Brief overview
- What is Kallmann syndrome? Congenital developmental disorder that leads to a deficiency of sex hormones and thus to the absence of puberty. In addition, most patients lack the sense of smell.
- Causes: Congenital gene alterations (mutations).
- Risk factors: The condition runs in families in about 30 percent of patients.
- Symptoms: Lack of pubertal development (underdevelopment of penis, testicles and prostate, low pubic, axillary and body hair, lack of beard growth, lack of first menstrual period), infertility, lack of desire, sense of smell is absent or severely diminished, long-term consequence: osteoporosis.
- Diagnosis: Physical symptoms such as lack of development of secondary sexual characteristics, hormone analysis, genetic test, ultrasound, magnetic resonance tomography, computer tomography, X-ray
- Treatment: Replacement therapy with hormone preparations
- Prevention: No prevention possible
What is Kallmann syndrome?
Kallmann syndrome (KS, olfactogenital syndrome, De-Morsier-Kallmann syndrome) is a congenital developmental disorder of the brain. It causes affected individuals to produce no sex hormones and therefore to fail to reach sexual maturity. In addition, most KS patients suffer from anosmia, which means that they do not perceive odors.
The disorder is named after the German psychiatrist Franz Josef Kallmann, who described it in 1944 as “hypogonadism (lack of sex hormones) and anosmia (lack of sense of smell)”. The synonymous name “De Morsier-Kallmann syndrome” additionally refers to the Swiss neurologist Georges de Morsier, who also conducted studies on Kallmann syndrome.
Secondary hypogonadism
Kallmann syndrome is a subtype of secondary hypogonadism. This refers to a deficiency of sex hormones caused by a malfunction in the hormonal control center in the brain (pituitary gland). The gonads (ovaries, testes) function normally but receive little or no signals to produce sex hormones. If anosmia (lack of sense of smell) is present in addition to the hormone deficiency, doctors refer to it as Kallmann syndrome.
Frequency
Kallmann syndrome is a rare disease; men are more frequently affected than women: On average, about one in 10,000 men and one in 50,000 women develop the disease.
Symptoms
The leading symptoms of Kallmann syndrome are a severely diminished or absent sense of smell and the absence of pubertal development. The degree to which symptoms are pronounced varies from patient to patient. If untreated, both sexes remain infertile.
Symptoms in boys:
- Low or absent pubic, underarm and body hair.
- Lack of beard growth
- Failure of the voice to break
- Micropenis and small testicles: Failure of the penis and testicles to develop in young males.
- Undescended testicles (often evident in infancy)
- High growth: In healthy individuals, the growth plates in the long bones close as soon as a certain sex hormone level is reached. If the hormones are missing, affected individuals grow disproportionately. Compared to their parents, they are taller and have long arms and legs.
Symptoms in girls:
In girls, symptoms are usually less severe. Often the only symptom is the absence of the first menstruation (primary amenorrhea), which is why the disease is often recognized late. In contrast to boys, physical development is largely normal despite the disease. For example, the breasts are usually normally developed.
Symptoms in adult males:
Men with Kallmann syndrome typically have reduced bone density (osteoporosis) and muscle mass. They often have a feminine external appearance due to a feminine fat distribution. They have erectile dysfunction and are infertile.
Malformations: More rarely, other physical malformations occur in KS patients. These are, for example, hearing disorders, cleft lip, jaw and palate or missing teeth. Some affected persons are born with only one kidney. Mental development is usually normal in KS.
Osteoporosis: Sex hormones such as testosterone and estrogen play an important role in bone mineralization. If the hormones are missing, the bones are not as stable as in healthy people – the risk of bone fractures increases.
Cause and risk factors
The cause of Kallmann syndrome is a congenital gene change (mutation). It usually develops spontaneously, but in around 30 percent of cases it is passed on to the offspring by one or both parents.
The gene change already has an effect during embryonic development in the womb: The cells for the sense of smell and those responsible for controlling the gonads (ovaries, testes) arise from common precursor cells.
In Kallmann syndrome, the development of these precursor cells is disturbed by the gene alteration. As a result, the cells responsible for the higher-level control of sex hormone production and the olfactory cells develop insufficiently. Affected individuals do not experience pubertal development and do not perceive odors.
Sex hormones
LH and FSH act on the gonads (ovaries, testes), which ultimately produce the sex hormones: In women, the female sex hormones estrogen and progesterone promote the maturation of eggs and trigger ovulation; in men, the hormone testosterone causes the formation of sperm.
At puberty, the production of sex hormones begins and with it sexual maturation. If, as in Kallmann syndrome, little or no GnRH is present, too few or no sex hormones are produced and pubertal development fails to occur. If untreated, affected individuals do not experience sexual maturation and remain infertile.
Risk factors
In most cases, the gene alteration occurs spontaneously. It is not clear how this occurs. In about 30 percent of all cases, the disease occurs in families: Affected individuals have inherited the mutation from one or both parents.
So far, several mutations have been described that trigger Kallmann syndrome. These include the mutations designated KAL1, FGFR1, FGF8, CHD7, SOX10, PROKR2 and PROK2.
Examination and diagnosis
In some cases, the condition is already apparent in infants: Affected boys may have undescended testicles (cryptorchidism) and/or a very small penis (micropenis).
The first person to contact if there are signs of KS syndrome is the pediatrician, and in the case of involuntary childlessness, the gynecologist or urologist.
The physician performs the following examinations:
Family history: if Kallmann syndrome is suspected, the physician inquires whether KS cases are known in the family.
Physical examination: Underdeveloped secondary sexual characteristics, such as a penis that is too small for the patient’s age or the absence of the first menstrual period, give the doctor the first indications of KS syndrome. He also pays attention to body size, underarm, breast and pubic hair and assesses beard growth.
Smell test: This test is available from around the age of five. The doctor uses pure odorants such as vanillin to check whether the patient can detect the smell.
Blood test: The doctor detects an altered hormone level by means of a blood test. Typically, GnRH, LH and FSH levels are decreased or at low-normal levels. The levels of sex hormones are at prepubescent levels in adolescent boys and girls.
Computed tomography (CT) or magnetic resonance imaging (MRI): With these examination procedures, the doctor checks whether the olfactory center in the brain (bulbus olfactorius) is developed.
X-ray examination of the hand: With the aid of an X-ray examination of the hand, the doctor determines whether the growth plates have already closed and body growth is thus complete.
Spermiogram: Here the doctor examines whether sperm are present in the ejaculate.
Genetic test: The genetic test is used to determine the exact mutation that causes the disease.
How is Kallmann syndrome treated?
Kallmann syndrome is easily treatable. Affected individuals receive replacement therapy with sex hormones. If the condition is detected and treated before puberty, affected individuals usually lead largely unrestricted lives. This includes regular pubertal development and a normal sex life.
Administration of sex hormones: Men receive testosterone, and women receive estrogens and progesterone. Hormone preparations are available in the form of injections, gels, or patches. Hormone therapy is usually continued for life in men and until menopause in women.
Administration of sex hormones in the desire to have children: In order for sperm to be formed, the body needs GnRH. For this reason, men who want to father a child are given the hormone GnRH instead of testosterone. It takes 18 to 24 months for sperm production to get going. In about 80 percent of cases, men are subsequently fertile. Men with undescended testicles have a somewhat less favorable prognosis.
Treatment of osteoporosis: Patients with reduced bone density receive calcium and vitamin D. In addition, exercise and sport are recommended to strengthen the bones.
Anosmia: Currently, there is no therapy to restore the sense of smell.
Psychotherapy: For some KS patients the disease means a heavy psychological burden. Here the psychotherapist is the right contact person.
Course of the disease and prognosis
The course of Kallmann syndrome varies from patient to patient. The symptoms vary from patient to patient. Thus, it is possible that the disease is already noticeable in infancy, is diagnosed in adolescence, or the hormone deficiency only appears in adulthood.
If KS is not detected and treated until after the age of 16, it is possible that a tall stature has already developed. This change cannot be reversed even with medication.
Prevention
Since it is a genetic disease, no prevention is possible.
