SUFU mutation

Germline SUFU mutation carriers should be recognized as a distinct group of patients carrying specific health risks, independent of meeting the BCNS criteria. Phenotypic prediction based on the specific SUFU mutation seems unfeasible. It is of utmost importance that the less apparent MHIBCC phenotype is recognized, to provide (second generation) germline SUFU mutation carriers appropriate healthcare.

Molecular screening of patients with GS who do not fulfill Evan's diagnostic criteria should only be offered in first intention to patients under 30 years of age. After 30 years, a careful clinical examination and complementary radiological exams should be enough to eliminate the diagnosis of GS among patients who do not fulfill diagnostic criteria.

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No abstract available

Radiation exposure by, for example, computed tomography, should be minimized as it induces new BCCs. Regular follow-up by a dermatologist for early diagnosis and treatment of (multiple) BCC's is recommended for life.

We present two patients with MHIBCC, along with a more complex cutaneous and extracutaneous phenotype. MHIBCC syndrome and BCNS may share clinical features and, indeed, both syndromes probably represent different degrees of upregulation in the Hh pathway.

In patients with NBCCS secondary to SUFU mutation, a precarious molecular environment is created that genetically predisposes for early medulloblastoma formation. Early genetic diagnosis and appropriate cancer screening were critical to this patient's favorable outcome.

In our limited cohort, we observed concordance with the new WHO 2021 criteria for Grade 3 meningiomas

SUFU was probably not involved in the development of a thyroid carcinoma in a patient with a germline SUFU mutation. Hence, we have proven that meningioma and leiomyoma of the testis are rare extracutaneous tumours that are part of BCNS.

This coincided with reduced responsiveness to upstream Shh pathway component Smoothened, while sensitivity to downstream components Sufu and Gli was retained. Together, these findings can explain the preference for SUFU mutations in infant medulloblastoma and suggest that drugs targeting the downstream SHH pathway will be most appropriate for infant patients.

In multivariate analysis correcting for age, gender, MC, and WHO grade, none of the individual mutations except TERT remained an independent significant prognostic factor for PFS. Molecular profiling including mutational analysis and DNA methylation classification may facilitate more precise prognostic assessment and identification of potential targets for personalized therapy in meningioma patients.

Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.

Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

Multivariate analysis identified histological type (p = 0.026), metastasis (p = 0.031) and KMT2C mutational status (p = 0.046) as independent prognosticators in our cohort. In summary, we identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their risk stratification and treatment.

Patients with SHH medulloblastoma should routinely undergo genetic testing. We propose that whole genome, whole exome sequence, or custom-designed panel-targeted exome sequencing should be performed.

This observation was of particular interest given that rare kindreds of the Multiple Hereditary Infundibulocystic BCC syndrome (MHIBCC), which is related, but possibly distinct from the nevoid BCC syndrome, harbored mutations in SUFU. Our results support the classification of the infundibulocystic variant as a subtype of BCC, and suggest that the level at which genetic alterations occur within the Hedgehog pathway may be an important determinant of the morphologic features in BCC.