SUFU-related nevoid basal cell carcinoma syndrome

Mendelian MONDO:0958189 Pathograph 5 nevoid basal cell carcinoma syndrome hereditary cancer predisposition syndrome Hedgehog pathway disease

SUFU-related nevoid basal cell carcinoma syndrome (basal cell nevus syndrome 2) is an autosomal dominant hereditary cancer predisposition syndrome caused by germline pathogenic variants in SUFU. The defining molecular lesion is loss of SUFU-mediated suppression of GLI transcriptional activity, producing downstream Hedgehog pathway dysregulation. Compared with PTCH1-related disease, this form shows substantially higher early-childhood medulloblastoma risk, lower jaw-cyst and BCC burden, and distinct surveillance priorities.

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Inheritance

Autosomal Dominant

SUFU-related basal cell nevus syndrome 2 is inherited as an autosomal dominant tumor predisposition syndrome.

Show evidence (1 reference)

PMID:29186568 SUPPORT

"Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families."

Supports familial dominant transmission of SUFU-associated disease.

⚙

Pathophysiology

SUFU Loss with GLI Derepression

SUFU is a negative regulator of Hedgehog pathway transcriptional output. Germline SUFU pathogenic variants, often followed by additional somatic events, reduce repression of GLI targets and predispose to early SHH-lineage tumors.

SUFU link

negative regulation of smoothened signaling pathway link ↓ DECREASED smoothened signaling pathway link ↑ INCREASED

Downstream

Early SHH-Medulloblastoma Predisposition Reduced SUFU control of GLI output increases susceptibility in cerebellar developmental windows.

Show evidence (2 references)

PMID:25403219 SUPPORT

"We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome."

Establishes SUFU as a direct causal locus for the syndrome.

PMID:29186568 SUPPORT

"Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma."

Supports high-risk early-childhood tumor predisposition in SUFU carriers.

Downstream-Pathway Therapeutic Constraint

Because SUFU alterations are downstream of SMO in pathway control, response to SMO inhibitors depends on lesion-level genomic architecture and can be limited when downstream reactivation is present.

Downstream

Reduced Predictability of SMO-Inhibitor Benefit Downstream pathway lesions can attenuate or bypass SMO-targeted suppression.

Show evidence (2 references)

PMID:26169613 PARTIAL

"Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor."

Supports genotype-position dependence of SMO inhibitor efficacy.

PMID:25759019 SUPPORT

"Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2."

Demonstrates downstream SUFU/GLI2 alterations in resistant HH-driven tumors.

⬡

Pathograph

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Referential integrity issues (2):

Target 'Early SHH-Medulloblastoma Predisposition' (from 'SUFU Loss with GLI Derepression') not found in named elements
Target 'Reduced Predictability of SMO-Inhibitor Benefit' (from 'Downstream-Pathway Therapeutic Constraint') not found in named elements

●

Phenotypes

Digestive 1

Odontogenic Keratocysts of the Jaw VERY_RARE Odontogenic keratocysts of the jaw (HP:0010603)

Show evidence (1 reference)

PMID:25403219 SUPPORT

"All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts."

Supports reduced jaw-cyst burden in SUFU-positive families.

Genitourinary 1

Ovarian Fibroma OCCASIONAL Ovarian fibroma (HP:0010618)

Show evidence (1 reference)

PMID:28596197 SUPPORT

"Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004)."

Supports increased ovarian fibroma frequency in SUFU disease.

Integument 1

Basal Cell Carcinoma OCCASIONAL Basal cell carcinoma (HP:0002671)

Show evidence (1 reference)

PMID:29186568 SUPPORT

"The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers."

Supports lower relative BCC burden in SUFU-associated syndrome.

Neoplasm 2

Medulloblastoma FREQUENT Medulloblastoma (HP:0002885)

Show evidence (3 references)

PMID:25403219 SUPPORT

"We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals."

Quantifies major relative medulloblastoma risk increase in SUFU carriers.

PMID:29186568 SUPPORT

"Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo)."

Supports very early-onset medulloblastoma in SUFU-related disease.

PMID:35768194 SUPPORT

"The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively."

Provides quantitative penetrance estimates for medulloblastoma and other tumors in SUFU carriers.

Meningioma OCCASIONAL Meningioma (HP:0002858)

Show evidence (1 reference)

PMID:28596197 SUPPORT

Supports SUFU-enriched meningioma risk relative to PTCH1 carriers.

🧬

Genetic Associations

SUFU (Causative (Primary))

Autosomal Dominant

Show evidence (1 reference)

PMID:25403219 SUPPORT

"We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome."

Supports SUFU as the primary causal gene in basal cell nevus syndrome 2.

💊

Treatments

Surgery and Chemotherapy-Centered Medulloblastoma Management

Action: Pharmacotherapy NCIT:C15986

Treatment often emphasizes surgery and chemotherapy to limit radiotherapy exposure in high-risk childhood SUFU-associated medulloblastoma.

Show evidence (1 reference)

PMID:29186568 SUPPORT

"Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients)."

Documents real-world treatment strategy and outcomes in SUFU-associated medulloblastoma.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Counseling and cascade testing are recommended because of inherited tumor risk.

Show evidence (1 reference)

PMID:29186568 SUPPORT

"Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families."

Supports counseling and family-based cascade testing in SUFU-associated disease.

Radiotherapy Avoidance

Action: radiation therapy MAXO:0000014

Radiotherapy should be avoided when reasonable alternatives exist, especially in childhood, because NBCCS predisposition can produce radiation-induced basal cell carcinomas and secondary malignancies in exposed fields. This is particularly important when treating SUFU-associated medulloblastoma.

Show evidence (2 references)

PMID:20301330 SUPPORT Human Clinical

"Agents/circumstances to avoid: Radiotherapy if there are alternative treatments, especially in childhood;"

GeneReviews directly states the clinical precaution to avoid radiotherapy when alternatives are available, especially during childhood.

PMID:33860896 PARTIAL Human Clinical

"Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies."

The SIOPE surveillance guideline supports the risk rationale for minimizing radiotherapy exposure, although this snippet addresses follow-up rather than avoidance itself.

🌍

Environmental Factors

Ionizing Radiation

Radiotherapy-associated long-term risk is a major management concern in predisposed patients, especially those treated in childhood.

Show evidence (1 reference)

PMID:33860896 SUPPORT

"Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies."

Supports radiotherapy-related secondary cancer concern in surveillance planning.

{ }

Source YAML

click to show

name: SUFU-related nevoid basal cell carcinoma syndrome
creation_date: '2026-03-04T09:02:38Z'
updated_date: '2026-04-11T21:17:25Z'
description: >-
  SUFU-related nevoid basal cell carcinoma syndrome (basal cell nevus syndrome 2)
  is an autosomal dominant hereditary cancer predisposition syndrome caused by
  germline pathogenic variants in SUFU. The defining molecular lesion is loss of
  SUFU-mediated suppression of GLI transcriptional activity, producing downstream
  Hedgehog pathway dysregulation. Compared with PTCH1-related disease, this form
  shows substantially higher early-childhood medulloblastoma risk, lower jaw-cyst
  and BCC burden, and distinct surveillance priorities.
category: Mendelian
parents:
- nevoid basal cell carcinoma syndrome
- hereditary cancer predisposition syndrome
- Hedgehog pathway disease
disease_term:
  preferred_term: basal cell nevus syndrome 2
  term:
    id: MONDO:0958189
    label: basal cell nevus syndrome 2
synonyms:
- SUFU-related Gorlin syndrome
- Basal cell nevus syndrome 2
inheritance:
- name: Autosomal Dominant
  description: >-
    SUFU-related basal cell nevus syndrome 2 is inherited as an autosomal
    dominant tumor predisposition syndrome.
  evidence:
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families."
    explanation: Supports familial dominant transmission of SUFU-associated disease.
prevalence:
- population: Derived from nevoid basal cell carcinoma syndrome cohorts
  percentage: Approximately 1 in 800,000-3,600,000 individuals
  notes: >-
    Direct SUFU-specific population prevalence is not well measured. This
    approximate range is inferred from overall nevoid basal cell carcinoma
    syndrome prevalence (1/57,000 to 1/256,000) and a genotype-phenotype cohort
    in which 9 of 126 molecularly diagnosed Gorlin syndrome patients carried SUFU
    pathogenic variants.
  evidence:
  - reference: PMID:19032739
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The estimated prevalence varies from 1/57,000 to 1/256,000, with a male-to-female ratio of 1:1."
    explanation: This Orphanet review provides the overall prevalence range for nevoid basal cell carcinoma syndrome.
  - reference: PMID:28596197
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation."
    explanation: This genotype-phenotype cohort shows that SUFU accounts for a small minority of molecularly diagnosed Gorlin syndrome cases, allowing an approximate gene-specific prevalence inference.
pathophysiology:
- name: SUFU Loss with GLI Derepression
  description: >-
    SUFU is a negative regulator of Hedgehog pathway transcriptional output.
    Germline SUFU pathogenic variants, often followed by additional somatic events,
    reduce repression of GLI targets and predispose to early SHH-lineage tumors.
  genes:
  - preferred_term: SUFU
    term:
      id: hgnc:16466
      label: SUFU
  biological_processes:
  - preferred_term: negative regulation of smoothened signaling pathway
    modifier: DECREASED
    term:
      id: GO:0045879
      label: negative regulation of smoothened signaling pathway
  - preferred_term: smoothened signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  evidence:
  - reference: PMID:25403219
    reference_title: "Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations."
    supports: SUPPORT
    snippet: "We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome."
    explanation: Establishes SUFU as a direct causal locus for the syndrome.
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma."
    explanation: Supports high-risk early-childhood tumor predisposition in SUFU carriers.
  downstream:
  - target: Early SHH-Medulloblastoma Predisposition
    description: Reduced SUFU control of GLI output increases susceptibility in cerebellar developmental windows.
    evidence:
    - reference: PMID:29186568
      reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
      supports: SUPPORT
      snippet: "Germline SUFU mutations strongly predispose to medulloblastoma in the first years of life, with worse prognosis than usually observed for SHH medulloblastoma."
      explanation: Supports the downstream consequence of SUFU loss as early SHH-medulloblastoma susceptibility.
- name: Downstream-Pathway Therapeutic Constraint
  description: >-
    Because SUFU alterations are downstream of SMO in pathway control, response
    to SMO inhibitors depends on lesion-level genomic architecture and can be
    limited when downstream reactivation is present.
  evidence:
  - reference: PMID:26169613
    supports: PARTIAL
    snippet: "Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor."
    explanation: Supports genotype-position dependence of SMO inhibitor efficacy.
  - reference: PMID:25759019
    supports: SUPPORT
    snippet: "Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2."
    explanation: Demonstrates downstream SUFU/GLI2 alterations in resistant HH-driven tumors.
  downstream:
  - target: Reduced Predictability of SMO-Inhibitor Benefit
    description: Downstream pathway lesions can attenuate or bypass SMO-targeted suppression.
    evidence:
    - reference: PMID:26169613
      supports: SUPPORT
      snippet: "Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses."
      explanation: Supports reduced SMO-inhibitor predictability when downstream pathway lesions are present.
phenotypes:
- category: Oncologic
  name: Medulloblastoma
  frequency: FREQUENT
  diagnostic: true
  description: >-
    SUFU carriers have markedly increased risk of medulloblastoma in infancy and
    early childhood, often with severe clinical course.
  evidence:
  - reference: PMID:25403219
    reference_title: "Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations."
    supports: SUPPORT
    snippet: "We found a < 2% risk in PTCH1 mutation-positive individuals, with a risk up to 20× higher in SUFU mutation-positive individuals."
    explanation: Quantifies major relative medulloblastoma risk increase in SUFU carriers.
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "Twenty-two patients from 17 families were identified with medulloblastoma and a germline SUFU mutation (median age at diagnosis: 16.5 mo)."
    explanation: Supports very early-onset medulloblastoma in SUFU-related disease.
  - reference: PMID:35768194
    supports: SUPPORT
    snippet: "The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively."
    explanation: Provides quantitative penetrance estimates for medulloblastoma and other tumors in SUFU carriers.
  phenotype_term:
    preferred_term: Medulloblastoma
    term:
      id: HP:0002885
      label: Medulloblastoma
- category: Oncologic
  name: Meningioma
  frequency: OCCASIONAL
  description: >-
    SUFU carriers have increased meningioma risk compared with PTCH1 carriers.
  evidence:
  - reference: PMID:28596197
    reference_title: "First evidence of genotype-phenotype correlations in Gorlin syndrome."
    supports: SUPPORT
    snippet: "Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004)."
    explanation: Supports SUFU-enriched meningioma risk relative to PTCH1 carriers.
  phenotype_term:
    preferred_term: Meningioma
    term:
      id: HP:0002858
      label: Meningioma
- category: Genitourinary
  name: Ovarian Fibroma
  frequency: OCCASIONAL
  description: >-
    Ovarian fibromas are part of the SUFU-associated extra-CNS tumor spectrum.
  evidence:
  - reference: PMID:28596197
    reference_title: "First evidence of genotype-phenotype correlations in Gorlin syndrome."
    supports: SUPPORT
    snippet: "Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004)."
    explanation: Supports increased ovarian fibroma frequency in SUFU disease.
  phenotype_term:
    preferred_term: Ovarian fibroma
    term:
      id: HP:0010618
      label: Ovarian fibroma
- category: Dermatologic
  name: Basal Cell Carcinoma
  frequency: OCCASIONAL
  description: >-
    BCC can occur in SUFU carriers but incidence is lower than in PTCH1-related disease.
  evidence:
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "The clinical spectrum differs between SUFU and PTCH1 mutation carriers, and BCC incidence is much lower in SUFU mutation carriers."
    explanation: Supports lower relative BCC burden in SUFU-associated syndrome.
  phenotype_term:
    preferred_term: Basal cell carcinoma
    term:
      id: HP:0002671
      label: Basal cell carcinoma
- category: Dental
  name: Odontogenic Keratocysts of the Jaw
  frequency: VERY_RARE
  description: >-
    Jaw keratocysts are uncommon to absent in reported SUFU-related disease and
    are a stronger feature of PTCH1-related nevoid basal cell carcinoma
    syndrome.
  evidence:
  - reference: PMID:25403219
    reference_title: "Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations."
    supports: SUPPORT
    snippet: "All three SUFU-positive families fulfilled diagnostic criteria for Gorlin syndrome, although none had odontogenic jaw keratocysts."
    explanation: Supports reduced jaw-cyst burden in SUFU-positive families.
  phenotype_term:
    preferred_term: Odontogenic keratocysts of the jaw
    term:
      id: HP:0010603
      label: Odontogenic keratocysts of the jaw
genetic:
- name: SUFU
  association: Causative (Primary)
  frequency: OCCASIONAL
  inheritance:
  - name: Autosomal Dominant
    evidence:
    - reference: PMID:35768194
      supports: SUPPORT
      snippet: "Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated."
      explanation: Supports predominantly inherited, autosomal dominant transmission in SUFU-associated disease.
  evidence:
  - reference: PMID:25403219
    reference_title: "Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations."
    supports: SUPPORT
    snippet: "We demonstrate convincing evidence that SUFU mutations can cause classical Gorlin syndrome."
    explanation: Supports SUFU as the primary causal gene in basal cell nevus syndrome 2.
  notes: >-
    SUFU defines basal cell nevus syndrome 2 (MONDO:0958189) and confers a
    distinctive tumor-risk profile dominated by early medulloblastoma.
environmental:
- name: Ionizing Radiation
  description: >-
    Radiotherapy-associated long-term risk is a major management concern in
    predisposed patients, especially those treated in childhood.
  evidence:
  - reference: PMID:33860896
    supports: SUPPORT
    snippet: "Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies."
    explanation: Supports radiotherapy-related secondary cancer concern in surveillance planning.
treatments:
- name: Surgery and Chemotherapy-Centered Medulloblastoma Management
  description: >-
    Treatment often emphasizes surgery and chemotherapy to limit radiotherapy
    exposure in high-risk childhood SUFU-associated medulloblastoma.
  evidence:
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "Despite treatment with surgery and chemotherapy, to avoid radiotherapy in all patients except one, the outcome was worse than expected for SHH medulloblastoma, due to the high incidence of local relapses (8/22 patients) and second malignancies (n = 6 in 4/22 patients)."
    explanation: Documents real-world treatment strategy and outcomes in SUFU-associated medulloblastoma.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Genetic Counseling
  description: >-
    Counseling and cascade testing are recommended because of inherited tumor risk.
  evidence:
  - reference: PMID:29186568
    reference_title: "Germline SUFU mutation carriers and medulloblastoma: clinical characteristics, cancer risk, and prognosis."
    supports: SUPPORT
    snippet: "Mutations were inherited in 79% of patients, and 34 additional SUFU mutation carriers were identified within 14 families."
    explanation: Supports counseling and family-based cascade testing in SUFU-associated disease.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
- name: Radiotherapy Avoidance
  description: >-
    Radiotherapy should be avoided when reasonable alternatives exist, especially
    in childhood, because NBCCS predisposition can produce radiation-induced
    basal cell carcinomas and secondary malignancies in exposed fields. This is
    particularly important when treating SUFU-associated medulloblastoma.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:20301330
    reference_title: "Nevoid Basal Cell Carcinoma Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Agents/circumstances to avoid: Radiotherapy if there are alternative treatments, especially in childhood;
    explanation: >-
      GeneReviews directly states the clinical precaution to avoid radiotherapy
      when alternatives are available, especially during childhood.
  - reference: PMID:33860896
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies.
    explanation: >-
      The SIOPE surveillance guideline supports the risk rationale for
      minimizing radiotherapy exposure, although this snippet addresses
      follow-up rather than avoidance itself.
diagnosis:
- name: SUFU-Targeted Surveillance Strategy
  description: >-
    Surveillance is intensified in early childhood for medulloblastoma, extends
    into adulthood for meningioma in SUFU carriers, and delays dermatologic
    screening relative to PTCH1 carriers.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  results: >-
    Recommended SUFU-focused surveillance includes brain MRI every three to four
    months until age three years, every six months until age five years, annually
    until age eight years for medulloblastoma surveillance, and brain MRI every
    three to five years beginning at age 30 years for meningioma surveillance.
  evidence:
  - reference: PMID:33860896
    supports: SUPPORT
    snippet: "In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers."
    explanation: Supports SUFU-specific delayed dermatologic start age compared with PTCH1 carriers.
  - reference: PMID:33860896
    supports: SUPPORT
    snippet: "For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only."
    explanation: Supports SUFU-specific early childhood brain MRI surveillance.
  - reference: PMID:20301330
    reference_title: "Nevoid Basal Cell Carcinoma Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brain MRI in those with SUFU-related NBCCS every three to four months until age three years, every six months until age five years, annually until age eight years for medulloblastoma, and then every three to five years beginning at age 30 years for meningioma; ovarian ultrasound in women at age 18 years.
    explanation: >-
      GeneReviews supplies the more specific medulloblastoma and adult
      meningioma MRI interval schedule requested by the review.
  - reference: PMID:33860896
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers.
    explanation: >-
      The SIOPE guideline independently supports adult tumor surveillance that
      includes meningioma MRI for SUFU carriers.
- name: Clinical and Molecular Diagnosis
  description: >-
    Nevoid basal cell carcinoma syndrome is diagnosed when a proband fulfills
    the established clinical diagnostic criteria, and is confirmed by
    identification of a heterozygous pathogenic variant in PTCH1 or SUFU;
    SUFU-related disease specifically elevates childhood medulloblastoma risk.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301330
    reference_title: "Nevoid Basal Cell Carcinoma Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of NBCCS is established in a proband who fulfills proposed diagnostic clinical criteria."
    explanation: >-
      GeneReviews anchors NBCCS diagnosis to the established clinical criteria,
      confirmed and subclassified by PTCH1/SUFU molecular testing.
datasets:
notes: >-
  This entry captures the SUFU-specific molecular route of Gorlin syndrome,
  centered on downstream GLI dysregulation and high early medulloblastoma risk.
  Relative to PTCH1-related disease, jaw cysts and BCC burden are lower and
  surveillance priorities differ.
references:
- reference: PMID:20301330
  title: "Nevoid Basal Cell Carcinoma Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1002/ajmg.a.63496
  title: 'Medulloblastoma and other neoplasms in patients with heterozygous germline <scp><i>SUFU</i></scp> variants: A scoping review'
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB).
    supporting_text: In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB).
    evidence:
    - reference: DOI:10.1002/ajmg.a.63496
      reference_title: 'Medulloblastoma and other neoplasms in patients with heterozygous germline <scp><i>SUFU</i></scp> variants: A scoping review'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB).
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.1007/s10689-021-00247-z
  title: 'Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)'
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: 'Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)'
    supporting_text: Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors.
    evidence:
    - reference: DOI:10.1007/s10689-021-00247-z
      reference_title: 'Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.1038/ng916
  title: Mutations in SUFU predispose to medulloblastoma
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
- reference: DOI:10.1111/ddg.15566
  title: S2k guideline basal cell carcinoma of the skin (update 2023)
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise.
    supporting_text: Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise.
    evidence:
    - reference: DOI:10.1111/ddg.15566
      reference_title: S2k guideline basal cell carcinoma of the skin (update 2023)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.1136/jmedgenet-2021-108385
  title: 'Cancer risk and tumour spectrum in 172 patients with a germline <i>SUFU</i> pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group'
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome.
    supporting_text: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome.
    evidence:
    - reference: DOI:10.1136/jmedgenet-2021-108385
      reference_title: 'Cancer risk and tumour spectrum in 172 patients with a germline <i>SUFU</i> pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.1158/1078-0432.ccr-23-4033
  title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood.
    supporting_text: Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-23-4033
      reference_title: Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.1172/jci.insight.176044
  title: Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis
    supporting_text: Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis
- reference: DOI:10.3390/cancers16122166
  title: 'Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study'
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway.
    supporting_text: Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway.
    evidence:
    - reference: DOI:10.3390/cancers16122166
      reference_title: 'Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.3390/cells12212534
  title: Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide.
    supporting_text: Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide.
    evidence:
    - reference: DOI:10.3390/cells12212534
      reference_title: Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.
- reference: DOI:10.3390/ijms231911968
  title: Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma
  found_in:
  - SUFU-related_Nevoid_Basal_Cell_Carcinoma_Syndrome-deep-research-falcon.md
  findings:
  - statement: Among human cutaneous malignancies, basal cell carcinoma is the most common.
    supporting_text: Among human cutaneous malignancies, basal cell carcinoma is the most common.
    evidence:
    - reference: DOI:10.3390/ijms231911968
      reference_title: Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among human cutaneous malignancies, basal cell carcinoma is the most common.
      explanation: Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

📚

References & Deep Research

References

PMID:20301330

Nevoid Basal Cell Carcinoma Syndrome.

No top-level findings curated for this source.

DOI:10.1002/ajmg.a.63496

Medulloblastoma and other neoplasms in patients with heterozygous germline <scp><i>SUFU</i></scp> variants: A scoping review

1 finding

In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB).

"In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB)."

Show evidence (1 reference)

DOI:10.1002/ajmg.a.63496 SUPPORT Human Clinical

"In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB)."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.1007/s10689-021-00247-z

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

1 finding

Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

"Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors."

Show evidence (1 reference)

DOI:10.1007/s10689-021-00247-z SUPPORT Human Clinical

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.1038/ng916

Mutations in SUFU predispose to medulloblastoma

No top-level findings curated for this source.

DOI:10.1111/ddg.15566

S2k guideline basal cell carcinoma of the skin (update 2023)

1 finding

Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise.

"Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise."

Show evidence (1 reference)

DOI:10.1111/ddg.15566 SUPPORT Other

"Basal cell carcinoma is the most common malignant tumor in the fair‐skinned population and its incidence continues to rise."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.1136/jmedgenet-2021-108385

Cancer risk and tumour spectrum in 172 patients with a germline <i>SUFU</i> pathogenic variation: a collaborative study of the SIOPE Host Genome Working Group

1 finding

Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome.

"Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome."

Show evidence (1 reference)

DOI:10.1136/jmedgenet-2021-108385 SUPPORT Human Clinical

"Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.1158/1078-0432.ccr-23-4033

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors

1 finding

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood.

"Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood."

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-23-4033 SUPPORT Human Clinical

"Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.1172/jci.insight.176044

Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis

1 finding

Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis

"Increasing Sufu gene dosage reveals its unorthodoxical role in promoting polydactyly and medulloblastoma tumorigenesis"

DOI:10.3390/cancers16122166

Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study

1 finding

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway.

"Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway."

Show evidence (1 reference)

DOI:10.3390/cancers16122166 SUPPORT Human Clinical

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.3390/cells12212534

Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma

1 finding

Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide.

"Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide."

Show evidence (1 reference)

DOI:10.3390/cells12212534 SUPPORT Human Clinical

"Non-melanoma skin cancers (NMSCs) are the most common human neoplasms world-wide."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

DOI:10.3390/ijms231911968

Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma

1 finding

Among human cutaneous malignancies, basal cell carcinoma is the most common.

"Among human cutaneous malignancies, basal cell carcinoma is the most common."

Show evidence (1 reference)

DOI:10.3390/ijms231911968 SUPPORT Human Clinical

"Among human cutaneous malignancies, basal cell carcinoma is the most common."

Deep research cited this publication as relevant literature for SUFU-related Nevoid Basal Cell Carcinoma Syndrome.

Deep Research

Falcon ▸

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

Edison Scientific Literature 36 citations 2026-04-05T22:53:16.511345

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

OMIM: Gorlin syndrome / NBCCS MIM 109400 (explicitly stated in SIOPE HGWG and SUFU scoping review). (guerrinirousseau2021currentrecommendationsfor pages 1-2, lee2024medulloblastomaandother pages 1-2)
Gene: SUFU (Suppressor of Fused homolog), located at 10q24 (reported in SUFU scoping review). (lee2024medulloblastomaandother pages 2-2)
MONDO / Orphanet / MeSH / ICD-10/ICD-11: Not directly retrievable from the current tool-accessible evidence set; therefore not asserted here.

1.3 Common synonyms / alternative names

Gorlin syndrome
Gorlin–Goltz syndrome
Nevoid basal cell carcinoma syndrome (NBCCS)
Basal cell nevus syndrome (BCNS) (These are explicitly listed as equivalent names in the 2024 SUFU scoping review and SIOPE surveillance paper.) (lee2024medulloblastomaandother pages 1-2, guerrinirousseau2021currentrecommendationsfor pages 1-2)

1.4 Evidence sources (patient-level vs aggregated)

Aggregated cohorts: 172-carrier collaborative cohort defining tumor spectrum/risk. (guerrinirousseau2022cancerriskand pages 1-1)
Aggregated guidelines: SIOPE HGWG genotype-stratified surveillance; AACR-focused surveillance update for childhood brain tumors. (guerrinirousseau2021currentrecommendationsfor pages 1-2, hansford2024updateoncancer pages 3-4)
Aggregated literature synthesis: scoping review of 176 patients across 30 studies. (lee2024medulloblastomaandother pages 1-2)
Clinical trial registry records: multiple BCC/Gorlin trials of Hedgehog inhibitors. (NCT01350115 chunk 1, NCT00957229 chunk 1, NCT00961896 chunk 1)

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)

SUFU is a causal gene for SUFU-related NBCCS. (lee2024medulloblastomaandother pages 2-2)

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)

Primary pathway: Sonic Hedgehog/Hedgehog signaling with downstream GLI transcription factors. (vallini2023signalingpathwaysand pages 2-3, lee2024medulloblastomaandother pages 2-2)

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

Skin (BCC): UBERON:0002097
Brain/cerebellum (medulloblastoma; meningioma): UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0001875 (meninges)
Gonads/ovary (gonadal tumors/ovarian fibromas): UBERON:0000992 (ovary)

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

Birth incidence of clinical Gorlin syndrome (PTCH1/SUFU combined) is reported in SIOPE HGWG, but SUFU-specific population prevalence is not directly provided in the accessible excerpt. (guerrinirousseau2021currentrecommendationsfor pages 1-2)

9.2 Penetrance and expressivity

In relatives in the 172-carrier cohort, cumulative incidence of any tumor reaches 44.1% by age 50, indicating incomplete penetrance. (guerrinirousseau2022cancerriskand pages 1-1)
In the 2024 scoping review subset, about one-third of patients had none of the three most frequent tumors (MB/BCC/meningioma), highlighting variable expressivity and incomplete penetrance. (lee2024medulloblastomaandother pages 1-2)

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

SIOPE HGWG notes molecular confirmation by testing PTCH1, PTCH2, SUFU (though PTCH2 is de-emphasized as rare/uncertain in some series); and specifically recommends germline testing for PTCH1 and SUFU in all children with SHH-medulloblastoma, particularly <5 years. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2021currentrecommendationsfor pages 4-5)

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

Avoidance of unnecessary ionizing radiation is a key preventive principle given secondary malignancy concerns and earlier tumor emergence after radiotherapy. (guerrinirousseau2021currentrecommendationsfor pages 1-2, guerrinirousseau2022cancerriskand pages 6-7)
Photoprotection to reduce BCC burden is clinically standard, though not SUFU-quantified in available evidence.

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

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)

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)
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)
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)

Guerrini-Rousseau et al. Familial Cancer (published online 16 Apr 2021). “Current recommendations for cancer surveillance in Gorlin syndrome…” https://doi.org/10.1007/s10689-021-00247-z (guerrinirousseau2021currentrecommendationsfor pages 1-2)
Guerrini-Rousseau et al. Journal of Medical Genetics (Jun 2022). “Cancer risk and tumour spectrum in 172 patients…” https://doi.org/10.1136/jmedgenet-2021-108385 (guerrinirousseau2022cancerriskand pages 1-1)
Lee et al. Am J Med Genet A (Jan 2024; accepted 24 Nov 2023). “Medulloblastoma and other neoplasms…” https://doi.org/10.1002/ajmg.a.63496 (lee2024medulloblastomaandother pages 1-2)
Hansford et al. Clin Cancer Res (Apr 2024). “Update on cancer predisposition syndromes and surveillance guidelines for childhood brain tumors.” https://doi.org/10.1158/1078-0432.CCR-23-4033 (hansford2024updateoncancer pages 3-4)
Vallini et al. Cells (Oct 2023). “Signaling Pathways and Therapeutic Strategies in Advanced Basal Cell Carcinoma.” https://doi.org/10.3390/cells12212534 (vallini2023signalingpathwaysand pages 2-3)
Murgia et al. Cancers (Jun 2024). “Gorlin Syndrome-Associated BCCs Treated with Vismodegib or Sonidegib.” https://doi.org/10.3390/cancers16122166 (murgia2024gorlinsyndromeassociatedbasal pages 5-7)
Lang et al. J Dtsch Dermatol Ges (Nov 2024; guideline update 2023). “S2k guideline basal cell carcinoma…” https://doi.org/10.1111/ddg.15566 (lang2024s2kguidelinebasal pages 11-12)

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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(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.
(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.
(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.
(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.
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(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.
(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.

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Environmental Factors

Source YAML

References & Deep Research

References

Deep Research

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

1. Disease Information

1.1 Disease overview (current understanding)

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

2.2 Inheritance pattern

2.3 Risk factors

2.4 Protective factors

2.5 Gene–environment interaction

3. Phenotypes (clinical spectrum)

3.1 Core tumor phenotypes (with frequencies and ages)

3.2 Developmental/congenital phenotypes (non-tumoral)

3.3 Phenotype ontology mapping (suggested HPO terms)

3.4 Quality of life impact

4. Genetic/Molecular Information

4.1 Causal gene(s)

4.2 Variant spectrum / pathogenic variant types

4.3 Functional consequences

4.4 Pathways / molecular function (ontology suggestions)

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Canonical mechanism: SUFU loss → Hedgehog pathway activation

6.2 Tissue- and context-dependence

6.3 Suggested causal chain to clinical manifestations

7. Anatomical Structures Affected (ontology suggestions)

7.1 Primary organs/tissues

7.2 Subcellular localization (mechanistically relevant)

8. Temporal Development (natural history)

9. Inheritance and Population

9.1 Epidemiology

9.2 Penetrance and expressivity

10. Diagnostics

10.1 Clinical diagnostic criteria

10.2 Genetic testing approach

10.3 Screening / surveillance as part of diagnostic and management pathway

11. Outcome / Prognosis

11.1 Tumor risks and mortality

11.2 Prognostic factors

12. Treatment

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

12.2 Pediatric medulloblastoma (SUFU carriers)

12.3 Clinical trials (selected; real-world implementations)

13. Prevention

13.1 Primary prevention

13.2 Secondary prevention (screening / early detection)

14. Other Species / Natural Disease

15. Model Organisms

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

15.2 Model utility and limitations

Consolidated risk and surveillance summary table

Key surveillance figure/table (from SIOPE HGWG)

Expert synthesis / analytical notes (authoritative interpretation)

URLs and publication dates (selected key sources)

Notes on evidence gaps