Kallmann Syndrome

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Kallmann Syndrome

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Kallmann syndrome is a genetic disorder that inhibits a person from starting or fully completing puberty. This syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. The additional symptom of a total lack of sense of smell or a reduced sense of smell distinguishes it from other forms of hypogonadotrophic hypogonadism. If the syndrome is left untreated, poorly defined secondary sexual characteristics, hypogonadism, infertility and increased risk of developing osteoporosis occur.

Kallmann syndrome is more commonly diagnosed in males than in females. The syndrome was first described by its present name in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist. The link between anosmia and hypogonadism had been first made by Spanish doctor Aureliano Maestre de San Juan wayback in 1856.


Changes in more than 20 genes have been implicated in causing Kallmann syndrome. Among the most common causes are mutations in the ANOS1, CHD7, PROK2, FGF8, FGFR1, or PROKR2 gene. In some cases, affected patient displays mutations in more than one of these genes. Additionally, certain types of mutations in other genes contribute to the development of Kallmann syndrome, but do not cause the disease on their own. About 40% of cases of Kallmann syndrome have an unknown genetic cause.

The ANOS1 gene defect was the first discovered mutation and the one most commonly tested for. This mutation causes the x-linked form of Kallmann syndrome and is associated with the additional symptoms of bimanual synkinesis, anosmia and unilateral renal agenesis.

Genes associated with Kallmann syndrome are also involved in the migration of neurons that produce GnRH. It controls the production of many hormones that govern and mediate sexual development before birth and during puberty. Studies suggest that mutations in associated genes disrupt the migration of GnRH-producing nerve cells and olfactory nerve cells in the developing brain. As the olfactory nerve cells do not extend to the olfactory bulb, sense of smell is either impaired or absent. Misplacement (due to disruption of migration) of GnRH-producing neurons in the brain prevents the production of sex hormones, which interferes with normal sexual development.

Signs and symptoms:

Main reproductive signs and symptoms include failure to start or complete puberty in both men and women, primary amenorrhoea (failure to start menstruation), and lack of testicle development in men (size of testis less than 4 ml). Secondary sexual characteristics are poorly defined in both men and women. In 5-10% cases, micropenis is evident. Cryptorchidism (undescended testicles) at birth is one of the striking features of this syndrome. There may be low levels of the gonadotropins LH and FSH. Hypogonadism is present due to low levels of testosterone in men and oestrogen or progesterone in females. Infertility is one of the cardinal features of Kallman syndrome.

Non-reproductive feature of Kallman syndrome include absence of sense of smell (anosmia) or markedly decreased sense of smell (hyposmia). This symptom is the defining feature of Kallmann syndrome. Other signs and symptoms include cleft palate, hare lip or other midline cranio-facial defects, sensorineural hearing impairment, unilateral renal agenesis (absence of one of the kidneys), split hand and foot (ectrodactyly), shortened middle finger, scoliosis, mirror movements of hands (manual synkinesis), hypodontia (missing teeth), poor balance, and incoordination. Eye defects include coloboma, ptosis and increased incidence of color-blindness. Kallman syndrome is also associated with increased risk of development of secondary osteoporosis or osteopenia, which can lead to weakened, fragile bones which are prone to get fractured.


Kallman’s syndrome is diagnosed by medical history, clinical examination, biochemical and radiological tests. Clinical tests include measuring and comparing of the height to standard growth charts. It is essential to determine the Tanner stage of sexual development. Other clinical tests include checking for micropenis and undescended testes, measurement of testicular volume, checking for menarche and breast development in females, checking sense of smell, checking for hearing impairment, checking for missing teeth or cleft lip and/or cleft palate, checking for pigmentation of skin and hair, checking for signs of neurodevelopmental delay & checking for mirror movements of the hands.

Laboratory tests include hormonal testing including testosterone, FSH, LH, oestrogen and prolactin. GnRH, hCG stimulation test help to assess the activity of hypothalamus and pituitary. Other tests include sperm test, liver function test, renal function test, and inflammation marker test. Karyotyping is recommended to check for chromosomal abnormalities. Wrist x-ray is advised to determine bone age. Brain MRI is advised to rule out any anatomical abnormalities in the hypothalamus or pituitary, and also to check for presence of olfactory bulbs. Ultrasound of kidneys helps with finding unilateral renal agenesis. Bone density scan (DXA) is used to check for osteoporosis or osteopenia.


The treatment aim in both males and females is the development of the secondary sexual characteristics that are normally seen at puberty. Once development of the secondary sexual characteristics has been achieved, continued hormone replacement therapy is required to maintain sexual function, libido, bone health, and general wellbeing. In males, testosterone replacement therapy is essential for the maintenance of normal muscle mass and strength.

To correct the abnormalities of undescended testis and micropenis, early treatment is usually required in the form of surgery or gonadotropin or DHT treatment. Females with Kallmann syndrome normally do not require any treatment before the age of adolescence. As of now, no treatments exist for the impaired sense of smell and mirror movement of the hands. Treatment for both males and females with the syndrome consists of one of three options: Sex hormone replacement (testosterone or oestrogen & progesterone), Gonadotropin therapy (administration of medications that replicate the activity of FSH and LH), and GnRH pulsatile therapy.

In males, the treatment monitoring requires the measurement of serum testosterone, haematocrit, inhibin B, and prostate-specific antigen (PSA). In females, monitoring to treatment usually consists of measurement of oestrogen, FSH, LH, inhibin B & anti-Mullerian hormone. Hormone replacement therapy is not associated with induction of fertility in either males or females. Gonadotropin therapy and Pulsatile GnRH therapy can be used (both male and female patients) in order to achieve fertility for some people. If gonadotropin therapy takes longer to achieve sperm production, assisted reproductive technology such as sperm retrieval using testicular sperm extraction or intracytoplasmic sperm injection might be used. Early treatment can help with psychological well being of the patients.

Other names of the condition:

Anosmic hypogonadism

Anosmic idiopathic hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism and anosmia

Hypogonadotropic hypogonadism-anosmia syndrome

Dysplasia olfactogenitalis of De Morsier

Olfacto-genital pathological sequence