Basal Cell Nevus/Hamartoma Syndrome (Gorlin-Goltz)

Inheritance
  • AD
  • de novo mutations in 20-30% of patients
 
Etiology
  • Mutation in tumor supressor gene PTCH (PTCH1 & PTCH2)
    • Results in overactivation of Sonic HedgeHog (SHH) pathway, which has importante roles in neurologic and anterior-posterior axis development as well as hair follicle formation (that’s why vismodegib patients have alopecia)
  • SUFU - more recently described gene, further down in the pathway
    • High risk of medulloblastoma (up to 33%) and a high risk of meningioma post radiation
    • Facial features are likely more subtle in individuals with an SUFU pathogenic variant
    • No jaw cysts reported
    • Resistence to Sonic Hedgehog inhibitors
      •  
      Sonic Hedgehog Pathway
      • Normalmente temos 2 proteínas transmembranares (Ptch & Smo).
      • Normally Ptch inhibits Smo.
      • Smo activates GLI1&2 transcription factors, activate transcription of cellular growth genes
      • Implicações clínica
        • If Ptch is mutated, Smo is allowed to run free → cancar
        • Sonic Hedgehog inhibitors (sonidegib or vismodegib) inhibit Smo → stop cancer
            • notion image
di Magliano et al. Nat Rev Cancer 2003
di Magliano et al. Nat Rev Cancer 2003
 
Clinical presentation
  • Skin
    • Multiple basal cell hamartomas → associated with high risk of developping basal cell carcinoma
    • Palmoplantar pits
      • Small clusters pf basaloid cells, explains very focal defect in keratinization
    • Comedones, epidermoid cysts, milia, molluscum pendulum, café-au-lait spots
  • Extracutaneous (Bone, nerve, eye and endocrine)
    • Maxillary cysts
    • Bone signs
      • Rib abnormalities (synostoses, bifidinites, partial agenesis)
      • Vertebral and metacarpophalangeal malformations (shortness of the 4th metacarpal)
    • Nervous system
      • Clacification of the falx cerebri
      • Meningiomas
      • Medulloblastomas
      • Agenesis of corpus callosum
    • Eye
      • Various ocular signs
    • Endocrine
      • Various sexual disorders
      • Pseudohypoparathyroidism
 
Diagnostic criteria: 2 major e 1 minor ou 1 major e 3 minor ou identificação da mutação
  • Critérios major:
    • >5 basaliomas
    • Basalioma antes dos 30 anos de idade
    • Calcificação lamelar da foice
    • Queratocisto da mandíbula
    • Pits palmo plantares
    • Familiar de primeira ordem afetado
  • Critérios minor
    • Meduloblastoma na infância (tumor também dependentes da via Hedgehog)
    • Quistos pleurais ou linfomesentéricos
    • Macrocefalia
    • Fenda do lábio ou palato
    • Anomalias costais ou vertebrais
    • Polidactilia preaxial ou pós axial
    • Fibromas cardíacos ou ováricos
    • Anomalias oculares
notion image
  • Perls
    • Palmar pits
    • BCC may look like skin tags
    • Calcification of the falx
    • Bifid ribs
 
Exames complementares de diagnóstico
  • Ressonância magnética na infância pelo risco de meduloblastoma se mutação SUFU
 
Treatment:
  • topical imiquimod
  • destructive lasers,
  • Curettage and eletrocoagulation
  • excision for nodular BCCs,
  • Vismodegib, sonidegib
    • Vismodegib inhibits Smo (doesn’t work with SUFU syndrome)
    • Vismodegib patients have alopecia because sonic hedghog pathway is also important for hair development
    • Also reduces size of maxillary cysts
  • Radioterapia não aconselhada pelo risco carcinogénico de novos basaliomas
 
Seguimento
  • Seguimento a cada 4-6 meses