Some of the genetic conditions with visual and ocular components that are of interest include:
Down syndrome
the most common of the chromosomal disorders
and a major cause of mental retardation
incidence = 1 in 800 in the US
95% of affected individuals have trisomy 21
clinical features
mental retardation [80% have IQ between 25
and 50], gentle, shy manner, flat facial profile, lowset ears, protruding
tongue, Simian crease in palm, abundant neck skin, very dry skin, congenital
heart defects [40%], predisposition to leukemia [OR 10 to 20], hypotonia,
gap between first and second toe, short, stubby fingers, abnormal immune systems
= lung infections, Alzheimer when > 40
ocular features
oblique palpebral fissures, strabismus, moderate/high
refractive error, broad epicanthal folds, Brushfield spots (pale gray irregular
discolorations in the midperipheral iris), iris hypoplasia, cataracts, blepharitis,
RPE disturbances at the disc margin
Marfan syndrome
a disorder of the connective tissues of
the body
70 to 85% of the cases are familial, AD
clinical features
skeletal abnormalities - tall with exceptionally
long extremities, and long, tapering fingers and toes; lax joint ligaments
in hands and feet; dolichocephalic (long-headed) with prominent supraorbital
ridges; scoliosis; caved-in chest (depressed sternum); potentially life threatening
cardiovascular changes, most commonly mitral valve prolapse and dilatation
of the ascending aorta owing to cystic medionecrosis = 30 to 45% of these
individuals die from aortic wall rupture.
ocular features
lens subluxation (usually outward and upward)
= ecotpia lentis, usually bilateral; also iris hypoplasia, cataracts, retinal
detachment, myopia, ptosis, strabismus
Usher syndrome
clinical features
profound congenital sensorineural hearing gloss
accounts for 10% of all hereditary deafness
ocular features
retinitis pigmentosa
Turner syndrome
this syndrome results from complete or partial
monosomy of the X chromosome and is characterized primarily by hypogonadism
in phenotypic females.
clinical features
for those with deletions or with mosaicism,
they may have almost normal appearance and may present only with primary amenorrhea.
Turner syndrome is the single most important cause of primary amenorrhea,
accounting for approximately one-third of the cases.
short stature, low posterior hairline, webbing
of the neck, streak ovaries, pigmented nevi, peripheral lymphedema at birth,
congenital heart disease, failure to develop secondary sex characteristics
at puberty; usually mentally normal
ocular features
prominent epicanthal folds, ptosis, strabismus,
blue sclerae, cataracts, color vision deficiencies at same rate as males
Klinefelter syndrome
best defined as male hypogonadism that occurs
when there are two or more X chromosomes and one or more Y chromosomes.
classic pattern is 47,XXY (82% of cases).
clinical features
distinctive body habitus with an increase in
length between the soles and the pubic bone, creating an appearance of an
elongated body.
other eunuchoid symptoms: small atrophic testes
and a small penis, and lack of secondary male characteristics such as deep
voice, beard, and male hair distribution.
mean IQ slightly lower but mental retardation
is rare.
FSH (follicle stimulating hormone) levels are
elevated; testosterone levels are reduced.
ocular features
corneal stromal opacities
Waardenburg syndrome
three characteristics: hearing, pigmentation,
facial structure
clinical features
lateral displacement of medial canthii and
lacrimal puncta (telecanthus), wide bridge, white forelock, heterochromic
irides, deafness (with extreme variability)
Fragile X syndrome
Fragile X syndrome is the prototype of disease
in which the mutation is characterized by a long repeating sequence of three
nucleotides. FraX is one of the most common causes of familial mental
retardation and second only to Down Syndrome in overall causes of genetic
mental retardation.
X-linked disorder, a cytogenic abnormality
seen as a discontinuity or constriction in the long arm of the X chromosome.
It is referred to as a fragile site because it is particularly liable to chromatid
breaks when cells are cultured.
I in 1000 in males and 1 in 2000 in females
clinical features
affected males are mentally retarded, with
IQs in the range of 40 to 70; long face with large mandible, large everted
ears, large testicles (macroorchidism).
There are some unique propertied of FraX transmission,
including carrier males, affected females, anticipation (the clinical features
worsen with each succeeding generation).
ocular features
strabismus, refractive error; likely perceptual
disorders associated with the retardation
few if any ocular health abnormalities
Prader-Willi syndrome
caused by an interstitial deletion of band
q12 in the long arm of chromosome 15. It is striking that in all cases,
the deletion affects the paternally derived chromosome 15.
clinical features
mental retardation, short stature, hypotonia,
obesity because of overeating tendencies – need to be controlled, small hands
and feet, and hypogonadism.
ocular features
iris transillumination, strabismus, myopia
Angelman syndrome
patients are born with a deletion of the
same chromosome region derived from their mothers.
1 in 25,000
clinical features
mental retardation, ataxic gait, seizures,
absent speech, and inappropriate laughter.
“happy puppets”
ocular features
occasionally hypopigmentation. Unusual
to have significant visual problems.
Apert syndrome
a craniosynostosis, i.e., premature closure
of a suture of the skull. Results in a deformity and may cause damage
to the brain and eye.
ocular features
the premature closure results in severe deformities.
The roof of the orbit is depressed, exophthalmos develops, and there may
be strabismus, nystagmus, papilledema, fundus hypopigmentation, optic atrophy
(#1) and vision loss.
neurofibromatosis
a disorder associated with defects in proteins
that regulate cell growth.
neurofibromatoses comprise at least 2 AD disorders
affecting about 100,000 people in the US.; 30-40 per 100,000.
referred to as neurofibromatosis type 1 (also
called vonRecklinghausen disease) and neurofibromatosis type 2 (also called
acoustic neurofibromatosis). they are genetically distinct.
NF-1 is a relatively common disorder with
a frequency of about 1 in 3000. 50% have a positive family history and
the rest represent new mutations. in familial cases, expressivity is
extremely variable but penetrance is 100%.
clinical features
three major features: multiple neural
tumors dispersed anywhere on or in the body; numerous pigmented skin lesions,
some of which are ‘cafe au lait’ spots; pigmented iris hamartomas.
the neurofibromas arise within or are attached
to nerve trunks anywhere in the skin, including the palms and soles, as well
as in every conceivable internal site, including the cranial nerves.
the neurofibromas in von Recklinghausen disease become malignant in about
3% of patients, malignant transformation being more common in the very large
plexiform tumors attached to large nerve trunks of the neck or extremities,
rather than the superficial lesions.
more than 90% have the cutaneous pigmentations.
the clinical maxim is if there are six or more spots over 1.5 cm in diameter,
the pat is likely to have neurofibromatosis.
patients can have skeletal lesions secondary
to the neurofibromas. they also are at higher risk for developing other
tumors like meningiomas, and optic gliomas
Type 2 is much less frequent; bilateral acoustic
nerve tumors are always present, cafe au lait spots too, but no Lisch nodules.
ocular features
the pigmented hamartomas of the iris are called
Lisch nodules and are present in more than 94% of patient who are more than
six years old.
they don’t produce any symptoms usually but
are helpful in the diagnosis.
glaucoma, proptosis, cataracts, optic atrophy
secondary to glioma of optic nerve, and ptosis are frequently seen as well,
also abnormal anterior chamber angles.
Tay-Sachs disease
one of a group of 3 lysosomal storage diseases
called the GM2 gangliosidoses. prevalent among Jews, particularly among
those of Eastern European origin, carrier rate of 1 in 30.
clinical features
GM2 ganglioside accumulates in many tissues
dominant clinical picture is involvement of
neurons in central and autonomic nervous systems and retina
neurons are ballooned with cytoplasmic vacuoles,
which are markedly distended lysosomes filled with gangliosides.
results in progressive destruction of neurons;
relentless motor and mental deterioration beginning at about 6 months; begins
with motor incoordination, mental obtundation, increasing dementia and blindness;
death follows at age 2 to 3 years.
ocular features
ganglion cells in the retina swell, particularly
at the margins of the macula. a cherry red spot thus appears at the
macula from accentuation of the normal color of the choroid contrasted with
the pallor produced by the swollen ganglion cells everywhere else, which
gives a white parafoveal halo.
phenylketonuria
deficiency in phenylalanine hydroxylase.
Prevents conversion of phenylalanine into tyrosine. So, build up of
phenylalanine and it is shunted into the formation of phenylketones.
clinical features
neurologic dysfunction, especially hyperirritability
and tremors, followed by slowly progressive mental deterioration. Also
are hypopigmented.
ocular features
delayed P100 latencies in VEP if off diet.
albinism
another example of tyrosine problems.
Really are three forms of albinism:
oculocutaneous albinism
defect in formation of melanin; at least 6 variants
most common, tyrosinase is not active [called tyrosinase negative]
second, tyrosinase is present in the melanosome, but transport of tyrosine
into the melanosome is absent
[called tyrosinase positive]
result = no melanin
incidence = 1 in 20,000 in US
clinical features
fair skin, fine silky hair
ocular features
no pigment in iris, sclera, fundus; iris transillumination because no pigment
in iris pigment epithelium
refractive errors, strabismus, nystagmus, photophobia, poor VA
partial albinism; AD
ocular albinism; X-linked
1 in 50,000
only retina or retina and iris; skin pigmentation normal but lighter
VA decreased, nystagmus (same as oculocutaneous albinos except iris)
Cockayne syndrome
a neurodegenerative disorder characterized
by degeneration of CNS white matter resulting in neurologic, ocular, cutaneous,
and musculoskeletal manifestations. Normal in the first few months,
followed by a drastic and progressive decline in physical and mental development
rare (<100 cases); males = females
onset early in life.
Deficiency in an enzyme involved in the repair
of cellular DNA following damage by UV light or chemical mutagens
clinical features
photosensitive dermatitis, segmental demyelination
central and peripheral nervous system (CNS > PNS) with preserved islands
of myelin, Two types, differentiated by time of onset – late or prenatal;
cerebellar dysfunction, MR, microcephaly, malformed ears, beaked nose, growth
retardation, loss of subcutaneous fat of the face, progressive kyphosis,
hearing impairment, poor feeding and aspiration pneumonia, significant dental
caries
ocular features
sunken eyes, impaired lacrimation, corneal
opacities, photophobia, poor pupillary responses, cataracts, hyperopia, speckled
pigmentation to fundus, optic atrophy resulting in decreasing acuity, macular
hypoplasia, nystagmus, slowed VEP.
the more ocular signs, the shorter the lifespan
(> 5).
