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Kallman syndrome
Classification and external resources

The structure of GNRH1
(from PDB 1YY1)
ICD-10 E23.0
ICD-9 253.4
OMIM 308700 147950 244200 138850 607002
DiseasesDB 7091
eMedicine med/1216 med/1342
MeSH D017436

Kallmann syndrome is a hypogonadism (decreased functioning of the glands that produce sex hormones) caused by a deficiency of gonadotropin-releasing hormone (GnRH), which is created by the hypothalamus. Kallmann syndrome is also called hypothalamic hypogonadism, familial hypogonadism with anosmia, and hypogonadotropic hypogonadism, reflecting its disease mechanism.

Kallmann syndrome is a form of secondary hypogonadism, reflecting that 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.

Kallmann syndrome was described in 1944 by Franz Josef Kallmann, a German-American geneticist.[1][2] However, others, such as the Spanish doctor Aureliano Maestre de San Juan in 1856, had noticed a correlation between anosmia and hypogonadism.

The best-known person who has Kallmann syndrome 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.

Contents

Features

Kallmann syndrome's characteristics:

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 is not clear how, if at all, these other problems have the same cause as the hypogonadism and anosmia. These problems are more common in those without Kallmann syndrome.

Males present with delayed puberty and may have micropenis (although congenital micropenis is not present in most male KS cases).

Females present with delayed puberty (i.e., primary amenorrhea) and lack of secondary sex characteristics, such as breast development.

A fraction of cases may present with post-pubertal onset, which results in a phenotypically normal penis in men with subsequent testicular atrophy and loss of some secondary sex traits. These men generally present with sexual impairment and low libido. In women, late-onset Kallmann Syndrome can result in secondary amenorrhea. Anosmia may or may not be present in these individuals.

Diagnosis

The diagnosis is often one of exclusion found during the workup of delayed puberty. The presence of anosmia with delayed puberty should suggest Kallmann syndrome.

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 does not create the normal amount of gonadotropins. The gonadotropins normally increase the production of gonadal steroids; so, when they are low, these steroids will be low as well.

In Kallmann syndrome, the GnRH neurons do not 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.

OMIM Name Gene Locus Description
308700 KAL1 KAL1 Xp22.3 Kallmann syndrome can be inherited as an X-linked recessive trait, in which case there is a defect in the KAL1 gene, which maps to chromosome Xp22.3.[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.
147950 KAL2 FGFR1 8p11.2-p11.1 An autosomal dominant gene on chromosome 8 {8p12} (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.
244200 KAL3 PROKR2 20p13 An additional autosomal cause of Kallmann syndrome has been reported[4] 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—hormone therapy (HT). Males are administered human chorionic gonadotropin (hCG) or testosterone. Females are treated with estrogen 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 maintained only during treatment with these hormones. Once fertility treatment stops, it is necessary to revert to the normal hormone-repleacement therapy (HRT) of testosterone for men and oestrogen and progestins for women.

The main health risk, for both men and women, of untreated Kallmann Syndrome is osteoporosis. Therefore, regular bone-density scans (every two years or so) are advisable, even if 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[5] 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 called the KAL-2 gene. This is thought to cause about 10% of cases. However, about 70% of KS cases seem to be the result of autosomal dominant genes, though the identity of those genes is not yet known.

Autosomal recessive mutations of the GnRH-receptor gene (4q13.2) have also been reported.[5] 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. There is debate about whether this is in fact Kallmann Syndrome, because the GnRH-receptor development is not related to anosmia.

There may also be no obvious family history of inheritance (sporadic cases). However, it is possible for Kallmann Syndrome genes to be passed on to children of a sporadic case.

Psychology

In some cases, the psychological effects of having this condition can outweigh the significance of any physical symptoms.

The social stigma of being left behind by the peer group at a vital stage of physical and emotional development can cause lasting damage in some patients. Some with Kallmann Syndrome find it difficult to fit in to social groups and may have trouble forming relationships, both physically and emotionally. This might be more profound in people who receive diagnoses later in life. There appear to be a range of psychological outcomes for people with KS from relatively mild to chronic in which the whole 'self' is shaped by having the syndrome. In these people their self-image is essentially filtered through the fact that they have KS. Feelings of inadequacy, being worth less than others and anxiety states may result in some patients.

Practical Issues

While the lack of sense of smell may not be important when compared to the lack of sexual development, it does give rise to some situations in which care should be taken, such as personal hygiene, gas leaks within the home (fitting gas detectors within the home is recommended), and spoilage of food and drink (extra care should be taken with the expiration dates).

References

  1. ^ Kallmann FJ, Schönfeld WA, Barrera SE. The genetic aspects of primary eunuchoidism. Am J Ment Defic 1943-1944;48:203-236.
  2. ^ synd/2549 at Who Named It?
  3. ^ MacColl G, Bouloux P, Quinton R (2002). "Kallmann syndrome: adhesion, afferents, and anosmia". Neuron 34 (5): 675–8. doi:10.1016/S0896-6273(02)00720-1. PMID 12062015.  
  4. ^ Dode C, et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet.2: e175, 2006.
  5. ^ a b Quinton R. Topical Endocrinology 22. (15-20)

External links








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