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A 16-year-old boy comes to the clinic because of a lack of sexual development. All of his friends have gone through puberty and he is embarrassed by his young appearance. His temperature is 37.0°C (98.6°F), pulse is 76/min, respirations are 12/min, and blood pressure is 121/76 mm Hg. Physical examination shows Tanner stage 1 development of the genitals and pubic hair. Neurologic examination shows an inability to identify different smells. Laboratory studies show decreased testosterone and luteinizing hormone. Which of the following is the most likely diagnosis?
Contributors:Sam Gillespie, BSc
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. 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.
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.