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SUFU-related nevoid basal cell carcinoma syndrome

SUFU-related nevoid basal cell carcinoma syndrome (SUFU-related NBCCS): Disease Characteristics Research Report

2026-04-05
Falcon MONDO:0958189 Model: Edison Scientific Literature 36 citations

SUFU-related nevoid basal cell carcinoma syndrome (SUFU-related NBCCS): Disease Characteristics Research Report

Scope: Mendelian cancer predisposition syndrome caused by germline pathogenic variants in SUFU, a core negative regulator of Sonic Hedgehog (SHH)/Hedgehog signaling. Evidence is drawn primarily from (i) the large collaborative SUFU cohort study (2022), (ii) a 2024 scoping review specific to germline SUFU variants, (iii) SIOPE HGWG surveillance recommendations (2021) and AACR-focused pediatric brain tumor predisposition surveillance update (2024), and (iv) 2023–2024 basal cell carcinoma (BCC) pathway and treatment literature plus clinical-trials records. Citations refer to the provided evidence context.

1. Disease Information

1.1 Disease overview (current understanding)

SUFU-related NBCCS is the SUFU-genotype form of Gorlin syndrome / nevoid basal cell carcinoma syndrome (NBCCS) / basal cell nevus syndrome (BCNS)—an autosomal dominant cancer predisposition condition characterized by developmental anomalies (often subtle) and increased risk of specific neoplasms, particularly infant SHH-medulloblastoma, adult basal cell carcinoma, and adult meningioma, with additional risk for gonadal/ovarian tumors. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 1-1, lee2024medulloblastomaandother pages 1-2)

1.2 Key identifiers and terminology

1.3 Common synonyms / alternative names

1.4 Evidence sources (patient-level vs aggregated)

2. Etiology

2.1 Disease causal factors

Primary cause: germline heterozygous pathogenic SUFU variants conferring cancer predisposition and variable developmental features. SUFU is a negative intracellular regulator of SHH signaling; impaired negative regulation is a central causal mechanism. (lee2024medulloblastomaandother pages 2-2, guerrinirousseau2021currentrecommendationsfor pages 1-2)

Molecular causal chain (high level): SUFU loss-of-function (or impaired SUFU–GLI binding) → derepression of GLI transcription factors → increased SHH target-gene expression → tumor predisposition (notably SHH-medulloblastoma and BCC). Mechanistic support includes statements that activated SMO can bind SUFU and enable GLI2 nuclear translocation and target gene transcription; sporadic BCC frequently harbors PTCH/SMO/SUFU lesions activating this axis. (vallini2023signalingpathwaysand pages 2-3, hoashi2022molecularmechanismsand pages 3-5)

2.2 Inheritance pattern

Autosomal dominant inheritance is explicitly stated for Gorlin syndrome/NBCCS in the SIOPE HGWG guideline and SUFU scoping review. (guerrinirousseau2021currentrecommendationsfor pages 1-2, lee2024medulloblastomaandother pages 1-2)

2.3 Risk factors

Genetic risk factors - Germline SUFU pathogenic variants are the defining risk factor, with 64 distinct pathogenic variants reported in the 172-carrier cohort. (guerrinirousseau2022cancerriskand pages 1-1) - In that cohort, inheritance was 73% inherited among those where inheritance could be evaluated, consistent with a substantial inherited component. (guerrinirousseau2022cancerriskand pages 1-1)

Environmental/iatrogenic risk factors (important in clinical practice) - Ionizing radiation: SIOPE HGWG notes prolonged and thorough follow-up is needed after radiotherapy due to secondary malignancy risk; SUFU carriers treated for childhood medulloblastoma may develop BCC/meningioma earlier, suggesting radiation can modify tumor emergence/timing. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 6-7) - Ultraviolet exposure: not quantified SUFU-specifically in the available evidence, but BCC risk is part of the syndrome and UV exposure is a known BCC driver; the SIOPE text highlights BCC risk variation across ancestry groups and increased BCC risk with irradiation. (guerrinirousseau2021currentrecommendationsfor pages 2-4)

Modifier genes (genetic risk modifiers) - SIOPE HGWG notes “evidence for modifier genes,” specifically referencing MC1R ‘red hair’ polymorphisms as modifiers of BCC risk/feature clustering. (guerrinirousseau2021currentrecommendationsfor pages 2-4)

2.4 Protective factors

No SUFU-specific protective alleles are identified in the provided evidence set.

Practical protective measures (risk reduction): avoidance of unnecessary ionizing radiation and rigorous photoprotection are supported indirectly by the radiation sensitivity/risk discussion and BCC risk context in guidelines/reviews. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2021currentrecommendationsfor pages 2-4)

2.5 Gene–environment interaction

Evidence suggests clinically meaningful interaction between germline SUFU predisposition and radiotherapy (earlier BCC/meningioma occurrence after MB therapy), and between predisposition and UV-related BCC risk (ancestry/skin type differences and modifier-gene effects). However, quantitative GxE interaction models were not available in the retrieved texts. (guerrinirousseau2022cancerriskand pages 6-7, guerrinirousseau2021currentrecommendationsfor pages 2-4)

3. Phenotypes (clinical spectrum)

3.1 Core tumor phenotypes (with frequencies and ages)

The best quantitative data are from the 172-carrier SUFU cohort: - Any tumor: 117/172 (68%) had ≥1 tumor; in relatives, cumulative incidence 44.1% by age 50. (guerrinirousseau2022cancerriskand pages 1-1) - Medulloblastoma (SHH subtype): 86/172 affected; median age 1.5 years; relative cumulative risk by age 50 13.3% (95% CI 6–20.1). (guerrinirousseau2022cancerriskand pages 1-1) - Basal cell carcinoma: 25/172 affected; median age 40 years; cumulative risk by age 50 28.5% (95% CI 13.4–40.9). (guerrinirousseau2022cancerriskand pages 1-1) - Meningioma: 20/172 affected; median age 44 years; cumulative risk by age 50 5.2% (95% CI 0–12). (guerrinirousseau2022cancerriskand pages 1-1) - Gonadal tumors: 11/172 affected; median age 14 years; cumulative risk by age 50 4.6% (95% CI 0–9.7). (guerrinirousseau2022cancerriskand pages 1-1)

The 2024 SUFU scoping review (176 literature cases) further highlights incomplete penetrance/variable expressivity: among 95 patients with data on the three most frequent tumors, 32.6% had none, 53.7% had one, 8.4% had two, and 5.3% had all three (medulloblastoma, BCC, meningioma). (lee2024medulloblastomaandother pages 1-2)

3.2 Developmental/congenital phenotypes (non-tumoral)

SIOPE HGWG notes Gorlin syndrome includes diverse developmental features such as macrocephaly, hypertelorism, skeletal anomalies, and palmar/plantar pitting, but also emphasizes that SUFU-related clinical features may be less prominent and that many SUFU carriers may not meet classic criteria even later in life. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2021currentrecommendationsfor pages 2-4)

3.3 Phenotype ontology mapping (suggested HPO terms)

Tumors - Medulloblastoma: HP:0002885 (medulloblastoma) - Basal cell carcinoma: HP:0002671 (basal cell carcinoma) - Meningioma: HP:0002858 (meningioma) - Ovarian fibroma / ovarian tumor: HP:0030680 (ovarian fibroma) / HP:0100615 (ovarian neoplasm)

Selected non-tumoral findings commonly used in Gorlin syndrome criteria (not SUFU-specific frequency in evidence) - Macrocephaly: HP:0000256 - Hypertelorism: HP:0000316 - Palmar pits / plantar pits: HP:0007400 (palmar pits), HP:0007418 (plantar pits) - Odontogenic keratocyst (jaw cyst): HP:0010603 (odontogenic keratocyst)

(These HPO mappings are standard; however, the evidence base here does not provide SUFU-specific frequencies for most non-tumoral features.)

3.4 Quality of life impact

QoL impacts are not quantified SUFU-specifically in the available evidence set. Nonetheless, guideline and treatment studies emphasize that multiple BCCs can drive repeated surgeries, scarring, and chronic treatment burden, and that tolerability issues with chronic Hedgehog inhibitor therapy are common. (lang2024s2kguidelinebasal pages 11-12, murgia2024gorlinsyndromeassociatedbasal pages 2-4)

4. Genetic/Molecular Information

4.1 Causal gene(s)

4.2 Variant spectrum / pathogenic variant types

The large SUFU cohort reports 64 different SUFU pathogenic variants across the gene, consistent with broad allelic heterogeneity. (guerrinirousseau2022cancerriskand pages 1-1)

Variant types are not enumerated in the extracted cohort snippet; however, tumor-derived SUFU mutations in sporadic BCC include loss-of-function variants that disrupt SUFU–GLI binding and inappropriately activate Hedgehog signaling. (taylor2002mutationsinsufu pages 1-2)

4.3 Functional consequences

Mechanistic statements strongly support loss of SUFU repression of GLI as a core functional consequence: - In advanced BCC review: activated SMO binds SUFU (a “crucial negative regulator”) enabling GLI2 nuclear translocation and transcription of HH targets. (vallini2023signalingpathwaysand pages 2-3) - In sporadic BCC sequencing study abstract: “SUFU normally binds… GLI1… to prevent it from initiating transcription of Hedgehog target genes”; loss-of-function SUFU variants “disrupt its binding to GLI, leading to constitutive pathway activation.” (taylor2002mutationsinsufu pages 1-2)

4.4 Pathways / molecular function (ontology suggestions)

Suggested GO biological process terms (mechanism-consistent) - Hedgehog signaling pathway: GO:0007224 - Regulation of transcription by RNA polymerase II: GO:0006357 - Negative regulation of signal transduction: GO:0009968

Suggested GO molecular function terms - Protein binding: GO:0005515 (SUFU–GLI interactions)

Suggested CL cell-type terms (disease-relevant) - Cerebellar granule neuron precursor: CL:0002603 (relevant to SHH medulloblastoma cell-of-origin context) - Keratinocyte: CL:0000312 (relevant to BCC pathogenesis)

5. Environmental Information

No SUFU-specific environmental exposures beyond general BCC/radiotherapy context were quantified in the retrieved evidence.

Key practical environmental/iatrogenic considerations include: - Ionizing radiation exposure: noted as a risk modifier for secondary malignancies and earlier BCC/meningioma after MB therapy. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 6-7)

6. Mechanism / Pathophysiology

6.1 Canonical mechanism: SUFU loss → Hedgehog pathway activation

SUFU is repeatedly described as a negative intracellular regulator of SHH signaling, and impaired SUFU function results in increased pathway output. (lee2024medulloblastomaandother pages 2-2, vallini2023signalingpathwaysand pages 2-3)

A particularly direct mechanistic statement from a sporadic BCC tumor sequencing/functional study abstract is: - “SUFU normally binds… GLI1… to prevent it from initiating transcription of Hedgehog target genes… loss of function SUFU variants… disrupt its binding to GLI, leading to constitutive pathway activation.” (taylor2002mutationsinsufu pages 1-2)

6.2 Tissue- and context-dependence

The SUFU scoping review emphasizes that while SUFU is a negative regulator, “the precise mechanisms… still not fully understood,” and that phenotype is poorly characterized due to limited longitudinal data—highlighting ongoing research needs. (lee2024medulloblastomaandother pages 2-2, lee2024medulloblastomaandother pages 1-2)

A major 2024 mouse-model paper suggests a more complex dosage-dependent role (expert-level nuance): increased SUFU gene dosage was associated with heightened SHH signaling and promoted medulloblastoma tumorigenesis in certain genetic contexts (Ptch1 ablation). (han2024increasingsufugene pages 1-2)

6.3 Suggested causal chain to clinical manifestations

Medulloblastoma (infant SHH-MB): germline SUFU PV → increased SHH pathway output in developing cerebellum → abnormal proliferation/survival of SHH-responsive progenitors → SHH-medulloblastoma in infancy. Tumor risk in carriers is concentrated in the first years of life, motivating high-frequency early MRI surveillance. (guerrinirousseau2022cancerriskand pages 1-1, guerrinirousseau2022cancerriskand pages 7-8)

Basal cell carcinoma (adult): germline SUFU PV (plus UV/radiation and somatic second hits) → derepressed GLI transcriptional program in keratinocytes → BCC emergence, often in adulthood; sporadic BCC commonly shows PTCH/SMO/SUFU lesions, supporting shared pathway etiology. (vallini2023signalingpathwaysand pages 2-3, guerrinirousseau2022cancerriskand pages 1-1)

7. Anatomical Structures Affected (ontology suggestions)

7.1 Primary organs/tissues

Supported by the tumor spectrum and surveillance focus (dermatologic exams, brain MRI, pelvic ultrasound). (guerrinirousseau2022cancerriskand pages 1-1, guerrinirousseau2022cancerriskand pages 7-8)

7.2 Subcellular localization (mechanistically relevant)

  • Nuclear/cytoplasmic control of GLI is central; SUFU’s role is described in preventing GLI transcriptional activation by binding GLI and affecting nuclear activity. (taylor2002mutationsinsufu pages 1-2)

8. Temporal Development (natural history)

Key temporal pattern (strongly supported): - Medulloblastoma: early childhood (median ~1.5 years). (guerrinirousseau2022cancerriskand pages 1-1) - Gonadal tumors: adolescence (median ~14 years). (guerrinirousseau2022cancerriskand pages 1-1) - Basal cell carcinoma: adulthood (median first BCC ~40 years). (guerrinirousseau2022cancerriskand pages 1-1) - Meningioma: adulthood (median ~44 years). (guerrinirousseau2022cancerriskand pages 1-1)

This age-stratified risk directly drives surveillance design. (guerrinirousseau2022cancerriskand pages 7-8)

9. Inheritance and Population

9.1 Epidemiology

9.2 Penetrance and expressivity

10. Diagnostics

10.1 Clinical diagnostic criteria

SIOPE HGWG provides standard diagnostic criteria and emphasizes integration with genetics: - Diagnosis requires “Two major diagnostic criteria and one minor diagnostic criterion or one major and three minor diagnostic criteria” and may be confirmed by identification of a heterozygous PTCH1 or SUFU pathogenic variant. (guerrinirousseau2021currentrecommendationsfor pages 1-2)

Major criteria listed include (among others): early/multiple BCCs, odontogenic keratocysts, palmar/plantar pits, falx calcification, medulloblastoma (typically desmoplastic), first-degree relative. Minor criteria include skeletal malformations, macrocephaly, cleft lip/palate, ovarian/cardiac fibroma, etc. (guerrinirousseau2021currentrecommendationsfor pages 1-2)

10.2 Genetic testing approach

10.3 Screening / surveillance as part of diagnostic and management pathway

The surveillance program is a major component of real-world implementation (see Section 11 and Table artifact below). (guerrinirousseau2022cancerriskand pages 7-8, hansford2024updateoncancer pages 3-4)

11. Outcome / Prognosis

11.1 Tumor risks and mortality

  • In the 172-carrier cohort, follow-up was available for 160 carriers: 137 alive and 23 deceased (cause not specified in the excerpt), emphasizing that medulloblastoma and other neoplasms can be life-threatening. (guerrinirousseau2022cancerriskand pages 1-1)

11.2 Prognostic factors

Not quantified SUFU-specifically in the available evidence beyond: - Strong age-dependence of tumor spectrum (early MB vs later BCC/meningioma). (guerrinirousseau2022cancerriskand pages 1-1) - Radiotherapy history as a modifier for later tumor risks. (guerrinirousseau2022cancerriskand pages 6-7)

12. Treatment

12.1 Management of basal cell carcinomas (real-world implementations)

Surgery remains first-line for most BCC, with systemic therapies reserved for advanced/multiple lesions; this is reflected in BCC guideline updates. (lang2024s2kguidelinebasal pages 11-12)

Targeted therapy: Hedgehog pathway inhibitors (HHIs) - Vismodegib (GDC-0449) and sonidegib (LDE225) are oral SMO inhibitors used in advanced/multiple BCC, including Gorlin syndrome cases. (murgia2024gorlinsyndromeassociatedbasal pages 2-4)

Recent real-world Gorlin cohort (2024): retrospective study of 16 Gorlin patients treated March 2012–Jan 2024. - At 4 months, clinical remission 61.5% with sonidegib vs 16.7% with vismodegib; adverse events occurred in 100% vismodegib vs 57.9% sonidegib patients (p<0.05). (murgia2024gorlinsyndromeassociatedbasal pages 5-7)

Advanced BCC trial context (2023 synthesis): - ERIVANCE 39-month update: ORR 48.5% (mBCC), 60.3% (laBCC); median DOR 14.8 months (mBCC), 26.2 months (laBCC). - STEVIE: laBCC RR 68.5%; mBCC RR 36.9%; DOR in laBCC subgroup 28.8 months with Gorlin vs 18.7 months without Gorlin. (vallini2023signalingpathwaysand pages 6-7)

Tolerability and intermittent dosing: - German S2k BCC guideline (update 2023; published 2024) notes in a long-term follow-up of a Gorlin vismodegib trial, only 3/18 (17%) tolerated continuous therapy for 36 months and intermittent regimens (e.g., 12 weeks on/8 weeks off) are proposed to improve feasibility. (lang2024s2kguidelinebasal pages 11-12)

MAXO (treatment action ontology) suggestions - Surgical excision of BCC: MAXO:0000455 (excision) - Mohs micrographic surgery: MAXO:0000462 (Mohs surgery) - Hedgehog pathway inhibitor therapy: MAXO:0001026 (targeted therapy) / MAXO:0000058 (drug therapy) - Dermatologic surveillance: MAXO:0000127 (screening)

12.2 Pediatric medulloblastoma (SUFU carriers)

Treatment details are not provided in full in the accessible SUFU-specific guideline excerpts; however, both SIOPE HGWG and AACR emphasize that identifying germline predisposition can affect management and surveillance. (guerrinirousseau2021currentrecommendationsfor pages 4-5, hansford2024updateoncancer pages 3-4)

12.3 Clinical trials (selected; real-world implementations)

ClinicalTrials.gov records document multiple interventional studies in Gorlin/NBCCS: - NCT00957229 (Vismodegib; Phase II; randomized; 41 participants; start Aug 2009; completed Jan 2014). Primary endpoint: number of new surgically eligible BCCs; linked NEJM publication (PMID 22670904, per registry). (NCT00957229 chunk 1) - NCT01350115 (Sonidegib/LDE225 oral; Phase II; randomized; 10 participants; start Apr 2011; completed Oct 2012; results posted Oct 19, 2015). (NCT01350115 chunk 1) - NCT00961896 (Topical LDE225; Phase II; 18 participants; started Jul 2009; primary completion Aug 2010; completed). (NCT00961896 chunk 1)

13. Prevention

13.1 Primary prevention

13.2 Secondary prevention (screening / early detection)

This is the most actionable prevention layer and is strongly evidence-based via guidelines and cohort-risk estimates.

Key surveillance table (SIOPE HGWG) image evidence: Table 5 extracted from the SIOPE HGWG surveillance guideline provides genotype-stratified recommendations (PTCH1 vs SUFU). (guerrinirousseau2021currentrecommendationsfor media 7a72a3c0)

14. Other Species / Natural Disease

No naturally occurring veterinary SUFU-NBCCS analogs were identified in the retrieved evidence.

15. Model Organisms

15.1 Mouse models relevant to SUFU/SHH tumorigenesis (selected)

  • A 2024 JCI Insight study reports that increasing Sufu gene dosage in mice can produce preaxial polydactyly and, in combination with Ptch1 ablation, can promote medulloblastoma tumorigenesis, highlighting complex dosage effects beyond a simple tumor-suppressor model. (han2024increasingsufugene pages 1-2)
  • Foundational human genetics demonstrate SUFU truncations can lead to SHH pathway activation by failing to export GLI from nucleus to cytoplasm; this establishes mechanistic plausibility for SUFU-driven SHH tumorigenesis and aligns with mouse SHH-pathway tumor models (Ptch+/− medulloblastoma; SHH/GLI skin models). (taylor2002mutationsinsufu pages 1-2)

15.2 Model utility and limitations

  • Utility: enables mechanistic dissection of SUFU–GLI regulation and testing of pathway inhibitors, though SUFU-driven tumors may be downstream of SMO and thus not responsive to SMO inhibitors in some contexts (not fully supported in the accessible mouse excerpts).
  • Limitations: phenotype penetrance varies by genetic background and cooperating hits; increased SUFU dosage effects complicate simplistic assumptions about SUFU as solely a negative regulator in vivo. (han2024increasingsufugene pages 1-2)

Consolidated risk and surveillance summary table

Table (click to expand)
Domain Item (tumor or test) Key quantitative estimate Age window/start Notes (e.g., SUFU vs PTCH1 differences) Source
Risk Any tumor 117/172 carriers (68%) developed ≥1 tumor; cumulative incidence in relatives 14.4% by age 5, 18.2% by age 20, 44.1% by age 50 Lifelong; strongest early-childhood risk for MB Multiple tumors in 28% of affected carriers; lifelong but age-stratified spectrum Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385 (guerrinirousseau2022cancerriskand pages 1-1, guerrinirousseau2022cancerriskand pages 6-7)
Risk Medulloblastoma 86/172 total cases in cohort; cumulative risk by age 50 = 13.3% (95% CI 6.0-20.1) in relatives Median age 1.5 years; largely before age 5, especially first 3 years Predominant SUFU-associated tumor; SHH subgroup; risk higher in SUFU than PTCH1 in prior literature/reviews Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Lee et al., Am J Med Genet A 2024, doi:10.1002/ajmg.a.63496 (guerrinirousseau2022cancerriskand pages 1-1, lee2024medulloblastomaandother pages 1-2, lee2024medulloblastomaandother pages 2-2)
Risk Basal cell carcinoma 25/172 total cases; cumulative risk by age 50 = 28.5% (95% CI 13.4-40.9) Median age 40 years for first BCC Adult-onset predominance; lower/less certain risk than classic PTCH1-related Gorlin syndrome; risk may be increased after radiotherapy Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Guerrini-Rousseau et al., Familial Cancer 2021, doi:10.1007/s10689-021-00247-z (guerrinirousseau2022cancerriskand pages 1-1, guerrinirousseau2021currentrecommendationsfor pages 2-4)
Risk Meningioma 20/172 total cases; cumulative risk by age 50 = 5.2% (95% CI 0-12) Median age 44 years Often later-onset; earlier/more frequent after prior cranial irradiation; considered more frequent in SUFU than PTCH1 carriers Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Lee et al., Am J Med Genet A 2024, doi:10.1002/ajmg.a.63496 (guerrinirousseau2022cancerriskand pages 1-1, lee2024medulloblastomaandother pages 16-16)
Risk Gonadal/ovarian tumors 11/172 total gonadal tumors; cumulative risk by age 50 = 4.6% (95% CI 0-9.7) overall Median age 14 years Adolescent-predominant; ovarian tumors/fibromas are emphasized in females; more frequent in SUFU than PTCH1 cohorts Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Guerrini-Rousseau et al., Familial Cancer 2021, doi:10.1007/s10689-021-00247-z (guerrinirousseau2022cancerriskand pages 1-1, guerrinirousseau2021currentrecommendationsfor pages 1-2)
Risk Spectrum in scoping review Among 176 literature cases: medulloblastoma 59, BCC 21, meningioma 19; among 95 with data on top 3 tumors, 32.6% had none, 53.7% had one, 8.4% had two, 5.3% had all three Germline SUFU diagnosis median age 4.5 years; MB median 1.42 years Demonstrates incomplete penetrance and variable expressivity Lee et al., Am J Med Genet A 2024, doi:10.1002/ajmg.a.63496 (lee2024medulloblastomaandother pages 1-2)
Surveillance Brain MRI for medulloblastoma Every 3-4 months during first 3 years, then every 6 months until age 5 From birth / diagnosis to age 5 SUFU-specific recommendation; not recommended routinely for PTCH1 carriers Guerrini-Rousseau et al., Familial Cancer 2021, doi:10.1007/s10689-021-00247-z; Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385 (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 7-8, lee2024medulloblastomaandother pages 14-14)
Surveillance Neurologic exams / head circumference Regular clinical monitoring with frequent neurologic exams and serial head circumference assessment in infancy/early childhood Infancy / diagnosis through first 5 years Supportive surveillance adjunct to MRI for SUFU carriers with early-childhood MB risk Hansford et al., Clin Cancer Res 2024, doi:10.1158/1078-0432.CCR-23-4033 (hansford2024updateoncancer pages 3-4, hansford2024updateoncancer pages 2-3)
Surveillance Brain MRI for meningioma Every 3-5 years Start at age 30 if no prior MB; after completion/healing of MB follow-up if previously treated Particularly relevant for SUFU carriers and those exposed to cranial irradiation Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Lee et al., Am J Med Genet A 2024, doi:10.1002/ajmg.a.63496 (guerrinirousseau2022cancerriskand pages 7-8, lee2024medulloblastomaandother pages 14-14)
Surveillance Dermatologic examination Annual skin examination Start at age 20 Later start than PTCH1 carriers (PTCH1: age 10); start earlier if prior radiotherapy Guerrini-Rousseau et al., Familial Cancer 2021, doi:10.1007/s10689-021-00247-z; Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385 (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 7-8)
Surveillance Pelvic ultrasound Every 3 years Begin at age 5 years Intended to screen ovarian/gonadal tumors/fibromas in females; SUFU carriers included Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385 (guerrinirousseau2022cancerriskand pages 7-8)
Surveillance Echocardiogram One-time baseline screen at diagnosis At diagnosis, ideally in first 6 months of life Cardiac fibromas are less clearly part of SUFU phenotype than PTCH1, but SIOPE table includes baseline echo Guerrini-Rousseau et al., J Med Genet 2022, doi:10.1136/jmedgenet-2021-108385; Lee et al., Am J Med Genet A 2024, doi:10.1002/ajmg.a.63496 (guerrinirousseau2022cancerriskand pages 7-8, lee2024medulloblastomaandother pages 16-16)

Table: This table summarizes the major tumor risks, ages of onset, and SUFU-specific surveillance recommendations for germline SUFU pathogenic variant carriers. It is useful as a quick-reference comparison of natural history and screening guidance drawn from the key cohort, scoping review, and SIOPE recommendations.

Key surveillance figure/table (from SIOPE HGWG)

A cropped image of the SIOPE HGWG surveillance recommendations table (Table 5) was retrieved to support implementation details. (guerrinirousseau2021currentrecommendationsfor media 7a72a3c0)

Expert synthesis / analytical notes (authoritative interpretation)

  1. SUFU genotype shifts clinical priorities toward early-life brain tumor surveillance (high-frequency MRI in infancy/early childhood), in contrast to PTCH1 where dermatologic and odontogenic manifestations often dominate early clinical suspicion. (guerrinirousseau2021currentrecommendationsfor pages 2-4, guerrinirousseau2022cancerriskand pages 7-8)
  2. Penetrance is incomplete and expressivity is variable: in aggregated SUFU datasets, a substantial fraction of carriers may remain asymptomatic for major tumors, necessitating careful counseling about probabilistic risk rather than deterministic outcomes. (lee2024medulloblastomaandother pages 1-2, guerrinirousseau2022cancerriskand pages 1-1)
  3. Therapeutic tradeoffs are prominent for chronic BCC control: HHIs suppress new and existing BCCs but often have substantial adverse-event burden and limited long-term tolerability; evidence in Gorlin cohorts suggests sonidegib may be better tolerated than vismodegib in some real-world settings, though datasets remain small. (murgia2024gorlinsyndromeassociatedbasal pages 5-7, lang2024s2kguidelinebasal pages 11-12)

URLs and publication dates (selected key sources)

Notes on evidence gaps

  • MONDO/Orphanet/MeSH/ICD identifiers were not available in the retrieved evidence and are not inferred.
  • SUFU-specific frequencies for non-tumoral developmental features, QoL scales, and robust environmental risk quantification were not present in the accessed excerpts.

References

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  2. (guerrinirousseau2022cancerriskand pages 1-1): Léa Guerrini-Rousseau, Julien Masliah-Planchon, Sebastian M Waszak, Pia Alhopuro, Patrick R Benusiglio, Franck Bourdeaut, Ines B Brecht, Giada Del Baldo, Sandeep Kumar Dhanda, Maria Luisa Garrè, Corrie E M Gidding, Steffen Hirsch, Pauline Hoarau, Mette Jorgensen, Christian Kratz, Lucie Lafay-Cousin, Angela Mastronuzzi, Lorenza Pastorino, Stefan M Pfister, Christopher Schroeder, Miriam Jane Smith, Pia Vahteristo, Roseline Vibert, Catheline Vilain, Nicolas Thomas Waespe Laredo, Ingrid M Winship, D Gareth Evans, and Laurence Brugieres. Cancer risk and tumour spectrum in 172 patients with a germline sufu pathogenic variation: a collaborative study of the siope host genome working group. Journal of Medical Genetics, 59:1123-1132, Jun 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108385, doi:10.1136/jmedgenet-2021-108385. This article has 18 citations and is from a domain leading peer-reviewed journal.

  3. (lee2024medulloblastomaandother pages 1-2): Stephanie G. Lee, Gareth Evans, Maddie Stephen, Rachel Goren, Melissa Bondy, and Steven Goodman. Medulloblastoma and other neoplasms in patients with heterozygous germline sufu variants: a scoping review. American Journal of Medical Genetics Part A, Jan 2024. URL: https://doi.org/10.1002/ajmg.a.63496, doi:10.1002/ajmg.a.63496. This article has 10 citations.

  4. (lee2024medulloblastomaandother pages 2-2): Stephanie G. Lee, Gareth Evans, Maddie Stephen, Rachel Goren, Melissa Bondy, and Steven Goodman. Medulloblastoma and other neoplasms in patients with heterozygous germline sufu variants: a scoping review. American Journal of Medical Genetics Part A, Jan 2024. URL: https://doi.org/10.1002/ajmg.a.63496, doi:10.1002/ajmg.a.63496. This article has 10 citations.

  5. (hansford2024updateoncancer pages 3-4): Jordan R. Hansford, Anirban Das, Rose B. McGee, Yoshiko Nakano, Jack Brzezinski, Sarah R. Scollon, Surya P. Rednam, Jaclyn Schienda, Orli Michaeli, Sun Young Kim, Mary-Louise C. Greer, Rosanna Weksberg, Douglas R. Stewart, William D. Foulkes, Uri Tabori, Kristian W. Pajtler, Stefan M. Pfister, Garrett M. Brodeur, and Junne Kamihara. Update on cancer predisposition syndromes and surveillance guidelines for childhood brain tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:2342-2350, Apr 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-4033, doi:10.1158/1078-0432.ccr-23-4033. This article has 49 citations.

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  9. (vallini2023signalingpathwaysand pages 2-3): Giulia Vallini, Laura Calabrese, Costanza Canino, Emanuele Trovato, Stefano Gentileschi, Pietro Rubegni, and Linda Tognetti. Signaling pathways and therapeutic strategies in advanced basal cell carcinoma. Cells, 12:2534, Oct 2023. URL: https://doi.org/10.3390/cells12212534, doi:10.3390/cells12212534. This article has 13 citations.

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  11. (guerrinirousseau2022cancerriskand pages 6-7): Léa Guerrini-Rousseau, Julien Masliah-Planchon, Sebastian M Waszak, Pia Alhopuro, Patrick R Benusiglio, Franck Bourdeaut, Ines B Brecht, Giada Del Baldo, Sandeep Kumar Dhanda, Maria Luisa Garrè, Corrie E M Gidding, Steffen Hirsch, Pauline Hoarau, Mette Jorgensen, Christian Kratz, Lucie Lafay-Cousin, Angela Mastronuzzi, Lorenza Pastorino, Stefan M Pfister, Christopher Schroeder, Miriam Jane Smith, Pia Vahteristo, Roseline Vibert, Catheline Vilain, Nicolas Thomas Waespe Laredo, Ingrid M Winship, D Gareth Evans, and Laurence Brugieres. Cancer risk and tumour spectrum in 172 patients with a germline sufu pathogenic variation: a collaborative study of the siope host genome working group. Journal of Medical Genetics, 59:1123-1132, Jun 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108385, doi:10.1136/jmedgenet-2021-108385. This article has 18 citations and is from a domain leading peer-reviewed journal.

  12. (guerrinirousseau2021currentrecommendationsfor pages 2-4): L. Guerrini-Rousseau, M. J. Smith, C. P. Kratz, B. Doergeloh, S. Hirsch, S. M. J. Hopman, M. Jorgensen, M. Kuhlen, O. Michaeli, T. Milde, V. Ridola, A. Russo, H. Salvador, N. Waespe, B. Claret, L. Brugieres, and D. G. Evans. Current recommendations for cancer surveillance in gorlin syndrome: a report from the siope host genome working group (siope hgwg). Familial Cancer, 20:317-325, Apr 2021. URL: https://doi.org/10.1007/s10689-021-00247-z, doi:10.1007/s10689-021-00247-z. This article has 51 citations and is from a peer-reviewed journal.

  13. (lang2024s2kguidelinebasal pages 11-12): Berenice M. Lang, Panagiotis Balermpas, Andrea Bauer, Andreas Blum, Thomas Dirschka, Markus Follmann, Jorge Frank, Bernhard Frerich, Klaus Fritz, Axel Hauschild, Ludwig M. Heindl, Hans‐Peter Howaldt, Stephan Ihrler, Vinodh Kakkassery, Bernhard Klumpp, Albrecht Krause‐Bergmann, Christoph Löser, Markus Meissner, Michael M. Sachse, Max Schlaak, Michael P. Schön, Lutz Tischendorf, Michael Tronnier, Dirk Vordermark, Julia Welzel, Michael Weichenthal, Susanne Wiegand, Roland Kaufmann, and Stephan Grabbe. S2k guideline basal cell carcinoma of the skin (update 2023). Journal Der Deutschen Dermatologischen Gesellschaft, 22:1697-1714, Nov 2024. URL: https://doi.org/10.1111/ddg.15566, doi:10.1111/ddg.15566. This article has 10 citations and is from a peer-reviewed journal.

  14. (murgia2024gorlinsyndromeassociatedbasal pages 2-4): Giulia Murgia, Luca Valtellini, Nerina Denaro, Gianluca Nazzaro, Paolo Bortoluzzi, Valentina Benzecry, Emanuela Passoni, and Angelo Valerio Marzano. Gorlin syndrome-associated basal cell carcinomas treated with vismodegib or sonidegib: a retrospective study. Cancers, 16:2166, Jun 2024. URL: https://doi.org/10.3390/cancers16122166, doi:10.3390/cancers16122166. This article has 15 citations.

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  17. (guerrinirousseau2022cancerriskand pages 7-8): Léa Guerrini-Rousseau, Julien Masliah-Planchon, Sebastian M Waszak, Pia Alhopuro, Patrick R Benusiglio, Franck Bourdeaut, Ines B Brecht, Giada Del Baldo, Sandeep Kumar Dhanda, Maria Luisa Garrè, Corrie E M Gidding, Steffen Hirsch, Pauline Hoarau, Mette Jorgensen, Christian Kratz, Lucie Lafay-Cousin, Angela Mastronuzzi, Lorenza Pastorino, Stefan M Pfister, Christopher Schroeder, Miriam Jane Smith, Pia Vahteristo, Roseline Vibert, Catheline Vilain, Nicolas Thomas Waespe Laredo, Ingrid M Winship, D Gareth Evans, and Laurence Brugieres. Cancer risk and tumour spectrum in 172 patients with a germline sufu pathogenic variation: a collaborative study of the siope host genome working group. Journal of Medical Genetics, 59:1123-1132, Jun 2022. URL: https://doi.org/10.1136/jmedgenet-2021-108385, doi:10.1136/jmedgenet-2021-108385. This article has 18 citations and is from a domain leading peer-reviewed journal.

  18. (guerrinirousseau2021currentrecommendationsfor pages 4-5): L. Guerrini-Rousseau, M. J. Smith, C. P. Kratz, B. Doergeloh, S. Hirsch, S. M. J. Hopman, M. Jorgensen, M. Kuhlen, O. Michaeli, T. Milde, V. Ridola, A. Russo, H. Salvador, N. Waespe, B. Claret, L. Brugieres, and D. G. Evans. Current recommendations for cancer surveillance in gorlin syndrome: a report from the siope host genome working group (siope hgwg). Familial Cancer, 20:317-325, Apr 2021. URL: https://doi.org/10.1007/s10689-021-00247-z, doi:10.1007/s10689-021-00247-z. This article has 51 citations and is from a peer-reviewed journal.

  19. (murgia2024gorlinsyndromeassociatedbasal pages 5-7): Giulia Murgia, Luca Valtellini, Nerina Denaro, Gianluca Nazzaro, Paolo Bortoluzzi, Valentina Benzecry, Emanuela Passoni, and Angelo Valerio Marzano. Gorlin syndrome-associated basal cell carcinomas treated with vismodegib or sonidegib: a retrospective study. Cancers, 16:2166, Jun 2024. URL: https://doi.org/10.3390/cancers16122166, doi:10.3390/cancers16122166. This article has 15 citations.

  20. (vallini2023signalingpathwaysand pages 6-7): Giulia Vallini, Laura Calabrese, Costanza Canino, Emanuele Trovato, Stefano Gentileschi, Pietro Rubegni, and Linda Tognetti. Signaling pathways and therapeutic strategies in advanced basal cell carcinoma. Cells, 12:2534, Oct 2023. URL: https://doi.org/10.3390/cells12212534, doi:10.3390/cells12212534. This article has 13 citations.

  21. (guerrinirousseau2021currentrecommendationsfor media 7a72a3c0): L. Guerrini-Rousseau, M. J. Smith, C. P. Kratz, B. Doergeloh, S. Hirsch, S. M. J. Hopman, M. Jorgensen, M. Kuhlen, O. Michaeli, T. Milde, V. Ridola, A. Russo, H. Salvador, N. Waespe, B. Claret, L. Brugieres, and D. G. Evans. Current recommendations for cancer surveillance in gorlin syndrome: a report from the siope host genome working group (siope hgwg). Familial Cancer, 20:317-325, Apr 2021. URL: https://doi.org/10.1007/s10689-021-00247-z, doi:10.1007/s10689-021-00247-z. This article has 51 citations and is from a peer-reviewed journal.

  22. (lee2024medulloblastomaandother pages 16-16): Stephanie G. Lee, Gareth Evans, Maddie Stephen, Rachel Goren, Melissa Bondy, and Steven Goodman. Medulloblastoma and other neoplasms in patients with heterozygous germline sufu variants: a scoping review. American Journal of Medical Genetics Part A, Jan 2024. URL: https://doi.org/10.1002/ajmg.a.63496, doi:10.1002/ajmg.a.63496. This article has 10 citations.

  23. (lee2024medulloblastomaandother pages 14-14): Stephanie G. Lee, Gareth Evans, Maddie Stephen, Rachel Goren, Melissa Bondy, and Steven Goodman. Medulloblastoma and other neoplasms in patients with heterozygous germline sufu variants: a scoping review. American Journal of Medical Genetics Part A, Jan 2024. URL: https://doi.org/10.1002/ajmg.a.63496, doi:10.1002/ajmg.a.63496. This article has 10 citations.

  24. (hansford2024updateoncancer pages 2-3): Jordan R. Hansford, Anirban Das, Rose B. McGee, Yoshiko Nakano, Jack Brzezinski, Sarah R. Scollon, Surya P. Rednam, Jaclyn Schienda, Orli Michaeli, Sun Young Kim, Mary-Louise C. Greer, Rosanna Weksberg, Douglas R. Stewart, William D. Foulkes, Uri Tabori, Kristian W. Pajtler, Stefan M. Pfister, Garrett M. Brodeur, and Junne Kamihara. Update on cancer predisposition syndromes and surveillance guidelines for childhood brain tumors. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:2342-2350, Apr 2024. URL: https://doi.org/10.1158/1078-0432.ccr-23-4033, doi:10.1158/1078-0432.ccr-23-4033. This article has 49 citations.