Information on the following diseases can be found in the Related Disorders section of this report:

• Klinefelter syndrome
• Noonan syndrome
• Turner syndrome

All three forms of Kallmann syndrome are characterized by abnormally small and even absent testes or ovaries (hypogonadism). All three forms are accompanied by the loss of smell (anosmia). The three forms also share the characteristic of the testes descending into the scrotum (cryptorchidism). While each form shares these symptoms, each form is accompanied by a variety of other symptoms:

Kallmann syndrome 1.
Mirror hand movements and ataxia are frequently found.
One of the two kidneys does not develop (renal agenesis)
Small penis and hardening of the testicles (atrophy)
High-arched and narrow palate
Unusual growth of breasts among males (gynecomastia)

Kallmann syndrome 2.
Failure of one of the nasal passages to open to the outside (choanal atresia)
Congenital heart defects
Short stature
Hearing loss

Kallmann syndrome 3.
Failure to close midline fissures of skull
Cleft palate and/or cleft lip
One of the usual two kidneys does not develop (renal agenesis)

In some of the more severe forms of Kallmann syndrome, abnormalities of the skeleton such as webbing of two or more fingers or toes (syndactyly), a short fourth finger of the hand, mental retardation, or an absence of symmetry in the skull and face (craniofacial asymmetry) may occur. A very rare form of Kallmann syndrome includes partial or total paralysis of the muscles in the lower half of the body (spastic paraplegia).

Kallmann syndrome is the result of errors in the development of the fetus. Under normal conditions, during fetal development, the gonadotropin-releasing hormone (GnRH) secreting cells (neurons) arise in the undeveloped or rudimentary nose tissue and migrate to the part of the brain known as the hypothalamus. Remarkably, the smell receptor cells originate in this region as well. The nerve fibers (axons) of these smell receptor cells enter the brain to link-up (synapse) with the olfactory bulb that acts as a central processing unit for the sense of smell. The cell bodies remain in the nose.

Patients with Kallmann syndrome lose the olfactory bulb because its growth depends on stimulation from the nerve fibers of the smell receptor cells. The malfunctioning gene prevents the axons from reaching and initiating the growth of the olfactory bulb, interrupting the migration of cells. Similarly, the malfunctioning gene prevents the migration of the GnRH secreting cells to reach the thalamus. If these cells cannot reach the thalamus to release the GnRH, then the pituitary is insufficiently stimulated to produce the luteinizing hormone in the male or follicle stimulating hormone in the female. Thus, in Kallmann syndrome, the testes and ovaries remain stunted.

As noted above, the inheritance pattern for the several forms of Kallmann syndrome vary. The gene for the more prevalent form, KAL1, has been traced to a site on the X chromosome at gene map locus Xp22.3, while the mutated gene associated with KAL2 has been traced to a site on chromosome 8, at gene map locus 8p11.2-p11.1. The X-Linked form is transmitted as an X-Linked recessive trait. The genetic malfunction represented by KAL2 is transmitted as an autosomal dominant trait. The location of the mutated gene responsible for KAL3 has not been determined, however, family studies strongly suggest autosomal recessive transmission of the trait.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xp22.3" refers to band 22.3 on the short arm of the X chromosome. Similarly "chromosome p11.2-p11.1" refers to a region on the short arm of chromosome 8 between bands 11.2 and 11.1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off’" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.

X-linked dominant disorders are also caused by an abnormal gene on the X chromosome, but in these rare conditions, females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females, and many of these males do not survive.

In the USA, Kallmann syndrome affects males (1 per 10,000) at about five times the rate at which women are affected (1 per 50,000). A study in Sardinia suggested a rate of 1 per 80,000. A study on army conscripts in France found the rate to be about 1 per 10,000.

In women, Luteinizing hormone deficiency stimulates estrogen and progesterone production from the ovary. A surge of LH in the midmenstrual cycle is responsible for ovulation. Development of the ovarian follicle is largely under FSH control, and the secretion of estrogen from this follicle is dependent on both FSH and LH.

Klinefelter syndrome
Klinefelter syndrome is a rare disorder that effects males. It is characterized by the presence of one or more extra X-chromosomes in at least one tissue. Abnormally decreased functional activity of the sex glands (gonad) results in retardation of growth and sexual development.

Other symptoms of Klinefelter syndrome may be abnormally large mammary glands in the breasts, small testes, lack of sperm, and abnormally small penis. (For more information on this disorder choose "Klinefelter syndrome" as your search term in the Rare Disease Database.)

Noonan syndrome
Noonan syndrome is a rare genetic disorder that can affect both males and females. This disorder is characterized by a lack of sexual development, short stature, possible mental retardation, a webbed neck, skeletal and/or heart defects, and deformity of the elbow. (For more information on this disorder choose "Noonan syndrome" as your search term in the Rare Disease Database.)

Sertoli-cell-only syndrome
Sertoli cell-only syndrome is a condition in which there are no sperm-producing cells in the testicle. When no sperm are seen on semen analysis, the question arises as to whether this is due to a failure of sperm production, or to a blockage between the testicle and the penis. To determine the reason for the lack of sperm cells, a blood test for FSH is performed. If FSH is elevated, this indicates a failure of sperm production that may be due to infection, injury, medication, radiation or genetics.

Multiple biopsies of tissues from various parts of the testicle are needed to determine whether sperm are being produced. Sertoli cell-only syndrome or an arrest in sperm development may be seen in one small section of the biopsy, while normal sperm can be retrieved from another. So if your diagnosis was made from a single biopsy, taking a sample from the other side may change the prognosis.

Turner syndrome
Turner syndrome is a rare genetic disorder that affects females. This disorder is characterized by a lack of sexual development, small stature, possible mental retardation, a webbed neck, or heart defects. Individuals with this disorder have female characteristics, but they do not develop secondary sexual characteristics. (For more information on this disorder choose "Turner syndrome" as your search term in the Rare Disease Database.)

The standard forms of medical treatment involve hormone replacement therapies to induce puberty and subsequently fertility or pregnancy. Assisted reproductive technologies are available for those who request and require them, such as in-vitro fertilization (IVF), etc. Surgical treatment may be necessary to correct some on the associated signs and symptoms, such as cleft lip or cleft palate. Genetic counseling may be of benefit for patients and their families. Other treatment is symptomatic and supportive.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

As of September 2006 the NIH listed two clinical trials for people affected by Kallmann syndrome. These trials are:

The National Institute of Child Health and Human Development (NICHD) is sponsoring a trial entitled "Follicle Stimulating Hormone (FSH) to Improve Testicular Development in Men with Hypogonadism". The study is designed to investigate the impact of hormonal treatment on men with Kallmann syndrome to see if their potential fertility can be maximized. The Clinical Trial Identifier Number is NCT00064987.

The Massachusetts General Hospital in Boston in collaboration with the National Institutes of health is sponsoring a study of "Letrozole Treatment in Normal and GnRF Deficient Women". The study is designed to better understand the role of estrogen in control of the hormone GnRH, which the sponsors hope will lead to new treatment for women who have difficulty in conceiving. The Clinical Trial Number is NCT00351416.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Kallmann Syndrome 1; KAL1. Entry Number; 308700: Last Edit Date; 3/31/2005.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Kallmann Syndrome 2; KAL2. Entry Number; 147950: Last Edit Date; 6/2/2006.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Kallmann Syndrome 3; KAL3. Entry Number; 244200: Last Edit Date; 3/17/2004.

TEXTBOOKS
Akbas GE. Taylor HS. Kallmann Syndrome. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:.

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS. Eds. Williams Textbook of Endocrinology. 10th ed. Elsevier Saunders. Philadelphia, PA. 2003:151-52; 1177-79.

Brook CGD, Clayton PE, Brown RS. Eds. Brook’s Clinical Pediatric Endocrinology. 5th ed. Blackwell Publishing. Malden, MA; 2005:202-04.

JOURNAL ARTICLES
Tsai PS, Gill JC. Mechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab. 2006;2:160-71.

Hudson ML, Kinnuen T, Cinar HN, Chisholm AD. C. eklegans Kallmann syndrome protein KAL-1 interacts with syndecan and glypican to regulate neuronal cell migrations. Dev Biol. 2006;294:352-65.

Pitteloud N, Ancierno JS Jr, Meysing A, Eliseenkova AV, et al. Mutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc Natl Acad Sci U S A. 2006;103:6281-86.

Sato N, Ohyama K, Fukami M, Okada M, Ogata T. Kallmann syndrome: somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son. J Clin Endocrinol Metab. 2006;95:1415-18.

MacColl G, Quinton R. Kallmann syndrome: bridging the gaps. J Pediatr Endocrinol Metab. 2005;18:541-43.

Karges B, de Roux N. Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev. 2005;8:67-80.

Pitteloud N, Acierno JS Jr, Meysing AU, Dwyer AA, Hayes FJ, Crowley WF Jr. Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab. 2005;90:1317-22.

FROM THE INTERNET
Kolatkar NS. Hypogonadotropic hypogonadism. Medical Encyclopedia. MedlinePlus. Update Date: 1/18/2006. 2pp.
www.nlm.nih.gov/medlineplus/ency/article/000390.htm

Robinson J. Brain development, fertility and Kallman’s syndrome. British Society for Neuroendocrinology. Last Updated (Tuesday, 14 June 2005). 2pp.
http://nuroendo.org.uk/index.php/content/view/6/11/