Sindrome di Birt-Hogg-Dubé: validazione dei criteri diagnostici e di selezione per il test genetico proposti dal consorzio europeo in una casistica

italiana

UNIVERSITA’ DEGLI STUDI DI FIRENZE

DIP.TO FISIOPATOLOGIA CLINICA

SEZIONE GENETICA MEDICA

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

A.O.U. CAREGGI

DIP.TO BIOMEDICINA

S.O.D.C. GENETICA MEDICA

A.O.U. MEYER

DIP.TO DIREZIONE MEDICA DI PRESIDIO

S.O.D.C. GENETICA MEDICA

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

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

Birt-Hogg-Dubé syndrome

FLCN gene, tumor suppressor

Possibly involved in the mTOR (Mammalian Target of Rapamycin) energy/nutrient-dependent signaling pathway

BHD Diagnostic criteria

• > 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

MAJOR MINOR

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

19 probands ascertained for renal or lung manifestations

•17: fulfilling EC genetic testing criteria

• 2: multiple renal tumors > 50 yrs

Patients

•Genomic sequencing

•7 different truncating mutations in 9 probands– 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)

Molecular analysis

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

2

PNXColon carcinoma

Bilateral parotid oncocytomas

Kidney tumor

Fibrofolliculomas

FCLN: c.347dupA mutation in exon 5

Fibrofolliculomas

mut

wt

wt

Parotid oncocytoma

Loss of heterozygosity in

parotid oncocytoma

Wild-type 07.01 Blood 07.01 Oncocytoma

8 cases reported

6 oncocytomas

Parotid tumors in BHDS

Mean age at diagnosis of parotid oncocytoma in general population: 64 yrsIn pt 04.01 diagnosis at 32 and 43 yrs, respectively

Conclusions

Validity of EC selection criteria confirmedMutations in 9/17 fulfilling criteria

Cutaneous hamartomas: major predictor of FLCN mutations

Age-related, reduced penetrance Parotid oncocytoma component

manifestation of BHDS