Kallman syndrome is a hereditary disease that manifests itself as anosmia and hypogonadotropic hypogonadism. The pathology is caused by several types of mutations in the X chromosome or autosomes. The syndrome is manifested by underdevelopment of primary and secondary sexual characteristics, impaired ability to distinguish odors, delayed psychomotor development. Hormonal and genetic studies, ultrasound of the pelvic organs in women and scrotum in men, magnetic resonance imaging are performed for diagnosis. Treatment includes lifelong hormone replacement therapy, surgical correction of concomitant defects.
General information
The combination of delayed sexual development and olfactory disorders was described in detail by the American psychologist and geneticist F.J. Kallman in 1944 in the scientific work “Genetic aspects of primary eunuchoidism”. However, the first mention of the disease dates back to 1856 and is associated with the name of the Spanish physician Aureliano Maestre de San Juan. Subsequently, the pathology was called Kallman syndrome (Kallman) or olfactogenital dysplasia. It occurs with a frequency of 1:10,000 among newborn boys and 1:50,000 in girls.
Causes
Pathology has a hereditary origin, occurs under the influence of point gene mutations. The disease occurs in the form of sporadic cases or as a family form. The mutant gene is transmitted by an autosomal dominant, X-linked recessive type of inheritance. Depending on the nature of changes in the genetic material, 3 typical forms of the disease are distinguished in genetics:
- KALIG1 mutation. The pathological gene is located on the X chromosome and causes the 1st type of Kallman syndrome. In addition to the basic signs, there are multiple anomalies of kidney development.
- KAL2 mutation. Changes occur on the short arm of the 8th chromosome, resulting in the 2nd type of olfactogenital dysplasia. Pathognomonic signs are complemented by hearing disorders, stunting and mental retardation.
- Mutation KAL3. Occurs in the pathology of the genes of the 20th chromosome, is the cause of the 3rd type of Kallman disease. It is characterized by multiple malformations, including lesions of the facial skeleton.
Pathogenesis
The disease is based on a genetically determined deficiency of gonadotropin-releasing hormones in the hypothalamus. Mutant genes are involved in the migration of neurons responsible for the synthesis and release of hormonal substances, therefore, with olfactogenital dysplasia, this process is disrupted. As a result, the release of luteinizing and follicle-stimulating hormones of the pituitary gland decreases, secondary congenital hypogonadism develops.
Anosmia in Kallman syndrome is associated with intrauterine hypoplasia or aplasia of olfactory bulbs. It is believed that mutant alels disrupt the normal location of neurons in olfactory structures, as a result of which the ability to perceive odors changes. It is not yet clear how genetic abnormalities affect the appearance of other congenital malformations, therefore, additional hereditary and environmental factors are assumed to be involved.
Symptoms
Clinical manifestations of the disease are variable, even members of the same family may have different forms of olfactogenital dysplasia in severity. Typical manifestations of the disease are mainly noted in the puberty period, when a lag in sexual development becomes noticeable. In boys, eunuchoidism is formed, manifested by underdevelopment of the scrotum and testicles, small penis size, lack of hair in hormone-dependent zones.
Women are characterized by underdevelopment of sexual characteristics: lack of roundness of the mammary glands in the puberty period, scant body hair, disproportion of the figure and violations of fatty tissue deposition. Adolescent girls have primary amenorrhea. The internal reproductive organs of women are also hypoplasized, the uterus and ovaries are small, the secretion of estrogens and progesterone is disrupted.
Pathologies of the sense of smell range from a slight decrease in the ability to recognize odors to complete anosmia. Up to 13-14 years of age, patients with Kallman syndrome do not lag behind their peers in body parameters, but they do not have a pubertal growth spurt, in the future the growth rate decreases. Often there is a delay in differentiation of skeletal structures, which is why the patient’s bone age will be less than the passport age.
Complications
About 5-10% of patients with Kallman syndrome have concomitant malformations of internal organs and skeleton. Typical complications of the disease are considered harelip, Gothic palate, kidney agenesis. The neurological consequences of olfactogenital dysplasia include bilateral synkinesia, ataxia, mental retardation of varying severity. In rare cases, the clinical picture is supplemented by heart defects.
A serious problem for patients is a violation of puberty. Male hypogonadism is accompanied by micropenis, a decrease in testosterone production and a decrease in sperm secretion, which causes objective and psychological difficulties when attempting sexual contacts. Women develop primary infertility, a persistent decrease in libido.
Diagnostics
Examination of patients with suspected Kallman syndrome is carried out by an endocrinologist with the participation of a neurologist, geneticist and other specialists, if necessary. During a physical examination, the formula of sexual development is determined, the correspondence of the physical parameters of the body to the age of the patient, the presence of visible signs of congenital malformations. Diagnosis of olfactogenital dysplasia is complex and includes the following research methods:
- Ultrasound of the genitals. Women undergo pelvic sonography to examine the size of the uterus and appendages, to assess the degree of ovarian hypoplasia. Men undergo an ultrasound of the scrotum, which determines a significant decrease in the volume of the testicles with their homogeneous structure and normal echogenicity.
- Olfactometry. To assess the degree of decrease in the sense of smell, a standard sample with a set of odorous substances is carried out. Additionally, rhinoscopy and radiography of the paranasal sinuses are performed to exclude the rhinogenic cause of anosmia.
- MRI of the brain. There are no pronounced structural changes in the brain in Kallman syndrome. Occasionally, heterogeneity of the structure of the adenohypophysis, signs of hypoxic encephalopathy and other nonspecific neurological signs are determined.
- Hormonal profile. Determining the level of sex hormones has diagnostic value in the puberty period, when puberty normally occurs. In boys, a decrease in testosterone levels is determined, in girls, a lack of estrogens is detected. Regardless of gender, a persistent decrease in the level of releasing hormones of the hypothalamus and pituitary gonadotropins develops.
- Genetic analysis. Determination of characteristic mutations is the only 100% method of confirming the diagnosis of Kallman syndrome. All patients with typical clinical manifestations are referred for consultation by a geneticist in order to differentiate olfactogenital syndrome from other forms of congenital pathology.
Differential diagnosis
When hypogonadism is detected, differentiation is carried out between its primary, secondary and tertiary forms, which requires functional tests with gonadoliberin and clomiphene. In the group of patients under 18 years of age, it is necessary to exclude a constitutional delay in puberty, which can mimic a mild variant of Kallman syndrome. Differential diagnosis of anosmia is performed with tumor and other organic lesions of the central nervous system.
Treatment
Conservative therapy
The main objective of treatment is to stimulate sexual development with the help of individual hormone therapy regimens. Therapy begins at puberty from the age of 13-13.5 years and is carried out for life. Additionally, cholecalciferol preparations and vitamin complexes are prescribed, which prevent the development of osteoporosis. Anosmia in patients is not subject to correction due to the lack of effective therapies.
For the treatment of infertility in women, chorionic gonadotropin is used in combination with gonadoliberin or menotropin, which are prescribed in a pulse mode for several years. In the period of preparation for pregnancy, hormonal stimulation of ovulation is used, while the probability of physiological conception is more than 70%. Replacement therapy with gonadoliberins and testosterone is carried out in men.
Surgical treatment
In adult men with Kallman syndrome and micropenis, it is possible to perform surgical correction — ligamentotomy, which is aimed at lengthening the penis and improving sexual function. In the presence of congenital anomalies of facial development, their plastic correction is performed at the appropriate time. Treatment of heart defects is carried out by cardiac surgeons according to the current protocols.
Prognosis and prevention
The quality of life of patients depends on the form of Kallman syndrome and the severity of its manifestations. Mild and subclinical variants of the disease have a favorable prognosis, with hormonal correction it is possible to achieve normal sexual development and reproductive function. A less optimistic prognosis for severe olfactogenital dysplasia in combination with other congenital malformations. Due to the complexity of etiopathogenesis, preventive measures have not yet been developed.