Kallmann Syndrome - Phenotypic Spectrum of KS / HH Cases

Phenotypic Spectrum of KS / HH Cases

Kallmann syndrome and hypogonadotropic hypogonadism do not exist as distinct conditions. Each case can show a different range of symptoms and a different severity of symptoms. Even family members will not always show the same degree of symptoms. Cases of KS/HH can be separated into different categories depending on the gene mutation(s) involved. Severity can range from total absence of puberty with anosmia to slightly delayed puberty with or without anosmia.

Classic HH

This type of HH is present from birth and is lifelong. Approximately two thirds of cases will have a low level of pulsatile GnRH release from the hypothalamus which will give rise to partial puberty while the other third of cases will have zero GnRH release and no puberty.

The non-reproductive symptoms as mentioned earlier in this article will be present in approximately half the cases. The most common of which being anosmia, which gives rise to the distinction between KS and HH. Males with classic HH may also have had a history of un-descended testicles and / or micropenis.

This type of HH has been shown to be caused by polyallelic mutations in males and females and autosomal dominant and x-linked recessive mutations in males mentioned in the table earlier in this article.

Adult-onset HH

This type of HH has only been shown to occur in males. The hypothalamic-pituitary-gonadal axis (HPG axis) functions normally at birth and well into adult life giving normal puberty.

The HPG axis then fails, either totally or is reduced to a very low level of GnRH release, in adult life with no obvious cause such as a pituitary tumor. This will lead to a fall in testosterone levels and infertility. This type of HH is not associated with any non-reproductive symptoms. This type of HH has been shown to be caused by monoallelic mutations.

Reversible KS / HH

This type of KS / HH will appear to be the classic lifelong form at first but at some point in adult life the HPG axis resumes its normal function and GnRH, LH and FSH levels return to normal levels. Has only been shown to occur in 10% of cases, primarily KS cases rather than HH cases and only found in patients who have undergone some form of testosterone replacement therapy. It is only normally discovered when testicular volume increases while on testosterone treatment alone and testosterone levels return to normal when treatment is stopped.

This type of KS / HH rarely occurs in cases where males have had a history of un-descended testes and / or micropenis and has been shown to be caused by monoallelic mutations.

Hypothalamic amenorrhea

This type of HH is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition. It is reversible with the removal of the stressor

This type of HH is not associated with any non-reproductive symptoms and has been shown to be caused by monoallelic mutations. A study suggested that there may have been an evolutionary advantage at one stage in the early development of man for these genes to exist where it could have been an advantage for the females not to be fertile at times when food was scarce in the community.

This type of HH has been shown to be caused by monoallelic mutations.

Normal puberty with non-reproductive symptom(s)

In this type of HH puberty occurs normally or is only slightly delayed and there might be a non-reproductive symptom, such as anosmia present. This type of HH has been shown to be caused by monoallelic mutations.