Kallmann Syndrome

A rare hormonal condition characterized by delayed or absence of puberty and an impaired sense of smell is Kallmann syndrome. This belongs to a larger group of conditions known as hypogonadotrophic hypogonadism. This condition is usually characterized by a failure to start or fully complete puberty. However hypogonadotrophic hypogonadism can be treated successfully by means of specialized hormone replacement therapy.

It is estimated that this syndrome affects 1 in 10,000 to 86,000 people and occurs more often in males rather than in females. Kallmann Syndrome 1 is the most common form of this condition. It was Franz Kallmann, an American scientist who first published a paper in 1914 about this syndrome. Therefore this genetic condition is named after him.

Characteristics of Kallmann Syndrome

Males with hypogonadotrophic hypogonadism are born with unusually small penis and undescended testes. Whereas, females affected, usually do not begin menstruating at puberty and have little or no breast development at all. In some women, puberty is either incomplete or delayed. In short, at puberty those affected do not develop secondary sexual characteristics.

In Kallmann syndrome, the sense of smell is particularly diminished or completely absent. This feature indeed distinguishes this syndrome from most other forms of hypogonadotrophic hypogonadism.

The significant aspect here is that most patients are not aware of this inability to detect odors until they are diagnosed. Some points to remember:

Inability to smell strong warning smells such as smoke or gas.

Inability to smell caustic products such as bleach.

Inability to smell rotten/spoilt food.

Personal hygiene, body odor and clothes.

Since the sense of smell is also linked to the sense of taste, some foods will not taste the same as with other people.

Signs and Symptoms

Kallmann Syndrome, even within the same family may vary in its features. Some additional symptoms and signs may include failure of one kidney to develop, a cleft lip with or without an opening in the roof of the mouth or a cleft palate, abnormal eye movements, hearing loss and abnormalities in tooth development.

In some affected persons, the movements of one hand are mirrored by the other hand - Bimanual Synkinesis. This can make it difficult to undertake tasks that require the hands to move separately such as playing a musical instrument. Kallmann syndrome has types designated from 1 through 4 distinguished by their genetic cause. The four types are identified as four forms of Kallmann syndrome, each characterized by an impaired sense of smell. Additional features of cleft palate occur only in types 1 and 2.

Causes

Kallmann syndrome and other related conditions are congenital in nature and are present from birth. Their genetic basis may not be fully understood and this syndrome can be inherited through the generations although it is difficult for the doctor to predict if this will occur.

The genetic factor: Certain mutations in the KAL1, FGFR1, PROKR2, and PROK2 genes cause Kallmann syndrome. Mutations in FGFR1 gene causes syndrome type 2 and mutations in PROKR2 and PROK2 cause Kallmann syndromes types 3 and 4 respectively.

These genes seem to play a role in the development of the brain much before birth. They are involved in the formation and movement of a group of nerve cells that are specialized in olfactory or smell process. The mutations KAL1, FGFR1, PROKR2, and PROK2 genes which play a role in the migration of neurons that produce a hormone called GnRH – Gonodotropin releasing hormone that controls several other hormones that direct sexual development before birth and during puberty. These hormones are necessary for the normal functioning of the ovaries in women and testes in men. These mutations disrupt the olfactory nerve cells and GnRH producing nerve cells in the brain. However these conditions and features vary among individuals and thus additional genetic and environmental factors may be involved.

Treatment

Without proper treatment, the affected female is likely to face infertility and have an increased risk of developing osteoporosis or brittle bones. However, with correct diagnosis and treatment, fertility can be achieved in many cases and risk of osteoporosis decreased.

Following clinical examination, certain biochemical parameters and various imaging tests are done to confirm the diagnosis. As this is a genetic condition, testing for various genetic forms of this disease may also assist in making the diagnosis.

Initially hormone replacement therapy - testosterone in males and estrogen and progesterone in females is used to help induce secondary sexual characteristics.

Once pubertal maturation happens, for fertility either injection of pituitary hormones – gonadotropins, LH and FSH and in some instances therapy with synthetic peptide, GnRH is given. Deficiency of these hormones causes syndromes, and these are required to induce the sex organs to make sperm in males and eggs in females.

In females, the steps taken may vary depending upon individuals and the desired outcome. In premenopausal women, a step-by-step increase in estrogen dosage is given. A bone scan is done to assess the bone age. Without the presence of estrogen, the bone age will be behind that normally seen at that chronological age. The aim is to match the estrogen dosage to the bone age such that the development of bone can be enhanced. The doctor usually monitors the stage of treatment very closely.

Specialist fertility treatments are available and these can induce a certain level of fertility. The aim is to produce hormones by the pituitary and hypothalamus glands and induce natural production of sex hormones. Results can take 6 to 18 months but it is possible to induce fertility in some cases.

There are various drugs available which are usually self-injected twice or thrice a week over a period of at least six weeks. To combat the risk of osteoporosis, it becomes necessary to take tablets that reduce the risk. These tablets help increase the calcium uptake by the bones to strengthen them. However, medication will not eliminate the risk of osteoporosis.

Early diagnosis, education, personal outlook and support from family and friends can help reduce the problems surrounding this syndrome. Kallmann syndrome is usually lifelong in nature and about 10-15% of patients may experience recovery of hormonal system.

GnRH

Gonadotropin-releasing hormone (GnRH) is a neurohormone consisting of ten amino acids which is produced by the arcuate nuclei of the hypothalamus. It is integral for starting the reproductive hormone cascade.

GnRH is secreted in the hypothalamus which is part of the brain. The hypothalamus is part of the 'Hypothalamus - Pituitary - Gonad' axis which regulates the reproductive system in men and women. Secretion of GnRH by the hypothalamus is delivered through a direct pathway between the hypothalamus and pituitary. GnRH stimulates the synthesis and secretion of two gonadotrophins namely, lutenizing hormone (LH) and follicle stimulating hormone (FSH) by the anterior pituitary gland. Controlled by internal and external factors, GnRH acts in a negative feedback loop. For instance, if there is excess FSH, LH or testosterone, then these hormones will inhibit GnRH production.

Lifestyles can also affect GnRH secretion. Lack of exercise, poor diet, opiad drugs and excessive stress can negatively affect GnRH production. What is so striking in GnRH is that under normal circumstances, GnRH is released at intervals of 90 to 120 minutes. Hence, in patients with GnRH deficiency, the releasing hormone should be administered in pulses. Constant administration of GnRH also suppresses gonadotropin secretion especially in children in puberty stage and in men with prostate cancer.

Why is GnRH treatment used?

This hormone is produced by the hypothalamus and it stimulates the pituitary gland to produce LH and FSH. Lack of GnRH in the hypothalamus can halt testosterone production in the testicles of men. In women, abnormal GnRH levels can be responsible for ovulatory disorders.

This is commonly used when Clomid treatment has not stimulated egg follicles to develop on the ovaries. GnRH works effectively to replace the natural GnRH in women and men who do not produce enough of it. Failure of release of GnRH can result in deficiency that can be partial or complete.

In a woman who is not ovulating because of lack of stimulation from hypothalamus.

In a man who is not producing sperm because his hypothalamus is not stimulating the hormones that trigger sperm production.

The use of GnRH can result in multiple pregnancies.

Some studies report that the pregnancy rate after treatment with GnRH is about 20%.

Side effects

Some side effects include:

• Breathing trouble
  
• Swelling of face, lips, tongue and throat
  
• Itching and redness at the site of the intravenous catheter
  
• Infection at the site of the IV catheter
  
• Ovarian hyper stimulation syndrome - GnRH poses less risk of this syndrome than does human menopausal Gonadotropin and other treatments for ovulation.

The small pump that is used for GnRH may bother some people and treatment requires daily monitoring by a doctor.

Although clinicians and scientists have observed the findings of olfactory disturbances and reproductive dysfunction, the syndrome comprising complete GnRH deficiency and lack of olfactory senses is named Kallmann Syndrome after the American geneticist Kallmann who identified this disorder in 1944.

Treatment

The choice of therapy depends upon the patient's desire to achieve one or more of the following options:

• Secondary sexual characteristics
  
• Fertility
  
• Bone and muscle mass

In males, treatment is decided to provide androgen replacement. The patient's age, potential adverse effects of therapy, patient's desire for fertility are considered. In the prepubertal male, GnRH stimulates penile growth, body and facial hair growth, bone and muscle development and voice changes. Androgens also stimulate growth hormone production, contributing to the adolescent growth spurt. Male androgen deficiency can result in social ridicule and therefore starting androgen therapy around age 14-15 is prudent.

Oral, injectable and transdermal and implantable pellets formulation are available for treatment of males with Kallmann syndrome. Oral androgen preparations should not be used due to their toxic effects on the liver and adverse effects on lipids. Injectable long-acting testosterone are low-cost, relatively safe and effective. The disadvantages include intramuscular injection and non physiologic pattern of testosterone over the dosing interval. There could be wide swings in libido in some men.

Transdermal patches and gel preparation of testosterone are currently available - adverse effect with these formulations include skin reactions at the application. In females as in males, treatment depends upon age and fertility desires. Estrogen replacement is a must to prevent osteoporosis.

Oral preparations, transdermal patches, vaginal cream and rings are available for standard hormone replacement therapy. Transdermally administered 17 beta estradiol has been shown as an effective regimen for preventing bone loss in normal menopausal women.

Women with intact uterus receive a cyclical progestin to accompany estradiol treatment. Optimal hormone therapy depends upon whether the patient has primary or secondary amenorrhea. Gradual dose escalation results in optimal breast development and allows time for young woman to adjust psychologically to her physical maturation.