Kallmann syndrome

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Kallmann syndrome

Definition

Kallmann syndrome is a disorder of hypogonadotropic hypogonadism, delayed puberty, and anosmia.

Description

Hypogonadotropic hypogonadism (HH) occurs when the body does not produce enough of two important hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). This results in underdeveloped gonads and often infertility. Anosmia, the inability to smell, was first described with hypogonadotropic hypogonadism in 1856, but it was not until 1944 that Kallmann reported the inheritance of the two symptoms together in three separate families. Hence, the syndrome of hypogonadotropic hypogonadism and anosmia was named Kallmann syndrome (KS).

Kallmann syndrome (KS) is occasionally called dysplasia olfactogenitalis of DeMorsier. Affected people usually are detected in adolescence when they do not undergo puberty. The most common features are HH and anosmia, though a wide range of features can present in an affected person. Other features of KS may include a small penis or undescended testicles in males, kidney abnormalities, cleft lip and/or palate, clubfoot , hearing problems, and central nervous system problems such as synkinesia, eye movement abnormalities, and visual and hearing defects.

Genetic profile

Most cases of Kallmann syndrome are sporadic. However, some cases are inherited in an autosomal dominant pattern, an autosomal recessive pattern, or an X-linked recessive pattern. In most cells that make up a person there are structures called chromosomes . Chromosomes contain genes, which are instructions for how a person will grow and develop. There are 46 chromosomes, or 23 pairs of chromosomes, in each cell. The first 22 chromosomes are the same in men and women and are called the autosomes. The last pair, the sex chromosomes, are different in men and women. Men have an X and a Y chromosome (XY). Women have two X-chromosomes (XX). All the genes of the autosomes and the X-chromosomes in women come in pairs.

Autosomal dominant inheritance occurs when only one copy of a gene pair is altered or mutated to cause the condition. In autosomal dominant inheritance, the second normal gene copy cannot compensate, or make up for, the altered gene. People with autosomal dominant inheritance have a 50% chance of passing the gene and the condition onto each of their children.

Autosomal recessive inheritance occurs when both copies of a gene are altered or mutated to cause the condition. In autosomal recessive inheritance, the affected person has inherited one altered gene from their mother and the other altered gene from their father. Couples who both have one copy of an altered autosomal recessive gene have a 25% risk with each pregnancy to have an affected child.

X-linked recessive inheritance is thought to be the least common form of inheritance in KS, but is the most well understood at the genetic level. With X-linked recessive inheritance, the altered gene that causes the condition is on their X chromosome. Since men have only one copy of the X chromosome, they have only one copy of the genes on the X chromosome. If that one copy is altered, they will have the condition because they do not have a second copy of the gene to compensate. Women, however, can have one altered copy of the gene and not be affected as they have a second copy to compensate. In X-linked recessive conditions, women are generally not affected with the condition. Women who are carriers for an X-linked recessive condition have a 25% chance of having an affected son with each pregnancy.

Though all three patterns of inheritance have been suggested for Kallmann syndrome, as of 2001 only one gene has been found that causes Kallmann syndrome. The gene, KAL, is located on the X chromosome and is responsible for most cases of X-linked recessive Kallmann syndrome. The gene instructs the body to make a protein called anosmin-1. When this gene is altered in a male, Kallmann syndrome occurs. Of those families who have an X-linked recessive form of KS, approximately 1/2 to 1/3 have identifiable alterations in their KAL gene.

Demographics

Kallmann syndrome is the most frequent cause of hypogonadotropic hypogonadism and affects approximately 1/10,000 males and 1/50,000 females. Kallmann syndrome is found in all ethnic backgrounds. Because the incidence of KS in males is about five times greater than KS in females, the original belief was that the X-linked form of Kallmann syndrome was the most common. However, as of 2001, it is now assumed that the X-linked recessive form is the least common of all KS. The reason for Kallmann syndrome being more frequent in males is not known.

Signs and symptoms

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.

As of 2001, 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.

Treatment and management

When a child with KS is born with structural abnormalities such as cleft lip and/or palate, clubfoot or heart defects, surgery is often required to fix the defect. Taking sex hormones treats delayed puberty; women take estrogen and men take testosterone. Once puberty is completed, taking GnRH or both LH and FSH can treat hypogonadism. For most affected individuals, treatment is successful and infertility is reversed. However, a small portion of people will not respond to treatment.

When an isolated case of Kallmann syndrome is diagnosed, evaluation of first-degree family members, such as parents and siblings, should be completed. This should include a detailed family history, measuring hormone levels, assessing sense of smell, and renal ultrasound to look for kidney abnormalities. This information may help to diagnosis previously unrecognized cases of Kallmann syndrome. Furthermore, this information may be important for genetic counseling and determining whom in the family is at risk for also having Kallmann syndrome.

Prognosis

For individuals with the most common features of Kallmann syndrome, hypogonadism and the inability to smell, prognosis is excellent. In most cases, hormone treatment is able to reverse the delayed puberty and hypogonadism. For those individuals with other symptoms of Kallmann syndrome, prognosis can depend on how severe the defect is. For example, structural heart defects can be quite complex and sometimes surgery can not fix them. Furthermore, no treatment is available for the mental retardation in the portion of affected individuals with this symptom.