Kallmann syndrome

Hypogonadotrophic Hypogonadism
its congenital disease, failure of communication between the hypothalamus and the anterior pituitary gland.
symptom of an altered sense of smell either completely absent (anosmia) or highly reduced (hyposmia).
for diagnosis wait and see" approach applied

1. KALLMANN
SYNDROME

2. ABHISHEK CHYAWAN JHA


Kallmann's Syndrome
Congenital hormonal condition characterized
by the failure of an individual to enter puberty. It is
a form of Hypogonadotrophic Hypogonadism
(HH). In particular it is a failure of communication
between the hypothalamus and the anterior
pituitary gland. It results in the sex organs or
gonads (testes or ovaries) not maturing in the usual
manner during puberty. It occurs when the

3. hypothalamic neurons that are responsible for
releasing gonadotropin-releasing hormone (GnRH
neurons) fail to migrate into the hypothalamus
during embryonic development.
Kallmann syndrome also features the additional
symptom of an altered sense of smell either
completely absent (anosmia) or highly reduced
(hyposmia).The sense of smell is only affected in
approximately 50% of HH cases and these cases are
termed Kallmann syndrome.
25 different genes have so far been implicated in
causing Kallmann syndrome or other forms of HH
through a disruption in the production or activity
of GnRH.
Kallmann syndrome was described in a paper
published in 1944 by Franz Josef Kallmann, a
German-American geneticist. The link between

4. anosmia and hypogonadism had already been noted
however, in particular by the Spanish doctor
Aureliano Maestre de San Juan in 1856.
The condition has a low prevalence, estimated as
being between 1 in 4,000 and 1 in 10,000 for male
HH cases overall and 1 in 50,000 for Kallmann
syndrome. It is three to five times more common in
males than females.


SIGNS AND SYMPTOMS
It can be split into two different categories
"reproductive" and "non-reproductive" depending on the
gene mutation involved. Not all symptoms will appear in
every case of KS/HH, not even amongst family members.
Each case can show a different range of symptoms and a
different severity of symptoms.
REPRODUCTIVE FEATURES

5.  Failure to start or fully complete puberty in both
men and women
 Lack of testicle development in men; size < 3 cm
3
.
The normal range is between 12 and 30 cm
3

 Primary amenorrhea or failure to start menstruation
in women
 Poorly defined secondary sexual characteristics in
both men and women.
 Infertility
NON REPRODUCTIVE FEATURES
 Hypogonadotropic hypogonadism (a lack of the
luteinizing hormone and follicle-stimulating
hormone)
 Congenital(present from birth)
 Total lack of sense of smell (anosmia) or markedly
reduced sense of smell (hyposmia). This is the
defining feature of Kallmann syndrome; it is not seen
in other cases of HH. Approximately 50% of HH

6. cases occur with anosmia and can be termed as
Kallmann syndrome.
 Cleft palate or other craniofacial defects.
 Unilateral renal agenesis or aplasia; absence or non-
functioning of one of the kidneys
 Cryptorchidism un-descended testicles at birth,
occurs in 30% of KS/HH cases
 Micropenis occurs in fewer than 5 to 10% of KS/HH
cases.
 Neural hearing defects
 Synkinesis or mirror movements of hands

Side effect of having KS/HH is the increased risk of
developing secondary osteoporosis or osteopenia.
Deficiency in either testosterone or estrogens can
increase the rate of bone resorption while at the same
time slowing down the rate of bone formation.

7. DAIGNOSIS
The main biochemical parameters in men are low serum
testosterone and in women low serum estrogens and
low levels of LH and FSH in both men and women.
The "wait and see" approach applied to "late bloomers" is
probably counterproductive to the needs of the patient
whereas a step-by-step approach with hormone
replacement therapy used with slowly increasing doses
can be used as a diagnostic tool
Normally testicular enlargement is the key sign for the
onset of puberty in boys however the use of nighttime
LH sampling can help predict the onset of puberty.
In females diagnosis is sometimes further delayed as
other causes of amenorrhea normally have to be
investigated first before a case of KS/HH is considered.
Normally the onset of puberty is marked in females by
the onset of menstruation however KS / HH can still
occur in females in cases when menstruation has begun
but stopped after one or two menstrual bleeds.

8. In males treatment with age-appropriate levels of
testosterone can be used to distinguish between cases of
KS/HH from a case of delayed puberty. If just delayed the
testosterone can "kick-start" endogenous puberty, as
demonstrated by testicular enlargement, whereas in the
case of KS/HH there will be no testicular enlargement
while on testosterone therapy alone.
X-rays-Bone age can be assessed using hand and wrist X-
rays. If the bone age is significantly lower than the
chronological age of the patient, this could suggest
delayed puberty.
Karyotype may be performed to rule out Klinefelter
syndrome and Turner syndrome.
Magnetic resonance imaging (MRI) scan can be used to
determine whether the olfactory bulb is present and to
check for any physical irregularities of the pituitary gland
or hypothalamus.
A standard smell test can be used to check for anosmia,
but it must be remembered that even in total anosmia

9. various substances (such as menthol and alcohol) can
still be detected by direct stimulation of the trigeminal
nerve.
PATHOGENESIS
KS/HH results from the disruption in the
communication between the hypothalamus and
pituitary in regard to one set of hormones only. All the
other actions of the hypothalamus and pituitary glands
remain unaffected.
GnRH is released from the hypothalamus in a pulsatile
manner at set intervals throughout the day via the
hypophyseal portal system and acts on the anterior
pituitary gland, causing it to release two hormones
luteinizing hormone (LH) and follicle stimulating
hormone (FSH), which has a direct action on the testes in
men and ovaries in women. LH and FSH are essential for
stimulating the development of secondary sexual
characteristics.

10. The GnRH is released by the hypothalamus by
specialized nerve cells or neurons .GnRH neurons
originate in an area of the developing brain called the
olfactory placode, they then pass through the cribriform
plate and into a structure called the olfactory bulb,
where the sense of smell is generated. From there they
migrate into the hypothalamus.
In KS/HH the release of GnRH is either totally blocked or
vastly reduced.
Any problems with the development of the olfactory
bulb will prevent the progression of the GnRH releasing
neurons through it. If the GnRH releasing neurons are
prevented from reaching the hypothalamus no GnRH
will be released, so in turn no FSH or LH will be released
which results in the failure of puberty.
Genes that have been associated with causing cases of KS
KAL1=KAL1
KAL2=FGFR1
KAL3=PROKR2-mutations in the prokineticin receptor-

11. 2 gene, various degrees of olfactory and reproductive
dysfunction.
GnRH1=GnRH1
TAC3-Signalling peptide, crucial for GnRH secretion,
high incidence of micropenis
LEP-Ligand for the receptor LRPR. Involved in pulsatile
GnRH secretion.
FGF8-Fibroblast growth factor 8, Associated with cleft
lip and / or palate and hearing loss

TREATMENT
1) Hormone replacement therapy
At first the treatment will produce most of the
physical and psychological changes seen at puberty, with
the major exception that there will be no testicular
development in men and no ovulation in women.
After the optimum physical development has been
reached HRT for men will continue to ensure that the

12. normal androgen function is maintained; such as libido,
muscle development, energy levels, hair growth, and
sexual function.
In women, a variety of types of HRT will either give a
menstruation cycle or not as preferred by the patient.
HRT is very important in both men and women to
maintain bone density and to reduce the risk of early
onset osteoporosis.
For the men testosterone replacement is achieved either
by using daily capsules, daily gel or patches, fortnightly
injections, three monthly injections, or six monthly
implants. Tablet/capsule forms of HRT rarely give
sufficient testosterone levels suitable for men with
KS/HH.
After the first two injections which are 6 weeks apart,
injections are taken every 3 months and give good
testosterone levels throughout the 3 month period with
no noticeable tailing-off of levels at the end of the
injection cycle

13. There are no specialist HRT treatments available just for
women with KS/HH but there are multitude of different
HRT products on the market including oral
contraceptives and standard post-menopause products.

2) Fertility treatments
Fertility treatments involve the administration of the
gonadotropins LH and FSH in order to stimulate the
production and release of eggs and sperm. Women with
KS or HH have an advantage over the men as their
ovaries normally contain a normal number of eggs and it
sometimes only takes a few months of treatment to
achieve fertility while it can take males up to 2 years of
treatment to achieve fertility.
Human chorionic gonadotropin (hCG) is sometimes
used to stimulate testosterone production in men and
ovulation induction in women. For men it acts in the
same way as LH; stimulating the Leydig cells in the testes
to produce testosterone. Common trade names for hCG

14. products include Pregnyl, Follutein, Profasi, or Choragon
Human menopausal gonadotropin (hMG) is used to
stimulate sperm production in men and for multiple egg
production and ovulation induction in women. It
contains a mixture of both LH and FSH. In men the FSH
acts on the sperm producing Sertoli cells in the testes.
This can lead to testicular enlargement but can take
anything from 6 months to 2 years for an adequate level
of sperm production to be achieved. Common trade
names for hMG products include Menopur, Menogon,
Repronex, or Pergonal.