Kallmann syndrome



A genetic disorder that prevents a person from starting or fully completing puberty. 


Kallmann syndrome is a group of conditions termed hypogonadotropic hypogonadism (HH).


Frequency: occurs in 1:30,000 (males), and 1:125,000 (females).


It has the additional symptom of a total lack of sense of smell or a reduced sense of smell.

Kallmann syndrome, a congenital Hypogonadic hypogonadism  with a lack of a sense of smell due to the altered migration of GnRH neurons on the olfactory placode. 

Kallmann syndrome can also be shown through MRI imaging with irregular morphology or aplasia of the olfactory bulb and olfactory sulci. 

Untreated,  will result in poorly defined secondary sexual characteristics, show signs of hypogonadism, infertility and are at increased risk of developing osteoporosis.


Other physical symptoms affecting the face, hands and skeletal system can also occur.


Findings: Absent or delayed puberty, infertility, inability to smell.


Complications include osteoporosis






Hormone replacement therapy 


Gonadotropin therapy


Associated with failure in the correct production or activity of gonadotropin-releasing hormone by the hypothalamus. 


Secondarily,results in low levels of the sex hormones testosterone in males or estrogen and progesterone in females. 


Diagnosis occurs during teenage years when puberty fails to start.


Lifelong treatment is normally required. 


Hormone replacement therapy (HRT) is to replace the missing testosterone or oestrogen and progesterone. 


The condition is more commonly diagnosed in males than in females.


Reproductive findings:


Failure to start or fully complete puberty.


Lack of testicle development in men (size < 4 ml) normal range is between 12 and 25 ml).


Primary amenorrhoea


Poorly defined secondary sexual characteristics.


Micropenis in 5-10% of male cases.




Low levels of the gonadotropins LH and FSH.


Hypogonadism is  due to low levels of testosterone in men or estrogen/progesterone in women.




Non-reproductive findings


Anosmia or markedly reduced sense of smell.


Approximately 50% of hypogonadotropic hypogonadism  cases occur with anosmia and can be termed as Kallmann syndrome.


Other findings include: Cleft palate, cleft lip or other midline cranio-facial defects, Neural hearing impairment, unilateral renal agenesis,  skeletal defects including split hand/foot, shortened middle finger or scoliosis, mirror movements of hands, missing teeth, poor balance or coordination due to cerebral ataxia,

eye defects such as coloboma or ptosis, and increased incidence of color-blindness.


The severity of the symptoms vary from individual to individual.


The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life, giving normal puberty and normal reproductive function. 


The HPG axis then either fails totally or is reduced to a very low level of GnRH release in adult life with no obvious cause, leading  to a fall in testosterone or estrogen levels and infertility.


In some instances KS reverses during adult life and the  the hypothalamic-pituitary-gonadal axis axis resumes its normal function and GnRH, LH, and FSH levels return to normal levels. 


This reversal occurs in an estimated 10 to 22% of people, primarily normosmic  cases rather than KS cases and only found in people who have undergone some form of testosterone replacement therapy. 


This type of KS/hypogonadotrophic hypogonadism rarely occurs in cases where males have had a history of un-descended testes.


Affected individuals with KS are almost invariably born with normal sexual differentiation, is due to the human chorionic gonadotrophin (hCG) produced by placenta at approximately 12 to 20 weeks gestation.


People with KS lack the surge of GnRH, LH, and FSH that normally occurs between birth and six months of age. 


This surge helps with testicular descent into the scrotum. 


The surge of GnRH/LH/FSH in non KS/HH children gives detectable levels of testosterone in boys and estrogen and progesterone in girls. 


Deficiency in either testosterone or estrogen can increase the rate of bone resorption while at the same time slowing down the rate of bone formation. 


Bone density scans are recommended to monitor the bone mineral density in KS.


At least 25 different genes have been implicated in causing Kallmann syndrome or other forms of hypogonadotropic hypogonadism through a disruption in the production or activity of GnRH 


Approximately 35-45% of cases of KS/CHH have an unknown genetic cause.


The ANOS1 gene defect causes the x-linked form of Kallmann syndrome and is associated with the additional symptoms of anosmia, bimanual synkinesis and renal agenesis. 


The ANOS1 gene defect is responsible for between 5 and 10% of all Kallmann syndrome/CHH cases.


In most cases of KS/HH the testes and ovaries function normally, but fail to do so because they have not had appropriate hormonal signals.


The hypogonadism found in HH is caused by a disruption in the production of the gonadotropin hormones normally released by the anterior pituitary gland known as luteinising hormone (LH) and follicle stimulating hormone (FSH).


Failure in GnRH activity can be due to the absence of the GnRH releasing neurons inside the hypothalamus. 


HH can occur as an isolated condition with just the LH and FSH production being affected or it can occur in combined pituitary deficiency conditions.


Diagnosis of KS/CHH normal involves a range of clinical, biochemical and radiological tests.


Comparing height to standard growth charts.


Determining the Tanner stage of sexual development. 


Checking for micropenis and cryptorchidism in males.


Measuring testicular volume.


Checking for breast development and age at menarche in females.


Checking sense of smell.


Checking for hearing impairment.


Checking for missing teeth or presence of cleft lip and/or cleft palate.


Checking for pigmentation of skin and hair.


Checking for mirror movements of the hands or signs of neurodevelopmental delay.


Early morning hormonal testing: including FSH, LH, testosterone, estrogen and prolactin.


GnRH and/or hCG stimulation test to determine activity of hypothalamus and pituitary.


Sperm test


Karyotype to check for chromosomal abnormalities.


Medical imaging tests that help in the diagnosis of Kallman  syndrome:


Wrist x-ray to determine bone age.


Brain MRI to evaluate structural abnormalities in the hypothalamus, pituitary and olfactory bulbs.


Abnormalities in the hypothalamus or pituitary and to check for presence of olfactory bulbs.


Ultrasound of kidneys to rule out unilateral renal agenesis.


Bone density scan (DXA) to findosteoporosis or osteopenia.


The initial treatment is for the development of the secondary sexual characteristics normally seen at puberty.


Subsequently, continued hormone replacement therapy is required for both males and females to maintain sexual function, bone health, libido and general wellbeing.


Testosterone replacement therapy is required for the maintenance of normal muscle mass in males.


For male infants with suspected KS/CHH correcting  un-descended testes and micropenis if present with the use or surgery or gonadotropin or DHT treatment may be needed.

Females with KS do not require any treatment before adolescence.

No treatments exist for anosmia, mirror movement of the hands or the absence of one kidney.




Sex hormone replacement +testosterone or estrogen & progesterone.


Gonadotropin therapy


GnRH pulsatile therapy.


Hormone replacement therapy will not normally induce fertility in either males or females.


Gonadotropin therapy can be used in order to achieve fertility for some people.


In males with KS/CHH, infertility is primarily due the lack of sperm production within the testes, and their production can be achieved through either the use of GnRH administered via a micro infusion pump or through the use of gonadotropin injections (hCG, FSH, hMG). 


In females with KS/CHH, infertility is primarily due to the lack of maturation of eggs located within the ovaries. 


Ovulation induction can be achieved  by pulsatile GnRH therapy or alternatively with gonadotropin injections (hCG, FSH, hMG) given at set intervals to trigger the maturation and release of the egg for natural conception.


Kallmann syndrome occurs about 4 times more often in males than females, but is only 2.5 times more common among males in familial cases.








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