Kallmann syndrome

Kallmann syndrome (also known as anosmic hypogonadism) is a rare genetic disorder characterized by the delayed puberty and impaired olfaction.


Kallmann syndrome

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Kallmann syndrome is a congenital disorder affecting both genders caused by genetic mutations which result in gonadotropin-releasing hormone (GnRH) deficiency (hypogondotropic hypogonadism) and, respectively, delayed or absent puberty and impaired or absent sense of smell. Individuals with Kallman syndrome are infertile. Usually, the diagnosis is made during teenage years when a child fails to develop puberty and distinct sexual characteristics. However, the disease may be suspected earlier, for example, in infant boys with undescended testicles or a small penis. If treated these persons may restore their fertility and develop normally. Nevertheless, treated or not the disease itself is not life-threatening.


The prevalence of the disease remains unknown. The approximate prevalence was estimated as 1 out of 8000 boys. In girls, the prevalence is about 5 times lower (1 out of 40000 girls).


Kallmann syndrome is a genetic disorder associated with different mutations in various chromosomes, sometimes several mutations are observed in one person.

  • In the X-linked recessive form of the disease a defective gene KAL1 is located on the short arm of the X-chromosome (Xp22.32);
  • In the autosomal dominant form of the disease the genes FGFR1 (8p12), FGF8 (10q25-q26), CHD7 (8q12.2) and SOX10 (22q13.1) appear defective;
  • In the autosomal recessive form of Kallmann disease PROKR2 (20p12.3) and PROK2 (3p21.1) are found to be defective;

The listed mutations disrupt the migration of the GnRH-synthesizing neurons from the olfactory epithelium in the brain, namely, the hypothalamus during embryonic development and affect the olfactory system formation. Since the gonadotropin-releasing hormone levels are low and the hypothalamus doesn’t stimulate the pituitary gland to produce FSH and LH resulting in hypogonadotropic hypogonadism. Olfactory disturbances are related to olfactory nerve hypoplasia or agenesis.


Kallmann syndrome is characterized by the hypogonadism and an- or hyposmia (complete absence or reduced sense of smell). Individuals born with Kallmann syndrome may also present other developmental failure, such as a harelip, cleft palate, color blindness, sensorineural deafness, renal agenesis (absence of one kidney, in case of bilateral kidney absence a child dies soon after the birth), dental agenesis (missing teeth), obesity and movement disorders such as spontaneous upper limb mirror movements and abnormal eye movements.  

As the result of low or absent steroid hormones right from after the birth, women with Kallmann syndrome are tall, don’t have periods (primary amenorrhea) or secondary sex characteristics (such as the growth of pubic hair, enlarged breasts, widened hips, etc.), experience dyspareunia (pain during sexual intercourse). The breasts may not develop or have limited development. Due to the low levels of sex hormones, women cannot conceive a baby.

The same principles apply to males – they experience incomplete spontaneous puberty or have no signs of puberty at all and micropenis due to low testosterone levels during infancy, in babies the testicles may be underdeveloped or undescended (a condition known as cryptorchidism). Males who have Kallmann syndrome present sexual infantilism and do not produce sperm – therefore, they are infertile. If left untreated males may have decreased muscle mass, small testicles (with a volume less than 4 mL), erectile dysfunction, diminished aggressiveness, low libido and infertility.

All individuals who have Kallman syndrome are at increased risk of developing osteoporosis – decreased bone density.


The diagnosis of Kallman syndrome can be made based on the characteristic features and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and low concentrations of sex steroids, testosterone or estradiol.


If the appropriate treatment is initiated in time individuals with Kallmann syndrome can achieve normal puberty and become fertile.

Continuous hormonal replacement therapy is recommended for Kallmann syndrome in order to induce puberty and fertility.

  • Androgens (testosterone) administered either parenteral, intranasal or transdermal promote the development of secondary sex characteristics, restore libido and erectile function.
  • Steroid female hormones (estrogens and estradiol) and progestins (medroxyprogesterone) are used to promote the establishment of the menstrual cycle and development of secondary sex characteristics. These medications are administered orally or transdermally.
  • Gonadotropins (follicle-stimulating hormone, human chorionic gonadotropin) are recommended to restore fertility.