Everything about Kallmann Syndrome totally explained
Kallmann syndrome is an example of
hypogonadism (decreased functioning of the sex hormone-producing glands) caused by a deficiency of
gonadotropin-releasing hormone (GnRH), which is created by the
hypothalamus. Kallmann syndrome is also known as
hypothalamic hypogonadism, familial hypogonadism with
anosmia, or
hypogonadotropic hypogonadism, reflecting its disease mechanism.
Kallmann syndrome is a form of tertiary hypogonadism reflecting the fact the primary cause of the defect in sex hormone production lies within the pituitary and hypothalamus rather than a physical defect of the testes or ovaries themselves.
Kallmann syndrome was described in
1944 by
Franz Josef Kallmann, a
German-
American geneticist. However, others - such as the Spanish doctor
Aureliano Maestre de San Juan - had noticed a correlation between anosmia and hypogonadism in 1856.
The most well known person who has Kallmann syndrome in modern times is the jazz vocalist
Jimmy Scott. In 2004, Canadian writer
Brian Brett published a memoir,
Uproar's Your Only Music, about growing up with Kallmann syndrome.
Features
Kallmann syndrome is characterized by:
It can occasionally be associated with optic problems, such as
colour blindness or optic atrophy, nerve deafness,
cleft palate,
cryptorchidism,
renal agenesis, and
mirror movement disorder. However, it isn't clear at this time how or if these other problems have the same cause as the hypogonadism and anosmia. These problems are more often present in those without Kallmann syndrome.
Males present with delayed puberty and may have
micropenis (although congenital micropenis isn't present in the majority of male KS cases).
Females present with delayed puberty (for example
primary amenorrhea) and lack of
secondary sex characteristics, such as
breast development.
Diagnosis
The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia together with
micropenis in boys should suggest Kallmann syndrome (although micropenis alone may have other causes).
Pathophysiology
Under normal conditions, GnRH travels from the hypothalamus to the
pituitary gland via the
hypophyseal portal system, where it triggers production and release of
gonadotropins (
LH and
FSH) from the
gonadotropes. When GnRH is low, the pituitary doesn't create the normal amount of gonadotropins. The gonadotropins normally increase the production of
gonadal steroids, so when they're low, these steroids will be low as well.
In Kallmann syndrome, the GnRH neurons don't migrate properly from the olfactory
placode to the hypothalamus during development. The olfactory bulbs also fail to form or have hypoplasia, leading to anosmia or hyposmia.
Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there's a defect in the
KAL1 gene, which maps to chromosome Xp22.3. KAL encodes a neural cell adhesion molecule,
anosmin-1. Anosmin-1 is normally expressed in the
brain,
facial mesenchyme,
mesonephros and
metanephros. It is required to promote migration of
GnRH neurons into the
hypothalamus. It also allows migration of olfactory neurons from the
olfactory bulbs to the hypothalamus.
An autosomal dominant gene on chromosome 8 (KAL-2 or FGFR-1 (fibroblast growth factor receptor 1)) is thought to cause about 10% of cases. There is some recent evidence to suggest a degree of linkage between the KAL-1 and FGFR-1 genes.
An additional autosomal cause of Kallmann syndrome has been reported by a mutations in the prokineticin receptor-2 gene (PROKR2)(KAL-3) at position 20p13 and its ligand prokineticin 2 (PROK2)(KAL-4) at position 3p21.1. It was noted that mutations in these genes brought about various degrees of olfactory and reproductive dysfunction, but not the other symptoms seen in KAL-1 and KAL-2 forms of Kallmann Syndrome. The authors of the paper suggested that up to 30% of all Kallmann Syndrome cases can be linked to known genetic mutations.
Treatment
Treatment is directed at restoring the deficient hormones -- known as
hormone therapy (HT). Males are administered
human chorionic gonadotropin (hCG) or
testosterone. Females are treated with
oestrogen and
progestins.
To induce fertility in males or females, GnRH (aka LHRH) is administered by an
infusion pump, or hCG/hMG/FSH/LH combinations are administered through regular injections. Fertility is only maintained whilst actually being treated with these hormones. Once fertility treatment stops it's necessary to revert to the normal HRT of testosterone for men and oestrogen + progestins for women.
The main health risk, for both men and women, of untreated Kallmann Syndrome is
osteoporosis. Therefore, regular bone density scans (every 2 years or so) are advisable, even if being treated with HRT. Additional medication specifically for osteoporosis is necessary in some cases.
Epidemiology
Kallmann syndrome occurs at a rate of 1 in 10,000 male births and 1 in 50,000 female births. It may be inherited as an X-linked condition, an autosomal dominant condition or as an autosomal recessive condition. Statistics are sparse, but it seems that autosomal dominant is the most common form of heredity.
One recent paper quoted an incidence in males of 0.025%, or 1 in 4,000, with the female incidence being 3 to 5 times less.
Even though mutations in the KAL-1 gene on the X chromosome can cause Kallmann syndrome, only 11-14% of patients with Kallmann syndrome have detectable KAL-1 mutations.
Autosomal dominant mutations have been described with the FGFR-1 (8p12) gene, sometimes referred to as the KAL-2 gene. This is thought to cause about 10% of cases.
Autosomal recessive mutations of the GnRH receptor gene (4q13.2) have also been reported. This defect appears to produce a wider spectrum of physical symptoms than with the other gene defects, and the defect lies in the ability of the pituitary gland to recognize GnRH, rather than the ability of the hypothalamus to produce GnRH. It is debatable as to whether this is in fact Kallmann syndrome since the GnRH receptor development isn't related to anosmia.
There may also be no obvious family history of inheritance (sporadic cases). However, it's possible for Kallmann syndrome genes to be passed on to children of a sporadic case.
Further Information
Get more info on 'Kallmann Syndrome'.
|
External Link Exchanges
Do you know how hard it is to get a link from a large encyclopaedia? Well we're different and will prove it. To get a link from us just add the following HTML to your site on a relevant page:
<a href="http://kallmann_syndrome.totallyexplained.com">Kallmann syndrome Totally Explained</a>
Then simply click through this link from your web page. Our crawlers will verify your link, extract the title of your web page and instantly add a link back to it. If you like you can remove the words Totally Explained and embed the link in article text.
As long as your link remains in place, we'll keep our link to you right here. Please play fair - our crawlers are watching. Your site must be closely related to this one's topic. Any kind of spamming, dubious practises or removing the link will result in your link from us being dropped and, potentially, your whole site being banned. |
