DEFINITION
A "Syndrome", characterized mainly by reduced hypothalamic function and consequent loss of GnRH release that reduces pituitary gonadotropic activity which results in hypogonadism and absent (anosmya) or reduced (hyposmia) sense of smell due to defects on the olfactory bulbs.
It occurs in both males and females and it is part of a group of conditions named “hypogonadotropic hypogonadism (HH)”; apart from the compromising sense of smell, there are no differences in the diagnosis or treatment of a case of HH or a case of Kallmann Syndrome (KS).
KS has been first described in 1944 by doctor Franz Josef Kallmann, but the firsts correlations between hypo / anosmia and hypogonadism were noticed by Spanish doctor Aureliano Maestre in 1856
EPIDEMIOLOGY
Kallmann syndrome affects 1 in 10000 to 86000 people and occurs more often in males than in females (5:1).
Researchers have identified 4 forms of KS: types 1, 2, 3, 4, which are distinguished by their genetic cause and are characterized by HH and impaired sense of smell. In addition, some other features occur in Types 1 and 2, such as cleft palate.
CLINICAL PRESENTATION
Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive. For women, symptoms include amenorrhea and dyspareunia. Notably, patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism do not experience hot flashes.
All patients with Kallmann syndrome have either anosmia or severe hyposmia and may exhibit symptoms of associated conditions including those of congenital heart disease ( fatigue, dyspnea, cyanosis, palpitations, syncope) or neurologic manifestations (color blindness, hearing deficit, epilepsy, paraplegia).
Patients with either classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism report no pubertal maturation; however, occasionally, individuals have a history of partial progression through puberty.
Primary amenorrhea develops in the vast majority of women with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Almost all untreated patients are infertile.
Individuals with adult-onset idiopathic hypogonadotropic hypogonadism may present with infertility and a history of previously documented fertility.
In either Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, restoring fertility is possible in patients who generally respond to treatment with pulsatile GnRH or gonadotropins.
All hypogonadal patients are at high risk of osteoporosis if untreated. Although asymptomatic, patients have a greater fracture risk. Androgen or estrogen replacement therapy may prevent or ameliorate osteoporosis in men or women, respectively. Male and female patients with Kallmann syndrome have either an absent or severely impaired sense of smell. Patients may not be aware of the deficit and must be specifically tested.
Family members of patients with Kallmann syndrome, including female obligate carriers in X-linked Kallmann syndrome pedigrees, may have anosmia or hyposmia without hypogonadism and may represent one end of the spectrum of Kallmann syndrome.
DIAGNOSIS
Serum (total or free) testosterone is always decreased in post pubertal-aged males with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. These patients usually have very low total serum testosterone levels (< 100 ng/dL in adults)
The serum estradiol level is decreased in post pubertal-aged females with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism but has limited diagnostic value.
Serum LH and FSH levels are low-normal or decreased in post pubertal-aged patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Gonadotropin levels are inappropriate relative to the serum levels of testosterone or estradiol.
These test results are of diagnostic value in post pubertal-aged patients because they help differentiate Kallmann syndrome or idiopathic hypogonadotropic hypogonadism from primary gonadal dysfunction, including Turner syndrome and Klinefelter syndrome.
Serum LH and FSH levels cannot reliably distinguish between Kallmann syndrome or idiopathic hypogonadotropic hypogonadism patients and individuals with constitutional delay in growth and development.
IMAGING
Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism (IHH) have a structurally normal hypothalamus and pituitary gland. MRI helps exclude hypothalamic or pituitary lesions in patients with hypogonadism and low or normal serum Gonadotropin levels.
Approximately 75% of patients with Kallmann syndrome have abnormal olfactory systems on MRI
MRI of the brain in patients with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH). In panel A we can see a coronal T1-weighted image of a male with KS showing (abnormal) medially oriented olfactory sulci (black arrows) and normal appearing olfactory bulbs (white arrows). Panel B is an axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). Panel C is a coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). Panel D is a coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows).
Trans thoracic echocardiogram:
This test is helpful in screening for congenital heart disease, which is present in a small subset of patients with Kallmann syndrome. These abnormalities include ASD, VSD, Ebstein anomaly, transposition of the great vessels, and right aortic arch.
Kidneys ultrasound:
This test is helpful in excluding unilateral renal agenesis, which affects a small proportion of patients with Kallmann syndrome.
Bone densitometry:
It is recommended for all hypogonadal patients, including those with Kallmann syndrome, IHH, or hypothalamic amenorrhea.
It is important in order to detect the presence of osteopenia or osteoporosis and to monitor the response of the skeleton to gonadal steroid replacement therapy.
Gonadotropin-releasing hormone stimulation test:
This test is performed by measuring the serum LH and FSH level responses to the intravenous or subcutaneous administration of 100 mcg of GnRH. Venous blood samples are obtained before GnRH (baseline) and at 15, 30, 45, and 60 minutes after GnRH administration.
Most patients with hypothalamic hypogonadism, including Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, have a diminished gonadotropin response in this test (normal adult response is a 2- to 5-fold increase in LH levels and a smaller increase in FSH levels).
PATHOGENESIS
KAL1 mutations are responsible for Kallmann Syndrome Type 1: it is involved in the production of Anosmin-1 protein; it is located on surface of cells and has been found in many tissues, including the respiratory tract, kidneys and digestive system. In the developing brain, it is involved in the migration of nerve cells and in the growth of axons; it may also play a role in regulating cell adhesion.
There are at least 60 mutations in the KAL 1 gene (The KAL1 gene is located on the short (p) arm of the X chromosome at position 22.32.) but, although the mutations alter the protein normal function, it is unclear how these changes lead to the features of Kallmann syndrome: maybe the altered anosmin-1 protein is unable to direct migration of olfactory nerve cells and GnRH – producing cells to their usual locations in the developing brain.
Kallmann Syndrome Type 2 results from mutations in FGFR 1 gene, the fibroblast growth factor receptor 1 gene. The protein is involved in cell divisions, cell growth and maturation, formation of blood vessels and embryonic development. This protein is located in the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This position allows the FGFR1 protein to interact with other proteins called fibroblast growth factors (FGF) outside the cell and to receive signals that help the cell respond to its environment. When a fibroblast growth factor links to the FGFR1 protein, the receptor triggers a cascade of chemical reactions inside the cell that instruct the cell to undergo certain changes. The FGFR1 protein is thought to play an important role in the development of the nervous system. This protein may also help regulate the growth of long bones, such as the large bones in the arms and legs.
More than 40 FGFR1 gene mutations can cause Kallmann syndrome type 2:
the FGFR1 gene is located on the short (p) arm of chromosome 8 at position 12.
These mutations change single amino acids in the FGFR1 protein and result in the production of an abnormally small, nonfunctional version of the protein. Because these mutations prevent the FGFR1 protein from transmitting signals properly, they are described as "loss-of-function" mutations.
During brain development, the altered FGFR1 protein disrupts the formation and migration of olfactory neurons that must come together into a bundle called the olfactory bulb for a person to perceive odors. Problems with the migration of nerve cells into the olfactory bulb underlie the impaired sense of smell in people with Kallmann syndrome. FGFR1 gene mutations also disrupt the migration of nerve cells that produce gonadotropin-releasing hormone (GnRH) in the developing brain. An altered FGFR1 protein prevents the normal migration of GnRH-producing nerve cells in the brain, which interferes with sexual development and causes puberty to be delayed or absent.
It is unclear how FGFR1 gene mutations lead to other signs and symptoms of Kallmann syndrome, including an opening in the roof of the mouth (a cleft palate) and abnormal tooth development. Because the features of this condition vary among individuals, researchers suspect that other genetic and environmental factors may be involved.
Mutations in the Prokineticin 2 gene (PROK2) cause the KS type 3.
Several additional functions of Prokineticin 2 and its receptor have been discovered in studies with animals.
This protein interacts with its specific receptor, the Prokineticin receptor 2 on the cell surface. When they are linked, they trigger a series of chemical signals that regulate various cell functions; it plays a role in the development of the olfactory bulb, in migration of GnRH- producing nerve cells, but also in angiogenesis, in coordinating circadian rhythms. Little is known about the functions of Prokineticin 2 and its receptor in humans. These proteins are produced in many organs and tissues, including the small intestine, certain regions of the brain, and several hormone-producing (endocrine) tissues. Researchers believe that the functions of these proteins in humans may be similar to their functions in other animals.
The PROK2 gene is located on the short (p) arm of chromosome 3 at position 13.
At least five mutations in the PROK2 gene have been identified in people with Kallmann syndrome type 4. Some of these mutations change single amino acids in Prokineticin 2, while other mutations result in the production of an abnormally short version of the protein or prevent any functional protein from being made. These mutations disrupt the activity of Prokineticin 2, but it is unclear how the genetic changes lead to the characteristic features of Kallmann syndrome. Probably the altered Prokineticin 2 is unable to direct the migration of olfactory nerve cells and GnRH-producing nerve cells to their usual locations in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person's sense of smell will be impaired. Misplacement of GnRH-producing neurons prevents the production of certain sex hormones, which interferes with normal sexual development and causes puberty to be delayed or absent.
The PROKR2 gene is located on the short (p) arm of chromosome 20 at position 12.3.
The Prokineticin receptor 2 mutations cause type 3 Kallmann Syndrome; the receptor interacts with the Prokineticin 2 protein as just said before; at least 10 mutations in the PROKR2 gene can cause Kallmann syndrome type 3. Most of the mutations change single amino acids in Prokineticin receptor 2. Researchers believe that these genetic changes disrupt the function of the receptor, but it is unclear how the altered protein leads to the characteristic features of Kallmann syndrome.
THERAPY
Androgen replacement in males with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism restores libido, erectile function, and well-being. In addition it promotes the development of secondary sex characteristics (facial, axillaries, and pubic hair) and increases muscle strength. Androgen replacement also improves bone density and may prevent osteoporosis. Either parenteral or transdermal testosterone is the drug of choice for androgen replacement.
Estrogen replacement therapy in females with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism promotes the development of secondary sex characteristics, including breast development and menstrual function, and it may prevent osteoporosis. Oral contraceptives may be used as replacement therapy in young women.
Medroxyprogesterone is usually administered to female patients on estrogen replacement therapy for 12-14 d/mo. Induces secretory changes in endometrium and leads to withdrawal bleeding, which is essential for prevention of estrogen-induced endometrial hyperplasia.
Pulsatile administration of gonadorelin (GnRH) by subcutaneous (SC) or preferably intravenous (IV) infusion restores pituitary-gonadal axis function and fertility in the majority of people with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.
Gonadotropins successfully restore fertility in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism (IHH). Patients with IHH may have an intrinsic defect in spermatogenesis and may not respond to gonadotropin therapy.
PROGNOSIS
Patients with Kallmann syndrome and those with IHH can survive for lengthy periods in the absence of associated life-threatening conditions.
Fertility can be restored in most patients with classic Kallmann syndrome and IHH . Women with hypothalamic amenorrhea may also experience complete recovery of gonadal function, particularly if precipitating factors are corrected.
Some patients with congenital heart disease or neurologic manifestations may experience a limited lifespan.
Adrenocortical insufficiency is fatal unless recognized and treated; however, patients who are treated adequately should have long-term survival.
Osteoporosis increases the risk of fracture, which may compromise patient survival and quality of life.
thanks for attention
Davide Rogovskis
Laura Guastavigna
References
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Google.
wikipedia.
ncbi.
disease database.
