9.Conditions associated with increased risk of malignancy

Knudson’s two-hit

suppressor genes, such gene defects are dominantly inherited.

hypothesis

However, loss of one allele is not sufficient for tumor development

and a second mutational event—a second hit—must occur. Knudson

proposed that the frequency and distribution of retinoblastomas in

familial and sporadic cases could be explained by a 'two-hit'

mutational mechanism.

242

Tumor predisposition and the eye

Conditions associated with increased risk of malignancy

243

MIM

175100

Clinical features

Ocular

Multiple bilateral congenital hypertrophic lesions of the retinal

pigment epithelium (CHRPE) are a strong marker of APC. In APC,

CHRPEs are often shaped like fish tails and have a pale halo around

them. Single CHRPEs are common in the general population.

244

Adenomatous polyposis of the colon

Conditions associated with increased risk of malignancy

245

Age of onset

CHRPEs present from birth. Polyps usually develop in the second

decade of life.

Epidemiology

Prevalence 2–3:100,000. Incidence 1:10,000.

Inheritance

Autosomal dominant

Chromosomal location

5q21–q22

Gene

Adenomatous polyposis of the colon (APC)

Mutational spectrum

Mutations are found in around two-thirds of families. Virtually all

mutations result in premature protein truncation. The large size of

the gene (the open reading frame is 8538 bp) makes conventional

mutation analysis laborious. However the presence of a genotype-

phenotype correlation may direct mutation analysis. CHRPEs

suggest the presence of a mutation between codons 463–1387.

Mutations of exons 4, 5, 9 and distal 15 produce an attenuated

phenotype, those between codons 1250 and 1464 produce a

severe phenotype.

Effect of mutation

Mutations lead to loss of protein function. Different domains of the

large APC protein have been shown to have a wide range of cellular

functions, including cell adhesion, migration and proliferation as

well as maintenance of normal apoptotic responses.

Diagnosis

In general those without a family history will be diagnosed at

colonoscopy. Family members will undergo genetic testing via PTT-

based or conventional mutation testing and linkage analysis if the

causative defect is known. For families in whom CHRPEs are a

marker of the disease, their observation may be a useful adjunct to

detection of carrier status.

246

Adenomatous polyposis of the colon

MIM

109400

Clinical features

The ocular features of BCNS have led to it being known as the

‘fifth phakomatosis’. The major morbidity is related to skin tumor

formation (multiple basal cell carcinomas).

Ocular

BCCs on the eyelid are a major consequence of BCNS. The condition

should remain part of the differential diagnosis in those patients

under the age of 25 years with multiple BCCs.

Conditions associated with increased risk of malignancy

247

248

Basal cell nevus syndrome

B

A. Segmentation defects including abnormalities of rib development.

B. Multiple BCCs in Gorlin syndrome.

Age of onset

Many features are present at birth (e.g. bifid ribs, cleft lip), although

the diagnosis may not be apparent until later. By the age of 25 years,

50% of Caucasians with BCNS have BCCs; by the age of 40 years

this has increased to over 95%. Odontogenic keratocysts generally

present in the second/third decade of life. Medulloblastoma is

relatively uncommon but may present in early childhood.

Epidemiology

Prevalence reported as between 1:56,000 and 1:164,000. This is

likely to be much higher amongst individuals under 20 years of age

who have BCCs.

Inheritance

Autosomal dominant. Around 15% represent new mutations.

Chromosomal location

9q22.3

Conditions associated with increased risk of malignancy

249

Gene

The human homolog of the Drosophila patched gene (PTCH).

Mutational spectrum

Around 80% of mutations result in premature protein truncation.

Mutations occur throughout the gene.

Effect of mutation

PTCH is the cell surface transmembrane receptor for the Shh

protein, a developmental signaling molecule. Shh is mutated in

some forms of holoprosencephaly. Signal transduction, through

the Shh/PTCH pathway results in developmental transcriptional

regulation. It is thought that a reduction in PTCH levels gives rise to

the developmental features of BCNS. In addition, PTCH is a tumor

suppressor gene and a ‘two-hit’ mechanism is required for the

development of BCCs.

Diagnosis

When suspected clinically, BCNS is usually confirmed through

clinical investigation. Genetic testing, using standard techniques,

may be useful to aid diagnosis in family members: this is available

through clinical genetic diagnostic laboratories.

250

Basal cell nevus syndrome

MIM

162200

Clinical features

NF1 is a completely penetrant highly variable autosomal dominant

disorder. The majority of patients escape the most severe

complications.

Ocular

Lisch nodules, melanocytic hamartomas of the iris, are the most

common ocular lesions, and are present in almost all patients.

Unilateral glaucoma is also described and may be congenital, often

with buphthalmos. Approximately 10% of NF1 patients develop

CNS tumors, half of which are optic nerve gliomas that generally

develop by the age of 5 years. Therefore, ophthalmic follow-up and

screening is advised through clinical examination of visual acuity,

orthoptic assessment, fundoscopy and/or field examination during

the first years of life. Prospective brain imaging is not generally

recommended as many patients (around two-thirds of children) have

asymptomatic gliomas or other unidentified bright objects (UBOs),

the identification of which is incidental and often unhelpful.

Extraocular

Multiple café-au-lait spots occur in the skin of nearly all patients.

The spots increase in number over the first few years of life and

fade later. Axillary or inguinal freckling is present in around 90%

of patients. Often, adults have many benign cutaneous or

subcutaneous neurofibromas. Plexiform neurofibromas are less

common and usually present before mid-teenage years. These often

grow and can undergo sarcomatous transformation. One site of

predeliction is the upper lid and this can become disfiguring.

Conditions associated with increased risk of malignancy

251

About 30% of patients have mild but specific learning difficulties,

although intelligence is generally normal. Skeletal manifestations

include scoliosis, especially during periods of growth, and

pseudarthrosis. Hypertension is common in adults and although

renal artery stenosis and pheochromocytoma have been reported,

it is generally found to be essential hypertension. Malignant

transformation of tumors to fibrosarcoma, neurofibrosarcoma or

malignant schwannoma is not uncommon and is seen in around

10% of patients.

Age of onset

The characteristic features of NF1 develop at different ages, hence

pseudoarthroses may be present at birth. Café-au-lait patches may

be noted in the first year of life but these increase in frequency

during the first decade. Optic nerve gliomas usually develop under

252

Neurofibromatosis type I

the age of 5 years. Most patients develop sufficient features for a

positive diagnosis by the age of 5 years.

Epidemiology

1:3000–4000

Inheritance

Autosomal dominant. 50% of individuals have new mutations.

Chromosomal location

17q11.2

Gene

Neurofibromin (NF1)

Mutational spectrum

A wide range of mutations has been described. Routine mutation

testing protocols define a mutation in one-half to one-third of

patients.

Effect of mutation

The majority of mutations result in premature protein truncation.

NF1 is a common condition that is highly variable. Little evidence of

a genotype-phenotype correlation exists suggesting the existence of

modifying environmental and genetic effects. Neurofibromin appears

to down regulate p21 (ras), a major regulator of cell growth. It has

been postulated that NF1 mutations result in abnormal ras signaling

and thereby contribute to tumor development.

Diagnosis

Diagnosis is clinical and is based on the presence of particular

criteria, such as Lisch nodules. Regular childhood assessment for

the multisystemic effects of NF1 is necessary. In addition, annual

ophthalmic review is recommended throughout childhood. DNA

testing is available through molecular diagnostic laboratories

although this is laborious and seldom undertaken.

Conditions associated with increased risk of malignancy

253

MIM

101000

Clinical features

Ocular

Pre-senile posterior subcapsular, cortical or wedge-shaped opacities

are found in the majority of patients (~80%). Prospective screening

for the opacities is of no value as they are seldom visually significant.

They may occasionally progress with time. Lisch nodules are not

found in NF2. Macular and paramacular epiretinal membranes and

hamartomatous lesions of the retina and RPE are seen in around

50% of patients.

Neuro-ophthalmic complications are a major result of vestibular

schwannomas (acoustic neuromas) or, more commonly, the

surgery required to remove them. Facial nerve palsy results in

lagophthalmos and decreased lacrimal secretion, while trigeminal

damage causes corneal anesthesia.

Extraocular

The tumors most frequently associated with NF2 are bilateral

vestibular schwannomas. These cause hearing loss, tinnitus and

balance dysfunction. Around two-thirds of patients develop spinal

tumors, most commonly schwannomas, although astrocytomas

and ependymomas have also been observed. Spinal tumors are a

significant cause of morbidity. Approximately 50% of patients with

NF2 develop meningiomas, both intracranial and spinal.

Patients rarely have more than five café-au-lait patches. Flat,

dysplastic skin tumors and subcutaneous spherical nodular tumors

on the trunk and limbs are common and represent cutaneous

schwannomas.

254

Neurofibromatosis type II

expression and/or protein function and thereby influences

phenotypic outcome. Therefore, there is evidence for genotype-

phenotype correlation.

Effect of mutation

Most of the mutations result in protein truncation, and are presumed

to result in severe diminution, or loss, of function. The NF2 protein,

merlin (moezin-ezrin-radixin like protein), is homologous to a family

of cytoskeleton-associated proteins. Abnormal protein products have

been shown to display altered cell adhesion, which may be an initial

step in tumorigenesis.

Diagnosis

Ocular abnormalities are common but generally do not result in

bilateral visual loss. When suspected clinically, as in patients

with isolated unilateral or bilateral vestibular schwannoma,

ophthalmologists may be asked to investigate for the presence of

lens opacities or retinal hamartomas. DNA testing is available

through recognized molecular diagnostic laboratories.

256

Neurofibromatosis type II

MIM

180200

Clinical features

Ocular

Retinoblastoma is a childhood malignancy derived from retinal cells.

The tumor develops between the ages of 1–4 years, very rarely

presenting later. Improvements in treatment have increased 5 year

survival to 94% in the UK.

The most common presentations are leukocoria and strabismus.

However, retinoblastoma may mimic developmental glaucoma,

orbital cellulitis, uveitis, hyphema or vitreous hemorrhage.

Tumors may spread towards the vitreous cavity (endophytic spread)

or towards the outer layers of the eye and subretinal space

(exophytic tumor). Histologically, they are characterized by necrosis

and calcification with primitive small cells, which may resemble

primitive photoreceptors and form Flexner-Wintersteiner rosettes.

Extraocular

Those with a germline mutation carry a predisposing mutation in

all cells and have an increased risk of non-ocular malignancy such

as osteosarcomas, soft tissue sarcomas and melanomas. Their

cumulative incidence, 50 years after diagnosis of retinoblastoma,

is 20–30% in non-irradiated patients and >50% in those receiving

external beam radiation. In addition there is a low risk of pinealomas

which have a poor prognosis.

A small number of patients carry large chromosomal deletions

encompassing the RB1 gene and the genes surrounding it on 13q

(see figure). The deletions may cause clinical manifestations due

to loss of these genes—a contiguous gene syndrome—including

developmental delay and facial dysmorphism.

Conditions associated with increased risk of malignancy

257

A

B

Retinoblastoma in first trimester fetus with multiple abnormalities. A visible

deletion of chromosome 13q was seen on karyotype analysis.

A. The fetus has a small jaw, low set ears, short, broad neck and short thumbs.

B. Swelling of the right eye was noted. Macroscopic and histopathological

analysis revealed a large retinoblastoma.

Age of onset

Mean age of onset for bilateral cases is 15 months and for unilateral

cases 24 months.

Epidemiology

Incidence of 4:1,000,000, or about 1:23,000 live births.

Inheritance

Autosomal dominant.

Penetrance is >99% for most mutations that abolish RB1 function.

However, in some families penetrance is reduced to around 40%.

258

Retinoblastoma

Chromosomal location

13q14.1–q14.2

Gene

Retinoblastoma (RB1)

Mutational spectrum

RB1 is a large gene containing 27 exons covering over 180 kb of

genomic DNA. While major deletions are reported, the majority of

mutations are single base changes. All forms of mutation have been

described including protein truncating mutations, splice-site

mutations and missense changes. The majority of mutations

(80–85%) result in premature termination.

Effect of mutation

RB1 is a tumor suppressor gene that expresses a nuclear protein

involved in cell cycle regulation and transition from G1–S phase.

RB1 acts to inhibit cellular transcription factors and tRNA/rRNA

gene transcription. Mutations in RB1 that cause low penetrance

forms of retinoblastoma have been shown to retain some function.

Diagnosis and

Clinical. Using sensitive screening techniques around 80–90% of

counselling issues

mutations can be found in patients with germline mutations.

Genetic testing is now widely available. Ongoing screening of both

affected children and unaffected siblings is a major cause of anxiety.

However, mutation testing may be useful in reducing the need for

examination under anesthetic and repeated fundoscopy in

unaffected siblings who are not mutation carriers.

A major area of concern is the possibility that the proband or one of

his or her parents has a germline mutation that may be passed on to

other family members. Family history and mutation analyses can be

used to help determine these risks.

In unilateral cases, negative screening of blood does not exclude the

possibility of mosaicism as both affected and unaffected germ cells

may exist and can be passed on to offspring. Molecular genetic

testing of tumor DNA may aid the search for mutations. If two

disease causing mutations are identified in a tumor, peripheral

blood from relatives can then be screened for these mutations.

Conditions associated with increased risk of malignancy

259

Family

Tumor type

Probability

Risk to offspring

Risk to siblings

history

of germline

mutation

Positive

Bilateral

100%

50%

-

retinoblastoma

Negative

Bilateral

95%

Assumed to be

Around 3–5%

retinoblastoma

50%

(due to germline

mosaicism)

Negative

Multifocal,

Uncertain

Difficult to

Difficult to

unilateral

determine

determine

retinoblastoma

Negative

Unifocal,

5–10%

2–5%

1%

unilateral

retinoblastoma

260

Retinoblastoma

MIM

191100 (TSC1); 191092 (TSC2)

Clinical features

TSC is a highly variable autosomal dominant disorder in which

affected individuals have a high risk of seizures and renal disease,

both of which are significant causes of premature mortality.

Ocular

These are usually asymptomatic. The classical lesions are retinal

astrocytic hamartomas, ‘mulberry tumors’, or small intraretinal

translucent patches. In addition, achromic patches analogous to

the hypopigmented skin lesions are present. One or more of these

lesions may be present in up to 75% of patients.

CNS

Tumors include subependymal glial nodules and giant cell

astrocytomas as well as cortical and subcortical tubers. Over 80%

of patients diagnosed with TSC have seizures, and at least 50%

have developmental delay.

Renal

Benign angiomyolipomas occur in at least 70% of patients and can

cause hemorrhage or replacement of renal tissue. Some patients

have a combined phenotype with features of TSC and PKD and in

these patients cystic disease may lead to renal failure.

Skin

Facial angiofibromas (adenoma sebaceum), periungual fibromas,

hypomelanotic macules and shagreen patches are all observed.

Conditions associated with increased risk of malignancy

261

262

Tuberous sclerosis complex

Cardiac

Cardiac rhabdomyoma

Other

Minor manifestations include multiple dental pits, hamartomatous

rectal polyps, bone cysts and gingival fibromas.

Age of onset

Signs of the disorder may be present from birth, although it is

generally diagnosed during childhood.

Epidemiology

The prevalence of TSC is suggested to be as high as 1:5800 births.

Inheritance

Autosomal dominant. About 70% of all cases are new mutations.

Chromosomal location

9q34 (TSC1); 16p13 (TSC2)

Gene

Tuberous sclerosis complex 1 and 2 (TSC1, TSC2)

Mutational spectrum

More than 300 mutations have been described in TSC1. None are

missense mutations.

Of over 250 mutations described in TSC2, around 75% are gene

rearrangements, splice mutations and nonsense mutations, 25%

are missense mutations.

Effect of mutation

Both TSC1 and TSC2 are thought to act as tumor suppressor genes.

The two genes have been shown to form heterodimers and are

believed to regulate cell cycle and cell proliferation.

Diagnosis

Clinical. The role of the ophthalmologist is to aid diagnosis by

recognition of retinal lesions. While mutation testing for both TSC1

and TSC2 is now available, this will only identify mutations in

60–80% of cases.

Conditions associated with increased risk of malignancy

263

(also known as: VHL)

MIM

193300

Clinical features

Ocular

About 70% of patients have retinal hemangioblastomas, which are

often the presenting feature of the disorder. Hemangioblastomas are

vascular tumors associated with feeder and draining vessels and are

mainly located in the temporal periphery of the retina, although they

may also be found at the posterior pole and optic disc. The angiomas

are usually asymptomatic when small. As they enlarge they may

cause exudation, hemorrhage and retinal detachment. Laser

photoablation or cryotherapy of early retinal angiomas results in

regression. Optic disc tumors are not amenable to treatment. The

average number of retinal angiomas per patient is two (there may

be up to 15); this number does not increase with age.

Extraocular

CNS hemangioblastomas are the classic lesion of VHL. Around 80%

develop in the cerebellar hemispheres, the remaining 20% in the

spinal cord. Multiple renal cysts are common. In addition, clear-cell

renal carcinoma occurs in >40% of patients. Pheochromocytoma,

either symptomatic or asymptomatic, may be seen within the

adrenal glands or elsewhere. Multiple pancreatic cysts are

frequent, and occasionally pancreatic tumors develop. Tumors of

the endolymphatic sac of the membranous labyrinth are rare but

may cause early deafness. Epididymal cystadenomas are relatively

common in males with VHL syndrome but rarely cause problems.

Age of onset

Symptoms are rare before the age of 5 years. Annual screening

should begin from around the age of 5 years because photoablation

can successfully treat retinal lesions and preserve vision.

264

von Hippel-Lindau syndrome

Epidemiology

Prevalence in the UK has been estimated to be approximately

1:50,000.

Inheritance

Autosomal dominant

Chromosomal location

3p25–p26

Gene

von Hippel-Lindau (VHL)

Mutational spectrum

Mutations are found in almost all patients. Around one-third are

caused by partial or whole gene deletion, the remainder result from

point mutations. A wide range of mutations including truncating,

splice-site and missense mutations have been described. There is

significant genotype-phenotype correlation for mutations in the VHL

gene: truncating and null mutations generally cause VHL without

pheochromocytoma, while patients with pheochromocytoma

generally have a missense mutation.

Effect of mutation

The VHL protein (pVHL) is involved in the regulation of hypoxically-

induced vascular endothelial growth factor (VEGF) and glucose

transporter-1 (GLUT-1). It is also involved in the degradation of

hypoxia-inducible factor-1 (HIF-1). HIF-1 usually controls factors

promoting the formation of blood vessels. If pVHL is abnormal, the

degradation of HIF-1 does not take place resulting in abnormal

proliferation of blood vessels. This could account for the vascular

tumors seen in VHL. Further work is ongoing to fully understand

the interactions of pVHL with other proteins and to understand the

genotype/phenotype correlation.

The VHL gene is a tumor suppressor gene requiring biallelic loss

for tumorigenesis, however, the presence of a genotype-phenotype

correlation suggests that some missense mutations retain aspects

of protein activity.

Diagnosis

Patients with retinal angiomas should be investigated for the

presence of other characteristic lesions. DNA testing is available

through molecular diagnostic laboratories.

Conditions associated with increased risk of malignancy

265