PICTORIAL ESSAY

Neuroimaging of nevoid basal cell carcinoma syndrome(NBCCS) in children

Kamyar Sartip & Adam Kaplan & George Obeid & Nadja Kadom

Received: 10 March 2012 /Revised: 4 July 2012 /Accepted: 10 July 2012 /Published online: 14 November 2012# Springer-Verlag 2012

Abstract Nevoid basal cell carcinoma syndrome (NBCCS,Gorlin syndrome) is an autosomal dominant conditionwith a wide range of manifestations, including multiplebasal cell carcinomas, medulloblastoma, odontogenic ker-atocysts (OKC) and skeletal abnormalities. Childrenwith NBCCS also have a predisposition for secondary can-cers after exposure to ionising radiation. In children under-going imaging for posterior fossa mass and/or maxillofacialcysts, certain additional findings can raise the possibilityof NBCCS. Making the diagnosis can significantly im-pact patient management, especially for children withmedulloblastoma.

Keywords Nevoid basal cell carcinoma . Odontogenickeratocysts . Medulloblastoma . Gorlin syndrome . Children

Introduction

Nevoid basal cell carcinoma syndrome (NBCCS) is anautosomal dominant condition affecting multiple organ

systems. A wide range of terminology has been applied todescribe this entity (Table 1), which is probably best knownby its eponymic name, Gorlin syndrome [1]. NBCCS iscaused by mutation in the PTCH1 gene, a tumour suppres-sor gene mapped on the long arm of chromosome 9 (q22.3-q31) [2]. Clinical hallmarks of the disease include multiplebasal cell carcinomas of the skin, medulloblastoma andodontogenic keratocysts of the oral cavity [2–5]. Thereported prevalence of NBCCS ranges from 1/57,000 to 1/256,000 [2, 3]. The disease has high penetrance and variableexpression [2]. No sexual predilection has been reported [2].

Children with NBCCS have a predisposition for sec-ondary cancers after exposure to radiation, both ultravi-olet and ionising [6]. Since medulloblastoma treatmentusually includes radiation therapy to the posterior fossa,and since management of odontogenic keratocysts mayrequire sequential CT imaging studies, it is important tomake a diagnosis of concomitant NBCCS in thesepatients to avoid unnecessary exposures to ionising radia-tion. It is also important to identify patients with NBCCS sothey can benefit from genetic counselling and receiveadvice regarding protection from exposure to sunlight. Ina cohort of nine children with NBCCS documented as primarypatients at or as referrals to our institution, the diagnosis wasnot initially made in three of them. These three childrenpresented initially with a medulloblastoma and underwentradiation therapy. They developed subsequent cancers, whichwere potentially radiation induced, and ultimately lethal fortwo of them.

We present characteristic neuroimaging and clinical signsof NBCCS that are accessible to the radiologist and can helpestablish the diagnosis. Recognising these neuroimagingsigns can significantly affect patient outcomes by avoidingradiation therapy, reducing imaging studies with ionisingradiation and providing counselling regarding ultravioletray exposure to affected patients [6–10].

K. Sartip (*)Department of Radiology,Howard University College of Medicine,2041 Georgia Ave,Washington, DC 20060, USAe-mail: ksartip@yahoo.com

A. Kaplan :G. ObeidDepartment of Oral and Maxillofacial Surgery, WashingtonHospital Center,Washington, DC, USA

N. KadomDepartment of Diagnostic Imaging and Radiology, Children’sNational Medical Center,Washington, DC, USA

Pediatr Radiol (2013) 43:620–627DOI 10.1007/s00247-012-2516-x

Review of neuroimaging signs in NBCCS

Imaging findings with different modalities for children withNBCCS are summarised in Table 2.

The diagnosis of NBCCS is usually clinically based onmajor and minor criteria (Table 3) [2]. The clinical presen-tation (Table 4) determines which initial neuroimaging studywill be performed: odontogenic keratocysts are usually eval-uated with radiographs and may be followed by maxillofa-cial CT, while macrocephaly screening or symptoms ofposterior fossa disease usually trigger an initial screeninghead CT, followed by brain MRI for posterior fossa masses.Several major and minor criteria of NBCCS are evident onneuroimaging studies. For example, on standard maxillofa-cial CT the radiologist could detect odontogenic keratocysts,

cleft lip/palate, falcine calcifications, bridging of the sella oreye anomalies (cataract, coloboma, microphthalmos); poten-tial findings on brain CT are medulloblastoma, macroce-phaly (usually in the child’s history), ectopic calcificationsor bridging of the sella; findings on brain MRI are medul-loblastoma, macrocephaly (usually in the child’s history),bridging of the sella, cleft lip/palate, odontogenic kerato-cysts or eye anomalies. On spine imaging with both radio-graphs and CT, bifid ribs and vertebral anomalies can beevident. Skin lesions may be seen on any imaging study(Table 2) [2, 3, 8–11].

Odontogenic keratocysts (OKCs) can be seen in themaxilla and mandible of children with NBCCS (Fig. 1),with reported incidence between 66% and 92% [2–5, 12,13]. Histopathologically, they are characterised by a thinexternal fibrous capsule and a uniform internal lining ofparakeratinised stratified squamus epithelium six to eightlayers thick [2]. The epithelium-connective tissue interfaceis flat with minimal to no ridges [2]. In our cohort of ninepatients, two initially presented with odontogenic kerato-cysts and in two others, the new occurrence of odontogenickeratocysts triggered the diagnosis 6 and 8 years after theinitial presentation (Table 4).

Patients with NBCCS can develop OKCs as early as 7 or8 years of age until about 30 years of age, at which time thecysts tend to decrease in rate of development [2, 14, 15]. Inseveral population studies of NBCCS, incidence of jawcysts was 13% before age 10 and 51–82% by age 20[2–5]. The cysts can be multiple: the reported mean numberof cysts over a lifetime is 2.7–6 in published series, and asmany as 28 cysts have been reported in a single patient [2, 3,

Table 1 Terminology for nevoid basal cell carcinoma syndrome(NBCCS)

Basal cell nevus (carcinoma) syndrome

Epithelioma naevique multiple

Fifth phakomatosis

Hereditary cutaneomandibular polyoncosis

Hermans–Grosfeld–Spaas–Valk syndrome

Gorlin syndrome

Multiple basal-cell carcinoma syndrome

Multiple basal-cell nevi syndrome

Multiple hereditary cutaneomandibular polyoncosis

Multiple naevoid basal-cell carcinoma syndrome

Naevus epitheliomatodes multiplex

Naevoid basal-cell epithelioma-jaw cyst-bifid rib syndrome

Ward syndrome II

Table 2 Imaging findings as best seen on commonly utilised modal-ities for children with NBCCS. Check marks in parentheses indicatethat presence of the sign depends on imaging technique, specific natureof the finding and/or provided history

Findings MaxillofacialCT

BrainCT

BrainMRI

Spineimaging

Skin lesions x x x x

Odontogenickeratocysts

x x

Cleft lip/palate x x

Dural/falcinecalcifications

(x) x (x)

Bridging of thesella

x x x

Medulloblastoma (x) x x

Macrocephaly (x) (x)

Eye anomalies (x) x

Bifid ribs (x)

Vertebralanomalies

x

Table 3 List of major and minor criteria in diagnosis of NBCCS

Major criteria

1. Multiple (> 2) BCCs or one under 20 years

2. Odontogenic keratocysts of the jaws proven by histopathology

3. Palmar or plantar pits (3 or more)

4. Bilamellar calcification of the falx cerebri

5. Bifid, fused or markedly splayed ribs

6. First-degree relatives with NBCCS

Minor criteria

1. Macrocephaly determined after adjustment for height

2. Congenital malformation: cleft lip or palate, frontal bossing,“coarse face,” moderate or severe hypertelorism

3. Other skeletal abnormalities: sprengel deformity, marked pectusdeformity, marked syndactyly of the digits

4. Radiologic abnormalities: bridging of the sella turcica, vertebralanomalies such as hemivertebrae, fusion or elongation of thevertebral bodies, modelling defects of the hands and feet, or flame-shaped lucencies of the hands or feet

5. Ovarian fibroma

6. Medulloblastoma

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12]. OKCs in patients with NBCCS can be more aggressivethan those in patients without the syndrome. The mostcommon sites are the mandible molar-ramus (43–44%),mandibular canine-incisor (17–18%), maxillary canine-incisor (15–24%) and maxillary molar tuberosity (10–13%) [12, 13].

OKCs are typically asymptomatic and are most common-ly detected on routine dental radiographs. Those cysts thatbecome secondarily infected present with symptoms of pain,swelling and drainage [16]. Lesions can be either unilocularor multilocular. They resorb intramedullary bone at a fasterrate than cortical bone, resulting in their classic anteropos-terior spread, as opposed to other cysts, which tend to spread

more buccolingually [17]. Lesions are usually treated viaenucleation and curettage. Various adjuncts such as marsu-pialisation, Carnoy’s solution, cryotherapy and peripheralostectomy can be used to reduce the risk of recurrence,reported between 9% and 18% [18, 19]. Occasionally, high-ly aggressive recurrent lesions require resection to eliminatethe lesion [18]. The preferred imaging modality to followNBCCS patients with odontogenic keratocysts is CT. How-ever, given the sensitivity of children with NBCCS to ionis-ing radiation, it is unclear if repeat CT imaging could causeadverse outcomes in these patients. At our institution, weattempt to reduce ionising radiation exposure by using MRIfor follow-up of jaw cysts (Fig. 2). In children with NBCCSwho require surveillance with CT, we advocate modifica-tions to MDCT techniques to lower radiation dose, or use ofcone-beam CT if available to minimise radiation exposure[20, 21].

Medulloblastoma can frequently be the first manifesta-tion of NBCCS (Fig. 3). The median age of onset of medul-loblastoma in NBCCS is much earlier than in sporadicmedulloblastoma, the average age of onset being 2 yearsof age in NBCCS compared with 6.9 years in sporadicmedulloblastoma [3, 5, 22]. Amlashi et al. [22] found theincidence of NBCCS in patients with medulloblastoma, ingeneral, to be 1–2%. At younger ages, the incidence washigher; for example, 10.7% for patients younger than 5 yearsand 25% for patients younger than 2 years [22]. Therefore,younger age of presentation with medulloblastoma shouldraise suspicion for NBCCS. In our cohort, four of ninepatients initially presented with medulloblastoma. Thesefour patients all were between 2 and 3 years old at the timeof presentation. One underwent genetic testing at the time ofpresentation and the diagnosis of NBCCS was made. In theremaining three, the additional diagnosis of NBCCS wasmade 5–9 years after medulloblastoma diagnosis (Table 4).

Table 4 List of clinical symp-toms at time of the initial pre-sentation, organised by absence(1–5) or presence (6–9) of me-dulloblastoma. The diagnosiswas made initially in only threepatients. In all others, the delayin diagnosis after the initial pre-sentation ranged from 5 to9 years. For patients in whomthe diagnosis was made at thetime of initial presentation, twowere based on the clinical examand the CT findings led to ge-netic testing that confirmed thediagnosis in one patient

Caseno.

Medullo-blastoma

Initial presentation Diagnosis made by Diagnosisdelay (years)

1 No Odontogenic keratocysts, family history Presentation & familyhistory

0

2 No Macrocephaly, hypertelorism,hydroceles

Skin lesions 8

3 No Macrocephaly, Wilms tumour Skin lesions 5

4 No Macrocephaly Jaw cyst 8

5 No Macrocephaly, cleft lip & palate, skinlesions, odontogenic keratocysts

Presentation 0

6 Yes (Unknown) Post-treatmentmeningioma

9

7 Yes Emesis, ataxia Jaw cyst 6

8 Yes Ataxia, mental status change Brain CT duralcalcifications, genetictesting

0

9 Yes (Unknown) (Unknown) 6

Fig. 1 Odontogenic keratocysts in an 11-year-old boy, non-contrastface CT, sagittal reformatted image in bone algorithm. Note the max-illary cysts surrounding the crowns of two molar teeth (asterisks), aswell as the root of one premolar tooth (arrow). There are no imagingfeatures that differentiate odontogenic keratocysts in patients withNBCCS from other odontogenic cysts. Multiplicity of odontogenickeratocysts could indicate NBCCS and warrant further clinical andradiologic investigations

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A histological subtype of medulloblastoma, the desmoplasticmedulloblastoma variant (DMB) has been strongly associatedwith NBCCS [22, 23]. In a review of the literature, Amlashiet al. [22] found the incidence of NBCCS in children withdesmoplastic medulloblastoma variant (DMB) to be approx-imately 20%. On imaging, desmoplastic medulloblastoma istypically more laterally situated within the cerebellar hemi-spheres [24]. Meningeal infiltration is more commonly seenthan in sporadic medulloblastoma, possibly related to its morelateral location [24]. When not associated with NBCCS, the

mean age of onset for desmoplastic medulloblastoma is17 years [24]. More recently, Garre et al. [23] found medul-loblastoma with extensive nodularity (MBEN), a histologicalsubtype of DMB, to be present in 5 of 12 patients withNBCCS. Both histological variants (DMB and MBEN) areconsidered to have favourable prognosis, an important con-sideration when the diagnosis of NBCCS coexists and radia-tion treatment is omitted [22, 23].

Ectopic calcifications of dural structures and ligamentsare a common finding on head CT in adults. The age of

Fig. 2 MRI of odontogenickeratocysts. Serial MRI axialT2 images with fat saturation ina child with OKCs from age 4to 8 years. Note on the initialscreen at age 4 years there wasno maxillary cyst (a), then atage 6 years a small cystappeared at the level of the leftcentral incisor (b, arrows) andprogressively enlarged over thefollowing 2 years, 7 years (c)and 8 years (d) (arrows). MRIcan be useful in detection andfollow-up ofcertain NBCCS patients withodontogenic keratocysts toreduce exposure to ionisingradiation

a b

cc d

*

Fig. 3 Atypicalmedulloblastoma in a 3-year-old boy. a Axial noncontrastCT. b Coronal post-contrast T1.c Axial T2. d Axial apparentdiffusion coefficient (ADC)map. Although there was nopost-surgical pathology reportin the medical records, theposterior fossa mass in thischild has two atypical featuresfor a medulloblastoma: thelesion is centred off the midlinein the right cerebellarhemisphere (a, b, arrows) andthere are cysts associated with it(c, arrow). Note a fluidcollection (b, asterisk) thatlikely represents a cysticreaction of cerebellar tissue tothe mass rather than a cysticcomponent of the mass. Thelesion also has a relatively darkT2 signal, isointense tocerebellar cortex (c, arrow),with restriction on ADC map(d, arrow) indicating highcellularity, which is typical ofmedulloblastoma

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Fig. 4 Ectopic calcifications. aAxial noncontrast head CT in a3-year-old boy with posteriorfossa mass shows dural calcifi-cations in the superior falx(arrows). The presence of duralcalcifications raised suspicionfor NBCCS, which wasconfirmed by genetic testing.b Axial noncontrast face CT inan 11-year-old boy with odon-togenic keratocysts showscalcifications of the petrocli-noid ligaments (arrows).c A reformatted sagittalnoncontrast face CT in bonealgorithm in a 13-year-old boywith odontogenic keratocystsshows calcifications of thetentorium cerebella (arrows)

Fig. 5 Sella turcica osseousbridging. a Axial noncontrastface CT images and (b) coronalreformatted images in an 8-year-old boy with odontogenickeratocysts show the sellacompletely surrounded by solidbone (arrows). c, d Axial T2MR images in two 5-year-oldchildren with medulloblastoma.There is complete bony enclo-sure of the sella (arrows), butthis finding can be difficult tomake on MR imaging, depend-ing on the image angulation inthe axial plane

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onset for physiological dural calcifications is not well estab-lished in the literature. Stavarous et al. [11] found no duralcalcifications in a series of 118 patients with a mean age of7 years and age ranging between 0.1 and 18 years. Theyestimated the incidence of dural calcifications to be lessthan 1% in the general paediatric population. Calcificationsof the falx cerebri (Fig. 4) are common in patients withNBCCS; the incidence ranges from 65% to 92% [3]. Othersites of ectopic calcifications in patients with NBCCSinclude the tentorium cerebelli (20–40%), petroclinoid lig-ament (20%) and diaphragma sellae (60–80%) (Fig. 4) [2].

Osseous bridging of the sella turcica is an uncommonfinding in the general population but represents an importantimaging clue for the diagnosis of NBCCS (Fig. 5) [2, 25].The incidence of bony bridging of the sella in the generalpopulation on several radiographic and autopsy seriesranges from 1.54% to 5.9% [25]. In patients with NBCCS,Kimonis et al. [3] reported the incidence of sellar osseousbridging to be as high as 68% in a series of 118 patients.

This finding can easily be identified on brain or maxillofa-cial CT, but is less readily seen on MRI (Fig. 5).

Macrocephaly is more commonly part of a patient’s his-tory provided as indication for brain imaging. In the contextof macrocephaly, it is important to look for ectopic calcifi-cations, bony bridging of the sella or other features compat-ible with NBCCS. The incidence of NBCCS among patientswith macrocephaly is not known. In our cohortof nine children, three had initial brain imaging formacrocephaly.

Basal cell carcinomas are skin lesions that are most likelyto occur between puberty and 35 years of age in patientswith NBCCS. In a series of 105 NBCCS patients, Kimoniset al. [3] reported the incidence of basal cell carcinoma to be80% in Caucasians and 38% in African Americans, poten-tially due to protective effects of skin pigmentation. Skinlesions vary in size and appearance (papules to ulceratingplaques) [2]. In one of our patients, a basal cell carcinoma ofthe scalp was visualised on brain MRI (Fig. 6).

Fig. 6 Skin lesion. Sagittalpostcontrast T1-weightedimages in a 23-year-old with ahistory of medulloblastomaresection at age 3, radiationtherapy, multiple meningiomas(a, arrows) and a skin lesion(b, arrow)

Fig. 7 Bifid ribs. a Chest radiograph AP in an 8-year-old boy with NBCCS and a bifid right 5th rib (arrows). b Three-dimensional reformations ofchest CT in a 7-year-old boy with multiple bifid ribs (white and black arrows)

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Rib anomalies have been reported in 38% of individualswith NBCC, including bifid and fused ribs. The 3rd–5th ribsare most commonly affected [2]. In two of our patients, abifid rib was seen on chest radiograph and spinal CT(Fig. 7). Other skeletal anomalies in patients with NBCCSinclude bifid vertebrae wedges, fused vertebrae and Spren-gel deformity with reported incidence ranging from 10% to40% of patients [2]. Cleft lip/palate is rare in patients withNBCCS with incidence of 4%, and is evident on clinicalexam and imaging modalities, such as maxillofacial CT andbrain/face MRI [3]. In our cohort, one child had a history ofcleft lip and palate.

Adverse outcomes in medulloblastoma patientswith missed diagnosis of NBCCS

The development of secondary tumours after craniospinalradiation for medulloblastoma is a known occurrence inpatients with NBCCS [6, 26]. Multiple meningiomas andbasal cell carcinomas in the radiation field are the mostfrequently reported radiation-induced neoplasms [6, 22,26]. Other less frequently reported tumours include sino-nasal undifferentiated carcinoma (SNUC), astrocytoma, cra-niopharyngioma, oligodendroglioma, schwannoma andliposarcoma [2, 6–9]. However, the exact risk of developingsecondary tumours after craniospinal radiation in NBCCS isunknown. Choudry et al. [6] reported development ofradiation-induced neoplasms in seven of eight patients aftercraniospinal radiation for medulloblastoma. Changes thathave been attributed to radiation therapy with some degreeof certainty by Kimonis et al. [3] are earlier onset of NBCCskin lesions in the radiation field when compared with themean onset of skin lesions in a NBCCS cohort withoutradiation treatment.

In our small cohort, four children presented initially withmedulloblastoma, only one of whom was immediately di-agnosed with NBCCS. He underwent surgical resectionfollowed by chemotherapy. Radiation therapy was avoided.The other three children with medulloblastoma underwentradiation therapy and all of them subsequently developedmeningiomas. Of these three, two died—one developedbasal cell carcinoma of the ear, the other had neuroendocrinecarcinoma of the nasopharynx [7]. The third was recentlydiagnosed with glioblastoma multiforme of the posterior fos-sa. Delay in diagnosis of NBCCS ranged from 5 to 9 years(Table 4) after diagnosis of medulloblastoma and was trig-gered by new skin lesions in one child, skin lesions and jawcysts in a second and an unknown trigger in the third.

It is impossible to tell if these complications were causedby radiation therapy or an expression of the disease itself[7]. The child for whom radiation therapy was omitted wasdiagnosed more recently and is much younger than the other

three patients. Therefore, it is unclear if he may still developsimilar lethal complications despite the fact he was notexposed to radiation therapy.

Conclusion

Children who initially present with medulloblastomaand/or odontogenic keratocysts may have NBCCS.Careful evaluation of brain and maxillofacial imagingstudies for ectopic calcifications, bony bridging of thesella and other features can lead to a diagnosis ofNBCCS. The radiologist’s vigilance in image assessmentcan dramatically alter treatment and management, andpotentially significantly improve patients’ long-termclinical outcomes.

Conflicts of interest None.

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