KALLMANN SYNDROME

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 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 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 SYMPTOMSIt 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

Failure to start or fully complete puberty in both men and women

Lack of testicle development in men; size < 3 cm3. The normal range is between 12 and 30 cm3

Primary amenorrhea or failure to start menstruation in women

Poorly defined secondary sexual characteristics in both men and women.

InfertilityNON 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

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.

DAIGNOSISThe 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 toolNormally 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. 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 various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.PATHOGENESISKS/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.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 KSKAL1=KAL1KAL2=FGFR1KAL3=PROKR2-mutations in the prokineticin receptor-2 gene, various degrees of olfactory and reproductive dysfunction.GnRH1=GnRH1TAC3-Signalling peptide, crucial for GnRH secretion, high incidence of micropenisLEP-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

TREATMENT1) 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 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 cycleThere 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 products include Pregnyl, Follutein, Profasi, or ChoragonHuman 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.