Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome)

Literature and regulatory information updated: 4 October 2026.

Nevoid basal cell carcinoma syndrome, basal cell nevus syndrome or Gorlin–Goltz syndrome—PTCH1- and SUFU-related forms, the question of PTCH2 and 9q22.3 microdeletion syndrome

0. Initial Reference Table

1. Introduction

Nevoid basal cell carcinoma syndrome is an autosomal dominant tumour predisposition syndrome combining developmental abnormalities—macrocephaly, facial dysmorphism, rib and vertebral abnormalities, ectopic dural calcification—with benign and malignant tumours arising from tissues in which Hedgehog signalling is crucial: skin basal cell carcinomas, odontogenic jaw keratocysts, early childhood medulloblastoma, and ovarian and cardiac fibromas [1, 2]. Reference works estimate frequency at approximately 1 in 50,000–1 in 60,000, while the northwestern England genetics registry found birth incidence of 1 in 18,976 [2, 7, 8]. Life expectancy does not differ significantly from the general population; morbidity mainly reflects cumulative multiple skin excisions, particularly facial, and repeated jaw surgery [1].

Early descriptions include Binkley and Johnson's 1951 clinical and autopsy study associating “adenoid cystic epithelioma” (basal cell naevi), corpus callosum agenesis and dental cysts [8]. Robert J. Gorlin, a University of Minnesota geneticist and oral pathologist, and dermatologist Robert W. Goltz recognised the wider malformation pattern in their 1960 New England Journal of Medicine article “Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome”. It defined the classic triad of multiple basal cell epitheliomas, jaw cysts and bifid ribs and established the association's syndromic, hereditary nature [8, 23]. Gorlin subsequently expanded the spectrum to palmoplantar pits, falx calcification, medulloblastoma and ovarian fibromas, publishing reviews that informed clinical diagnosis [24].

Two population studies established the still-used criteria: Evans and colleagues' 1993 population-based study in northwestern England and Kimonis and colleagues' 1997 series of 105 patients seen at the US National Institutes of Health (NIH) [9, 10]. In 1996, Hahn and colleagues (Cell) and Johnson and colleagues (Science) nearly simultaneously identified loss-of-function variants in the human homologue of the Drosophila segment polarity gene patched, placing Hedgehog at the centre of hereditary and sporadic BCC biology [25, 26]. The 2011 First International Colloquium on Basal Cell Nevus Syndrome revised diagnostic criteria and proposed surveillance [11]. In 2014, Smith and colleagues showed germline SUFU variants causing classic syndrome without keratocysts, with gene-dependent medulloblastoma risk—below 2% in PTCH1 and up to approximately 20-fold higher in SUFU—redefining childhood neurological surveillance [2, 27]. Pathway understanding led to oral SMO inhibitors vismodegib (FDA-approved 2012) and sonidegib (2015), also tested in syndrome patients [13, 14, 28].

2. Molecular Genetics and Pathophysiology

2.1 Hedgehog signalling

Hedgehog regulates embryonic cell proliferation and differentiation and adult skin, hair follicle and cerebellar stem cell homeostasis. Secreted ligands (Sonic, Indian and Desert hedgehog; SHH, IHH and DHH) bind transmembrane receptor PTCH1. Without ligand, PTCH1 transports cholesterol, depleting the outer membrane leaflet and maintaining Smoothened (SMO) inactive. Ligand binding suppresses this activity, activating SMO in the primary cilium; transcription factors GLI (GLI1, GLI2 and GLI3) are released from inhibitory SUFU complexes, enter the nucleus and activate pathway targets including GLI1 and PTCH1 [1, 6]. SUFU is the main cytoplasmic inhibitor: it retains GLI1, GLI2 and GLI3 and, in the cilium, recruits GSK3B kinase to promote GLI3 processing into its repressor form [1]. PTCH1 or SUFU loss therefore produces constitutive GLI-dependent transcription at different cascade points, with treatment implications: SMO inhibitors act downstream of PTCH1 and upstream of SUFU, theoretically making them ineffective in SUFU-loss-driven tumours [12, 29].

2.2 PTCH1

PTCH1 lies at 9q22.32 and encodes an integral membrane protein with 12 transmembrane domains, two extracellular loops and a sterol-sensing domain; human cells have at least three isoforms [1]. It is a tumour suppressor: patients' BCCs, keratocysts and medulloblastomas show PTCH1 loss of heterozygosity, a second somatic event in the normal allele. Congenital malformations (in approximately 5%) are attributed to dosage changes in a protein-level-sensitive pathway [1, 2]. More than 500 individuals with PTCH1-related disease have been described [1, 30].

Truncating variants (nonsense, frameshift and splicing) distributed throughout the gene predominate, with missense variants a minority. Sequencing detects 50–85% of variants in PTCH1-related probands, while deletion/duplication analysis (MLPA or equivalent) adds 6–21%; partial or whole-gene deletions account for approximately 6% of cases [1, 8]. Deep intronic variants creating cryptic splicing sites require RNA analysis or sequencing covering these regions. Strong clinical suspicion with negative conventional sequencing warrants laboratories offering PTCH1 RNA analysis [1, 31, 32]. At referral centres, overall detection in clinically diagnosed patients is approximately 70%: Manchester identified pathogenic PTCH1 variants in 134 of 193 (69.4%), SUFU in 11 (5.7%) and none in 48 (24.9%) [12].

2.3 SUFU

SUFU, at 10q24.32, encodes suppressor of fused. ClinGen dosage curation assigns haploinsufficiency score 3 (sufficient evidence) and triplosensitivity 0, consistent with tumour suppression [1]. Germline variants were first associated with paediatric medulloblastoma in 2002, and shown to cause classic Gorlin syndrome in 2014: among Manchester PTCH1-negative families, three had SUFU variants (a nonsense variant detected by exome, another by Sanger sequencing and a large MLPA-detected deletion). All met criteria, none had keratocysts, and each included medulloblastoma, versus only 2 of 115 PTCH1 carriers (1.7%) [27, 33]. By 2024, 176 heterozygous germline SUFU carriers had been described; median molecular diagnosis age was 4.5 years, with 13.4% de novo variants [1, 33].

Heterozygous germline SUFU variants also occur in a neurodevelopmental phenotype at the mild end of Joubert syndrome, with congenital ocular motor apraxia attributed to haploinsufficiency; tumour-syndrome manifestations have not yet been reported in these patients [1, 34]. A Finnish family with familial multiple meningiomas had a loss-of-function SUFU variant, with ovarian and basal cell tumours in some members [35]. Isolated sporadic medulloblastoma or BCC may harbour somatic SUFU or PTCH1 variants absent from the germline; this does not represent hereditary predisposition [1].

2.4 PTCH2: an unconfirmed gene

PTCH2 (1p34.1) is a more restricted PTCH1 paralogue not essential for viability. Isolated reports—a missense variant in a Chinese family and a frameshift in a 13-year-old girl with keratocysts and rib abnormalities—suggested association [36, 37]. Contrary evidence is consistent: a healthy woman homozygous for a PTCH2 frameshift was reported; no pathogenic variants were identified in 21 PTCH1-/SUFU-negative Gorlin families; none of the published variants meets pathogenicity criteria; and loss-of-function variants, including healthy homozygotes, are common in the population [4, 38]. ClinGen rates the association “limited”, OMIM assigns no germline phenotype, GeneReviews restricts molecular diagnosis to PTCH1 and SUFU, and the Dutch guideline strongly recommends against PTCH2 testing because of insufficient evidence [1, 4, 6]. Somatic PTCH2 alterations in some sporadic BCCs and medulloblastomas do not establish hereditary predisposition [29].

2.5 9q22.3 microdeletion syndrome

Nonrecurrent contiguous 9q22.3 deletions encompassing PTCH1 (352 kb critical region including FANCC and adjacent genes) cause Gorlin manifestations with developmental delay or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, pre- and postnatal macrosomia, seizures and increased Wilms tumour risk; severity partly depends on deletion size [1, 8]. The Oxford Desk Reference recommends genomic microarray for developmental delay because PTCH1 or SUFU deletions occur in some patients [2]. PTCH1 and SUFU variants have been reported in nonsyndromic holoprosencephaly but not replicated in several large cohorts, leaving the association unestablished; a Brazilian case of alobar holoprosencephaly with severe ocular and cutaneous involvement was attributed to a PTCH1 variant in a girl born to consanguineous parents [1, 39].

2.6 Mosaicism, modifiers and genotype–phenotype correlations

Some blood-negative patients have postzygotic mosaicism: the same PTCH1 variant in two or more independent tumours, absent from leucocyte DNA (or with allele fraction below 50%), confirms mosaicism [1, 40]. The Oxford Desk Reference and Smith's Recognizable Patterns note that the first affected family member may have milder signs for this reason and recommend testing at least two different tumours in blood-negative de novo cases [2, 8]. Among 182 Manchester patients, identified variant carriers were diagnosed earlier and had more keratocysts, bifid ribs and skeletal abnormalities; PTCH1 missense carriers were diagnosed later and less likely to develop ten or more BCCs and keratocysts [41]. BCC number does not correlate with variant type or sex [42]. Common MC1R variants linked to red hair and skin type I (e.g. rs1805007) lower BCC onset age, explaining part of familial skin-severity clustering [1, 43].

3. Clinical Spectrum and Manifestations by System

3.1 Overview and gene-specific frequencies

Presentation is strongly age-dependent: macrocephaly is the first sign, present at birth; congenital skeletal abnormalities emerge radiologically; keratocysts appear from late in the first decade; palmoplantar pits and falx calcification accumulate in the second; BCCs proliferate from puberty [1, 2]. The table combines GeneReviews gene-specific frequencies (based on Evans 2017) with classic clinical series.

3.2 Skin

BCCs give the syndrome its name. Brown, pink or orange basal cell naevi may appear in early childhood and remain quiescent for years; actual BCCs rarely occur before puberty, although reported at 2 years, and usually arise between puberty and 35 years, with mean age approximately 20 [1, 8]. Lesions are raised, 1–10 mm, pearly, skin-coloured or light brown, most common on the face and sun-exposed areas but also affecting the trunk and unexposed skin. They may arise from pre-existing naevi or apparently normal skin, scale, bleed, ulcerate or present as local infection [1, 2]. Numbers range from a few to many hundreds: excluding irradiated patients in the NIH series, White individuals had 1 to more than 1000 BCCs (median 8), and African Americans 1–3 (median 2) [10]. Frequency increases with age—51.4% above 20 and 72% above 40 in Smith's—but approximately 10% never develop a BCC [1, 8]. Among 202 Manchester patients, cumulative BCC incidence was 13% in men and 12% in women at 20, and 80% and 76.5% respectively at 50, with median first-BCC age 33 [12, 42]. Skin phototype I and excessive ultraviolet exposure markedly increase lesion number; some show radiosensitivity with numerous BCCs in irradiated fields [1]. Prepubertal behaviour is usually indolent; thereafter growth, ulceration, bleeding or crusting warrants concern [8].

Other skin findings include palmoplantar pits, small circular 1–2 mm depressions in thick palm and sole skin, present in 65–80%, age-dependent and more visible after 10–15 minutes in warm water as white excavated depressions or pink dots [1, 2, 8]. Facial milia (52% in Smith's), epidermoid cysts, eyelid meibomian cysts, sebaceous and dermoid cysts, basaloid follicular hamartomas and cervical skin tags are also frequent; the latter resemble BCC histologically without aggressive behaviour [1, 6, 8].

3.3 Jaws and oral cavity

Odontogenic keratocysts — termed "keratocystic odontogenic tumours" in the 2005 World Health Organization (WHO) classification and again "odontogenic keratocysts" since 2017, a term retained in the 5th edition of 2022, which devotes a section to familial tumour syndromes of the head and neck — are the most frequent sign of the PTCH1 form and often the first to prompt diagnosis [12, 44]. They affect the mandible and maxilla, may appear from age 5, peak in adolescence (mean age at onset about 15 years) and rarely appear after age 30 [1, 8]. Age-dependent penetrance is 80% by age 20 and over 90% by age 40 [2]. They present as painless swellings, visible on orthopantomography as radiolucent areas, and, if untreated, cause marked tooth displacement and mandibular fractures; they recur after curettage in 15.4–50% of cases, with a mean time to recurrence of 32 months [1, 6, 8]. They have not been described in the SUFU form [1, 27]. Ameloblastoma, a rare transformation of a keratocyst, has been described at least six times [1, 45]. Malformed or carious teeth, prognathism (33%) and coronoid process hyperplasia complete the oral picture [8].

3.4 Skull, face and eyes

Macrocephaly is the first recognisable sign: many newborns have head circumference above the 97th percentile, a substantial proportion are delivered by caesarean section for cephalopelvic disproportion, and postnatal head growth resembles arrested hydrocephalus, maintaining its percentile from 10–18 months; hydrocephalus requiring treatment is rare [1]. Facial features include frontoparietal bossing (66%), a broad nasal root (59%), prominent supraorbital ridges, thick and sometimes confluent eyebrows, mild hypertelorism and prognathism. Features become more evident after puberty and are subtler in SUFU forms [1, 8]. Ocular abnormalities include strabismus (63%), congenital cataract (18%), nystagmus (9%), colobomas (9%) and less frequently orbital cyst, microphthalmia, congenital glaucoma, myelinated nerve fibres and retinal pigment epithelium changes [1, 6, 8].

3.5 Skeleton

Rib abnormalities (bifid, fused, widened or partially absent ribs) occur in approximately 60%, and thoracic or cervical vertebral abnormalities in approximately 40% [1, 8]. Sloping narrow shoulders (41%), scoliosis, Sprengel deformity, pectus excavatum or carinatum, short metacarpals (especially the fourth), pre- or postaxial polydactyly, immobile thumbs, pseudocystic “flame-shaped” lytic phalangeal, metacarpal and carpal lesions (30% in NIH series), and sacral lumbarisation are described [8, 10]. The NIH series did not confirm significant increases in short fourth metacarpal, scoliosis, cervical ribs or spina bifida occulta, previously considered syndrome components [10]. Severe multiple-costovertebral skeletal defects and open spina bifida are uncommon [1].

3.6 Central nervous system

Ectopic dural calcification is an important radiological marker: lamellar falx cerebri calcification affects more than 90% by 20 and 90% by 30, rarely detectable in early childhood; falx cerebelli calcification occurs in approximately 40%, petroclinoid ligament calcification in 20%, and sella turcica bridging in 60–80% [1, 2, 8]. Medulloblastoma, an embryonal cerebellar tumour, occurs in approximately 5% of all syndrome children, peaking at 1–2 years (mean approximately 2.5 in Oxford Desk Reference) versus 7 years in sporadic disease. It is more frequent in males (3:1), usually desmoplastic/nodular and of the SHH molecular subgroup [1, 2, 46, 47]. Risk is strongly gene-dependent (3.9). Syndrome-associated desmoplastic medulloblastoma generally has favourable prognosis, but recurrence despite standard treatment occurs [1, 48]. Meningiomas affect approximately 2% of PTCH1 patients and 11–30% of SUFU carriers, particularly after radiotherapy [1, 33]. Corpus callosum agenesis, vermian dysgenesis, hydrocephalus and anosmia are occasionally reported [8]. A 2026 Portuguese report (Unidade Local de Saúde de Santo António, Porto) described a 10-year-old girl with genetically confirmed PTCH1 syndrome and lifelong anosmia, absent olfactory function on psychophysical and electrophysiological testing, bilateral olfactory bulb hypoplasia on MRI and exclusion of hypogonadotropic hypogonadism, distinguishing Kallmann syndrome. This single case supports an association without estimated frequency [49]. Some motor delay is common, resolving by 5 years; psychometric evidence of global delay is absent, but the Dutch guideline cites intellectual disability in 4–21% of cohorts and recommends developmental surveillance [1, 6].

3.7 Heart, gonads and other organs

Cardiac fibromas occur in approximately 2% (3–5% in Dutch guidance), usually present at birth or in the first months, and may be asymptomatic or cause arrhythmias, outflow obstruction or heart failure; late diagnosis up to 60 years is reported [1, 6, 12]. Ovarian fibromas affect approximately 20% of women (6–60% depending on series and detection; 17% with systematic NIH ultrasonography, mean age 30), often bilateral, calcified and multinodular. They may cause adnexal torsion but apparently do not affect fertility; malignant transformation is rare [1, 6, 10]. Gonadal teratoma and testicular fibrosarcoma occur in SUFU forms, and male hypogonadism occasionally [1, 8]. Rare lymphomesenteric and pleural cysts tend to calcify and are usually asymptomatic [1, 8]. Other occasional manifestations include renal abnormalities (horseshoe kidney, unilateral agenesis, pelviureteric duplication), subcutaneous calcification, deep voice in women and marfanoid habitus [6, 8].

3.8 Other tumours

No increase in the risk of other malignancies has been demonstrated [1]. Isolated cases of lymphoma, chronic lymphocytic leukaemia, melanoma, rhabdomyosarcoma, thyroid carcinoma, breast and lung cancer, eyelid carcinomas, hepatic mesenchymal tumour and fetal tongue rhabdomyoma have been described, without an established relative risk [1, 8, 12]. Early-onset breast cancer and leiomyosarcoma have been reported in SUFU carriers [1].

3.9 Gene-specific distinction: PTCH1 and SUFU

PTCH1 disease represents the classic phenotype: keratocysts in approximately 90%, recognisable facial features in 60%, multiple BCCs from the second or third decade and medulloblastoma risk below 2% [1, 27]. Manchester found medulloblastoma in only 2 of 115 PTCH1 carriers (1.7%); Dutch guidance estimates 1.2%–2.4% [6, 27].

SUFU disease is generally milder—subtler face, fewer BCCs, no keratocysts—but with a distinct tumour profile and reduced penetrance [1, 41]. Medulloblastoma estimates vary with ascertainment: up to 33% (3 of 9) among Manchester Gorlin-criteria carriers; 13.3% cumulative risk by 50 among carrier relatives (Nelson–Aalen estimator to reduce ascertainment bias) in the 172-carrier SIOPE Host Genome Working Group cohort; and 7–9.2% in a population estimate combining medulloblastoma incidence and gnomAD SUFU frequency [1, 12, 50]. Among 172 carriers, 68% developed at least one tumour—medulloblastoma (86 patients), BCC (25), meningioma (20) and gonadal tumours (11)—at median ages 1.5, 40, 44 and 14 respectively. Cumulative tumour incidence in carrier relatives was 14.4% at 5, 18.2% at 20 and 44.1% at 50; age-50 cumulative risks were 13.3% for medulloblastoma, 28.5% BCC, 5.2% meningioma and 4.6% gonadal tumour [50]. In the 176-carrier scoping review, commonest tumours were medulloblastoma (59 patients, median 1.42 years, range 1 month–3 years), BCC (21) and meningioma (19) [33]. Some carriers present solely with meningioma or meningioblastoma without other features [1, 35]. Conversely, only one of 34 SUFU carrier relatives identified through a medulloblastoma case (median age 51.3) had developed BCC [12].

4. Clinical Recognition and Warning Signs

Recognition mainly depends on examination age. The Oxford Desk Reference recommends a three-generation pedigree specifically addressing skin cancer, jaw cysts and large head size, plus previous surgery history. Examination includes head circumference and height to assess relative macrocephaly, mild hypertelorism, frontal bossing and prominent mandible, skin inspection for BCCs, palm examination for pits, and brachydactyly and thumb abnormalities [2]. Its macrocephaly approach recommends asking about early or multiple BCCs and family medulloblastoma with isolated macrocephaly because PTEN and PTCH1 may have few syndromic signs [51].

Warning signs warranting suspicion are: (1) BCC before 20–30 years or a number disproportionate to sunlight exposure and phototype; (2) childhood or adolescent odontogenic keratocysts, particularly multiple or recurrent—dentists and maxillofacial surgeons often first encounter patients [52]; (3) desmoplastic/nodular or SHH-subgroup medulloblastoma before age 5—SIOPE recommends germline PTCH1/SUFU testing in all such cases, with variants in 21% of infant SHH medulloblastomas (17 of 80) and 11% of paediatric cases (18 of 170) [12, 53]; (4) infant cardiac fibroma or bilateral calcified ovarian fibroma, particularly at young ages; (5) macrocephaly with frontal bossing and cleft lip/palate, polydactyly or rib abnormalities; (6) palmoplantar pits; and (7) young-adult lamellar falx calcification, often incidentally detected by CT [1, 6, 11]. An iatrogenic warning sign is multiple BCCs in a radiotherapy field, for example after craniospinal medulloblastoma irradiation, prompting retrospective diagnostic review [1, 54].

Early diagnosis enables avoidance of radiotherapy and unnecessary diagnostic radiation and initiation of gene-appropriate surveillance. Dutch guidance recommends following clinically suspected patients or those with an affected parent as affected until diagnosis is safely excluded [6].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria

No consensus criteria have been validated for their sensitivity–specificity balance. Current criteria derive from Evans and colleagues (1993) and Kimonis and colleagues (1997), revised by Bree and colleagues' 2011 consensus [1, 6]. The Oxford Desk Reference provides the following adaptation (Box 4.8), requiring two major criteria or one major and two minor [2].

GeneReviews uses Evans' original rule: clinical diagnosis with two major and one minor or one major and three minor. Major criteria comprise lamellar falx calcification (or obvious calcification before 20), keratocyst, two or more palmoplantar pits, multiple BCCs (more than 5 lifelong) or one before 30—adjusted for lower dark-skin risk and greater fair-skin risk in sunny climates—and an affected first-degree relative. Minor criteria are medulloblastoma, lymphomesenteric or pleural cysts, macrocephaly (head circumference above the 97th percentile), cleft lip/palate, costovertebral abnormalities, polydactyly, ovarian or cardiac fibromas and ocular abnormalities [1].

The Bree 2011 consensus, adopted by Dutch guidance, allows diagnosis with (1) one major criterion and genetic confirmation, (2) two major criteria or (3) one major and two minor [6, 11].

Promoting medulloblastoma to a major criterion is controversial. GeneReviews warns of reduced specificity because children with sporadic medulloblastoma receiving radiotherapy tend to develop multiple BCCs; restricting the criterion to nodular/desmoplastic medulloblastoma and excluding post-radiotherapy BCCs as major criteria might improve sensitivity without losing specificity. The 2017 American Association for Cancer Research (AACR) consensus did not adopt Bree's criteria [1, 20]. As manifestations appear with age, clinical criteria are more informative in adults than children [1, 55].

5.2 Additional investigations

Confirmation of a clinical diagnosis usually requires frontal and lateral skull radiographs (falx calcification, sellar bridging), panoramic dental radiography (keratocysts, from 7–8 years of age), chest radiography (bifid, fused or widened ribs) and spine radiography (hemivertebrae) [1, 2]. These radiographs should be avoided in children when they are not needed to confirm the diagnosis, and, where earlier radiographs exist, they should be retrieved and reviewed rather than repeated; bifid ribs, bifid vertebrae and falx calcification are often omitted from reports because they are normal variants in the general population [1]. The Dutch guideline recommends (strong recommendation, very low-quality evidence) avoiding, as far as possible, radiological examinations performed solely to fulfil criteria and without therapeutic consequence [6]. Panoramic dental radiography has a low dose (approximately 0.010 mSv), and MRI may replace it where available; cone-beam CT (approximately 0.05 mSv) or conventional CT (approximately 2.1 mSv) is reserved for surgical planning [6]. Histological examination confirms BCC and keratocyst; skin ultrasonography helps to measure lesion thickness before photodynamic therapy [1].

5.3 Genetic testing

A heterozygous pathogenic or likely pathogenic PTCH1 or SUFU variant establishes diagnosis when clinical findings are inconclusive; a variant of uncertain significance neither confirms nor excludes it [1]. Dutch guidance strongly recommends genetic testing for all suspected patients, enabling predictive family testing and gene-specific surveillance [6].

Source: GeneReviews [1].

The combined GeneReviews/Dutch algorithm is: (1) simultaneous PTCH1 and SUFU sequencing and dosage analysis for suspected patients, preferably a dedicated two-gene panel, since broad panels may be less sensitive and omit deletions or PTCH1 RNA analysis; (2) alternatively, sequential testing—PTCH1 first with personal or family keratocysts, SUFU first with medulloblastoma without keratocysts; (3) if both are negative despite strong suspicion, PTCH1 RNA analysis and deep intronic investigation; (4) if still negative, sensitive next-generation DNA sequencing of at least two different BCCs (for PTCH1 and SMO) to detect postzygotic mosaicism; (5) genomic microarray for developmental delay or atypical dysmorphism; (6) exome or genome for atypical phenotypes where the diagnosis was not considered [1, 2, 6]. Germline GPR161 and ELP1 predispose to paediatric medulloblastoma but were absent in 27 clinically diagnosed PTCH1-/SUFU-negative patients [1, 56]. Consider proband DNA banking if molecular confirmation is unavailable [1].

5.4 Presymptomatic diagnosis in children

Clinical examination and radiographs effectively function as a genetic test in apparently unaffected relatives, with the same predictive implications, which patients should understand. They are less informative in young children because manifestations are age-dependent [1]. When the familial variant is known, testing at-risk relatives including children is indicated because surveillance—particularly neurological in SUFU families—begins in the first year [1, 12].

5.5 Genetic test limitations and report content

Sensitivity depends on coverage. Exon and exon–intron boundary sequencing misses single/multiexon or whole-gene deletions (6–21% of PTCH1 variants), requiring MLPA, sequencing-based copy-number analysis or microarray; deep intronic cryptic-exon variants, requiring RNA analysis or targeted genome interpretation; and low blood-allele-fraction postzygotic mosaicism, requiring sensitive sequencing of two or more independent tumours [1, 31, 32, 40]. Consulted sources describe neither repeat expansions nor homology regions limiting PTCH1/SUFU sequencing, unlike pseudogene-associated genes; practical limitations are structural rearrangements, deep intronic variants and mosaicism. Even comprehensive negative testing does not exclude unequivocal clinical diagnosis: approximately one quarter of criteria-positive patients remain variant-negative [1, 12]. Conversely, a PTCH1 or SUFU variant confined to a BCC, keratocyst or medulloblastoma does not prove germline predisposition; constitutional DNA or two independent tumours support diagnosis [1].

Reports should state the gene, versioned reference transcript—PTCH1 NM_000264.5 and SUFU NM_016169.4, both MANE Select—normalised coding-DNA and protein HGVS, zygosity (constitutional heterozygosity; allele fraction for suspected mosaicism), ACMG/AMP classification and supporting evidence, method, coverage (including copy-number and RNA analysis) and limitations [5]. Published literature often uses historical notation: the Azorean family variant “c.290dupA (p.Asn97LysfsX43)” corresponds to NM_000264.5(PTCH1):c.290dup, p.(Asn97Lysfs*43), pathogenic in ClinVar (VCV000650991, multiple concordant submissions) [57, 58]. Both historical and normalised forms with transcript should be provided to enable unambiguous database searches and relative testing.

A VUS is not reclassified as pathogenic because of an SMO-inhibitor response—reflecting Hedgehog dependence shared with sporadic BCC—or presence in one or two affected relatives. Family segregation is investigational and contributes only with ACMG/AMP-assigned weight [1]. PTCH2 variants should not be reported as diagnostic for the reasons in 2.4 [4, 6].

6. Differential Diagnosis

In medulloblastoma, molecular differentiation is decisive: SUFU- or PTCH1-associated tumours belong exclusively to SHH, while germline predisposition in other subgroups involves different genes (e.g. APC in WNT, TP53 in older-child SHH, BRCA2 and PALB2) [12, 53].

7. Treatment and Risk Management Strategies

7.1 Care organisation and initial assessment

Manifestations require specialists experienced in the syndrome (dermatologist, maxillofacial surgeon and dentist, ophthalmologist, orthopaedic surgeon, plastic surgeon, neurosurgeon, paediatric oncologist, gynaecologist), ideally through a multidisciplinary referral-centre clinic; a UK national survey found only 15% under multidisciplinary care [1, 6]. In the EU, ERN GENTURIS thematic group 4 includes the syndrome, with providers available for referral and complex-case discussion; Section 0 patient organisations provide family educational material [22]. Recommended postdiagnosis assessments are: baseline head circumference preferably on a height-adjusted chart, investigating hydrocephalus with rapidly rising percentiles; ophthalmology (strabismus, cataract, orbital cyst, microphthalmia, retinal pigment changes, intraocular pressure where possible); examination for clinically relevant malformations (orofacial clefts, spine abnormalities, polydactyly); dermatologist skin examination; dentist or orthodontist assessment with panoramic dental radiography from 8 years; first-year echocardiography (ideally within 6 months) to exclude cardiac fibroma; ovarian ultrasound at 18; patient and family psychological assessment; and genetic counselling [1, 6, 12]. GeneReviews also includes initial contrast brain MRI, while Dutch guidance considers it unnecessary with adult diagnosis [1, 6].

7.2 BCC prevention and treatment

Prevention requires avoiding direct sunlight, particularly midday, covering skin with long sleeves, high collars, caps and hats, and regular broad-spectrum sunscreen; discuss photoprotection at every visit [1, 2, 6]. BCCs are less frequent in dark skin and far more abundant on sun-exposed areas [2]. Early treatment eradicates aggressive lesions and preserves normal tissue, avoiding facial disfigurement [1].

According to the 2023 European guideline (EADO, EDF, ESTRO, UEMS and EADV) and the Dutch guideline, surgical excision is the first-line treatment; Mohs micrographic surgery is preferred for high-risk and recurrent lesions and for lesions in critical anatomical areas such as the face [1, 6, 21]. Because multiple excisions leave numerous scars and carry a psychological burden, non-surgical therapies are useful alternatives for superficial and low-risk lesions: photodynamic therapy (with methyl aminolevulinate, according to consensus recommendations specific to Gorlin syndrome, suitable for lesions less than 2 mm thick on ultrasonography), cryotherapy, laser for early lesions, topical 5-fluorouracil (useful in superficial multicentric BCC without follicular involvement, not indicated for deep infiltrative lesions) and imiquimod 5% cream [1, 21, 60]. For biopsy-confirmed superficial BCC with a maximum diameter of 2 cm on the trunk, neck or extremities (excluding the hands, feet and anogenital region), the imiquimod 5% label specifies application once daily at bedtime, five times per week, for six full weeks, leaving the cream on the skin for approximately 8 hours; the European SmPC for Aldara® specifies the same regimen [61, 62]. One review reported control rates close to 90% with imiquimod in superficial BCC and approximately 50% in aggressive or nodular BCC [1]. Systemic retinoids (for example etretinate) are a possible option but are poorly tolerated [1].

7.3 Radiotherapy and ionising radiation

Radiotherapy is relatively contraindicated: most—but not all—families develop multiple new BCCs in irradiated fields, sometimes thousands, with additional high postirradiation meningioma risk in SUFU carriers [1, 2, 6]. Avoid it where alternatives exist, particularly in childhood; if no other modality is possible, use the fewest skin entry fields [1]. Use diagnostic radiography sparingly, avoid CT where MRI is an alternative, and minimise environmental radiation [1, 2]. Previously irradiated patients require earlier dermatological surveillance and prolonged follow-up for secondary meningioma, BCC and thyroid carcinoma [12].

7.4 Hedgehog pathway inhibitors

Vismodegib and sonidegib are small oral molecules binding SMO and blocking signalling downstream of PTCH1, restoring inhibition absent in PTCH1-loss BCC [1, 29]. Both are approved for adult advanced BCC, neither specifically for Gorlin syndrome or prevention of new BCCs. Syndrome use outside advanced disease is off-label, supported by Tang and colleagues' trials [13, 14, 28, 63].

In pivotal ERIVANCE BCC, vismodegib 150 mg/day produced independently assessed objective responses in 30% of 33 metastatic and 43% of 63 locally advanced patients (21% complete responses), with median response duration 7.6 months [64]. BOLT found sonidegib 200 mg/day responses in 43% of locally advanced and 15% of metastatic patients, with fewer interruptions and discontinuations than 800 mg. At final 42-month analysis, central-review 200 mg response rates were 56% locally advanced and 8% metastatic [65, 66].

In Gorlin syndrome, Tang and colleagues' randomised double-blind placebo-controlled phase 2 trial (41 patients, NCT00957229) showed vismodegib 150 mg/day reducing new surgically eligible BCCs from 29 to 2 per patient-year and existing size by 65% (versus 11% placebo). Of biopsied clinically regressed sites, 83% lacked residual tumour, but 54% (14 of 26) discontinued for adverse effects [28]. At final 36-month analysis, reduction persisted (2 versus 34 new BCCs per patient-year), but only 3 of 18 (17%) tolerated continuous treatment for 36 months. Continuous treatment exceeded interrupted treatment efficacy (0.6 versus 1.7 new BCCs per patient-year), and stopping was followed by recurrence [63]. In six keratocyst patients, 18 months of vismodegib reduced largest diameter by a mean 50% without new cysts [67]. Vismodegib benefits periocular BCC where surgery threatens function [1, 68]. Some vismodegib-intolerant syndrome patients tolerated sonidegib [69]. Dutch guidance considers oral inhibitors for multiple BCCs (moderate evidence, strong recommendation), stressing adverse effects and postcessation recurrence preclude lifelong use; GeneReviews reports UK NICE considered vismodegib not cost-effective [1, 6]. A Portuguese-authored systematic review (31 publications, 351 syndrome patients, mean age 52) estimated complete response 44% with vismodegib, mean duration 9.3 months in those stopping and 25.1 in those continuing, with interruptions mainly from adverse effects (69.1%) and secondary resistance (9.1%). Predominantly uncontrolled series and cases with heterogeneous response definitions describe published experience rather than replace randomised evidence [70].

Evidence extrapolation applies findings from another population to a syndrome patient—for example ERIVANCE and BOLT advanced-BCC response rates rather than new-BCC prevention. Off-label use is defined by jurisdictional label wording: US vismodegib covers metastatic or locally advanced recurrent BCC or disease unsuitable for surgery and radiotherapy, sonidegib only locally advanced disease; EU vismodegib requires symptomatic metastasis or locally advanced disease unsuitable for surgery/radiotherapy, sonidegib locally advanced disease unsuitable for curative surgery/radiotherapy [13–16]. Oral inhibitors for multiple resectable syndrome BCCs to reduce tumour or surgical burden are therefore off-label in both, despite Tang trial support [28, 63]. Both paediatric labels lack established safety/efficacy and describe premature epiphyseal fusion, making any childhood use off-label and practically discouraged [13, 14]; pregnancy use is contraindicated for embryofetal toxicity [13, 14]. Against SUFU-associated medulloblastoma, the objection is also mechanistic: SUFU loss is downstream of SMO, predicting ineffectiveness [12, 29].

Adverse effects are class-related. The vismodegib label (138 advanced-BCC patients) lists muscle spasms (72%), alopecia (64%), dysgeusia (55%), weight loss (45%; grade 3 in 7%), fatigue (40%), nausea (30%), diarrhoea (29%), decreased appetite (25%), constipation (21%), arthralgia (16%), vomiting (14%) and ageusia (11%); amenorrhoea in reproductive-age women and childhood premature epiphyseal fusion progressing after cessation are reported [13]. Sonidegib commonly causes muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhoea, weight loss and elevated CK; BOLT permanent discontinuation and interruption for adverse effects were 34% and 20% [14]. Management includes advance counselling, scheduled interruptions (reducing efficacy), nutritional support and weight surveillance, plus sonidegib CK/renal monitoring; an exploratory syndrome study evaluated calcium-channel blockade for vismodegib cramps [14, 63, 71]. Both are contraindicated during pregnancy and in growing children [13, 14].

In patients with locally advanced or metastatic BCC who progress on, are intolerant of or are not candidates for Hedgehog pathway inhibitors, the European guideline proposes the anti-PD-1 antibody cemiplimab (Libtayo®) as second-line therapy; the FDA label specifies 350 mg as a 30-minute intravenous infusion every 3 weeks until progression, unacceptable toxicity or 24 months; the European SmPC specifies the same dose and route, without the 24-month limit (treatment until progression or unacceptable toxicity) [21, 72, 73]. Specific experience in Gorlin syndrome is limited to isolated cases.

7.5 Investigational treatments

Patidegib (cyclopamine derivative, also IPI-926 or saridegib) was formulated topically to achieve adequate skin concentrations without oral inhibitor systemic effects. A UK phase 2A study applying 2% or 4% gel to the face twice daily for 6 months suggested reduced new surgically eligible BCCs and Hedgehog signalling in post hoc analyses, with very low systemic levels and minimal adverse effects [74]. Multicentre randomised double-blind vehicle-controlled phase 3 SGT-610-01 (NCT06050122; 113 adults; 2% gel or vehicle for 12 months; primary endpoint: new facial BCC count at 12 months) reached primary completion on 20 August 2026 and completion on 14 September 2026, without registry results [17]. Sponsor Securities and Exchange Commission (SEC) announcements report 102 of 113 completing, maintained blinding in September 2026 and topline results expected late November 2026; orphan and breakthrough therapy designations are sponsor-reported [18, 75]. Until results are published—first announcement, then peer-reviewed article—and potential regulatory decision, patidegib remains experimental and unauthorised anywhere. European single-arm phase 2 SIBLINGS (EU CT 2024-515989-14-00) tests sonidegib 200 mg/day for 16 weeks followed by intermittent 2 weeks on/2 off, with discontinuation as primary endpoint; only a non-peer-reviewed protocol preprint exists [76]. Aminolevulinic acid photodynamic treatment and other topical applications remain under study [1].

7.6 Odontogenic keratocysts

Keratocysts usually require surgical excision, balancing eradication given recurrence risk against jaw growth and tooth preservation. Individualised conservative marsupialisation followed by enucleation reduces paediatric surgical trauma, illustrated by a Brazilian case without recurrence at 32 months [1, 12, 52]. Inform the dentist of confirmed or suspected diagnosis [2].

7.7 Medulloblastoma, meningioma and other manifestations

Medulloblastoma requires neurosurgical and paediatric oncology care; prior syndrome recognition is decisive because craniospinal irradiation produces extensive radiation-field BCCs and SUFU meningiomas [1, 2, 12]. Syndrome-associated desmoplastic medulloblastoma may be treated with intensive chemotherapy, avoiding radiotherapy where possible [48, 54]. SMO inhibitors theoretically do not act in SUFU-loss tumours and cause childhood epiphyseal fusion, so are not standard infantile medulloblastoma treatment [12, 13]. Asymptomatic cardiac fibromas may be monitored by paediatric cardiology; obstruction, arrhythmia or failure require excision [1, 6]. Ovarian fibromas requiring surgery should be removed with ovarian tissue preservation, accepting recurrence risk; asymptomatic surgery is discouraged because of reduced fertility or premature menopause [1, 6]. Macrocephaly rarely requires hydrocephalus treatment; orofacial clefts follow craniofacial team protocols, and skeletal abnormalities (scoliosis, Sprengel) orthopaedic care [1].

7.8 Surveillance

Recommendations differ particularly for medulloblastoma, meningioma and ovarian fibromas but converge on gene stratification. All are expert consensus without trials demonstrating survival benefit [1, 6, 12].

Sources: [1, 6, 12, 20].

The Oxford Desk Reference summarises British practice: annual or more frequent skin surveillance from 12, annual panoramic dental radiography from 8, medulloblastoma MRI investigation avoiding CT, and radiotherapy avoidance [2]. Infant MRI often requires general anaesthesia, whose neurodevelopmental effects remain debated, and causes family anxiety, contributing to the decision against routine PTCH1 screening [6, 12]. Clinical follow-up therefore relies on informing parents about medulloblastoma warning signs (morning vomiting, headache, ataxia, motor regression, rapidly increasing head circumference) and immediate symptomatic MRI [12].

7.9 Pregnancy

Affected fetuses frequently have increased head circumference; assess the need for early labour induction or caesarean section for cephalopelvic disproportion [1]. SMO inhibitors are teratogenic and contraindicated; the vismodegib label requires exclusion of pregnancy within 7 days before initiation and effective contraception during treatment and after the last dose (24 months vismodegib, 20 months sonidegib), discouraging breastfeeding for the same interval [13, 14].

7.10 Comparative regulatory status and trial interpretation

No medicine is authorised specifically for Gorlin syndrome or BCC prevention in the US or EU. Authorised drugs cover advanced or superficial BCC generally; syndrome use follows 7.4. The table distinguishes initial approval from current indications; none has a paediatric indication [13–16, 61, 72, 77, 78].

Sources: FDA labels and registries (Drugs@FDA/openFDA) and EMA medicines data file, accessed 4 October 2026 [13–16, 61, 72, 77–79].

Evidence hierarchy matters. Tang's trial is the only randomised peer-reviewed evidence in the syndrome; phase 3 patidegib data until November 2026 comprise ClinicalTrials.gov registration and sponsor announcements without efficacy results. Positive CHMP opinion precedes but does not replace Commission authorisation, and centralised authorisation guarantees neither national marketing, reimbursement nor access—dependent on INFARMED in Portugal—nor ANVISA registration or CONITEC SUS incorporation in Brazil [15–18, 28, 63].

These trials cannot rank drugs. ERIVANCE and BOLT measured advanced-BCC objective response in different populations (BOLT primary efficacy excluded incompletely evaluable locally advanced disease) without head-to-head comparison; matching 43% locally advanced responses or differences between 30% and 15% metastatic responses do not validly compare vismodegib and sonidegib [64–66]. Tang measured a different outcome, new surgically eligible BCC incidence as a mean patient-year rate, not an individual's expected count. Relative reduction is large, but half could not tolerate treatment, only 17% maintained continuous dosing for 36 months, and cessation led to recurrence; residual rate depends mainly on adherence [28, 63]. Patidegib phase 2A efficacy signals arise from hypothesis-generating post hoc analyses rather than proof [74]. SIBLINGS tests intermittent sonidegib in adults aged 18–50 with syndrome or difficult-to-treat sporadic BCC, with discontinuation rather than efficacy as primary endpoint [76].

8. Reproductive Options and Family Counselling

The syndrome follows autosomal dominant inheritance, and each child of an affected individual has a 50% chance of inheriting the variant [1, 2]. Approximately 70–80% of probands have an affected parent, whereas 20–30% have a de novo variant; the Oxford Desk Reference reports 35–50% de novo cases and the Dutch guideline 20–40%, reflecting differences in ascertainment [1, 2, 6]. In SUFU-related disease, 73% of variants were inherited among cases in which inheritance could be assessed [50].

Assessment of the parents of an apparently isolated case should include a detailed skin examination, skull radiographs (anteroposterior and lateral), chest and spinal radiographs, and molecular testing if the proband's variant is known [1]. An apparently negative family history requires parental assessment, since the syndrome may have gone unrecognised, a parent may have died before manifestations developed, or reduced penetrance (SUFU-related disease) or somatic mosaicism may produce a mild phenotype [1]. If neither parent carries the variant in blood, the sibling recurrence risk is estimated at approximately 1% because of possible germline mosaicism, by analogy with other dominant disorders; if the parents are clinically unaffected but untested, the risk is low but exceeds the population risk [1]. Children of an individual with a mild syndrome due to somatic mosaicism may have a less than 50% chance of inheriting the variant, but a child who inherits it has the full constitutional form [1, 40].

Predictive testing requires identification of the familial variant. Since surveillance begins in childhood and is particularly consequential in SUFU families, determining the genetic status of children at risk is appropriate; many parents wish to know the result before investigations begin, to avoid unnecessary procedures in a child who has not inherited the variant. Testing should be preceded by formal counselling, a plan for communicating results to parents and children, and discussion of psychosocial and socioeconomic implications [1, 12]. Children's participation, including that of young children, should be age appropriate, and relatives' right not to know should be respected [12].

Once the familial variant is known, prenatal diagnosis (chorionic villus sampling or amniocentesis) and preimplantation genetic testing are possible [1, 2]. Views on prenatal diagnosis for pregnancy termination may differ among professionals and within families, particularly for a disorder with near-normal life expectancy; most centres regard this as a personal decision [1]. Genetic risk and reproductive options are best discussed before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. Under the Dutch guideline, the clinical geneticist reviews the patient at diagnosis, during transition to adult care, and whenever family planning decisions arise [6]. Men and women receiving SMO inhibitors require specific contraceptive counselling, including condom use by men even after vasectomy [13, 14].

For isolated tumours with a somatic PTCH1 or SUFU variant and no other features of the syndrome, counselling should explain that the predisposition is not hereditary; confirming or excluding germline origin, for example in blood or normal-tissue DNA, determines the implications for patient and family management [1].

9. Special Considerations: Population Diversity and Epidemiology

Prevalence estimates depend on the method used. The North West England genetic register found a birth incidence of 1 in 18,976 (5.3 per 100,000) and a point prevalence of 1 in 30,827 (3.2 per 100,000), which Orphanet records as validated figures; GeneReviews cites these numbers as a range, although they represent different measures [1, 3, 7]. Orphanet also records 2.0 per 100,000 in Europe (a 2018 European Medicines Agency estimate), 1.1 per 100,000 worldwide, 0.61 per 100,000 in Australia and 0.39 per 100,000 in Italy [3]. A more recent estimate of the birth incidence of the clinical syndrome is 1 in 14,963, and the frequency of pathogenic PTCH1 variants in gnomAD (approximately 1 in 3356) suggests that many carriers never receive a clinical diagnosis; the estimated population frequency for SUFU is 1 in 41,395 (1 in 55,400 among non-Finnish Europeans) [12]. The true prevalence is probably higher than recorded, as patients with mild phenotypes may remain unrecognised [1].

Cutaneous expression depends on skin phototype and sun exposure, illustrating gene–environment interaction. In the NIH series, 80% of White patients and 38% of African American patients had at least one BCC, with median lesion counts of 8 and 2, respectively [10]. A Japanese nationwide survey identified 311 patients and characterised 157; BCC frequency above 20 years of age was 51.4%, compared with 91% in the United States, 85% in Australia and 73% in the United Kingdom, and the mean age at first BCC was 37.4 years, supporting prolonged skin surveillance in Asian patients [80]. Conversely, keratocyst frequency in the Japanese series (86%) was similar to or higher than that in Western series (75% in the Australian and 74% in the US series) [12]. The recorded prevalence in South Korea is very low (approximately 1 in 14 million), probably reflecting underdiagnosis [3, 81]. Patients with dark skin may have few or no BCCs, with diagnosis instead based on keratocysts, palmoplantar pits, calcifications and medulloblastoma; the GeneReviews criteria explicitly allow this adjustment [1, 54]. MC1R variants associated with red hair confer earlier BCC onset [43].

The literature consulted describes no PTCH1 or SUFU founder variants of appreciable population frequency, unlike some other tumour predisposition syndromes. No population prevalence studies were identified for Brazil, Portugal, Latin America, Africa or the Middle East; the available case reports and hospital series describe patients seen at individual centres and cannot establish prevalence. In Portugal, targeted searches identified a Coimbra family with two directly related individuals diagnosed on three major criteria, one of whom achieved complete remission with vismodegib after excisions [82]; a northern Portuguese family affected across three generations, diagnosed on clinical and radiological grounds alone (described in 10.3) [83]; an Azorean boy with congenital orbital teratoma who, at 15 years, met four major and four minor criteria and carried PTCH1 c.290dup [57]; a Lisbon infant with acral BCCs [84]; a Porto child with congenital anosmia and olfactory bulb hypoplasia [49]; and a systematic review of vismodegib use in the syndrome by Portuguese authors [70]. In Brazil, alongside conservative management of multiple keratocysts in a child and a case of PTCH1-associated holoprosencephaly [39, 52], an Afro-Brazilian family with three affected individuals was diagnosed following an oral complaint, challenging the assumption that the syndrome is exceptional in Black populations [85]. An oral pathology service also identified 97 keratocysts over 31 years, 10 in children, two of whom had signs of the syndrome, with recurrences and new cysts in all cases—a service series rather than a frequency estimate [86]. In a country with high ultraviolet exposure and a population encompassing widely varied phototypes, such as Brazil, earlier cutaneous expression in fair-skinned patients is plausible, but this extrapolation has not been studied. The absence of referral centres and limited access to PTCH1 and SUFU testing in many countries mean that diagnosis remains based on clinical and radiological criteria [6].

BCC incidence is similar in men and women; medulloblastoma is more common in males (3:1) [2, 42].

10. Illustrative Clinical Case

10.1 Multiple keratocysts in a Brazilian child

De Arruda and colleagues reported in 2024 an 11-year-old girl evaluated in Brazil for multiple odontogenic jaw keratocysts, which led to a diagnosis of nevoid basal cell carcinoma syndrome [52]. Chest and skull radiographs showed neither rib abnormalities nor falx calcification, and cephalometric analysis revealed mandibular retrusion, a skeletal class II relationship and a convex profile. The team selected an individualised strategy for each cyst, using marsupialisation followed by enucleation to minimise surgical trauma to the growing facial skeleton and reduce recurrence risk. After 32 months of regular follow-up, there were no recurrences or new cysts [52].

In children, keratocysts are often the first manifestation, and the dentist or maxillofacial surgeon is frequently the first clinician to suspect the diagnosis [12]. Absence of falx calcification and bifid ribs at 11 years does not exclude the syndrome, since these signs are age dependent and often omitted from radiology reports; diagnosis may rest on major criteria (keratocysts before 20 years) supplemented by family history, palmoplantar pits, macrocephaly or genetic testing [1, 11]. Keratocysts suggest PTCH1-related disease, and molecular diagnosis determines subsequent surveillance: annual dermatological review from 10 years, periodic panoramic dental radiography (or MRI), pelvic ultrasonography in late adolescence and, for a PTCH1 variant, no routine brain MRI [6, 12]. Diagnostic radiation exposure should be considered for every investigation, favouring MRI when available [6].

10.2 Multifocal desmoplastic medulloblastoma and avoidance of radiotherapy

Smucker and Smith reported a 2-and-a-half-year-old African American boy with multifocal desmoplastic medulloblastoma [54]. Nevoid basal cell carcinoma syndrome was suspected before adjuvant treatment on the basis of clinical examination, personal and family history, and tumour histology; radiotherapy was withheld, and identification of a previously unreported PTCH1 variant confirmed the diagnosis. The authors noted that this was the first reported African American child with medulloblastoma diagnosed with the syndrome before radiotherapy, and that irradiation in these patients may trigger BCCs and other intracranial neoplasms within the irradiated field [54].

Any desmoplastic/nodular or SHH-subgroup medulloblastoma in a child younger than 5 years warrants assessment for syndrome features (macrocephaly, frontal bossing, palmar pits, clefting, bifid ribs, cardiac fibroma and a family history of BCCs or jaw cysts) and germline PTCH1 and SUFU testing before a radiotherapy decision [12, 53]. In a child with dark skin, absence of familial BCCs does not exclude the syndrome [10]. If the variant is in SUFU, carrier siblings should begin periodic brain MRI from birth, and the patient requires prolonged meningioma follow-up, particularly after irradiation [1, 12]. Case series describe children with the syndrome and recurrent desmoplastic medulloblastoma who survived after salvage treatment without irradiation [48].

10.3 A Portuguese family diagnosed clinically and the role of dermoscopy

Moreira and colleagues (Centro Hospitalar de São João, Porto) described a 50-year-old woman with a uterine fibroma excised 26 years previously and a facial BCC excised 7 years previously, who presented with three facial nodular lesions [83]. She had scattered facial milia, coarse facial features with hypertelorism and prognathism, and subtle palmar pits (Figure 1); dermoscopic skin examination identified eight lesions suggestive of BCC, showing arborising vessels, ulceration, blue-grey globules and spoke-wheel areas (Figure 2), and showed palmar pits as irregular, slightly depressed, skin-coloured lesions, some with red globules (Figure 3). Her mother had died at 65 years with a destructive periorbital BCC; her 26-year-old daughter had a mandibular keratocyst at 17 years, a uterine fibroma at 19 and three facial BCCs from 19 years, with hypertelorism, prognathism, milia and prominent palmar pits (Figure 4); two of the patient's brothers had multiple BCCs from their fourth decade. Imaging (radiographs and CT of the skull, face, chest and spine) showed falx calcification, a mandibular keratocyst, bilateral bifid ribs and thoracic scoliosis with a hemivertebra (Figure 5); echocardiography, abdominopelvic ultrasonography and ophthalmological examination were normal. Diagnosis was clinical and familial, with no molecular study reported, and all excised lesions were confirmed as BCCs [83].

Teaching points. The case meets several major criteria (multiple BCCs, keratocyst, palmar pits, falx calcification and an affected first-degree relative), while illustrating the additional contribution of current guidelines: PTCH1 and SUFU testing would enable predictive testing of grandchildren, nieces and nephews, and MRI or panoramic dental radiography would replace CT wherever possible because of radiation sensitivity [1, 6]. Uterine fibromas, unlike ovarian fibromas, are not a recognised manifestation in the sources consulted and should not count as a criterion. Dermoscopy is a low-cost means of detecting small BCCs and visualising palmar pits, which are often overlooked on physical examination [83].

11. Prognosis and Long-Term Follow-Up

Life expectancy does not differ significantly from the average: in the North West England register, patients with Gorlin syndrome had a life expectancy of 73.4 years, the longest among the tumour predisposition syndromes studied, and those diagnosed after establishment of the genetic register gained 11.2 years of survival, reaching the local population level (80.0 years) in recent years [1, 87]. The principal morbidity is cosmetic and functional: lifelong treatment of dozens or hundreds of BCCs, especially on the face, and repeated jaw surgery may cause disfigurement, social difficulties and problems retaining employment [1]. The Dutch guideline recommends psychological assessment at diagnosis and attention to psychological distress during follow-up, and proposes syndrome-specific BCC patient-reported outcome questionnaires [6].

In PTCH1-related disease, the principal prognostic determinants are the number and location of BCCs, adherence to photoprotection and avoidance of radiotherapy; medulloblastoma is rare (less than 2%) and usually has desmoplastic histology with a favourable prognosis [1, 27]. In SUFU-related disease, risk is dominated by medulloblastoma before 5 years, gonadal tumours during adolescence, and BCCs and meningiomas in adulthood: in the SIOPE cohort, 23 of 160 patients with follow-up had died, and cumulative tumour incidence in carrier relatives reached 44.1% at 50 years, supporting lifelong, age-adjusted surveillance [50]. Among patients with germline predisposition to medulloblastoma overall, 5-year progression-free and overall survival were 52% and 65%, respectively, with significant differences between genes [53].

Long-term follow-up requires annual visits with a clinical geneticist or oncologist familiar with the syndrome, who checks completion of investigations, provides education on warning signs and coordinates specialist care; at a referral centre, a case manager and same-day appointments reduce the number of journeys [6, 12]. Transition from paediatric to adult care provides an essential opportunity to review genetic counselling and family planning [6]. Oral SMO inhibitors may reduce the burden of multiple BCCs, but adverse effects limit prolonged use and lesions recur after withdrawal; results of the phase 3 topical patidegib trial may alter facial BCC prevention [17, 63]. The Dutch guideline's proposed audit measures include a documented family history, a known genetic test result, counselling on photoprotection and the disadvantages of radiation, and scheduled surveillance across all relevant specialties [6].

12. Summary and Concluding Remarks

Nevoid basal cell carcinoma syndrome is an autosomal dominant disorder of the Hedgehog pathway, caused principally by loss-of-function PTCH1 variants (67–79%) and, in a minority, SUFU variants (approximately 6%); the association with PTCH2 is unconfirmed, and this gene should not be included in diagnostic panels [1, 4, 6]. Approximately one quarter of patients meeting clinical criteria have no identified variant, and some have postzygotic mosaicism detectable through analysis of two or more tumours [1, 12].

The phenotype combines developmental abnormalities—macrocephaly, frontal bossing and hypertelorism, costovertebral abnormalities, lamellar falx calcification, palmoplantar pits and orofacial clefting—with age-dependent tumours: odontogenic keratocysts (approximately 90% in PTCH1-related disease, absent in SUFU-related disease), multiple BCCs from adolescence, ovarian and cardiac fibromas, and desmoplastic medulloblastoma in early childhood [1, 2, 8]. Clinical diagnosis uses the Evans and Kimonis criteria, revised by Bree in 2011, while molecular PTCH1 and SUFU testing, including dosage and RNA analysis, confirms the diagnosis and determines surveillance [1, 9–11].

The distinction between genes has the greatest clinical implications: medulloblastoma risk is below 2% in PTCH1-related disease and approximately 8–33% in SUFU-related disease, depending on the estimation method; only SUFU carriers (and, according to some authors, clinically diagnosed patients without testing) should undergo serial brain MRI until 5 years and meningioma surveillance from 30 years [6, 12, 27, 50]. General principles include avoiding radiotherapy and unnecessary ionising radiation, photoprotection, early conservative BCC treatment (surgery, Mohs surgery, photodynamic therapy and topical treatments), keratocyst excision that preserves facial growth, and multidisciplinary follow-up [1, 6, 21]. The SMO inhibitors vismodegib (Erivedge®, 150 mg/day) and sonidegib (Odomzo®, 200 mg/day) are approved for advanced adult BCC and reduce BCC burden in patients with the syndrome, but toxicity (cramps, alopecia, dysgeusia and weight loss), teratogenicity and recurrence after withdrawal limit prolonged use [13, 14, 63]. No medicine is authorised for the syndrome or BCC prevention; preliminary results of the phase 3 topical patidegib trial, announced by the sponsor for late November 2026, represent the next relevant development, and only peer-reviewed publication and a regulatory decision could change practice [17, 18]. Remaining gaps include absent epidemiological data for Latin America, Portugal, Africa and the Middle East, selection bias in SUFU risk estimates, and lack of evidence that surveillance strategies improve survival [6, 12].

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