Clinical characteristics.

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. Approximately 60% of individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years. Life expectancy in NBCCS is not significantly different from average.

Diagnosis/testing.

The diagnosis of NBCCS is established in a proband who fulfills existing diagnostic clinical criteria. Identification of a heterozygous germline pathogenic variant in PTCH1 or SUFU on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Best provided by specialists experienced with the condition; keratocysts usually require surgical excision; early treatment of BCCs to ensure complete eradication of aggressive BCCs and to preserve normal tissue to prevent disfigurement; sonic hedgehog inhibitors such as vismodegib to treat severe BCCs; preservation of ovarian tissue whenever ovarian fibromas require surgical treatment. However, the cost of treatment has meant that the National Institute for Health and Care Excellence in the UK has judged the treatment not cost effective.

Prevention of primary manifestations: Avoidance of direct sun exposure through the use of complete sunblock and covering of exposed skin with long sleeves, high collars, and hats.

Surveillance: Monitoring of head circumference throughout childhood; developmental assessment and physical examination every six months in the first years of life because of increased risk for medulloblastoma; in those older than age eight years, orthopantogram every 12-18 months to identify jaw keratocysts; skin examination at least annually.

Agents/circumstances to avoid: Radiotherapy if there are alternative treatments, especially in childhood; diagnostic x-rays should be used sparingly; direct sun exposure should be limited; excessive sun exposure increases the likelihood of developing BCCs.

Evaluation of relatives at risk: Because of the need for surveillance for complications of NBCCS (medulloblastoma in children; jaw cysts and BCCs in adults) and the need to avoid sun exposure, clarification of the genetic status of at-risk relatives, including children, is appropriate.

Genetic counseling.

NBCCS is inherited in an autosomal dominant manner. Approximately 70%-80% of individuals with NBCCS have an affected parent and about 20%-30% have NBCCS as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting NBCCS. Prenatal testing for pregnancies at risk is possible if the PTCH1 or SUFU pathogenic variant has been identified in an affected family member.Go to:

Diagnosis

Suggestive Findings

Nevoid basal cell carcinoma syndrome (NBCCS) should be suspected in individuals with the following findings, which constitute major or minor diagnostic criteria.

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 (see Notes regarding radiographs).
  • Jaw keratocyst. Odontogenic keratocyst histologically; seen on orthopantogram as an area of translucency
  • Palmar/plantar pits (≥2); 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 basal cell carcinomas (BCCs) (>5 in a lifetime) or a BCC before age 30 years. Provision needs to be made for decreased risk of BCC in individuals with dark skin and increased risk in those with light skin living in hot sunny climates, particularly those with type 1 Celtic skin and red hair, and of this group, particularly those with the common MC1R variant (rs1805007), which can modify age of onset for NBCCS [Yasar et al 2015].
  • First-degree relative with NBCCS

Minor criteria

  • Childhood medulloblastoma (also called primitive neuroectodermal tumor)Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion 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 individuals with medulloblastoma 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. These changes have not yet been adopted. A consensus conference on screening recommendations convened by the American Association of Cancer Research did not propose adopting the Bree et al criteria [Foulkes et al 2017].
  • 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 Notes regarding radiographs): bifid/splayed/extra ribs; bifid vertebrae
  • Preaxial or postaxial polydactyly
  • Ovarian/cardiac fibromas
  • Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium)

Notes regarding 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 pathogenic variant 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 2005Veenstra-Knol et al 2005].

Establishing the Diagnosis

The diagnosis of NBCCS is established in a proband with the following findings:

  • 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.
  • Identification of a heterozygous germline PTCH1 or SUFU pathogenic variant on molecular genetic testing (see Table 1). This finding establishes the diagnosis if clinical features are inconclusive.Note: (1) Occasional variants in PTCH2 have been found in individuals with NBCCS but these may not be conclusive [Fujii et al 2013]. Likewise, SUFU pathogenic variants may not always cause typical NBCCS (see Genetically Related Disorders). (2) Identification of an identical PTCH1 pathogenic variant in two or more separate tumors but not present (or present at a lower-than-normal ratio) in lymphocyte DNA confirms the presence of mosaicism [Evans et al 2007].

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing. Suggested order:1.

Sequence analysis of PTCH12.

Gene-targeted deletion/duplication analysis of PTCH13.

Sequence analysis of SUFU4.

Gene-targeted deletion/duplication analysis of SUFU5.

RNA analysis of PTCH1

Note: SUFU molecular testing should be considered first in families with medulloblastoma and without jaw keratocysts [Smith et al 2014].

multigene panel that includes PTCH1, SUFU and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) If only NBCCS is being considered, a bespoke panel of just PTCH1 and SUFU should be considered optimal as large multigene panels may have decreased sensitivity and may not include gene-targeted deletion/duplication analysis or PTCH1 RNA analysis necessary to identify large rearrangements [Smith et a 2014Smith et al 2016]. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (3) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is mot likely to identify the genetic cause of condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
PTCH1Sequence analysis 3, 450%-85% 4, 5
Gene-targeted deletion/duplication analysis 66%-21% 7
SUFUSequence analysis 35% 8
Gene-targeted deletion/duplication analysis 6~1% 8
UnknownNA15%-27% 9

1.

See Table A. Genes and Databases for chromosome locus and protein.2.

See Molecular Genetics for information on allelic variants detected in this gene.3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missensenonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4.

Sequence analysis that detects deep intronic variants may be appropriate. Rare deep intronic variants that alter splicing are predicted to cause loss of function of protein patched homolog 1 [Bholah et al 2014].5.

Sequence analysis of exons 2-23 with intronexon junctions and one of the splice forms of exon 1 of transcript variant NM_000264​.4 detects pathogenic variants 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 pathogenic variant [Klein et al 2005Marsh et al 2005Evans et al 2017].6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.7.

Eight of 38 individuals with NBCCS had large deletions that were not identified using sequence analysis [Nagao et al 2011].8.

Smith et al [2014]9.

Smith et al [2014]Evans et al [2017]Go to:

Clinical Characteristics

Clinical Description

More than 100 features that are variable within and among families have been associated with nevoid basal cell carcinoma syndrome (NBCCS) [Farndon 2004]. Findings are presented here in the usual order of manifestation.

Macrocephaly. The first feature likely to be observed is relative macrocephaly. A large proportion of babies with NBCCS require delivery by cesarean 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.

Other 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 2003Ragge et al 2005].

Gross motor delay. 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.

Medulloblastoma. Approximately 5% of all individuals with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuroectodermal tumor) [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 one to two years, compared to age seven years in its sporadic form [Cowan et al 1997Amlashi et al 2003].

More recently, nonsense and missense variants and multiexon deletion of SUFU were identified in three families with classic NBCCS features; one individual in each family had medulloblastoma [Smith et al 2014]. SUFU-related NBCCS is associated with a high risk for medulloblastoma of up to 33% (3/9) and a high meningioma risk post radiation. The risk for medulloblastoma in PTCH1-related NBCCS was less than 2% [Smith et al 2014].

Facies. Approximately 60% of individuals with a PTCH1 pathogenic variant have a recognizable appearance with frontal bossing, coarse facial features, and facial milia. Facial features are likely more subtle in individuals with an SUFU pathogenic variant.

Skeletal features. Congenital bone anomalies are present at birth but will not be evident clinically in a newborn. The shoulders slope downward. 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 1995Kimonis et al 2004]. Sella calcification, when present, is visible on lateral x-rays of the skull.

Jaw keratocysts. Approximately 90% of individuals with PTCH1-related NBCCS 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.

Jaw cysts have not been reported in individuals with SUFU-related NBCCS [Smith et al 2014].

A rare malignant transformation of a keratocyst called ameloblastoma has been reported in individuals with NBCCS at least six times [Ponti et al 2012].

Basal cell carcinomas (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 appear to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy.

Other skin manifestations include meibomian cysts in the eyelids, sebaceous cysts, and dermoid cysts. 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 1993Gorlin 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 occur with both SUFU and PTCH1-related NBCCS and may be more common in individuals with SUFU-related NBCCS [Evans et al 2017]. They are usually an incidental finding on ultrasound examination or at cesarean 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 for 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.

Phenotype Correlations by Gene

PTCH1

A recent review of 182 genotyped individuals with NBCCS found that individuals with PTCH1-related NBCCS were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002), and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003), than individuals with no identified pathogenic variant [Evans et al 2017].

Approximately 90% of individuals with PTCH1-related NBCCS develop multiple jaw keratocysts.

Approximately 60% of individuals with a PTCH1 pathogenic variant have a recognizable appearance with frontal bossing, coarse facial features, and facial milia.

The risk for medulloblastoma in PTCH1-related NBCCS was lower than 2% [Smith et al 2014].

SUFU

SUFU-related NBCCS is associated with a high risk for medulloblastoma of up to 33% (3/9) and a high meningioma risk post radiation.

Facial features are likely more subtle in individuals with an SUFU pathogenic variant.

Overall, clinical features are milder in individuals with SUFU-related NBCCS with less BCCs, and no jaw cysts reported [Evans et al 2017].

Genotype-Phenotype Correlations

PTCH1. Individuals with PTCH1 missense variants were diagnosed later (p=0.03) and were less likely to develop ten or more BCCs and jaw cysts than those with other PTCH1 pathogenic variants (p=0.03).

Penetrance

Although NBCCS shows intra- and interfamilial variation in expression, experience clinically and from molecular testing is compatible with complete penetrance [Author, personal observation]. A previous report of reduced penetrance in a family with medulloblastoma based on PTCH1 linkage analysis was refuted when the family was shown to have an SUFU pathogenic variant. [Smith et al 2014]. The penetrance of SUFU pathogenic variants is more difficult to determine, but is likely to be reduced.

Prevalence

Few studies of NBCCS 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 individuals with milder features may not be recognized.

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

Birth incidence has been confirmed to be as high as1:18,976 [Evans et al 2010].Go to:

PTCH1

Ming et al [2002] reported heterozygous PTCH1 pathogenic missense variants in five of 100 unrelated probands with holoprosencephaly. The authors hypothesized that the pathogenic missense variants 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 PTCH1Ribeiro et al [2006] reported four further PTCH1 pathogenic missense variants associated with holoprosencephaly.

A non-recurrent deletion (i.e., a deletion with many different possible breakpoints and many different sizes) at chromosome 9q22.3 encompassing a 352-kb critical region including 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, and seizures. Affected individuals are also at increased risk for Wilms tumor. The clinical spectrum of the 9q22.3 deletion is variable and the clinical findings depend somewhat on the size of the microdeletion. The 9q22.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques, except with extremely large deletions [Muller et al 2012].

SUFU

Heterozygous germline truncating SUFU pathogenic variants were identified in two families that included several children with medulloblastoma. None of the family members with the SUFU pathogenic variant had clinical features of NBCCS [Brugières et al 2010]. Seventeen individuals with medulloblastoma and germline SUFU pathogenic variants reported by Guerrini-Rousseau et al [2018] did not meet NBCCS diagnostic criteria.Go to:

Differential Diagnosis

The 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 three cardinal clinical features: a distinctive facial appearance, learning disability, and overgrowth (increased height and head circumference ≥2 SD above the mean). Major features of Sotos syndrome include behavioral problems, advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity/pes planus, maternal preeclampsia, neonatal jaundice, neonatal hypotonia, renal anomalies, scoliosis, and seizures. The risk for sacrococcygeal teratoma and neuroblastoma is slightly increased. The diagnosis is established in a proband by identification of a heterozygous NSD1 pathogenic variant. Sotos syndrome is inherited in an autosomal dominant manner with more than 95% of individuals having a de novo pathogenic variant.

Beckwith-Wiedemann syndrome (BWS) is a disorder of growth variably characterized by neonatal hypoglycemia, macrosomia (large body size), macroglossia, hemihyperplasia, omphalocele, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), visceromegaly, adrenocortical cytomegaly, renal abnormalities (e.g., medullary dysplasia, nephrocalcinosis, medullary sponge kidney, nephromegaly), and ear creases/pits. 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. A provisional diagnosis of BWS based on clinical assessment may be confirmed by molecular/cytogenetic testing. BWS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5.

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. Brooke-Spiegler syndrome presents in the second or third decade. It is caused by pathogenic variants in CYLD 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.
  • 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 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 features

Acquired 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 a germline heterozygous pathogenic variant in SUFU [Brugières et al 2012]. Brugières and colleagues found that 3/3 individuals with nodular medulloblastoma and 4/20 individuals with desmoplastic medulloblastoma caused by a germline heterozygous pathogenic variant in SUFU had some features of NBCCS. Furthermore, a germline pathogenic variant in SUFU is associated with macrocephaly and 1/8 individuals with an