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Hypospadias
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Types
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This is a common anomaly of the penis manifesting as an opening on the lower aspect
instead of at its end.
It is important to differentiate between several types:
- The isolated (non-syndromic) type, in which hypospadias is the sole finding.
- Hypospadias as part of a general syndrome:
- Syndromes involving other defects of varying degrees of severity in the reproductive
system. These usually arise from disorders in hormone secretion or hormone receptors
in the genitalia.
- General genetic syndromes involving other organs or systems apart from the reproductive
system.
In many cases hypospadias is associated with a downward bending of the penis, a
condition called chordee. This can be of varying degrees of severity. In the severe
cases (20%) the opening is at the lower end, i.e. at the base of the penis close
to where it arises from the body. In the milder cases (60%), the opening is close
to its normal site.
Some of the cases are accompanied by other defects, such as a narrowing of the urethral
opening (8%), micropenis, inguinal (groin) hernia (8%), or cryptorchidism, where
the testes are in the abdomen (8 - 15%). Sometimes there are also upper urinary
tract defects (2 - 12%). These defects are not usually severe and can be detected
by ultrasound.
It is important to carry out
chromosome analysis in order to confirm that this is normal male, 46,XY.
The finding of other defects or abnormalities is also important. Ultrasound examination
in pregnancy cannot be used to ensure that the internal reproductive organs are
normal, for example to detect whether a uterus is present, or ovaries or testes,
etc. It is important to look for abnormalities in the descent of the testes and
to ascertain whether the testes themselves are normal. It is also important to know
whether there are other cases in the family, which helps to differentiate between
the different types, as detailed below.
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Clinical signs
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Isolated (non-syndromic) hypospadias
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This has a frequency of about 1 - 3 in every thousand newborns.
In most of the cases (approximately 90%) hypospadias with or without chordee is
the only abnormality and the children do not have any other problems.
The hypospadias can be surgically repaired, preferably at the age of about a year
and a half, especially if the opening is far from the usual site and the chordee
is severe, leaving the foreskin in order to allow greater operative success.
There may be a hernia or cryptorchidism associated with the hypospadias, which nevertheless
is still the isolated non-syndromic type.
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This type of hypospadias may be transmitted by autosomal dominant inheritance. If there are
other cases in the families of either or both parents, for example the father, this
supports hereditary transmission. Sometimes it becomes apparent that there are other
family members with this condition only after a thorough examination, as some cases
are very mild and are not noticed by other relatives. If this condition is found
in the father or in other relatives, it is important to examine them to ensure that
the hypospadias is the isolated (non-syndromic) type with no other associated defects.
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The syndromic form: hypospadias as part of a general syndrome.
- Syndromes involving other defects
of varying degrees of severity in the reproductive system:
An example of a mild condition is a syndrome where hypospadias is associated with
cryptorchidism, where the testes have not descended into the scrotum and remain
in the abdomen or in the inguinal canal leading to the scrotum. A more severe and
less common type is incomplete male development due to hermaphroditism, a condition
where there are present elements of both male and female reproductive organs. This
usually results from abnormalities in the secretion of various hormones or defects
of the hormone receptors in the reproductive organs, such as a deficiency in certain
enzymes in the adrenal gland, which interferes with the normal secretion of male
hormones. Examples are a deficiency in the enzyme desmolase or other enzymes in
the body's steroid cycle. Another example is a lack of, or reduction in the level
of, the receptor for the main male hormone, a condition called androgen insensitivity.
Because of this the male hormones do not function, resulting in a lack of development
of normal male external sexual characteristics of varying degrees of severity, up
to a completely female appearance, in which case there is no hypospadias, as the
external genitalia are female.
- Syndromes also involving other organs
apart from the reproductive system:
Here the hypospadias is mainly associated with defects such as heart defects,
deafness, congenital anal atresia, hydrocephalus (dilation of the ventricles
of the brain), defects in the closure of the abdomen,
and defects in the neuromuscular system. Some of the classic syndromes are: various
chromosomal syndromes, Smith Lemli Opitz syndrome.
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Inheritance pattern
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The isolated (non-syndromic) type
Hereditary transmission here is most probably multifactorial, i.e. a number of genes
act together, possibly in association with environmental effects. In some families
in which some family members have non-syndromic hypospadias, hereditary transmission
is autosomal dominant limited to males only.
The syndromic type
Here the type of inheritance depends on which syndrome the patient has. Some cases,
mainly those associated with hormonal deficiencies or a defect in the hormone receptors
in the reproductive organs, such as Smith Lemli Opitz syndrome, are transmitted
by autosomal
recessive inheritance. In other cases, mainly androgen insensitivity, the
inheritance is X-linked.
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Penetrance
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In the isolated type, this is incomplete. This means that there may be instances
where some members of a family that has several individuals with hypospadias may
be born without hypospadias, but their children will be affected. These family members
carry the gene for hypospadias but do not express it.
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Associated features that can be demonstrated in tests performed during pregnancy
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If hypospadias is detected in pregnancy, it is very important to perform additional
tests in order to look for a multisystem syndrome.
- Amniocentesis
should be considered in order to look for a chromosome disorder and to determine
the karyotype (chromosome arrangement) - if this is 46,XY it is normal male.
- It is necessary to perform a comprehensive and thorough ultrasound scan. The purpose of this examination is
to look for defects such as micropenis and also defects in the upper urinary tract
(2% - 12%). It is important to look for other defects as well, especially heart
defects, deafness, anal atresia, hydrocephalus (dilated brain ventricles), defects
in the closure of the abdominal wall, and neuromuscular defects. Ultrasound examination
in pregnancy cannot be used to ensure that the internal reproductive organs are
normal, for example to detect whether a uterus is present, or ovaries or testes,
etc. It is important to look for abnormalities in the descent of the testes and
to ascertain whether the testes themselves are normal. It is important to know,
of course, whether there are other cases in the family. Other affected individuals
should be referred to an endocrinologist and geneticist for examination and to undergo
laboratory tests if necessary. In this way, different types may be differentiated.
- Sometimes it is necessary to perform hormone tests on the amniotic fluid or blood
in order to rule out a disorder of the male hormones, and/or special tests such
as cholesterol and steroid levels in amniotic fluid or blood in order to test for
Smith Lemli Opitz syndrome.
If the hypospadias is the only abnormality and the results of these tests are normal,
this indicates a significantly decreased risk for a genetic syndrome. However, there
is still a small extra risk of approximately 2%, although there are no precise,
reliable figures, in excess of the normal risk in the general population for defects
and mental retardation, which is 2% - 4% when all the test results are normal. As
mentioned, there may be syndromes that are not detected by the tests that can be
performed during pregnancy without additional signs, such as G syndrome etc., but
these are not very likely.
In all these cases it is important to refer the couple for genetic counseling, to
which they should bring all available data, including the results of other tests
performed during the pregnancy such as alpha-fetoprotein, nuchal translucency, etc.
It is advisable to refer the parents to a multidisciplinary clinic in a hospital
for professional counseling by a geneticist, an expert in ultrasound examinations,
a pediatric endocrinologist, a plastic surgeon or urologist, and a neonatologist,
in order to collate all the data and discuss the various possibilities and courses
of treatment that are available, etc. The decisions taken will depend on the severity
of the problem, the presence of additional findings, etc.
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What is the risk of recurrence in a subsequent pregnancy?
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Isolated (non-syndromic) hypospadias
In cases where the affected individual
is the only one in the family:
If this is the first case in the family, and it is the isolated (non-syndromic)
type of hypospadias, the risk of recurrence in another child is approximately 15%.
A father with hypospadias has an increased risk of fathering a child with the same
condition. 8% of men with hypospadias have an affected child or affected children.
The risk for more distant relatives depends on the number of affected individuals
in the family, the relationship to the affected individuals, etc. This risk is ascertained
within genetic counseling.
If there are many affected individuals
in the family:
In a small percentage of families there may be hereditary transmission of a specific
abnormal gene that can be identified. It is important to examine these cases thoroughly
and to check for such a specific gene that is transmitted by autosomal dominant
or X-linked inheritance,
and whether it may also be involved in defects other than hypospadias. As the gene
for these defects is not always expressed, especially in the mother, each of the
parents can carry it without actually being affected. In such a case there is a
risk of recurrence in subsequent pregnancies. Recurrence can also occur in more
distant relatives carrying the same abnormal gene.
In cases of syndromic hypospadias, the exact risk of recurrence must be evaluated.
This varies according to which syndrome the patient has. In some cases the syndrome
is sporadic, either as a result of a new mutation or a chromosome disorder, and
in other cases there is a hereditary syndrome such as Smith Lemli Opitz syndrome,
an autosomal
recessive disease with a recurrence risk of 25%, or an X-linked syndrome
such as androgen insensitivity syndrome.
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Genetic molecular information
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The gene for the disease
No gene exclusively responsible for isolated hypospadias has been found. Conversely,
genes for syndromes in which hypospadias is a part have been found, particularly
the genes for Smith Lemli Opitz syndrome and androgen insensitivity syndrome.
Location
The gene for androgen insensitivity syndrome is located on the X chromosome.
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Genetic testing
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Diagnostic testing
There is currently no simple genetic test for diagnosing the defect associated with
isolated (non-syndromic) hypospadias. In very large families, it is possible to
perform linkage analysis tests (see: Indirect testing for genetic markers
in a family that has one or several patients - when there are a number of different
genes that can each cause the disease - the gene, or most of the genes not having
been located / identified / mapped - multifactorial diseases).
- It is possible to test for the Smith Lemli Opitz gene, but this is not usually necessary,
because there is a biochemical test that can be used to diagnose patients, including
fetuses, where the amniotic fluid can be examined.
- It is possible to test for the gene for androgen insensitivity syndrome located
on the X chromosome, and it is worth doing this in families in whom there is apparent
X-linked inheritance
of hypospadias with or without other defects in the urinary tract.
Carrier testing
For the isolated type - as
for diagnostic testing. For syndromes
of which hypospadias is a part - if the mutation has been found in the
gene responsible for hypospadias in the family, carriers can be identified - see
for each disease individually.
Fetal testing
When hypospadias is detected in pregnancy and there are no other known cases in
the family, it cannot be proved that this is isolated hypospadias. Some differential
diagnoses can be ruled out mainly by the tests listed above.
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