Transcript Sindrome di Birt-Hogg-Dubé

A.O.U. CAREGGI
DIP.TO BIOMEDICINA
S.O.D.C. GENETICA MEDICA
UNIVERSITA’ DEGLI STUDI DI FIRENZE
DIP.TO FISIOPATOLOGIA CLINICA
SEZIONE GENETICA MEDICA
A.O.U. MEYER
DIP.TO DIREZIONE MEDICA DI PRESIDIO
S.O.D.C. GENETICA MEDICA
Sindrome di Birt-Hogg-Dubé:
validazione dei criteri diagnostici e di
selezione per il test genetico proposti
dal consorzio europeo in una casistica
italiana
Antonella Maffé, Benedetta Toschi, Giuliana Circo, Daniela Giachino, Sabrina Giglio,
Antonio Rizzo, Angelo Carloni, Venerino Poletti, Sara Tomassetti, Lucia Inaudi, Susanna
Orsini, Silvana Ribero, Michele Zuccarofino, Bruno Bossi, Carmelo Ginardi, Silvana
Ungari, Maurizio Genuardi
S.S. Genetica e Biologia Molecolare, A.O. S Croce e Carle di Cuneo, Cuneo
Dipartimento Fisiopatologia Clinica, Università degli Studi di Firenze, Firenze
Pediatria . P. O. Muscatello di Augusta AUSL n. 8, Siracusa
Dipartimento di Scienze Cliniche e Biologiche, Universtità di Torino, Torino
Servizio di Anatomia Patologica, Ospedale San Giacomo, Castelfranco Veneto.
U.O. di Radiologia A.O. Santa Maria di Terni, Terni
S.C. Pneumologia Interventistica Ospedale GB Morgagni, Forlì
Birt-Hogg-Dubé syndrome
Clinical triad:
 Cutaneous follicular hamartomas
 Lung cysts/spontaneous pneumothorax
 Kidney tumors
 Estimated prevalence : 1/200.000
 Autosomal dominant transmission with variable
expressivity and incomplete penetrance
 FLCN gene, tumor suppressor
 Possibly involved in the mTOR (Mammalian Target
of Rapamycin) energy/nutrient-dependent
signaling pathway
BHD Diagnostic criteria
MINOR
MAJOR
• > 5 fibrofolliculomas or
trichodiscomas (1 histologically
confirmed)
• Constitutional pathogenic
FLCN mutation
•
•
Multiple lung cysts, basal,
+ pneumothorax
Renal tumors
–
–
–
–
•
Early onset (< 50 yrs)
Multifocal
Bilateral
or Mixed
chromophobe/oncocytic
1st degree relative with BHDS
Diagnosis: > 1 major or > 2 minor
Menko FH, van Steensel MA, Giraud S et al. European BHD
Consortium. Birt-Hogg-Dub´e syndrome: diagnosis and management.
Lancet Oncol. 2009: 10: 1199–1206
Selection criteria for FLCN genetic testing
• Early-onset renal cancer (< 50 yrs), especially if
–
–
–
–
Multifocal
Bilateral
Chromophobe
or Oncocytic
• Unexplained cystic lung disease, especially if
basal, or unexplained pneumothorax
• Familial cystic lung disease or pneumothorax
• Familial renal cancer
• Or any combination of spontaneous
pneumothorax and kidney cancer in an
individual or family
Menko FH, van Steensel MA, Giraud S et al. European BHD
Consortium. Birt-Hogg-Dub´e syndrome: diagnosis and management.
Lancet Oncol. 2009: 10: 1199–1206
Patients
19 probands ascertained for renal or lung
manifestations
•17: fulfilling EC genetic testing criteria
• 2: multiple renal tumors > 50 yrs
Molecular analysis
•Genomic sequencing
•7 different truncating mutations in 9 probands
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–
–
–
–
–
–
c.1285dupC (p.H429Pfs*27)  3 families
c.1429C>T (p.477R>X)
c.1300+2T>C (r.1276-1300del)
c.347dupA (p.L117Afs*16)
c.1127G>A (p.376 W>X)
c.1379 1380del (p.L460Qfs*25)
c.1286dupA (p.H429Qfs*27)
Clinical Correlations
•
•
All 9 FLCN +ve probands had involvement of at least 2 BHD target tissues
(skin, lung, kidney)
8/9 FLCN +ve probands had relatives with BHDS or at least 1 manifestation
in a target tissue
•
•
8/10 FLCN –ve probands had a single tissue involved
9/10 FLCN –ve probands did not have relatives with BHDS manifestation
(only one FLCN –ve proband had a 2nd degree relative with pneumothorax)
•
•
•
FLCN mutations in all probands with multiple cutaneous hamartomas
Cutaneous hamartomas present in 8/21 FLCN +ve subjects (probands +
relatives) > 20 yrs
No cutaneous hamartomas in FLCN –ve probands
•
7/16 FLCN +ve relatives > 20 yrs have no manifestation
Renal tumors in families tested for FLCN
mutations
HISTOLOGY
MUTATION POSITIVE
MUTATION NEGATIVE
Clear cell carcinoma
3 (33%)
8 (80%)
Chromophobe carcinoma
1 (11%)
1 (10%)
Oncocytoma
1 (11%)
1 (10%)
Hybrid chromophobe/oncocytic
2 (22%)
-
Hybrid chromophobe/clear cell
2 (22%)
-
Hybrid clear cell/oncocytic
1 (11%)
-
Hybrid chromophobe/clear
cell/oncocytic
1 (11%)
-
Total families with renal tumors
8 (89%)
9 (90%)
Total families
9
10
Maffé et al. , Clin. Genet. 2010
Patient 07.01
wt
wt
mut
2
PNX
Fibrofolliculomas
Kidney
tumor
Fibrofolliculomas
FCLN: c.347dupA mutation in exon 5
Colon carcinoma
Bilateral
parotid
oncocytomas
Parotid oncocytoma
Loss of heterozygosity in
parotid oncocytoma
Wild-type
07.01 Blood
07.01 Oncocytoma
Parotid tumors in BHDS
8 cases reported
6 oncocytomas
Mean age at diagnosis of parotid oncocytoma in general population: 64 yrs
In pt 04.01 diagnosis at 32 and 43 yrs, respectively
Conclusions
 Validity of EC selection criteria
confirmed
Mutations in 9/17 fulfilling criteria
 Cutaneous hamartomas: major predictor
of FLCN mutations
 Age-related, reduced penetrance
 Parotid oncocytoma component
manifestation of BHDS