Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

esembling mainly chromophobe and
clear cell renal carcinomas and renal
oncocytomas as well as fibrofolliculomas
and pulmonary cysts {246,1891,2033,
2631,2924}.
B
Definition
Birt-Hogg-Dubé (BHD) syndrome is a
syndrome characterised by benign skin
tumours, specifically fibrofolliculomas,
trichodiscomas and acrochordons.
Multiple renal tumours and spontaneous
pneumothoraces are frequent in patients
with BHD syndrome.
MIM No. 135150 {1679}.
A
Fig. 1.13 A Early facial fibrofolliculomas in BHD syndrome. B,C CT scan images of abdomen in BHD patient
showing multiple bilateral renal carcinomas which necessitated bilateral nephrectomy and subsequent
renal transplant.
vation of FH has been detected in almost
all HLRCC tumours {52,1329,1330,1450}.
FH mutations
Germline mutations in FH have been
found in 85% (89/105) of the HLRCC
families {52,1330,1469,2627,2632}.
Altogether 50 different germline mutations
have been identified. Two founder
mutations have been detected in the
Finnish population, a missense mutation
H153R (in 3 out of 7 families) and a 2-bp
deletion in codon 181 (in 3 out of 7 families).
Most of the families with these
mutations included renal cell cancer
and/or uterine leiomyosarcoma
{1330,1469,2627}. A splice site mutation
IVS4+1G>A was detected in families of
Iranian origin {465}. In addition, a missense
mutation R190H was reported in
35% of the families from North America.
To date, the role of FH in sporadic tumorigenesis
has been evaluated in three different
studies {169,1330,1469}. Somatic
FH mutations seem to be rare, but have
been found in uterine leiomyomas and a
high-grade sarcoma.
FH deficiency
This is a recessive disease caused by
biallelic germline mutations in FH. The
syndrome is characterized by neurological
impairment, growth and developmental
delay, fumaric aciduria and absent or
C
reduced enzyme activity in all tissues.
Heterozygous parents are neurologically
asymptomatic heterozygous carries of the
mutation with a reduced enzyme activity
(approximately 50%). Tumour predisposition
similar to HLRCC is likely {2627}. Thus
far, 10 different FH mutations have been
reported in 14 FH deficiency families (Fig
3.).
Genotype-phenotype correlations
No clear pattern has emerged to date.
Three mutations (K187R, R190C, and
R190H) have been reported in both
HLRCC and FH deficiency. Renal cell cancer
and uterine leiomyosarcoma occur only
in a minority of families, but the same mutations
(a 2-bp deletion in codon 181, R190H,
and H275Y) have been identified in families
with or without malignancies.
Because some families appear to have
high risk of cancer at early age, and others
little or no risk, modifying gene/s could play
a key role in the development of renal cancer
and uterine leiomyosarcoma in HLRCC
{697,2627,2632}.
Birt-Hogg-Dubé syndrome
(BHD)
The BHD syndrome conveys susceptibility
to develop renal epithelial tumours
Diagnostic criteria
Renal tumours
Renal pathology may vary in individuals
with BHD syndrome. Tumours can be
multiple and bilateral. Renal oncocytoma
is well described and is usually thought
of as a benign tumour. Other
histopathologies have been described
including papillary and chromophobe
adenocarcinoma with a mixed population
of clear and eosinophillic cells. The age
at clinical manifestation is approximately
50 years and the mean number of
tumours present is 5 per patient.
Metastatic disease is rare and appears
to only occur if the primary tumour has a
diameter of >3 cm {2031}.
Skin tumours
Fibrofolliculomas (FF), trichodiscomas
(TD) and acrochordons are the classical
skin lesions in BHD syndrome. The FF
and TD lesions look the same and present
as smooth dome-shaped, skin
coloured papules up to 5mm in diameter
over the face, neck and upper body with
onset typically in the third or fourth
decade of life. Skin lesions are initially
subtle but remain indefinitely and
become more obvious with increasing
age as illustrated by Toro et al 1999
{2631}. Acrochordons (skin tags) are not
always present. Biopsy will usually
demonstrate an epidermis with aberrant
follicular structures, thin columns of
epithelial cells and small immature sebocytes
clustered within the epithelial
cords. Alcian blue demonstrates the
presence of abundant mucin within the
stroma.
Other lesions
Spontaneous pneumothorax and the
20 Tumours of the kidney