Kallman syndrome is a rare disease that causes fertility problems and affects both the production of sex hormones and the sense of smell, causing hypogonadism and anosmia, respectively. This disorder occurs more in men than in women, in a ratio of 5:1.

In this article we will see what Kallman syndrome consists of, what its main manifestations and clinical symptoms are, how it is diagnosed and what the indicated treatment is.

What is Kallman syndrome?

Kallman syndrome is a rare hereditary disease characterized by the combination of hypogonadotropic hypogonadism and anosmia or hyposmia (absence or decreased sense of smell), due to a deficiency in the secretion of gonadotropin-releasing hormones secondary to a defect in the migration of neurons that release these same substances from the nostrils to the hypothalamus.

The syndrome is named after psychiatrist Franz Kallman , who in 1944 described this disease in detail in three families, postulating the hereditary nature of the disease.

People with hypogonadotropic hypogonadism have insufficient or no sexual development due to a deficiency of sex hormones and low levels of luteinizing and follicle-stimulating hormone (hormones released by the pituitary gland that regulate sexual reproduction), and also infertility. Anosmia or hyposmia, on the other hand, is related to the absence or hypoplasia (the incomplete development) of the olfactory bulb and its tracts.

Kallman syndrome can be sporadic or familial, and although it can affect both men and women, women tend to suffer from it less frequently, about 5 times less than men.

It is a genetically heterogeneous condition and in 60% of cases it is sporadic, with no family history. Research has determined that there are three types of inheritance patterns: X-linked, autosomal dominant and autosomal recessive .

Symptoms

The clinical symptoms of Kallman syndrome show great variability among patients, even at the intra-family level.

In men, hypogonadotropic hypogonadism secondary to gonadotropin-releasing hormone deficiency may manifest itself with: micropenis, cryptorchidism (incomplete descent of one or both testicles into the scrotum), absence or incomplete development of secondary sexual characteristics, decreased libido, infertility and erectile dysfunction.

In women, amenorrhea, absence of breast development and dyspareunia (painful intercourse),

may occur

On the other hand, patients suffering from Kallmann’s syndrome may present other associated symptoms, which are also due to defects in embryonic genesis and are therefore related to the chain of fibroblast growth factors (substances responsible for functions such as blood vessel formation or embryonic development).

Among the most common alterations associated with this syndrome are the following: synkinesias (involuntary and unconscious shaking that occurs when performing voluntary movements), agenesis of the corpus callosum, visuospatial disorder, congenital palpebral ptosis, auditory alterations , hypodontia (defective development of one or more teeth), unilateral renal agenesis, cleft lip or palate, structural alterations in the feet or hands, obesity and other less frequent disorders.

Diagnosis

The vast majority of cases of Kallman syndrome are diagnosed in adolescence, due to the absence of secondary sexual characteristics, which translates, for men, into pre-pubertal testicles and lack of virilization; and in women, poor breast development and presence of primary amenorrhea.

Low or normal serum levels of luteinizing hormone and follicle-stimulating hormone may be found in diagnosing Kallman syndrome, with a poor initial response to gonadotropin-releasing hormone (GnRH) administration, but a normal response when the hormones are injected repeatedly in pulses.

On the other hand, the pituitary gland is maintained in normal conditions, as is the secretion of pituitary hormones. There is a decrease in steroid sex hormones and serum prolactin levels are at normal levels. Anosmia or hyposmia can be confirmed by medical history or by using specific olfactory tests for odor identification.

Neuroimaging techniques , such as magnetic resonance imaging, contribute to the diagnosis, since they allow the detection of the absence or hypoplasia of the olfactory bulbs; however, in up to 25% of patients this brain structure may be in perfect condition, and in those cases genetic studies should be performed that may yield more clues for an accurate diagnosis.

To make the diagnosis of Kallman syndrome there are also molecular techniques such as: fluorescent in situ hybridization, a chromosome marking technique by which chromosomes are hybridized with probes that emit fluorescence and allow the visualization, distinction and study of chromosomes and their abnormalities; and comparative genomic hybridization, another cytogenetic technique that allows the analysis of the quantity and structure of chromosomes by comparing them with a reference one.

Treatment

The treatment of patients with Kallman syndrome has two goals: improve fertility and treat hypogonadism . For the latter, it is necessary to stimulate the development of secondary sexual characteristics. This is achieved through hormone replacement therapy with testosterone, in the case of men; and with combined estrogens and progesterone, if women are affected.

Testosterone therapy is nowadays a safe treatment and can be performed by intramuscular injections, or by using topical gels and fluids.

Hormone replacement treatment in women usually consists of taking pills and oral drugs, with medical follow-up to ensure a correct therapeutic process.

As far as fertility treatment is concerned, human menopausal gonadotropin or recombinant follicle-stimulating hormone (FSH) can be used to stimulate sperm production; and recombinant FSH or pulsed gonadotropin-releasing hormone can be administered to stimulate follicle-genesis, the maturation process of the ovarian follicle.

With regard to anosmia or hyposmia, also characteristic of Kallman syndrome, there is no specific treatment available yet. Patients are often advised to reduce the associated risks, such as: avoiding meals that may have expired, if there is no one else who can confirm whether a food is fresh; or not cooking or having natural gas heating in the home, as they may have difficulty detecting possible leaks.

Finally, it should be noted that it is possible that the person suffering from this disease may suffer other types of alterations, such as deterioration of bone health, for example. It is important to perform a bone mineral density test to measure the amount of calcium and other minerals and to prevent the development of osteoporosis.

Bibliographic references:

  • González, G. C., & Bonet, M. U. (2006). Etiopathogenesis of Kallmann’s syndrome. Genotypic-phenotypic relationship. Endocrinology and Nutrition, 53(8), 519-524.
  • Gutiérrez-Amavizca, B. E., Figuera, L. E., & Orozco-Castellanos, R. (2012). Kallmann’s syndrome. Genetic aspects and phenotypic variants. Medical Journal of the Mexican Institute of Social Security, 50(2), 157-161.
  • Rubio, L. R., de Paz Balboa, F., Sánchez, J. D., Herrera, P. A., & Fernández, J. T. (1981). Hypogonadotrophic hypogonadism and anosmia (Maestre San Juan-Kallman’s syndrome)(author’s transl). Spanish Annals of Pediatrics, 15(4), 390-396.