|The jazz singer "Little" Jimmy Scott was diagnosed with |
Kallman syndrome, preventing him from reaching puberty
and leaving him with a high, undeveloped voice
Kallmann syndrome is a rare genetic disorder characterized by delayed or absent puberty and an impaired sense of smell. It is estimated to affect 1 in 10,000 to 86,000 people and occurs more often in males than in females. The disorder is a form of hypogonadotropic hypogonadism, which is a condition affecting the production of hormones that direct sexual development. Males with Kallman syndrome are often born with an unusually small penis (micropenis) and undescended testes (cryptorchidism). At puberty, most affected individuals do not develop secondary sex characteristics, such as the growth of facial hair and deepening of the voice in males. Affected females usually do not begin menstruating at puberty and have little or no breast development.
Other than impaired sense of smell and delayed or absent pubert, features of Kallmann syndrome vary, even among affected people in the same family. Additional signs and symptoms can include a failure of one kidney to develop (unilateral renal agenesis), a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a condition called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.
The most common mutations in Kallmann syndrome are in the KAL1, FGFR1, PROKR2, and PROK2 genes. These genes play a role in the development of certain areas of the brain before birth. Although some of their specific functions are unclear, these genes appear to be involved in the formation and movement (migration) of a group of nerve cells that are specialized to process smells (olfactory neurons). These nerve cells come together into a bundle called the olfactory bulb, which is critical for the perception of odors. The KAL1, FGFR1, PROKR2, and PROK2 genes also play a role in the migration of neurons that produce a hormone called gonadotropin-releasing hormone (GnRH). GnRH controls the production of several other hormones that direct sexual development before birth and during puberty. These hormones are important for the normal function of the gonads (ovaries in women and testes in men).
Studies suggest that mutations in these genes disrupt the migration of olfactory nerve cells and GnRH-producing nerve cells in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person's sense of smell will be impaired or absent. Misplacement of GnRH-producing neurons prevents the production of certain sex hormones, which interferes with normal sexual development and causes the characteristic features of hypogonadotropic hypogonadism.
The diagram on the right shows the migration of the GnRH neurones from the olfactory placode and into the hypothalamus which occurs within the first 10 to 12 weeks of life. The diagram also lists 18 different genes that have been identified in being involved in the whole process. Some of the genes like KAL1 are well-known, others have only recently been identified. Also very recently, researchers found a genetic fault that prevent a molecule, called SEMA3E, from working correctly in two brothers with Kallmann syndrome.
It is still unclear how gene mutations lead to the other possible signs and symptoms of Kallmann syndrome. Because the features vary among individuals, and researchers suspect that additional genetic and environmental factors may be involved.
The 18 genes that have been implicated in causing Kallmann syndrome, still only account for less than 50% of total cases. This shows that it is a long way to go before there is a full understanding of the genetics of the disorder.
The diagnosis of Kallmann syndrome is often found during the workup of delayed puberty. One of the biggest problems in the diagnosis, however, is the ability to distinguish between a normal delay of puberty and Kallmann syndrome.
Female diagnosis is sometimes further delayed as other causes of amenorrhoea normally have to be investigated first before a case of Kallmann syndrome is considered. In males, treatment with age-appropriate levels of testosterone can be used to distinguish between Kallmann syndrome from delayed puberty. If just delayed the testosterone can "kick-start" endogenous puberty, as demonstrated by testicular enlargement, whereas in the case of Kallmann syndrome there will be no testicular enlargement while on testosterone therapy alone.
A full endocrine workup will be required to measure the levels of the other pituitary hormones, especially prolactin, to check that the pituitary gland is working correctly.
Bone age can be assessed using hand and wrist X-rays. If the bone age is significantly lower than the chronological age of the patient, this could suggest delayed puberty unless there is another underlying reason for the discrepancy.
A karyotype may be performed to rule out Klinefelter syndrome and Turner syndrome, although the hormones levels would also rule out both these conditions.
A magnetic resonance imaging (MRI) scan can be used to determine whether the olfactory bulb is present and to check for any physical irregularities of the pituitary gland or hypothalamus.
A standard smell test can be used to check for anosmia, but it must be remembered that even in total anosmia various substances (such as menthol and alcohol) can still be detected by direct stimulation of the trigeminal nerve.
Genetic screening can be carried out, especially for the KAL1 mutation, but in light of the uncertain genetic origin of the majority of KS and HH cases a negative result will not rule out a possible diagnosis.
The treatment for Kallman syndrome are often split into two categories: hormone replacement therapy and fertility treatments.
The aim for hormone replacement therapy (HRT) for both men and women is to ensure that the level of testosterone for men and oestrogen/progesterone for women is at the normal level for the age of the patient. At first the treatment will produce most of the physical and psychological changes seen at puberty, with the major exception that there will be no testicular development in men and no ovulation in women. After the optimum development has been reached, continued HRT for men will continue to maintain libido, muscle development, energy levels, hair growth, and sexual function. In women, a variety of types of HRT will either give a menstruation cycle or not as preferred by the patient. HRT is very important in both men and women to maintain bone density and to reduce the risk of early onset osteoporosis.
Fertility treatments for people with Kallmann syndrome will require specialist advice from doctors experienced in reproductive endocrinology. There is a good success rate for achieving fertility, with some experts quoting up to a 70% success rate, if IVF techniques are used as well. However there are factors that can have a negative effect on fertility and specialist advice will be required to determine if these treatments are likely to be successful. Fertility treatments involve the administration of the gonadotropins follicle-stimulating hormone (FSH), luteinizing hormone (LH) in order to stimulate the production and release of eggs and sperm. Women have an advantage over the men as their ovaries normally contain a normal number of eggs and it sometimes only takes a couple of weeks of treatment to achieve fertility while it can take males up to two years of treatment to achieve fertility. For both men and women, an alternative method (but not widely available), is the use of an infusion pump to provide GnRH (or LHRH) in pulsatile doses throughout the day. This stimulates the pituitary gland to release natural LH and FSH in order to activate testes or ovaries.
In The British Medical Journal a 22 year old man diagnosed with Kallmann syndrome describes the consequences of his late diagnosis. There is also a list of useful resources for patients and health professionals at the bottom of the article.
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