (2009), analyzed the PTCH1 gene but found no mutations. Analysis of the SUFU gene (607035), which like PTCH1 and PTCH2 is a component of the SHH (600725) signaling pathway, revealed a splice site mutation (607035.0003) in the proband and his father. The clinically unaffected paternal grandparents were negative for the mutation, suggesting that it arose de novo in the father.
Farndon et al. (1992) estimated that the minimum prevalence of basal cell nevus syndrome is 1 per 57,000; 1 in 200 patients with basal cell carcinomas had the syndrome, but the proportion was much higher among those in ... Farndon et al. (1992) estimated that the minimum prevalence of basal cell nevus syndrome is 1 per 57,000; 1 in 200 patients with basal cell carcinomas had the syndrome, but the proportion was much higher among those in whom a basal cell carcinoma developed before age 19. Only a few of the nevi grew and became locally invasive, and basal cell carcinomas did not develop at all in about 15% of affected persons. In some cases, radiation treatment resulted in fresh crops of aggressive basal cell carcinomas and led to severe disfigurement.
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. ...
DiagnosisClinical DiagnosisNevoid 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 a pathogenic PTCH1 (formerly PTCH) mutation. (An individual who is the first in the family to be affected may have milder signs because of somatic mosaicism.) Major criteriaLamellar (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 (see Note re radiographs) 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 in whites living in hot sunny climates. First-degree relative with NBCCS Minor criteria Childhood medulloblastoma (also called primitive neuroectodermal tumor [PNET]) Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criteria and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [Bree et al 2011]. The concern would be that this would reduce the specificity of diagnostic criteria, as medulloblastoma cases undergoing radiotherapy without NBCCS are likely to develop more than one BCC. Confining the medulloblastoma diagnosis to nodular/desmoplastic and disallowing BCCs occurring after radiotherapy as a major criterion may improve sensitivity without losing specificity.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 (see Note re radiographs): 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. Clinicians should avoid using x-rays in childhood if the diagnosis is obvious without them or if a known mutation exists in the family.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. 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. 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].TestingCytogenetic 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 should be considered when both of the following are present: Clinical features consistent with NBCCSAdditional features, including severe developmental delay or short staturePresence of the latter features suggests that additional chromosomal material has been lost.Molecular Genetic TestingGene. PTCH1 (formerly PTCH) is the only gene in which mutations are known to cause NBCCS. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma SyndromeView in own windowGene 1Test MethodMutations DetectedMutation Detection Frequency by Test Method 2Test AvailabilityPTCH1Sequence analysisSequence variants 350%-85% 4ClinicalDeletion / duplication analysis 5 Exonic, multiexonic, and whole-gene deletions 6%-21% 6Linkage analysis Not applicableNot applicable 71. See Table A. Genes and Databases for chromosome locus and protein name.2. The ability of the test method used to detect a mutation that is present in the indicated gene3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. 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]. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. Eight of 38 individuals with NBCCS had large deletions that were not identified using sequence analysis [Nagao et al 2011].7. If the family pedigree structure is sufficient and family members cooperate with 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.Test characteristics. Information on test sensitivity, specificity, and other test characteristics can be found online [Lo Muzio et al 2013; click here for full text].Interpretation of test results Missense mutations are relatively common and it may be difficult to determine whether they are pathologic or benign in an individual who has no family history of NBCCS and does not fulfill diagnostic criteria. However, demonstrating that the missense mutation is de novo in the absence of a known family history is supportive of pathogenicity.The identification of an inactivating allele that is highly likely to be pathologic (e.g., 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 one 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 StrategyTo 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 can be followed by deletion/duplication analysis. In individuals suspected of having the somatic mosaic form of NBCCS it is probably better to initially test a tumor (e.g., 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) DisordersMing 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 protein patched homolog 1 encoded by PTCH1. Ribeiro et al [2006] reported four further PTCH1 missense mutations associated with holoprosencephaly. 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.
More than 100 features that are variable within and among families have been associated with nevoid basal cell carcinoma syndrome (NBCCS) [Farndon 2004]....
Natural HistoryMore 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. A rare malignant transformation of a keratocyst called ameloblastoma has been reported in individuals with NBCCS at least six times [Ponti et al 2012]. 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 caesarean 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 [Pereira et al 2011] and meningioma have been reported [Kijima et al 2012].Morbidity/mortality. Life expectancy in NBCCS is not significantly different from average [Wilding et al 2012]. 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.
Early reports did not find a genotype-phenotype correlation [Wicking et al 1997]. In particular there is no evidence for genotype affecting age at onset of BCCs [Jones et al 2011]. Predictions about clinical severity are not yet possible for specific PTCH1 mutations, which are likely to be modified by the effects of other genes. ...
Genotype-Phenotype CorrelationsEarly reports did not find a genotype-phenotype correlation [Wicking et al 1997]. In particular there is no evidence for genotype affecting age at onset of BCCs [Jones et al 2011]. 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]. 9q22.3 microdeletion syndrome. Large chromosomal deletions that involve PTCH1 are the cause the 9q22.3 microdeletion syndrome. This syndrome is characterized by developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, pre- and postnatal macrosomia, and seizures, in addition to the features of NBCCS [Muller et al 2012].
The differential diagnosis depends on the mode of presentation....
Differential DiagnosisThe differential diagnosis depends on the mode of presentation.Macrocephaly. If the proband is a baby with macrocephaly and other birth defects, a limited number of overgrowth syndromes including Sotos syndrome and Beckwith-Wiedemann syndrome need to be considered: Sotos syndrome is characterized by a typical facial appearance, intellectual impairment, and overgrowth (increased height and head circumference). It is associated with neonatal jaundice, scoliosis, seizures, strabismus, conductive hearing loss, congenital cardiac anomalies, renal anomalies, and behavioral problems. The risk of sacrococcygeal teratoma and neuroblastoma is slightly increased. Approximately 80%-90% of individuals with Sotos syndrome have a demonstrable mutation or deletion of NSD1. Sotos syndrome is inherited in an autosomal dominant manner, with more than 95% of individuals having a de novo mutation. Beckwith-Wiedemann syndrome is a disorder of growth characterized by macrosomia (large body size), macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Macroglossia and macrosomia are generally present at birth but may have postnatal onset. Growth rate slows around age seven to eight years. Hemihyperplasia may affect segmental regions of the body or selected organs and tissues. The diagnosis relies primarily on clinical findings, but molecular genetic testing reveals diagnostic changes in some affected individuals. Isolated hydrocephaly or megalencephaly may be distinguished by clinical examination, family history, and x-rays. Basal cell carcinomas (BCCs). If the initial presentation is multiple BCCs, clinical examination and radiographs should nearly always establish the diagnosis of NBCCS. Other inherited disorders with similar skin findings include the following: Brooke-Spiegler syndrome, characterized by trichoepitheliomas, milia, and cylindromas presenting in the second or third decade and inherited in an autosomal dominant manner (OMIM 605041). The milia are miniature trichoepitheliomas and appear only in sun-exposed areas. Bazex syndrome, characterized by multiple BCCs, follicular atrophoderma on the dorsum of hands and feet, decreased sweating, and hypotrichosis (OMIM 301845). The pitting on the backs of the hands is reminiscent of orange peel and quite unlike the palmar and plantar pits of NBCCS. The inheritance pattern is either autosomal dominant or X-linked dominant. Rombo syndrome, a dominantly inherited condition similar to Bazex syndrome, reported in a single family (OMIM 180730). Skin findings are vermiculate atrophoderma, milia, hypotrichosis, trichoepitheliomas, BCCs, and peripheral vasodilation with cyanosis. The skin is normal until later childhood; BCCs develop in adulthood. Sweating is normal. An autosomal dominant or X-linked dominant syndrome of hypotrichosis and BCCs reported in a single family [Oley et al 1992] (OMIM 301845) Autosomal dominant inheritance of multiple basal cell carcinomas in the absence of other featuresAcquired causes of multiple BCCs include arsenic exposure. Jaw keratocysts. If the initial presentation is jaw keratocysts, clinical examination and radiographs should nearly always establish the diagnosis of NBCCS. In addition to examination of the child, a medical history and examination of the parents is advised. Medulloblastoma. Children presenting with medulloblastoma need to be assessed for NBCCS, particularly if they are younger than age three years and/or have desmoplastic histology. In addition to examining the child, a medical history and examination of the parents is advised. Children with nodular or desmoplastic medulloblastoma also need to be assessed for mutations in SUFU [Brugières et al 2012]. Brugières and colleagues demonstrated that 3/3 individuals with nodular meduloblastoma and 4/20 individuals with desmoplastic medulloblastoma caused by mutations in SUFU had some features of NBCCS. Furthermore, mutations in SUFU are associated with macrocephaly and 1/8 individuals with SUFU mutations who had medulloblastoma developed BCCs in the radiation field [Brugières et al 2012]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs in an individual diagnosed with nevoid basal cell carcinoma syndrome (NBCCS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs 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 Medical genetics consultationBecause mesenteric and pleural cysts are rare, evaluation is not necessary in the absence of symptoms. Treatment of ManifestationsManifestations 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 ManifestationsUse of radiotherapy can lead to the development of thousands of BCCs in the radiation field [Strong 1977, Evans et al 1991a] and therefore should be avoided if there are alternative treatments, especially in childhood. If the treating team believes that no other treatment modality is possible, radiotherapy should be used through as few skin ports as possible. Diagnostic x-rays should be used sparingly.Individuals with NBCCS should be advised to avoid direct sun exposure as much as possible. Excessive sun exposure increases the likelihood of developing BCCs. Affected individuals should cover up exposed skin by wearing long sleeves, high collars, and hats; complete sunblock should be used. SurveillanceHead 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. A recent consensus meeting has suggested annual head MRI scans until age eight years in affected children [Bree et al 2011], but this would require general anesthesia for many children.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 AvoidSee Prevention of Primary Manifestations.Evaluation of Relatives at RiskBecause 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.Pregnancy ManagementSince individuals with NBCCS 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 caesarean section delivery due to cephalopelvic disproportion.Therapies Under InvestigationPhotodynamic 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]. Systemic use of sonic hedgehog antagonists in individuals with NBCCS who have advanced or refractory BCCs has also been effective [Sekulic et al 2012, Tang et al 2012], with a 43% response rate in 63 affected individuals with locally advanced BCCs. Response rates were very high in individuals with NBCCS but 53% discontinued therapy due to adverse side effects [Tang et al 2012]. A recent case report suggests that anti sonic hedgehog agents may also resolve keratocysts when given for BCC treatment [Goldberg et al 2011].Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Nevoid Basal Cell Carcinoma Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPTCH19q22.32Protein patched homolog 1Catalogue of Somatic Mutations in Cancer (COSMIC) PTCH1 homepage - Mendelian genesPTCH1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Nevoid Basal Cell Carcinoma Syndrome (View All in OMIM) View in own window 109400BASAL CELL NEVUS SYNDROME; BCNS 601309PATCHED, DROSOPHILA, HOMOLOG OF, 1; PTCH1Molecular Genetic PathogenesisThe 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 PTCH1 allele in tumors [Cowan et al 1997] confirm PTCH1 as a tumor suppressor in medulloblastoma as well as in BCC. Inactivation of the normal allele 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.Table 2. Frequency of Pathogenic Genetic MechanismsView in own window% of Individuals Affected with NBCCS 1 Type of Mutation65%Premature termination codon (predicting a protein truncation16%Missense13%Splice-site6%Exonic, multiexonic, or large-scale deletions or rearrangementsSource: literature and 395 samples from diagnostic laboratory, Birmingham Women's Hospital, UK, August 2007 (Proportions of types of mutation have remained the same over several years.)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.