Kallmann Syndrome Health Article

Embryology

Normally, a structure in the brain called the hypothalamus makes a hormone called gonadotrophin releasing hormone (GnRH). This hormone acts on the pituitary gland, another structure in the brain, to produce the two hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both of these hormones travel to the gonads where they stimulate the development of sperm in men and eggs in women. FSH is also involved in the release of a single egg from the ovary once a month. Hypogonadotropic hypogonadism results when there is an alteration in this pathway that results in inadequate production of LH or FSH. In Kallmann syndrome, the alteration is that the hypothalamus is unable to produce GnRH.

How hypogonadotropic hypogonadism and the inability to smell are related can be explained during the development of an embryo. The cells that eventually make the GnRH in the hypothalamus are first found in the nasal placode, part of the developing olfactory system (for sense of smell). The GnRH cells must migrate, or move, from the nasal placode up into the brain to the hypothalamus. These GnRH cells migrate by following the path of another type of cell called the olfactory neurons. Neurons are specialized cells that are found in the nervous system and have long tail-like structures called axons. The axons of the olfactory neurons grow from the nasal placode up into the developing front of the brain. Once they reach their final destination in the brain, they form the olfactory bulb, the structure in the brain that helps process odors allowing the sense of smell. The GnRH cells follow the pathway of the olfactory neurons up into the brain to reach the hypothalamus.

In Kallmann syndrome, the olfactory neurons are unable to grow into the brain. Hence, the GnRH cells can not follow their pathway. As a result, the olfactory bulb does not form, resulting in the inability to smell. The GnRH cells can not follow the pathway of the axons and do not reach their final destination in the hypothalamus. Hence, no GnRH is made to stimulate the pituitary to make FSH and LH, resulting in hypogonadotropic hypogonadism.

In X-linked recessive KS, the KAL gene instructs the body to make the protein anosmin-1. This protein is involved in providing the pathway in the brain for which the olfactory axons grow. If it is altered in any way, the axons will not know where to grow in the brain and the GnRH cells will be unable to follow. The protein anosmin-1 is also found in other parts of the body, possibly explaining some of the other symptoms sometimes seen in Kallmann syndrome.

Other features

The features of Kallmann syndrome can vary among affected individuals even within the same family. The two features most often associated with Kallmann syndrome are HH and the inability to smell. Males can also have a small penis and undescended testicles at birth (testicles are still in body and have not dropped down into the scrotal sac). Clubfoot, cleft lip and/or cleft palate can also be present at birth. Clubfoot occurs when one or both feet are not properly placed onto the legs and can appear turned. Cleft lip and/or cleft palate occur when the upper lip and/or the roof of the mouth fail to come together during development. Kidney abnormalities, most often unilateral renal agenesis (one kidney did not form) are especially common in those males with X-linked recessive KS. Choanal atresia (pathway from the nose is blocked at birth) and structural heart defects have also been seen in KS.

Central nervous system problems can also occur in Kallmann syndrome. These can include nystagmus (involuntary eye movement), ataxia (involuntary body movement), hearing loss and problems with vision. Synkinesia is especially common in men with the X-linked recessive form of KS. Some people with KS are also mentally retarded. Holoprosencephaly, when the brain fails to develop in two halves, can also be seen in some individuals with KS.

Diagnosis

Individuals with Kallmann syndrome are usually diagnosed when they do not undergo puberty. Hormone testing shows that both LH and FSH are decreased. Affected individuals often do not realize they cannot smell. MRI can often detect the absence of the olfactory bulb in the brain. Renal ultrasound can determine if a kidney is missing.

Genetic testing for alterations in the KAL gene is the only genetic testing available. Even with families with clear X-linked recessive inheritance, genetic testing does not always detect an alteration in the KAL gene. Hence, diagnosis is still very dependent upon clinical features.