bb5_29.qxd 13.9.2006 13:58 Page 349
CHAPTER 21
Congenital and Inherited Syndromes Associated with
Bone and Soft Tissue Tumours
During the past decade, rapid progress has been made in our
understanding of how inherited genetic aberrations may influ-
ence cancer risk. A large number of neoplasia-associated syn-
dromes following Mendelian inheritance has been defined both
clinically and at the DNA level, providing a solid basis for genet-
ic counselling of patients and their families. The identification of
specific genes involved in inherited cancer predisposition pro-
vides, in addition, important insights into genetic pathways
involved in the development of sporadic neoplasia.
Although inherited susceptibility accounts for only a minority of
all bone and soft tissue tumours, several syndromes and disor-
ders have been identified, and for many of them the underlying
genetic cause has been identified. In the attached Table, well
characterized familial disorders associated with bone and soft
tissue tumours are listed, including congenital malformation syn-
dromes in which no clear pattern of inheritance has as yet been
noted.
On the following pages, a more detailed description of the clini-
cal, histopathological, and genetic data is provided for those
syndromes that are well characterized at the DNA level, or for
which the associated neoplasms display features that are dis-
tinct from those of their sporadic counterparts. Cowden disease,
Li-Fraumeni syndrome and neurofibromatosis type 1 and 2 have
been dealt with in the WHO Classification of Tumours of the
Nervous System.
bb5_29.qxd 13.9.2006 13:58 Page 350
Table 21.01
Congenital syndromes associated with bone and soft tissue tumours.
OMIMa Disorderb Inheritance Locusc Gene Bone and soft tissue tumours
103580 Albright hereditary osteodystrophy AD 20q13 GNAS1 Soft tissue calcification and osteomas
153480 Bannayan-Riley-Ruvalcaba syndrome AD 10q23 PTEN Lipomas, haemangiomas
130650 Beckwith-Wiedemann syndrome Sporadic/AD 11p15 Complex, Embryonal rhabdomyosarcomas,
incl. CDKN1C myxomas, fibromas, hamartomas
and IGF2
210900 Bloom syndrome AR 15q26 BLM Osteosarcomas
160980, Carney complex AD 17q23-24 PRKAR1AK Cardiac and other myxomas,
605244 2p16 - melanocytic schwannomas
112250 Diaphyseal medullary stenosis AD 9p21-22 - Malignant fibrous histiocytomas of bone
with malignant fibrous histiocytoma
151623 Li-Fraumeni syndrome AD 17p13 TP53 Osteosarcomas, rhabdomyosarcomas
22q11 CHEK2 and other soft tissue sarcomas
151800 Lipomatosis, symmetrical Sporadic - - Lipomas, lipomatosis of the head and neck
166000 Maffucci syndrome Sporadic - - Enchondromas, chondrosarcomas,
spindle cell haemangiomas,
haemangiomas, angiosarcomas
- Mazabraud syndrome Sporadic 20q13 GNAS1 Polyostotic fibrous dysplasia,
osteosarcomas, intramuscular myxomas
174800 McCune-Albright syndrome Sporadic 20q13 GNAS1 Polyostotic fibrous dysplasia,
osteosarcomas
133700, Multiple osteochondromas, AD 8q24, EXT1 Osteochondromas, chondrosarcomas
133701 non-syndromic 11p11-12 EXT2
228550 Myofibromatosis AR - - Myofibromas
162200 Neurofibromatosis type 1 AD 17q11 NF1 Neurofibromas, malignant peripheral
nerve sheath tumours
101000 Neurofibromatosis type 2 AD 22q12 NF2 Schwannomas
166000 Ollier disease (enchondromatosis) Sporadic 3p21-22 PTHR1 Enchondromas, chondrosarcomas
350 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:58 Page 351
OMIMa Disorderb Inheritance Locusc Gene Bone and soft tissue tumours
167250; Paget disease of bone, familial AD 18q21 TNFRSF11A Osteosarcomas
602080 5q31 -
5q35 -
176920 Proteus syndrome Sporadic - - Lipomas
180200 Retinoblastoma AD 13q14 RB1 Osteosarcomas, soft tissue sarcomas
601607 Rhabdoid predisposition syndrome AD 22q11 SMARCB1 Malignant rhabdoid tumours
268400 Rothmund-Thomson syndrome AR 8q24 RECQL4 Osteosarcomas
180849 Rubinstein-Taybi syndrome AD 16p13 CREBBP Myogenic sarcomas
138000 Venous malformations AD 1p21-22 - Glomus tumors
with glomus cells
277700 Werner syndrome AR 8p11-12 WRN Various bone and soft tissue sarcomas
a OMIM = entry number in McKusick s Online Mendelian Inheritance in Man {1376}.
b Syndromes associated with tumours affecting only the skin or parenchymatous organs are not included.
cAD = autosomal dominant; AR = autosomal recessive.
Congenital syndromes associated with bone and soft tissue tumours 351
bb5_29.qxd 13.9.2006 13:58 Page 352
M. Nilbert
Familial adenomatous polyposis
C.M. Coffin
Definition germline, disease-causing mutation of dermoid cysts, and desmoid-type fibro-
Familial adenomatous polyposis (FAP) the APC gene or 3) a family history of matoses {766,768,1544,1606,1705}. In
is characterized by the development of FAP and at least one of the following: addition to these lesions, a variety of
multiple colorectal polyps, which are epidermoid cysts, osteomas or desmoid other soft tissue masses have been clin-
premalignant lesions with a strong ten- tumour. Other types of extracolonic ically described, with varying extents of
dency to progress into carcinomas. manifestations are associated with FAP, pathological analysis. These include ill
Gardner syndrome, characterized by including adenomatous polyps of the defined connective tissue masses, "lipo-
colorectal polyps as well as extra- upper gastrointestinal tract, congenital mas" {1705}, "fibrous dysplastic lesions"
colonic manifestations such as dental hypertrophy of the retinal pigment {1544}, "familial infiltrative fibromatosis"
abnormalities, osteomas, epidermoid epithelium (CHRPE), an increased risk {1913}, fibromatous mesenteric plaques
cysts and desmoid tumours, was initial- of hepatoblastoma and tumours of the {363}, juvenile nasopharyngeal angiofi-
ly considered a separate entity, but has endocrine system, most commonly pap- broma {784}, Gardner fibroma {2227},
now been recognized as a variant of illary carcinoma of the thyroid. Further- and rhabdomyosarcoma {84}.
FAP. FAP is caused by mutations in the more, an association with brain The association of desmoids, including
adenomatosis polyposis coli (APC) tumours, especially medulloblastomas, those with childhood onset, with adeno-
gene on chromosome 5. occurs in the Turcot syndrome, which in matous polyposis of the coli is now well
two-thirds of the cases is caused by recognized {175,312,361,362,566,768,
OMIM number 175100 APC mutations. In familial infiltrative 769,1032,1068,1913}. The incidence of
fibromatosis (OMIM No. 135250), which desmoid tumours in patients with poly-
Synonyms is also caused by germline mutations of posis has been estimated to be around
Bussey-Gardner polyposis, adenoma- APC, there is an inherited predisposition 10%. Pathological features of desmoid-
tous polyposis coli, familial polyposis to desmoid tumours, but only few or no type fibromatosis are described else-
coli, familial multiple polyposis, etc. colonic polyps. where in this book (see page 83).
Particular APC mutation types are asso-
Incidence Clinical features ciated with a higher frequency of des-
Estimates of the incidence of FAP vary Colorectal adenomas usually develop moid tumours {175, 312, 859, 931, 957,
between 1/7,000 and 1/30,000 {1033}. into endoscopically detectable lesions 1015,1047,1137,1286,1685,1799,1993}.
Whereas dental abnormalities and at 10-20 years of age and increase in The Gardner fibroma {2227}, described
osteomas occur in more than half of the number and size over time. Untreated elsewhere in this book (see page 76),
patients, desmoid tumours and epider- FAP patients develop colorectal cancer is similar to the fibromatous mesenteric
moid cysts develop in a minority of the at a median age of about 40 years. FAP plaques reported in patients with ade-
patients. Overall, FAP accounts for less patients should be screened with nomatous polyposis coli {363}. These
than 1% of all colorectal cancers. endoscopy with 1-2 year intervals from lesions are associated with develop-
10-15 years of age up to 40 years of age ment of desmoid-type fibromatosis in
Diagnostic criteria and prophylactic colectomy is per- the same site, either following surgery
The diagnosis of FAP requires 1) at least formed when adenomas are detected. or de novo {361,2227}. Recognition of
100 colorectal adenomas or 2) a Extraintestinal manifestations, in partic- the Gardner fibroma in childhood can
ular epidermoid cysts, dental abnormal- serve as the sentinel event for diagnosis
ities, osteomas and CHRPE often pre- of adenomatous polyposis of the colon
ceed the development of adenomas {2227}. Juvenile nasopharyngealangio-
and may serve as clinical markers of fibroma has also been reported in asso-
FAP. ciation with adenomatous polyposis of
the colon {8,10,784}. However, some
Bone and soft tissue tumours have questioned whether this associa-
The description of Gardner syndrome in tion is coincidental or whether it is actu-
the 1950 s highlighted the association of ally related to another alteration of the
familial polyposis coli with a spectrum of APC gene {850}. Rhabdomyosar-coma
extracolonic manifestations, including has been reported in rare instances in
lesions of soft tissue and bone {766- individuals or families with adenoma-
769}. The most commonly encountered tous polyposis of the colon {84,1299},
Fig. 21.01 Epidermoid cyst on the dorsal surface of
bone and soft tissue lesions are osteo- but it is unclear whether this is a spo-
the hand of a patient with familial adenomatous
polyposis. mas, cortical thickening of bone, epi- radic occurrence or another syndromic
352 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 353
thereby targets ß-catenin for degrada-
tion. ß-catenin is involved in the
cytoskeletal organisation with micro-
tubule binding and in cell adhesion
through interaction with E-cadherin.
APC mutations, presumably trough loss
of binding sites and degradation sites
for ß-catenin lead to intracellular accu-
mulation of ß-catenin, which is trans-
ferred to the nucleus and through inter-
A B
action with transcription factors of the
Fig. 21.02 Mesenteric fibromatosis (desmoid tumour) in a patient with FAP. A The lesion entraps loops of
TCF/LEF family regulates expression of
small intestine. B Histopathology is dominated by collagen bands and small vessels.
downstream target genes such as MYC
and CCND1 {2011, 2104}. The C-termi-
manifestation. posed of 15 coding exons and contains nal mediates binding to microtubule-
Bone lesions associated with adenoma- an open reading frame of 8,538 bp. associated proteins of the EB1/RP1
tous polyposis of the colon are entirely Several alternatively spliced forms of family. Truncated APC thereby promotes
benign and are viewed as dysplasias. APC with different 5´regions have been chromosomal instability through disrupt-
Multiple osteomas formed by membra- identified. ed interaction between the kinetochores
nous ossification, especially of calvarial and the spindle microtubules {693}.
and mandibular surfaces, characterize Gene expression
the "ivory exostosis" of Gardner syn- The 2,843 amino-acid APC protein is Mutations
drome {285, 331, 1075, 1690}. Histologi- ubiquitously expressed in most normal Analyses of the APC gene in patients
cally, the Gardner osteoma is a nodular tissues with the highest expression with FAP reveal mutations in about 80%
excrescence of mature lamellar bone found in the central nervous system. of the kindreds examined, and the
involving the cortical surface, especially APC is a multifunctional protein with remaining patient are likely to carry APC
the outer table of the skull, the mandibu- several functional domains through gene mutations leading to large dele-
lar cortex, or rarely other sites. Like which APC exerts its main function as a tions or impaired protein expression.
desmoid fibromatosis, particular APC negative regulator of the Wnt signalling Over 95% of the mutations identified
gene mutations are associated with pathway {312,693,921,1819}. Normal result in protein truncation, which large-
more severe osseous manifestations Wnt signalling inhibits the function ly result from nonsense point mutations
{451, 1180, 2080}. Diffuse craniofacial of glycogen synthase 3ß (GSK3B), or deletions causing frameshifts.
sclerotic bone changes and dental mal- dephosphorylates axin / conductin and Genotype-phenotype correlations exist;
formations are also encountered. The
bony lesions of adenomatous polyposis
of the colon do not evolve into other
benign neoplasms, such as osteoblas-
tomas, or into malignant lesions.
Genetics
Germline mutations of the APC gene is
the only identified cause of FAP. FAP is
autosomally dominantly inherited with
an almost complete penetrance.
However, at least one-fifth of the
patients lack a family history and are
thus assumed to carry de novo muta-
tions of the APC gene {204}.
Gene structure
The APC gene was in 1986 localized to
5q21-22 through observation of a
patient with polyposis and a constitu-
tional interstitial deletion of 5q followed
by an establishment of linkage to this
locus in several FAP kindreds {940,
Fig. 21.03 Functional and disease-related domains of the APC gene. ß-catenin binding is achieved through
1241}. The APC gene was isolated in
the 15-amino acid and 20-amino acid repeat-containing regions and the C-terminal of APC which interacts
1991 and was found to be mutated in
with microtubule-associated proteins of the EB/RP family and with DLG, a human homologue of the
the germline of patients with FAP {840,
Drosophila discs large tumour suppressor protein. Mutations between codons 1403 and 1578 have been
1123}. The gene spans 120 kb, is com- associated with the extracolonic manifestations, e.g. desmoid tumours.
Familial adenomatous polyposis 353
bb5_29.qxd 13.9.2006 13:59 Page 354
truncating mutations in the 5´ end of with multiple polyps at young age, and identical mutations can develop dissi-
the gene have been associated with mutations between codons 1444 and milar clinical features and the genotype
attenuated FAP, mutations in the central 1578 are associated with an increased clinically serves as a risk determinant
region of gene, including the mutational incidence of desmoid tumours {451, rather than as an absolute predictor of
hotspot at codon 1309, are associated 1124, 2011}. However, patients with the extent of the disease.
M. Mannens
Beckwith-Wiedemann syndrome
Definition nephromegaly and hemihypertrophy). seem to be a favourable prognostic fac-
The Beckwith-Wiedemann syndrome DeBaun is less strict in his classification tor since tumours are not, or only very
(BWS) is a complex overgrowth disorder i.e. two or more of the five most common rarely associated with this group of
caused by a number of genes that are features (macroglossia, birth weight > patients. Recurrence risks for a second
subject to genomic imprinting. A high 90th percentile, hypoglaecemia in the pregnancy can be assessed with UPD
incidence of solid childhood tumours, first month of life, ear creases/pits and studies. In case of a UPD in a mosaic
including rhabdomyosarcoma, is seen in abdominal wall defects). form, there is no increased recurrence
patients that present with BWS. BWS can be diagnosed in the laboratory risk for BWS in a second pregnancy
by chromosome banding analysis (< 5%) since the genetic defect occurred post-
OMIM number 130650 or DNA-diagnostics. The current major fertilisation.
test involves methylation assays or loss
Synonyms of imprinting (LOI) studies at the RNA Clinical features
EMG syndrome (Exomphalos-Macro- level. The majority of cases (50-80%) The BWS is a disorder first described by
glossa-Gigantism syndrome), WBS demonstrates aberrant methylation of Beckwith in 1963 at the 11th annual
(Wiedemann-Beckwith syndrome). KCNQ1OT1, with or without aberrant meeting of the Western Society for
methylation of IGF2/H19. These latter Pediatric Research. Later, Wiedemann
Incidence cases often show uniparental disomy and Beckwith described the syndrome in
The syndrome occurs with an estimated (UPD), in a mosaic form, for 11p15, more detail {149, 2266}. BWS is charac-
incidence of 1:13,700 and most cases which explains this aberrant methylation. terized by a great variety of clinical fea-
(85%) are sporadic. However, the majority of cases with tures, among which are abdominal wall
KCNQ1OT1 defects and some cases defects, macroglossia, pre- and postna-
Diagnostic criteria with H19/IGF2 defects have no UPD tal gigantism, earlobe pits or creases,
Patients can be classified as having BWS 11p15. Therefore, an imprinting switch facial nevus flammeus, hypoglycemia,
according to the clinical criteria pro- can be assumed involving an imprinting renal abnormalities and hemihypertrophy.
posed by Elliot or DeBaun {479, 580} centre, analogous to the Prader-Willi and
although cases of BWS are known that Angelman syndromes. The current data Tumours
do not comply with either set of criteria. are most compatible with two distinct BWS patients have a risk of 7.5% for the
Elliot classifies patients as BWS when imprinting centres for either KCNQ1OT1 development of (mostly intra-abdominal)
they present with three major features or or IGF2/H19. CDKN1C mutation analy- childhood tumours. Tumours most fre-
two major features plus three or more ses might be considered, especially in quently found are Wilms tumour, adreno-
minor features (major features: anterior familial cases of BWS. The increased cortical carcinoma, embryonal rhab-
abdominal wall defects, macroglossia tumour risk for BWS patients seems to be domyosarcoma, and hepatoblastoma.
and pre- and/or postnatal growth > 90th associated with UPD in general and H19 Also myxomas, fibromas, and chest wall
centile; Minor features: ear creases or methylation defects in particular. hamartomas have been reported to
pits, naevus flammeus, hypoglycaemia, KCNQ1OT1 methylation defects only occur at increased frequencies.
354 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 355
defects. Another strong candidate for
involvement in the aetiology of BWS is
IGF2. Mouse models overexpressing
Igf2 displayed a phenotype overlapping
with the BWS phenotype. Loss of IGF2
imprinting is often seen in BWS patients.
Down-stream from IGF2 lies H19, again
a non-coding gene. The expression of
IGF2 and H19 seems to be linked. H19
is important for the maintenance of the
imprinting status of IGF2. Mouse studies
underline the link between IGF2 and
H19 expression and overgrowth phe-
notypes were found. H19 loss of im-
printing is frequently seen in BWS
cases although not always in combi-
nation with IGF2 LOI. Finally, a gene
Fig. 21.04 Imprinted genes on 11p15 involved in BWS. The parental expression (imprinting) of these genes
called ASCL2 is localized to the 11p15-
is indicated.
imprinted region. Although no direct
involvement in the BWS aetiology is
Genetics BWSCR1 known, this gene might account for
BWS is caused by genetic changes in This region consists of a number of the fact that most, if not all, BWS cases
chromosome band 11q15, as shown by imprinted genes. All known transloca- with UPD present in a mosaic form.
linkage studies, and the detection of tion breakpoints disrupt KCNQ1, a The mouse homologue codes for a
chromosome abnormalities, LOI, and gene coding for a potassium channel transcription factor, which is expressed
gene mutations. The syndrome is sub- in-volved also in inherited cardiac during early mouse development and
ject to genomic imprinting since mater- arrhythmia syndromes. This imprinted is essential for the development of the
nal transmission seems to be predomi- gene, however, is most likely not direct- placenta. Therefore, also in humans,
nant. In addition, chromosomal translo- ly involved in BWS. A gene transcribed complete lack of expression might be
cations are of maternal origin, dupli- in the antisense orientation of KCNQ1 lethal.
cations and UPD of paternal origin. All clearly is. This gene, KCNQ1OT1, shows
hitherto known causative genes are aberrant methylation in 50-80% of BWS BWSCR2
imprinted. The translocation breakpoints cases. It does not code for a protein Two patients define this second chromo-
on chromosome 11 map to three distinct and may function through its RNA. somal region, one of whom developed a
regions within 11p15.3-pter. Beckwith- CDKN1C is an inhibitor of cyclin- Wilms tumour {34}. Both translocations
Wiedemann syndrome chromosome dependent kinases. Heterozygous in 11p15.4 disrupt a paternally imprint-
region 1 (BWSCR1) near INS/IGF2, mutations have been identified in ed zinc-binding finger gene ZNF215.
BWSCR2 5 Mb proximal to BWSCR1, about 20% of BWS patients in two stud- Parts of the 3 end of this gene are tran-
and BWSCR3 2 Mb even more proximal ies. Others, however, have not been scribed from the antisense strand of a
{967}. This already points to genetic able to confirm this mutation frequency. second zinc-finger gene, ZNF214.
heterogeneity but also at the clinical Although not a major cause of BWS, it is Although putative mutations in these
level there seems to be heterogeneity. possible that in certain countries, e.g., genes in other sporadic BWS cases
Chromosomal translocations in BWSCR1 in Asia, the mutation frequency is ele- were found, their involvement in BWS
and BWSCR3 are associated with the vated. In addition, it has been needs to be further elucidated by func-
classical BWS phenotype and BWSCR2 reported that this gene is more fre- tional studies.
with minor BWS features but pronoun- quently involved in familial cases More detailed information on the struc-
ced hemihypertrophy. BWSCR 1 and of BWS. CDKN1C mouse models ture and expression of genes involved in
BWSCR2 have been cloned and genes revealed some of the clinical BWS BWS could be found at:
isolated from these regions were shown features such as omphalocele and renal http://www.infobiogen.fr/services/
to be involved in the development of this adrenal cortex anomalies. In humans, chromcancer/Kprones/Beckwith
disorder. All genes involved are subject CDKN1C also seems to be more fre- WiedemannID10037.html
to genomic imprinting {1326, 2023}. quently associated with abdominal wall {1325}.
Beckwith-Wiedemann Syndrome 355
bb5_29.qxd 13.9.2006 13:59 Page 356
F. Mertens
Enchondromatosis:
K. Unni
Ollier disease and Maffucci syndrome
Definition biochemical marker for either Ollier dis- The skeletal features in Maffucci syn-
Ollier disease is a developmental disor- ease or Maffucci syndrome has as yet drome are indistinguishable from those in
der characterized by the occurrence of been identified. Ollier disease, but the risk of developing
multiple cartilaginous masses, particular- chondrosarcoma is possibly even higher
ly affecting the short and long tubular Clinical features and tumours among patients with Maffucci syndrome,
bones of the limbs. When cutaneous, soft Ollier disease usually manifests already with incidence figures reaching 20-30%
tissue or visceral haemangiomas are in early childhood, commonly presenting in some series {1067,2055}. An
also present, the disorder is referred to as swelling of the fingers. Enchondromas increased incidence has also been sug-
as Maffucci syndrome. in the metaphyseal regions of long bones gested for other malignancies, including
may also result in deformity and limb angiosarcomas, brain tumours, and
OMIM number 16600L {1376} asymmetry, as well as pathological frac- tumours of the hepatobiliary system {538,
tures. Although careful examination will 1901}, as well as certain benign tumours.
Synonyms reveal that the vast majority of patients In both forms of enchondromatosis, care-
Ollier disease is also referred to as multi- have bilateral enchondromatosis, there is ful surgical and orthopedic intervention
ple enchondromas or dyschondroplasia. a tendency for one side of the body to be may avoid or minimise deformities.
more severely affected. The extent of a Furthermore, all patients should be
Incidence patient s orthopedic complications, instructed to pay close attention to signs
Rare, but exact incidence is unknown. which is highly variable and difficult to or symptoms heralding malignant trans-
Enchondromatosis has been described predict, is largely dependent on the num- formation.
in many different ethnic groups, and ber and skeletal distribution of enchon- The more widespread the disease, the
there is no significant gender bias. dromas. greater is the likelihood for malignant
The enchondromas primarily affect the transformation {538}. The prognosis for
Diagnostic criteria short and long tubular bones of the patients developing secondary chon-
The diagnosis is based on the extremities, but flat bones, such as the drosarcoma is similar to that for patients
roentgenographic appearance and clini- pelvis and ribs, may be involved. The with sporadic chondrosarcomas, and
cal features. No distinctive genetic or craniofacial bones and vertebrae, how- depends on tumour size and location,
ever, are usually spared. With few excep- and histological malignancy grade
tions, the enchondromatous lesions stop {1230}.
growing at puberty. Continued or
renewed growth in adults should raise Roentgenographic features
the suspicion of malignancy. Whereas Roentgenographic features of Ollier dis-
sarcomatous transformation of solitary ease and Maffucci syndrome are similar
enchondromas is rare, patients with except for the presence of phleboliths in the
Ollier have a markedly increased risk, soft tissue haemangiomas in the latter con-
ranging from 15 to 30%, of developing dition. The cartilage present has expansile
malignant bone tumours, in particular masses at the metaphyseal region with cal-
chondrosarcomas {1274,1901}. Some cification in the form of longitudinal striation.
patients even develop multiple sarcomas
A
{303}.
Most patients with Maffucci syndrome
present at birth or in early childhood with
cavernous haemangiomas, varying in size
from a few millimetres to several centime-
tres, that are typically located in the dermis
or subcutaneously on the distal parts of
the limbs. However, haemangiomas may
also be found in internal organs. In addi-
tion, spindle cell haemangioma, a vascu-
lar lesion with a high propensity for local
B
recurrence but no potential for metastasis,
Fig. 21.05 Enchondromas and calcified thrombi in Fig. 21.06 Multiple enchondromas causing
is overrepresented among patients with
soft tissue haemangiomas in the left hand of a swelling and angular deformity in the left hand of a
Maffucci syndrome {639,1688}.
patient with Maffucci syndrome. patient with Ollier disease.
356 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 357
Microscopic features from a patient with Ollier disease re- of PTHR1, was shown to cause in-
The cartilage in enchondromas is pre- vealed loss of heterozygosity for the creased cAMP signalling, which is ana-
sent as well circumscribed nodules in chromosomal bands harbouring the RB1 logous to the situation in Jansen meta-
the medullary cavity and occasionally on and CDKN2A tumour suppressor genes physeal chondrodysplasia (OMIM
the surface. The matrix does not show as well as TP53 overexpression, but 156400), an autosomal dominant disor-
myxoid change. The lesion is hypercellu- none of these changes were found in der sharing some radiographic and his-
lar and the chondrocyte nuclei are tissue from an enchondroma {243}. tological features with Ollier disease.
enlarged and irregular. Recently, a study of patients with Ollier The hypothesis that a mutant PTH/PTHrP
disease revealed mutations of the receptor could delay the differentiation
Genetics PTHR1 gene, encoding a receptor for of proliferating chondrocytes by consti-
Most cases of enchondromatosis are parathyroid hormone and parathyroid tutively activating Hedgehog signalling
sporadic, but families with multiple hormone-related protein (PTH/PTHrP), in {1885} was further substantiated by
affected members have been reported, two of six cases; in one as a germline studies of transgenic mice carrying the
possibly suggesting autosomal domi- mutation, and in one as a somatic mu- same R150C PTHR1 mutation {968}. The
nant inheritance with reduced pene- tation in enchondroma tissue {968}. The R150C substitution could not be detec-
trance {1376}. Molecular genetic analy- detected mutation, resulting in an R150C ted in a series of 50 sporadic chon-
sis of a high grade chondrosarcoma substitution in the extracellular domain drosarcomas {968}.
M.M. Cohen, Jr.
McCune-Albright syndrome
G.P. Siegal
Definition OMIM number 174800L other abnormalities are found with low
McCune-Albright syndrome (MAS) is a frequency: gastrointestinal polyps;
sporadically occurring disorder consist- Incidence hyperplasia of the thymus, spleen, and
ing of polyostotic fibrous dysplasia, café- No accurate incidence has ever been pancreatic islet cells; hepatobiliary dis-
au-lait spots, and hyperfunctioning determined for MAS. Fibrous dysplasia ease; cardiac disease; failure to thrive;
endocrinopathies. The syndrome is may occur without MAS and the over- metabolic acidosis; abnormalities in
caused by mutations in the GNAS1 gene. whelming majority of these cases are serum electrolytes, glucose, or insulin
monostotic. Polyostotic fibrous dyspla-
sia occurs much less frequently and
Table 21.02
about 3% of the these cases represent GNAS1 mutations in solitary, sporadic neoplasms.
MAS {382,383}.
Neoplasm
Diagnostic criteria
Osteosarcoma
Polyostotic fibrous dysplasia, café-au-lait
Pituitary adenoma
spots, and hyperfunctioning endocrino-
Thyroid adenoma
pathies {31-33,1375}.
Thyroid carcinoma
Parathyroid adenoma
Leydig cell tumour
Clinical features
Ovarian cyst
Cardinal features include café-au-lait
Intramuscular myxoma*
spots, polyostotic fibrous dysplasia, mul-
Breast carcinoma
tiple endocrinopathies including sexual
precocity, pituitary adenoma, and hyper-
* Mazabraud syndrome, the combination of polyosto-
thyroidism. There is high expression of
tic fibrous dysplasia and intramuscular myxomas, is
the FOS proto-oncogene in cells popu-
also caused by GNAS1 mutations. From Cohen {382}
lating the bone marrow spaces. Many
Fig. 21.07 Fibrous dysplasia in Albright syndrome.
Enchondromatosis: Ollier disease and Maffucci syndrome / McCune-Albright syndrome 357
bb5_29.qxd 13.9.2006 13:59 Page 358
Table 21.03
Mutations in the GNAS1 gene.
Disorder Exon Nucleotide Change Amino Acid Substitution
McCune-Albright syndrome 8 C -> T Arg201Cys
-
8 G -> A Arg201His
-
Polyostotic fibrous dysplasia 8 C -> T Arg201Cys
-
Monostotic fibrous dysplasia 8 C -> T Arg201Cys
-
8 G -> A Arg201His
-
Panostotic fibrous dysplasia 8 C -> A Arg201Ser
-
Solitary pituitary adenoma 8 C -> T Arg201Cys
-
8 G -> A Arg201His
-
8 C -> A Arg201Ser
-
9 A -> G Gln227Arg
-
9 G -> T Gln227His
-
From Cohen and Howell {383}
levels; hyperphosphaturic hypophos- Individuals with MAS are also suscepti- Fig. 21.08 (A) G protein composed of Ä… , ², and Å‚
subunits. This is the inactive form. B) Ligand (L)
phatemia; osteo-sarcoma (4%); devel- ble to endocrine tumours, including
binding produces conformational change in
opmental delay; microcephaly; and sud- adrenocortical and pituitary tumours
receptor (R) and guanosine diphosphate (GDP) is
den or premature death {302,382,383, {1133,1637}.
replaced by guanosine triphosphate (GTP), result-
392,1936}.
ing in dissociation of the Ä… subunit. (C) Binding of
Genetics
Ä… subunit to adenylyl cyclase activates 3',5'-
Bone and soft tissue tumours McCune-Albright syndrome (MAS) is
cyclic adenosine monophosphate (cAMP) from
As noted above, one of the primary caused by mutations in the GNAS1
adenosine triphosphate (ATP). (D) Hydrolysis of
pathological conditions which defines gene located in chromosome band
GTP to GDP by GTPase, causing dissociation of
MAS is polyostotic fibrous dysplasia. 20q13. GNAS1 (guanine nucleotide- the Ä… subunit from adenylyl cyclase and binding
Other benign lesions associated with binding protein, Ä…-stimulating activity to the ² and Å‚ subunits, the inactive form. Ligand
binding causes repetition of the cycle {383}.
this condition include mucoceles of polypeptide 1) encodes the G-protein Ä…
the head and neck {547,745}, simple stimulatory subunit (GsÄ…), a component
(unicameral) bone cysts {1001,1129} of heterotrimeric G-protein complexes.
and aneurysmal bone cysts {76,
1288,1759}. Perhaps the best known Gene function Binding of the active form of the Ä… sub-
concordance is with soft tissue, usu- G proteins (guanine nucleotide proteins) unit to adenylyl cyclase (C) activates
ally intramuscular, myxomas, known as are a family of molecules composed of this enzyme, resulting in the formation of
the Mazabraud syndrome {2108}. three subunits designated Ä…, ², and Å‚. cAMP from ATP. Hydrolysis of GTP to
Interestingly, activating mutation in the The function and specificity of each G GDP is catalysed within seconds by the
GNAS1 gene have been detected in protein is determined by the Ä… subunit, intrinsic GTPase (guanosine triphos-
myxoma cells {1605}, but not in leuko- which is unique for each type. The ² and phatase) activity of GsÄ… which causes
cytes or fibroblasts, from patients with Å‚ subunits tend to be more homoge- dissociation of the a subunit from
Mazabraud syndrome. neous. Like all G proteins, the inactive adenylyl cyclase and binding to the ²,
Malignant bone tumours have also form of GsÄ… contains bound GDP and Å‚ subunits, resulting in the inactive
been associated with the fibrous (guanosine diphosphate). A GPCR (G form {382,383}.
dysplasia seen in MAS. Osteosarco- protein-coupled receptor) facilitates the
ma, and possibly also conventional exchange of bound GTP (guanosine Mutations
and dedifferentiated chondrosarco- triphosphate) for GDP producing the MAS, polyostotic fibrous dysplasia
ma, appear to occur with increased active form {382,383}. (PFD), monostotic fibrous dysplasia
frequency {212, 872, 932, 1282, 1630, Adenylyl cyclase is activated following (MFD), and solitary pituitary adenoma
1725, 1823}. Although other sarcomas, ligand-binding to G-protein-coupled (PA) have the same causal genesis  a
including fibrosarcoma and malignant receptor. Ligand-binding (B) produces ligand-independent, activating GNAS1
fibrous histiocytoma, have been linked a conformational change in the receptor mutation in the a subunit of stimulatory
to fibrous dysplasia {1822}, these have and GDP is replaced by GTP, which G protein (GsÄ…). Mutations are located
not been reported in patients with MAS. results in dissociation of the a subunit. near the site which interacts with the Å‚-
358 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 359
phosphate of GTP, thus interfering with
hydrolysis of GTP to GDP. Because GsÄ…
cannot dissociate from adenylyl cyclase
and bind to G²Å‚, adenylyl cyclase
remains active, producing increased
cAMP activity which results in the
pathology of MAS, PFD, MFD, and PA
{382,383,1934,1936,1937,2230}. GNAS
mutations have also been recorded in
various solitary tumours {382}.
MAS, PFD, MFD, and PA occur sporadi-
cally. Mutations in the GNAS1 gene
occur postzygotically in a somatic cell.
Clinical manifestations are variable in
distribution and appearance. More gen-
eralized vs. more localized expression
depends on (a) how small or how large
the cell mass is during embryogenesis
when the mutation occurs, and (b)
where in the cell mass the mutation
occurs {382, 383}.
Fig. 21.09 (A) Activating mutations (Arg201Cys or Arg201His) in the gene encoding the Ä… subunit of stimu-
GNAS1 mutations for MAS, PFD, MFD,
latory G protein (GsÄ…), causing inappropriate stimulation of adenylyl cyclase interfering with hydrolysis of
and PA are of the gain-of-function type.
GTP by GTPase to GDP. The PKA pathway (protein kinase A or cAMP-dependent protein kinase pathway)
It should be carefully noted that GNAS1
is shown on the right. The PKC pathway (protein kinase C pathway) is shown on the left. Because the Ä… sub-
mutations of the loss-of-function type
unit (GsÄ…) cannot dissociate from adenylyl cyclase, cAMP is overproduced which, in turn, overactivates the
are found in endocrine disorders char-
PKA pathway. PKA is composed of two regulatory subunits (RS) that have binding sites for cAMP, and two
acterized by hormone resistance, such
catalytic subunits (CS) that, when dissociated, phosphorylate serine/threonine kinases (STK). The dissoci-
as type 1a pseudohypothyroidism, glu-
ated ²Å‚ subunit overactivates the PKC pathway. PLC (phospholipase C) cleaves PIP2 (phosphatidylinositol
bisphosphate) into two intracellular messengers: DAG (diacylglycerol) and IP3 (inositol trisphosphate). The cocorticoid deficiency, and nephro-
latter triggers the release of sequestered calcium ions (Ca2+) which together with DAG activate PKC {383}.
genic diabetes insipidus {1934}.
Fig. 21.10 How mutations cause McCune-Albright syndrome, polyostotic fibrous dysplasia, and monostotic
fibrous dysplasia depend on when during embryonic development or during postnatal life the mutation
occurs. Somatic mutation in a small cell mass is likely to result in McCune-Albright syndrome. Mutation in
a larger cell mass may result in polyostotic fibrous dysplasia. A mutation in postnatal life  during infancy,
childhood, or adult life  may result in monostotic fibrous dysplasia {383}.
McCune-Albright syndrome 359
bb5_29.qxd 13.9.2006 13:59 Page 360
J.V.M.G. Bovée
Multiple osteochondromas
P.C.W. Hogendoorn
Definition more common than the occurrence within the severity of angular deformity was
Multiple osteochondromas (MO) is an the context of MO. The incidence of MO found to be correlated with the number of
autosomal dominant condition. It is is approximately 1:50,000 persons within sessile osteochondromas {309}.
genetically heterogeneous and is caused the general population {1887}. Males are The most important complication of MO
by mutations in one of the EXT genes. more often affected (male: female ratio is malignant transformation of an osteo-
1.5:1) {1236, 2265}, due in part to an chondroma, which is estimated to occur
OMIM numbers incomplete penetrance in females {1236}. in 0.5-3% of MO patients {815, 1236,
According to the gene involved, the fol- Approximately 62% of the patients with 1695, 1887, 2265}. The suspicion of se-
lowing OMIM numbers have been multiple osteochondromas have a posi- condary chondrosarcoma is indicated by
assigned: tive family history {1236}. growth of the tumour after puberty, the
EXT1 133700 presence of pain, or a thickness over 1
EXT2 133701 Diagnostic criteria cm of the cartilaginous cap in adults. The
EXT3 600209 A diagnosis of multiple exostoses can be size of the cartilaginous cap can be well
TRPS2 / Langer Giedion syndrome 150230 made when radiologically at least two established with T2-weighted MR imag-
Potocki-Shaffer syndrome 601224 osteochondromas of the juxta-epiphy- ing. There are no universally accepted
seal region of long bones are observed guidelines for surveillance of individuals
Synonyms {1236}. MO is diagnosed in case of a with MO so far.
EXT, diaphyseal aclasis, (multiple hered- positive family history and/or a proven Other complications of the osteochon-
itary) osteochondromatosis, multiple car- germline mutation in one of the EXT dromas include osseous and cosmetic
tilaginous exostoses, hereditary multiple genes. deformities, fracture, bursa formation,
exostoses. arthritis (14%) {2265}) and impingement
Clinical features on adjacent tendons, nerves (23%)
Incidence Osteochondromas develop and increase {2265}, vessels (11%) {2265} or spinal
The solitary (sporadic) form of osteo- in size in the first decade of life, ceasing cord (<1%) {2187, 2265}.
chondroma is approximately 6 times to grow when the growth plates close at
puberty. They are pedunculated or ses- Bone and soft tissue tumours
sile (broad base) and can vary widely in Hereditary osteochondromas and sec-
size. The majority are asymptomatic and ondary peripheral chondrosarcomas
located in bones that develop from carti- developing within the cartilaginous cap
lage, especially the long bones of the of hereditary osteochondromas are
extremities, predominantly around the histopathologically similar to their spo-
knee. The number of osteochondromas radic counterparts. Morphologically two
may vary significantly within and between types of osteochondroma can be recog-
families. In addition, in the majority of MO nized: broad based sessile cases with
patients bone remodelling defects are irregular cartilaginous linings and those
observed resulting in deformities of the with a well defined cartilaginous cap.
forearm (shortening of the ulna with se- Both may occur within and outside the
condary bowing of radius) (39-60%) context of MO. Malignant transformation
{1887, 1929}, inequality in limb length of osteochondroma leads to a secondary
(10-50%) {1887,1929}, varus or valgus peripheral chondrosarcoma in 94% of
angulation of the knee (8-33%) {1887, the cases {2276}. Very rare cases of
1929}, deformity of the ankle (2-54%) other sarcomas developing in osteo-
{1887, 1929} and disproportionate short chondroma have been described, most
stature (37-44%) {1236, 2265}. It has long often in solitary cases of osteochon-
been thought that these abnormalities droma {56, 1214, 1576, 1902, 1968, 2181}
are the result of skeletal dysplasia, including osteosarcomas, and spindle
although recent evidence indicates that cell sarcomas {1214,1356}. These tu-
osteochondromas are neoplastic (see mours develop in the stalk of the osteo-
chapter 10), and it has been suggested chondroma, in contrast to secondary
that the growth retardation in MO may peripheral chondrosarcomas, which
result from the local effects of enlarging develop in the cap of the pre-existing
Fig. 21.11 Multiple osteochondromas in a patient
osteochondromas {1717}. Moreover, osteochondroma. A few cases of MO
with hereditary multiple osteochondromas.
360 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 361
Fig. 21.12 Genomic structure of the EXT1 and EXT2 genes. Fig. 21.13 706 Hypothesized function of EXT within
the normal early embryonic growth plate.
patients have been reported to develop demonstrate the Langer-Giedion syn- level of sequence homology {1266,
other sarcomas as well {239, 2139}. drome (LGS or trichorhinophalangeal 1279}. Additional homologues have been
These osteosarcomas and spindle cell syndrome type II (TRPS2; OMIM identified in Caenorhabditis elegans
sarcomas (malignant fibrous histiocy- 150230), which is characterized by cran- {369} and Drosophila melanogaster
tomas and fibrosarcomas) display an iofacial dysmorphism and mental retar- {156}.
indistinguishable phenotype from their dation in addition to multiple osteochon- The EXT2 gene was also identified by
non osteochondroma-related counter- dromas {975,1297,1298,1491}. LGS is positional cloning {2031,2310} and con-
parts. Even more rare is the occurrence due to loss of functional copies both of tains 16 exons, two of which (1a and 1b)
of "conventional" dedifferentiated periph- the TRPS1 gene, encoding a zinc-finger are alternatively spliced {369}. The gene
eral chondrosarcoma, in which case the protein {1491}, and the EXT1 gene at spans approximately 108 kb of genomic
osteochondroma gives rise to peripheral 8q24 {975,1298}. Trichorhinophalangeal DNA {369}. The cDNA consists of
low grade chondrosarcoma that in turn syndrome type I (TRPS1) (OMIM 190350) approximately 3 kb, defining a single
"dedifferentiates" into a high grade sarco- is similar to LGS although multiple osteo- open reading frame of 2154 bp. The
ma that may appear as fibrosarcoma, chondromas are absent. Patients carry- mRNA demonstrates alternative splicing
malignant fibrous histiocytoma or ing a deletion of 11p11.2-p12 demon- {2031,2310}. A highly significant similari-
osteosarcoma {183}. No soft tissue neo- strate Potocki-Shaffer syndrome (proxi- ty with the EXT1 gene product has been
plasms are described within the context mal 11p deletion syndrome {2307}, found, especially in the carboxy terminal
of MO. DEFECT11, 11p11.2 contiguous gene region {2031,2310}. Homologues are
deletion syndrome). These patients found on mouse chromosome 2 {369,
Genetics demonstrate enlarged parietal foramina, 2032} and in Caenorhabditis elegans
MO is a genetically heterogeneous disor- multiple osteochondromas, and some- {369}.
der for which two genes, EXT1 and EXT2 times craniofacial dysostosis and mental
located respectively at 8q24 and 11p11- retardation {134,1721}. The syndrome is Gene expression
p12, have been isolated {20, 395, 2031, caused by deletion of EXT2 and proba- Both EXT1 and EXT2 mRNA is ubiqui-
2310}. Additional linkage to chromosome bly of ALX4; haploinsufficiency of the lat- tously expressed {20, 2031, 2310}. A
arm 19p has been found, suggesting the ter was shown to potentially cause high level of expression of Ext1 and Ext2
existence of an EXT3 gene {1229}. Loss enlarged parietal foramina {134, 2303}. mRNA has been found in developing
of heterozygosity however is absent at limb buds of mouse embryos {1265,
this locus {236, 924, 1760} and the gene Gene structure 2032} and expression was demonstrated
has never been identified. Three new The EXT1 gene was identified by posi- to be confined to the proliferating and
genes, EXTL1, EXTL2 and EXTL3 have tional cloning {20}. The gene is com- prehypertrophic chondrocytes of the
been identified based on their homology posed of 11 exons, and spans approxi- growth plate {2030}. The gene products,
with the EXT1 and EXT2 genes {2180, mately 350 kb of genomic DNA {1296}. exostosin-1 (EXT1) and exostosin-2
2283,2309}. However, no association The cDNA has a coding region of 2238 (EXT2), are endoplasmic reticulum local-
with disease has been documented. bp {20}. The promoter sequence is char- ized type II transmembrane glycopro-
Both EXT genes are involved in a con- acteristic of a housekeeping gene teins which form a Golgi-localized het-
tiguous gene deletion syndrome. {1296}. A mouse-homologue is found on ero-oligomeric complex that catalyzes
Patients carrying a deletion of 8q24 mouse chromosome 15 with a very high heparan sulphate (HS) polymerisation
Multiple osteochondromas 361
bb5_29.qxd 13.9.2006 13:59 Page 362
Table 21.04
have been studied extensively in
The EXT gene family.
Caucasian as well as Asian popula-
tions {2306} (For overview see also:
Gene Chromosomal Associated Function:
The human gene mutation database
localization disease glycosyltransferase activity involved in
Cardiff www.hgmd.org {1176}). In EXT1,
heparan sulphate (HS) biosynthesis:
mutations are more or less randomly
EXT1 8q24 {907} MO HS chain elongation {1267, 1372, 1954} distributed over the first 6 exons, while
the last 5 exons, containing the con-
EXT2 11p11-p12 {977,961} MO HS chain elongation {1267, 1372, 1954}
served carboxyterminal region, contain
significantly less mutations {2306}.
EXTL1 1p36.1 {971} Unknown HS chain elongation {1108}
Similarly, in EXT2 most mutations are
found in the first exons. No mutational
EXTL2 1p11-p12 {976} Unknown HS chain initiation {1127}
hotspots are found {2306}. Appro-
ximately 80% of the mutations are
EXTL3 8p12-p22 {966} Unknown HS chain initiation and elongation {1108}
either non-sense, frameshift, or splice-
site mutations leading to premature
{1267,1372,1373,1954}. Heparan sul- polarity protein called Hedgehog (Hh) termination of EXT proteins {714,1656,
phate proteoglycans (HSPG) are large {156, 2107, 2126}, a homologue of mam- 1761,1917,2308,2313}. The majority of
macromolecules composed of heparan malian Indian Hedgehog (IHh). It is missense mutations also lead to defec-
sulphate glycosaminoglycan chains therefore hypothesized that EXT muta- tive EXT protein function {340}.
linked to a protein core. Four HSPG fam- tions affect FGF and IHh signalling within Loss of the remaining wildtype allele
ilies have been identified: syndecan, the normal growth plate. has been demonstrated {238}, indica-
glypican, perlecan and isoforms of ting that the EXT genes act as tumour
CD44. HSPGs are required for high-affin- Mutations suppressor genes. The limited number
ity binding of fibroblast growth factor to The EXT1 gene was reported to show of genotype-fenotype correlational stu-
its receptor {1275}. Furthermore, an linkage in 44%-66% of the MO families dies performed so far provide no uniform
EXT1 homologue in Drosophila (tout- {1235, 1761}, whereas EXT2 would be data {309,714}. The risk of malignant
velu, Ttv) has been shown to be required involved in 27% {1235}. Germline muta- transformation would be higher in pa-
for diffusion of an important segment tions of EXT1 and EXT2 in MO patients tients carrying EXT1 mutations {714}.
362 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 363
W.K. Cavenee O. Bögler
Retinoblastoma syndrome
T. Hadjistilianou I.F. Newsham
Definition Clinical features important since ectopic intracranial
Retinoblastoma (RB) is a malignant Retinoblastoma can be unifocal or multi- retinoblastoma requires therapy to the
tumour originating from the embryonic focal. In bilateral cases, one eye is usu- whole neuraxis as well as high-dose
neural retina. Familial retinoblastoma is ally in a more advanced stage, while the equivalent radiotherapy to the primary
typically bilateral, caused by a germline contralateral eye has one or more tumour tumour.
mutation in the RB1 tumour suppressor foci. The average age at diagnosis is 12
gene and is often associated with the months for bilateral and 18 months for Pathology of retinoblastoma
development of second site primary unilateral cases, with 90 percent of the Retinoblastoma occurs as a mass
tumours, including osteosarcoma, fibro- cases diagnosed before the age of 3 {29, between the choroid and retina (exo-
sarcoma, chondrosarcoma, Ewing sarco- 1157,1860,2123}. Retinoblastoma can phytic) or bulge from the retina toward
ma, pinealoblastoma, epithelial tumours, be a part of the 13q-deletion syndrome in the vitreous (endophytic). Most ad-
leukaemia, lymphoma, mela-noma and association with moderate growth and vanced tumours show both patterns
brain tumours. mental retardation, broad prominent of growth. The tumour is histologi-
nasal bridge, short nose, ear and dental cally characterized by rosettes and
OMIM number 180200 {1376}
abnormalities, and muscular hypotonia fleurettes, which are believed to rep-
{38,717}. resent maturated or differentiated neo-
Synonym Trilateral retinoblastoma describes the plastic cells. Rosettes are spherical
Retinoblastoma / osteogenic sarcoma association between bilateral retinoblas- structures (circular in section) of uni-
syndrome. toma and midline brain tumours, usually form cuboidal or short columnar cells
in the pineal region {554}. Pineal tumours arranged about a small round lumen
Incidence resembling well differentiated retinoblas- (Flexner-Wintersteiner rosette) or with-
Retinoblastoma, the most common tomas are also called ectopic retinoblas- out any lumen (Homer-Right rosette).
intraocular tumour of children, has a toma. CT scanning and MRI have The latter also appears in other neuro-
worldwide incidence between 1/3500 reduced the misinterpretation of pineal ectodermal tumours such as medul-
and 1/25000 with no significant differ- tumours as intracranial spread of loblastoma. Fleurettes are arranged
ences between the sexes or races {28, retinoblastoma {2346}. This is clinically with short, thin stromal axes surroun-
147,511,1856}.
Diagnostic criteria
Presentation is a white, pink-white, or
yellow-white pupillary reflex termed
"leukocoria'' resulting from replacement
of the vitreous by tumour, or by a large
tumour growing in the macula {718}.
Another common symptom, strabismus
(exotropia or esotropia), can occur alone
or associated with leukocoria. Less
frequent presenting signs include a red,
painful eye with secondary glaucoma,
low-vision orbital cellulitis, unilateral
mydriasis, and heterochromia {2346}.
The tumour can be difficult to differenti-
ate from a variety of simulating lesions
such as persistent hyperplastic primary
vitreous, retrolental fibroplasia, Coats
disease, Toxocara canis infection, retinal
dysplasia, or chronic retinal detach-
ment {582,976}. These can be distin-
guished using CT, MRI, ultrasonography
Fig. 21.14 Genomic and protein domain organization of the 105kD retinoblastoma protein. Mutational
or fine-needle aspiration biopsy and a
hotspots for frameshift and nonsense mutations are identified above individual exons. Examples of some of
careful history of the family and affected
the known cellular binding proteins and their region of interaction are depicted below the protein domains.
child {582}.
Sites of phosphorylation are also noted.
Retinoblastoma syndrome 363
bb5_29.qxd 13.9.2006 13:59 Page 364
2017, 2044}, molecular genetic {317,
318} and molecular biological {558, 969}
methods suggests as few as two
required stochastic mutational events in
the RB1 locus for tumour formation. The
first mutation can be inherited through
the germ line or somatically acquired,
whereas the second occurs somatically
in either case. RB1 locus inactivation is
also found in non-hereditary retinoblas-
toma {552}, osteogenic and other sarco-
mas occurring as second primary
tumours in retinoblastoma patients and
some primary sarcomas in the absence
of retinoblastoma involvement {724,
882}.
Gene structure and expression
The RB1 locus in chromosome band
13q14.1 {317, 716, 2006, 2044} encom-
passes 200 kb of genomic DNA organ-
Fig. 21.15 Regulation of the cell cycle through oscillating phosphorylation of the p105 retinoblastoma
ized into 27 exons {228, 744, 1233}. The
protein.
105 kD RB1 protein is ubiquitously
expressed in normal human and rodent
tissues, including brain, kidney, ovary,
ded by differentiated neoplastic cells tumours in the irradiated area, (b) spleen, liver, placenta, and retina. RB1 is
with their apical part facing the exter- tumours outside and remote from the differentially phosphorylated {1234}, with
num. Tumours can be necrotic, with sur- irradiated area, (c) tumours in patients the unphosphorylated form predomi-
viving cells around blood vessels, not receiving radiotherapy, (d) tumours nantly found in the G1 stage of the cell
creating ``pseudo-rosettes.'' Calcified unable to be determined as primary or cycle, and an initial phosphorylation
foci and debris from nucleic acids can metastases, and (e) tumours in members occurring at the G1/S boundary {284,
be found in necrotic areas giving rise of retinoblastoma families who were free 482}. Viral proteins bind the p105RB pro-
to basophilic vessel walls {29, 1860, of retinal tumours. Two important obser- tein {481, 564, 2262} using regions nec-
2123}. vations have emerged from analysing essary for their transforming function.
Growth patterns and other histological these patients: (a) the great majority of Over 100 intracellular pRB binding pro-
parameters are not useful for determin- children in whom second neoplasms teins have also been identified including
ing prognosis. The degree of differentia- develop have or will have bilateral E2F transcription factors, tumour sup-
tion and number of mitoses show a weak retinoblastoma, and (b) the incidence of pressor BRCA1 and the RB-like proteins
correlation. Stronger relationships exist second neoplasms in this group was p107 and p130 {1508}. Complexing of
with invasion of the choroids, optic similar whether they received radiation or the two latter factors also oscillates in a
nerves and sclera. Progressive invasion not. Osteogenic sarcomas are the most cell-cycle-dependent manner linking the
of the eye coats, even in the horizontal frequent second site neoplasms in all the tumour-suppressing function of RB1 with
plane, is highly informative for determi- published series {12, 336a, 502, 550, transcriptional regulation.
ning prognosis {1157, 2123}. 1720a,1723a,1793,1837}.
Mutations
Genetics
Bone and soft tissue tumours Mutations that result in loss of RB1 func-
Second-site primary malignant tumours Retinoblastoma has served as the proto- tion have been described for retinoblas-
refer to nonmetastatic tumours arising in typic example of a genetic predisposi- toma patients and their tumours at the
"disease-free'' patients treated for initial tion to cancer. It is estimated that 60 per- DNA, RNA, and protein levels. RB1 alter-
disease. Tumours associated with cent of cases are nonhereditary and uni- ations have also been detected in a vari-
retinoblastoma include osteosarcoma, lateral, 15 percent are hereditary and ety of clinically related second-site pri-
fibrosarcoma, chondrosarcoma, epithe- unilateral, and 25 percent are hereditary mary tumours including osteosarcoma,
lial malignant tumours, Ewing sarcoma, and bilateral. In the latter two types, as well as other non-secondary tumours
leukaemia, lymphoma, melanoma, brain autosomal dominant inheritance with such as breast and small-cell lung car-
tumours, and pinealoblastoma {12, 502, nearly complete penetrance is observed. cinoma. Detection of RB1 mutations pro-
550, 1793, 1837}. These second tumours Analysis of such cases by epidemiolo- vides for accurate prenatal risk assess-
are classified into five groups: (a) gical / cytogenetic {716,941,1145,2006, ment {319, 970, 2267, 2318}.
364 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 365
N.M. Lindor
Rothmund-Thomson syndrome
Definition cases, and laboratory tests that can in Bloom syndrome), no excess of
Rothmund-Thomson syndrome (RTS) is exclude some other, similar disorders. bleomycin-induced chromosome break-
a constellation of various skin abnormal- age (as seen in ataxia telangiectasia),
ities, skeletal defects, juvenile cataracts, Clinical features and no chromosomal radial formation
premature ageing, and a predisposition The cardinal feature of RTS is a sun-sen- with mitomycin-C exposure (as seen in
to osteosarcoma, skin cancer, and other sitive erythematous rash that typically Fanconi anaemia). Ultraviolet sensitivity
tumours. At least a subset of cases are appears during the first 6 months. It studies have yielded inconsistent
caused by inherited mutations in the usually starts in the face and then results.
RECQL4 helicase gene. spreads to the buttocks and extremities.
With time, the rash enters a chronic Bone and soft tissue tumours
OMIM number 268400 phase resulting in skin atrophy, telang- Osteosarcomas, involving any bone and
iectasias, and marbleized mixed hyper- especially in non-common sites, have
Synonym and hypopigmentation (poikiloderma) been reported to occur in up to one third
Poikiloderma congenitale. {1735, 2198, 2199, 2212}. Other fea- of the patients, with a median age of
tures associated with RTS include short diagnosis at 11.5 years {2212}. Also
Incidence stature (~2/3 of the cases), premature cutaneous malignancies, in particular
RTS is a rare, autosomal recessive dis- greying and loss of hair (50-65%), squamous cell carcinomas, have been
order. The exact incidence is unknown, sparse eyebrows/lashes (60-75%), juve- reported to be overrepresented in RTS
but more than 250 cases have been nile cataracts (7-50%), photosensitivity {1735, 2212}.
reported in the world literature from a (35%), radial ray anomalies (>20%) and
variety of ethnic backgrounds. A slight other bony abnormalities, dystrophic Genetics
male preponderance (M:F = 2:1) has nails and teeth, hypogonadism, and At least a subset of the cases of RTS are
been reported {2212}. hypersensitivity to cytotoxic drugs and caused by mutations in the RECQL4
radiotherapy {1735, 2198, 2199, 2212}. (also known as RECQ4) helicase gene
Diagnostic criteria RTS does not seem to be associated in chromosome band 8q24.3 {1128}.
Specific criteria for the diagnosis of RTS with intellectual or immunological Only a small number of patients has as
have not been established. The diagno- impairment. There are no specific or yet been investigated, with mutations
sis is based upon clinical findings, the consistently identifiable laboratory fea- being detected in approximately 40% of
identification of RECQL4 in a subset of tures in RTS. There have been several the cases {749}. The RECQL4 gene
reports of acquired, clonal somatic has a predicted protein product of
mosaicism for chromosome abnormali- 1208 amino acids. It is highly ex-
ties, especially trisomies, isochromo- pressed in the thymus and testis with
somes, and translocations frequently low levels of intranuclear expression
involving chromosome 8, often found in in multiple other tissues. RECQL4 mu-
fibroblast cultures {1269}. There is no tation analysis is available only in
evidence of mismatch repair deficiency specialized centres. Mutations have
in the form of tumour microsatellite included frameshift mutations, non-
instability, as seen in tumours associat- sense mutations, and deletions in-
ed with the hereditary non-polyposis cluding part of the consensus heli-
colon cancer syndrome, due to case domain. This gene is homologous
germline mutations in genes of the DNA to the genes that cause Bloom syn-
mismatch repair complex). Furthermore, drome and Werner syndrome, which
there is no increase in chromosomal sis- might explain some of the clinical over-
Fig. 21.16 Osteosarcoma of the rib in a patient with
ter-chromatid exchange rates (as seen lap {749}.
Rothmund-Thomson syndrome.
Rothmund-Thomson syndrome 365
bb5_29.qxd 13.9.2006 13:59 Page 366
R.J. Monnat, Jr.
Werner syndrome
Definition A definite diagnosis can be established A clinical scoring system has been
Werner syndrome (WS) is a rare, autoso- on clinical grounds when all of the con- devised to identify more reliably definite,
mal recessive genetic instability syn- sistent features and at least two addi- probable or possible WS patients.
drome and is caused by mutations in the tional findings are present. Additional Additional information on this scoring
WRN gene. Affected patients develop a diagnostic aids include evidence of ele- system and the clinical diagnosis of
prematurely aged appearance in the vated 24 hr urinary hyaluronic acid WS can be found on the Internatio-
second and third decades of life, and are secretion; loss of WRN protein from nal Registry of Werner Syndrome
at increased risk of developing both neo- fibroblasts or peripheral blood lympho- Web site:
plastic and non-neoplastic diseases. cytes; and mutations in the WRN gene www.pathology.washington.edu/
Tumours include soft tissue sarcomas, on chromosome arm 8p. research/werner/registry/diagnostic.html
thyroid carcinoma, malignant melanoma,
meningioma, haematological neoplasms,
Table 21.05
and osteosarcoma. The most common
Histopathological spectrum of neoplasia in Werner syndrome.
causes of death are cancer and athero-
A wide spectrum of neoplasms has been identified in Werner syndrome (WS) patients, who are clearly at
sclerotic cardiovascular disease.
elevated risk of developing one or more of the neoplasms listed in the left column ( frequent ). These neo-
plasms represent 71% of all neoplasms reported in WS patients. WS patients may be at elevated risk of
OMIM number 277700
developing neoplasms listed in the right column, although the number of affected patients is too small in
most cases to firmly establish this suspicion. A total of 257 neoplasms were represented in this analysis
Synonym {820, 1494} (Y. Ishikawa, personal communication). The percentage of neoplasms from this analysis in each
column or tumour type is indicated in parentheses.
Progeria of the adult.
Incidence Frequent (71%) Less common (29%)
WS patients have been identified world-
wide {819}. Estimates of the frequency or
Soft tissue sarcomas (15.5% of cases) Non-melanoma skin cancer (5.8%)
prevalence of WS, obtained by case
malignant fibrous histiocytoma
counting and from consanguinity data,
leiomyosarcoma Hepatobiliary carcinomas (5.3%)
range from 1/22,000 to 1/106 (reviewed in fibrosarcoma hepatocellular
malignant schwannoma cholangiocarcinoma
{1883}). The frequency of WS in different
synovial sarcoma gallbladder
countries is strongly influenced by the
rhabdomyosarcoma
presence of founder mutations and the
Genito-urinary (4.8%)
frequency of consanguinity or inbreed-
Thyroid carcinomas (14%) bladder carcinoma
ing. The range of frequency estimates
follicular uterine/ovarian carcinoma
also undoubtedly reflects the variable
papillary renal cell carcinoma
and delayed development of the WS clin-
anaplastic prostate carcinoma
ical phenotype {604, 819}, with conse-
seminoma
quent underdiagnosis.
Malignant melanoma (12.6%)
acral lentigenous melanoma Gastro-intestinal carcinoma (4.3%)
mucosal malignant melanoma gastric
Clinical features and diagnostic criteria
oesophagus
The most consistent clinical findings
Meningioma (11.1%) pancreas
develop after age 10. These include bi-
benign colon
lateral cataracts, dermatological patho-
multiple / malignant
logy resembling scleroderma, short
Breast carcinoma (3.9%)
stature and premature greying and loss
Haematological (11.1%)
of scalp hair {604,819}. There may be
acute myelogenous Oro-pharyngeal carcinoma (2.4%)
affected siblings as well as evidence
leukaemias (M1-5)
of parental consanguinity (3rd cousin or
erythroleukaemia (M6)
closer). Additional, less consistent find- megakaryocytic leukaemia (M7)
ings include diabetes mellitus, hypogo- myelofibrosis/myelodysplasia
aplastic anaemia
nadism, osteoporosis, soft tissue calcifi-
cation, premature atherosclerotic cardio-
Osteosarcoma (6.3%)
vascular disease, high pitched,  squeeky ,
or hoarse voice and flat feet.
366 Congenital and inherited syndromes associated with bone and soft tissue tumours
bb5_29.qxd 13.9.2006 13:59 Page 367
Neoplastic disease spectrum have been reported in WS patients (fol- readily detectable in cell lines and tis-
WS patients are at increased risk of licular, papillary and anaplastic), with a sue samples from normal individuals
developing both sarcomas and epithe- predominance of the less common fol- and heterozygous carriers of single
lial neoplasms {820, 1494}. The elevat- licular variant. There has been no mutant copies of the WRN gene by
ed risk of neoplasia is selective, and reported case of medullary thyroid car- Western blot analysis {1510}. No sys-
includes the following neoplasms in cinoma in a WS patient. The risk of tematic study of the level of expression
order of decreasing frequency: soft tis- malignant melanoma is confined almost of WRN protein as a function of cell type
sue sarcomas, thyroid carcinoma, exclusively to the relatively rare variants or of development has as yet been pub-
meningioma, malignant melanoma, that arise on the palms and soles (acral lished. The WRN protein encodes both
malignant or pre-neoplastic haemato- lentigenous melanoma) or in mucosa DNA helicase and exonuclease activi-
logical disease and osteosarcoma. of the nasal cavity or esophagus. ties {1931}, and is likely to play an
Many other neoplasms, including com- Melanoma risk is most clearly elevated important physiologic role in homolo-
mon adult epithelial malignancies, have in Japanese WS patients {820}. gous recombinational repair in human
been observed in WS patients. The spectrum of haematological dis- somatic cells {1728}.
However, it is not clear whether the risk ease in WS includes acute myelogenous
of developing these neoplasms is ele- leukaemia (M1-5), erythroleukaemia Mutations
vated above population controls. This (M6) and megakaryocytic leukaemia WS is an autosomal recessive disease,
histo-pathological spectrum of neo- (M7); atypical leukemia arising in the and thus patients have mutations in both
plasms overlaps with, though is distinct context of myelodysplasia; and the pre- WRN alleles. Virtually all of the WRN
from, that observed in patients with two malignant conditions myelodysplasia, patient mutations thus far identified
other RecQ helicase deficiency syn- myelofibrosis, and aplastic anaemia. truncate the WRN open reading frame,
dromes, Bloom syndrome and The elevated risk of developing marrow- lead to protein reduction or loss from
Rothmund-Thomson syndrome {1494}. associated pre-malignant or malignant patient cells and thus can be detected
Several features of neoplasia in WS disease may be related to the progres- by Western blot analysis {821,1510}.
patients indicates that this human RecQ sive accumulation of genetic damage in Further mutation characterization can
helicase deficiency syndrome is a heri- bone marrow cell lineages {1509}. be performed by a combination of muta-
table cancer predisposition: patients tion-specific allele identification and / or
develop neoplasms at a comparatively Genetics DNA sequencing. Mutation analysis can
early age; often have unusual sites of WS is an autosomal recessive disease: be especially helpful in the diagnosis of
presentation (e.g., osteosarcoma of the no cases are known to have been WS in young patients, where the diag-
patella) or less common histopathologic acquired or to have been caused by nosis is suspected but the clinical phe-
subtypes (e.g., follicular as opposed to other agents. WS constitutes, together notype may be incompletely developed.
papillary thyroid carcinoma); and can with Bloom syndrome and Rothmund- A HUGO Locus-Specific WRN Muta-
have multiple concurrent or sequential Thomson syndrome, a group of inherit- tional Database summarizes patient
neoplasms, e.g., thyroid carcinoma and ed human genetic instability / cancer mutation data and mutation designa-
osteosarcoma. Estimates of the predisposition syndromes that result tions, polymorphism data, and re-
increased risk of neoplasia in WS from loss of function of a human RecQ lated clinical data and cross-refere-
patients range from 30-fold elevated helicase protein. nces these to the primary literature
overall lifetime risk across all tumour (www.pathology.washington.edu/
types to 1000-fold elevated risk for acral Gene structure and expression r esear ch/ wer ner / ws_ wr n. ht ml )
lentigenous melanoma. The WRN gene consists of 35 exons in a {1511}. Additional information on WRN
Soft tissue sarcomas that have been 165 kb region of chromosome region mutation analysis for the purpose of
identified in WS patients include malig- 8p11-12 {2331}. confirming a diagnosis of Werner
nant fibrous histiocytoma, malignant Two stable RNAs are encoded by the syndrome can be obtained through
peripheral nerve sheath tumour, fibro- WRN gene, and the shorter, of 5.8 kb, is the International Registry of Werner
sarcoma, rhabdomyosarcoma, lipo-sar- ubiquitously expressed at varying levels Syndrome Web site (www.pathology.
coma, and synovial sarcoma. Three his- in many cell types, tissues and organs washington.edu/research/werner/reg-
tological subtypes of thyroid carcinoma {2331}. The 162 kDa WRN protein is istry/diagnostic.html).
Werner syndrome 367