Definition

Nail-patella syndrome, is a genetic disease of the
connective tissue that produces defects in the fingernails,
knee caps, and kidneys.

Description

Nail-patella syndrome is also known as Fong Disease,
Hereditary Onycho-Osteodysplasia (H.O.O.D.),
Iliac Horn Disease, and Turner-Kieser syndrome.
Patients who have nail-patella syndrome may show a
variety of physical defects. The hallmark features of this
syndrome are poorly developed fingernails, toenails, and
patellae (kneecaps). Other common abnormalities
include elbow deformities, abnormally shaped pelvis
bone (hip bone), and kidney (renal) disease.

Less common medical findings include defects of
the upper lip, the roof of the mouth, and unusual skeletal
abnormalities. Skeletal abnormalities may include poorly
developed scapulae (shoulder blades), sideways bent
fingers (clinodactyly), clubfoot, scoliosis, and unusual
neck bones. There are also other effects, such as thickening
of the basement membrane in the skin and of the
tiny clusters of capillaries (glomeruli) in the kidney. Scientists
have recognized an association between nailpatella
syndrome and colon cancer. Nail-patella syndrome
is associated with open-angle glaucoma, which,
if untreated, may lead to blindness. Patients may also
have cataracts, drooping eyelids (ptosis), or corneal
problems such as glaucoma.

People with nail-patella syndrome may display only a
few or many of the recognized signs of this disease. Symptoms
vary widely from person to person. Signs even vary
within a single family with multiple affected members.
The incidence of nail-patella syndrome is approximately
one in 50,000 births. This disorder affects males
and females equally. It is found throughout the world and
occurs in all ethnic groups. The strongest risk factor for
nail-patella syndrome is a family history of the disease.

Causes and symptoms

Nail-patella syndrome has been recognized as an
inherited disorder for over 100 years. It is caused by
mutations in a gene known as LIM Homeobox Transcription
Factor 1-Beta (LMX1B), located on the long arm of
chromosome 9.

The LMX1B gene codes for a protein that is important
in organizing embryonic limb development. Mutations
in this gene have been detected in many unrelated
people with nail-patella syndrome. Scientists have also
been able to interrupt this gene in mice to produce defects
similar to those seen in human nail-patella syndrome.
Nail-patella syndrome is inherited in an autosomal
dominant manner. This means that possession of only one
copy of the defective gene is enough to cause disease. When
a parent has nail-patella syndrome each of their children has
a 50% chance to inherit the disease-causing mutation.
A new mutation causing nail-patella syndrome can
also occur, causing disease in a person with no family history.
This is called a sporadic occurrence and accounts for
approximately 20% of cases of nail-patella syndrome. The
children of a person with sporadic nail-patella syndrome
are also at a 50% risk of developing signs of the disorder.
Medical signs of nail-patella syndrome vary widely
between patients. Some patients with this disorder do not
display symptoms. These patients are discovered to have
the nail-patella syndrome only when genetic studies trace
their family history. Scientists are now working to learn
what causes different people to display such different
symptoms of nail-patella syndrome.

The most obvious sign associated with nail-patella
syndrome is absent, poorly developed, or unusual fingernails.
Fingernail abnormalities are found in over 80% of
patients with this disorder. Abnormalities may be found
in one or more fingernails. Only rarely are all fingernails
affected. This disease most commonly affects the fingernails
of the thumbs and index fingers. The pinky fingernail
is least likely to be affected. Fingernails may be
small and concave with pitting, ridges, splits, and/or discoloration.
Toenails are less often affected. The lunulae,
or light-colored crescent moons, at the base of the fingernail
bed next to the cuticle are sometimes triangularlyshaped
in people with nail-patella syndrome.

Kneecap abnormalities are the second most common
sign associated with this disorder. Either or both
kneecaps may be missing or poorly formed. If present,
kneecaps are likely to be dislocated. The knees of people
with nail-patella syndrome may have a square appearance.
Besides the kneecap, other support structures
including bones, ligaments, and tendons may also be
malformed. These support structures stabilize the knee,
therefore patients with some leg malformations may have
difficulty in walking.

The hip bones of approximately 80% of patients
with nail-patella syndrome have unusual bony projections
called posterior iliac horns. These bony projections,
or spurs, are internal and not obvious unless they are
detected on x ray. This unusual pelvic anatomy is not
associated with any other disease.

Kidney disease is present in at least 30% of people
with nail-patella syndrome. Biopsy shows lesions that
resemble those of inflammation of the clusters of capillaries
in the kidneys (glomerulonephritis), but without
any infection present. Kidney failure is the most dangerous
consequence of nail-patella syndrome. It occurs in
about 30% of patients who have kidney involvement. An
early sign of kidney involvement is the presence of protein
or blood in the urine (chronic, benign proteinuria
and hematuria.) Kidney involvement is progressive, so
early diagnosis and treatment of renal disease is important.
Kidney disease has been reported in children with
nail-patella syndrome, but renal involvement more commonly
develops during adulthood.

Various skeletal symptoms may occur. Patients with
nail-patella syndrome may not be able to fully straighten
their arms at the elbow. This may create a webbed appearance
at the elbow joint. Patients may have sideways bent
fingers, poorly developed shoulder blades, clubfoot, hip
dislocation, unusual neck bones, or scoliosis.

Eye problems may be present and vary from person
to person. Nail-patella syndrome is associated with open
angle glaucoma. Open angle glaucoma is caused by fluid
blocked into the front chamber of the eye. This blocked
fluid builds increasing pressure into the eye. If untreated,
this increased pressure may lead to permanent damage of
the optic nerve and irreversible blindness. Some patients
with nail-patella syndrome have ptosis, or drooping eyelids.
Nail-patella syndrome has also been associated with
abnormalities of the cornea, cataracts, and astigmatism.
Additionally, the irises of the eye may be multicolored,
possibly displaying a clover-shaped pattern of color.

Diagnosis

As of early 2001, genetic testing for nail-patella
syndrome is available only through research institutions
that are working to further characterize this disorder.
Genetic testing cannot predict which signs of the disease
will develop. Nor can genetic testing predict the severity
of disease symptoms. Improved genetic testing for nailpatella
syndrome is anticipated in the future.

Diagnosis of this disease is most often made on
visual medical clues such as the characteristic abnormalities
of the fingernails and kneecaps. Diagnosis is confirmed
by x-ray images of the affected bones and, when
indicated, kidney biopsy. The bony pelvic spurs found
in 80% of patients with nail-patella syndrome are not
associated with any other disease.

Prenatal diagnosis for nail-patella syndrome by
third-trimester ultrasound was documented in 1998. Prenatal
diagnosis via genetic testing of cells obtained by
chorionic villus sampling was reported the same year.
As of 2001, prenatal genetic testing for nail-patella syndrome
is not yet widely available. There is controversy
surrounding the use of prenatal testing for such a variable
disorder. Prenatal testing cannot predict the extent of an
individual