Kallmann syndrome

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Introduction0:00–0:23

Kallmann syndrome is an endocrine disorder caused by a decrease in sex hormones, either testosterone in males or estrogen and progesterone in females.
That decrease leads to a failure to start or complete puberty. The syndrome is named after Dr.
Franz Kallmann, the geneticist who first described it. Normally, during fetal development there’s a region of the brain called the olfactory placode.

Embryology0:23–0:58

Two groups of neurons emerge from that region. The first group contains olfactory neurons that eventually help with sensing smells.
These neurons migrate down from the olfactory placode and get embedded in the cribriform plate, which is a bone plate that separates the nasal cavity from the brain, forming the olfactory bulb.
The second group contains neurons that release gonadotropin-releasing hormone. And these neurons migrate through the cribriform plate, and settle in the hypothalamus.

Physiology0:58–3:12

The hypothalamic-pituitary-gonadal axis is a system of hormone signaling between the hypothalamus, pituitary gland, and gonads, either the testes or ovaries, to control sexual development and reproduction.
Gonadotropin-releasing hormone is released into the hypophyseal portal system, which is a network of capillaries connecting the hypothalamus to the hypophysis, or pituitary.
When gonadotropin-releasing hormone reaches the pituitary gland, it stimulates cells in the anterior pituitary, called gonadotrophs, to release gonadotropin hormones, luteinizing hormone and follicle-stimulating hormone into the blood.
These gonadotropin hormones then stimulate the gonads to produce sex specific hormones. These are estrogen and progesterone in women and testosterone in men.
Early on in male development, testosterone helps the external sex organs to differentiate into male genitals and causes the testes to descend from the abdomen into the scrotal sac.
During puberty, the Leydig cells of the testes respond to the luteinizing hormone by converting more cholesterol into testosterone.
The high levels of testosterone leads to the development of primary sex characteristics, like penile and testicular growth.
In addition, the Sertoli cells of the testes respond to follicle-stimulating hormone by producing more sperm. Increased testosterone also leads to the development of secondary sex characteristics like growth of facial and pubic hair, increased height and muscle mass, and a deepening of the voice.
In females, the theca cells respond to luteinizing hormone by producing progesterone and androstenedione. Then, follicle stimulating hormone causes the granulosa cells to convert the androstenedione into estrogen.
During puberty, waves of estrogen and progesterone regulate primary sex characteristics, like monthly changes to the ovary stroma to promote egg maturation and ovulation, and changes to the uterine wall lining as part of the menstrual cycle.
They also direct secondary sex characteristic development like increased height, growth of pubic hair and breasts. In Kallmann syndrome, there’s a defect in the migration of the neurons coming out of the olfactory placode.

Pathology3:12–4:01

That includes the olfactory neurons which can results in hyposmia, which is the reduced sense of smell, or anosmia which is the complete loss of smell.
It also includes the gonadotrophin-releasing hormone neurons which results in a decrease in gonadotrophin-releasing hormone.
And that leads to low levels of the gonadotropin hormones, luteinizing and follicle-stimulating hormones, and low levels of gonadal function.
In males, there’s a decrease in testosterone, and in females there’s a decrease in progesterone and estrogen. The disruption in hormones prevents puberty from beginning or successfully completing.
Because of this, Kallmann syndrome is a type of hypogonadotropic hypogonadism disorder. In Kallmann syndrome there’s an under-development of primary and secondary sex characteristics.

Signs and symptoms4:01–4:52

In males, primary sex characteristic dysfunction includes having a small penis and testes, improper testicular descent, and a low sperm count.
Secondary sex characteristic dysfunction includes a lack of facial hair, low muscle mass, and not developing a deep voice.
In females, primary sex characteristic dysfunction includes amenorrhea or absence of menstruation, or oligomenorrhea or irregular menstrual cycle.
Secondary sex characteristic dysfunction includes a lack of breast development and pubic hair. For both males and females, Kallmann syndrome often leads to infertility.
Other non-reproductive symptoms include osteoporosis or osteopenia because testosterone and estrogen are protective against bone resorption.

Diagnosis4:52–5:20

A diagnosis of Kallmann syndrome is made based on identifying low levels of gonadotrophin-releasing hormone, low gonadotropins (LF and FSH) and sex hormones, with normal levels of other pituitary hormones.
Genetic tests for known gene mutation associated with Kallmann syndrome can also be done. And finally, there’s usually an abnormal smell test and sperm count as well.

Treatment5:20–5:33

Treatment is focused on hormone therapy which can stimulate puberty and the development of secondary sex characteristics.
There’s also infertility treatments which can make reproduction possible in some cases. So, to recap: Kallmann syndrome is a type of hypogonadotropic hypogonadism where olfactory neurons and gonadotropin-releasing hormone neurons don’t function normally.

Review5:33–6:57

The decrease in sex hormones inhibits the development of primary and secondary sex characteristics during puberty.