What is Kallmann syndrome

Kallmann syndrome combines an impaired sense of smell with a hormonal disorder, hypogonadotropic hypogonadism, that delays or prevents puberty. The hypogonadotropic hypogonadism (lack of production of certain hormones that direct sexual development) is due to underdevelopment of specific neurons, or nerves, in the brain that signal the hypothalamus. Without these neurons, the hypothalamus cannot properly stimulate the production and release gonadotropin-releasing hormone (GnRH) by the pituitary gland. In normal development, the hypothalamus secretes bursts of gonadotropin-releasing hormone (GnRH) at puberty. These bursts of GnRH trigger the pituitary gland to produce hormones that in turn prompt the release of male and female sex hormones by the gonads (testicles and ovaries) and the development of sperm and egg cells. In Kallmann syndrome, the hypothalamus fails to secrete these bursts of GnRH in utero, during infancy, and at puberty.

The early development of the hypothalamus and sense of smell in the human embryo are both affected in Kallmann sydnrome. The portion of the hypothalamus that produces GnRH originally forms as part of the nose and migrates during the early stages of embryonic development to join the rest of the hypothalamus. In Kallmann syndrome, both this portion of the hypothalamus and the smell-detecting (olfactory) neurons in the brain do not develop fully.

The main symptom of Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism is delayed or incomplete puberty. In Kallmann syndrome, this is paired with an impaired sense of smell, a condition present from birth but often not brought to a doctor’s attention until asked about it in the course of diagnosing the cause of delayed puberty.

Kallmann syndrome is often diagnosed at puberty due to lack of sexual development. Kallmann syndrome may first be suspected in infancy in males with undescended testicles or a small penis. Symptoms in untreated, adult males may include decreased bone density and muscle mass; small testicles; erectile dysfunction; low sex drive; and infertility. Untreated adult females with Kallmann syndrome usually do not have menstrual periods (amenorrhea) and normal, little, or no breast development. Rarely, a person with Kallmann syndrome will have failure of kidney development (renal agenesis); hearing impairment; cleft lip or palate; and/or dental abnormalities. Most cases of Kallmann syndrome are sporadic (not inherited) but some cases are inherited. The mode of inheritance depends on the gene involved. Treatment includes hormone replacement therapy for sexual development. Fertility can be achieved in most cases ¹⁾.

In Kallmann syndrome, the sense of smell is either diminished (hyposmia) or completely absent (anosmia). This feature distinguishes Kallmann syndrome from most other forms of hypogonadotropic hypogonadism, which do not affect the sense of smell. Many people with Kallmann syndrome are not aware that they are unable to detect odors until the impairment is discovered through testing.

When a person has the hormone deficiency characteristic of Kallmann syndrome but has a normal sense of smell, the condition is known as normosmic idiopathic hypogonadotropic hypogonadism.

Kallmann syndrome occurs more often in males than in females, with an estimated prevalence of 1 in 30,000 males and 1 in 120,000 females ²⁾.

Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism are treated with hormone replacement therapy, with the specific medications and doses tailored to the patient’s needs. This treatment focuses first on inducing puberty and maintaining normal hormone levels. Later, the treatment may be changed to induce fertility.

Medication may also be needed to restore bone health, as the same absence of hormones that leads to delayed puberty can also lead to a weakening of bone density and strength.

Longer term, hormone replacement therapy for males may be reduced or withheld periodically to see if the body has reversed the condition and is producing normal levels of hormones. This reversal was found to occur in 10 to 15 percent of male patients in a study at one center.

Is it possible for me to have kids if I have Kallmann syndrome?

In most women and men with Kallmann syndrome, fertility can be restored. Almost all untreated people are infertile, but restoring fertility is possible in those who respond to treatment with pulsatile GnRH or gonadotropin therapy.

Studies have found that in women with Kallmann syndrome, ovulation induction and pregnancy is not hard to achieve. For example, one study found that in 4 affected women who wanted children, 5 pregnancies were achieved in 3 of the women (and 2 of the women had a second pregnancy) ³⁾.

Assisted reproductive technologies (ART) have been used successfully when affected males don’t have adequate sperm counts on either GnRH or gonadotropin therapy. Technologies used have included in vitro fertilization (IVF); intracytoplasmic sperm injection (ICSI); zygote intrafallopian transfer (ZIFT); and gamete intrafallopian transfer (GIFT) ⁴⁾.

While Kallmann syndrome is typically a life-long condition, about 10-15% of affected people have spontaneous recovery of their hormonal system (without treatment). The reason that this happens in a few affected people is unclear ⁵⁾.

Doctors can’t predict whether a specific person with Kallmann syndrome can have children, because each person may respond to treatment differently. People with questions about their personal chances to have children, and fertility treatment options, should speak with an endocrinologist.

How is Kallmann syndrome inherited?

Kallmann syndrome may be inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner depending on the responsible gene ⁶⁾. For example:

• Kallmann syndrome due to mutations in the KAL1 gene (also called the ANOS1 gene), causing Kallmann syndrome 1, is inherited in an X-linked recessive manner ⁷⁾.
• Kallmann syndrome due to mutations in the FGFR1, PROKR2, PROK2, CHD7 or FGF8 genes (causing Kallmann syndrome types 2, 3, 4, 5 and 6, respectively) is usually inherited in an autosomal dominant manner ⁸⁾.
• Kallmann syndrome due to mutations in PROKR2 and PROK2 can also be inherited in an autosomal recessive manner ⁹⁾.

The majority of people with Kallmann syndrome have a negative family history (the condition occurs sporadically) ¹⁰⁾. However, affected people are still at risk to pass the responsible mutation(s) on to their children, or to have an affected child. The risk for each child to be affected depends on the genetic cause in each case, and may be up to 50%.

People with personal questions about the genetic cause and inheritance of Kallmann syndrome are encouraged to speak with a genetic counselor or other genetics professional. The genetic cause in many cases remains unknown, and a thorough family history should be obtained to understand the mode of inheritance in each family and to aid in genetic testing and counseling. Information about whether specific features are present in all family members can help determine the mode of inheritance ¹¹⁾.

Are the children of a person with Kallmann syndrome at increased risk for birth defects or other conditions?

The children of a person with Kallmann syndrome may be at risk for having Kallmann syndrome or being a carrier of Kallmann syndrome. Experts are not aware of information in the literature suggesting that children of affected people are otherwise at increased risk for other birth defects or developmental disabilities.

How can I find a genetics professional in my area?

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself.

People with questions about the chance to have a child with Kallmann syndrome are encouraged to speak with a genetic counselor or other genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Kallmann syndrome causes

Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism are genetic conditions. They are caused by mutations in any of several different genes. Some, but not all, of these have been identified and the inheritance patterns mapped.

Different gene mutations causing Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism have different inheritance patterns.

• Some must be inherited from both parents (autosomal recessive inheritance). In these types, both parents may be carriers, which means they have no symptoms of the disease.
• Others can be inherited from either the mother or the father (autosomal dominant inheritance).
• In other types, females are carriers and males have (express) the condition (X-linked inheritance). In these types, the condition can be passed from mothers to sons but not from fathers to sons. Either parent can pass the condition to a daughter as a carrier.
• Researchers have more recently identified a fourth inheritance pattern in which mutations in more than one gene may combine to cause the condition (oligogenic inheritance).

Researchers are working to identify all of the genetic mutations associated with Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism.

Kallmann syndrome karyotype

Changes in more than 20 genes have been associated with Kallmann syndrome. Among the most common causes of the condition are mutations in the ANOS1, CHD7, FGF8, FGFR1, PROK2, or PROKR2 gene. In some cases, affected individuals have mutations in more than one of these genes. Additionally, researchers have identified mutations in other genes that may contribute to the development and features of Kallmann syndrome, but are unlikely to cause the disease on their own.

The genes associated with Kallmann syndrome play roles in the development of certain areas of the brain before birth. Although some of their specific functions are unclear, these genes appear to be involved in the formation and movement (migration) of a group of nerve cells that are specialized to process the sense of smell (olfactory neurons). These nerve cells originate in the developing nose and then migrate together to a structure in the front of the brain called the olfactory bulb, which is critical for the perception of odors. Studies suggest that the genes associated with Kallmann syndrome are also involved in the migration of neurons that produce a hormone called gonadotropin-releasing hormone (GnRH). Like olfactory neurons, GnRH-producing neurons migrate from the developing nose to the front of the brain. GnRH controls the production of several hormones that direct sexual development before birth and during puberty. These hormones are important for the normal function of the ovaries in women and testes in men.

Studies suggest that mutations in genes associated with Kallmann syndrome disrupt the migration of olfactory nerve cells and GnRH-producing nerve cells in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person’s sense of smell will be impaired or absent. Misplacement of GnRH-producing neurons in the brain prevents the production of other sex hormones, which interferes with normal sexual development and causes the characteristic features of hypogonadotropic hypogonadism. It is unclear how gene mutations lead to the other signs and symptoms that can occur in Kallmann syndrome. Because the features of this condition vary among individuals, additional genetic and environmental factors likely contribute to this disease.

Together, mutations in known genes account for about 30 percent of all cases of Kallmann syndrome. In cases without a mutation in one of the identified genes, the cause of the condition is unknown. Researchers are looking for additional genetic changes that can cause this disorder.

Kallmann syndrome inheritance pattern

When Kallmann syndrome is caused by ANOS1 gene mutations, the condition has an X-linked recessive pattern of inheritance. The ANOS1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to be present in both copies of the gene to cause the disorder. No females with two ANOS1 gene mutations have been reported in the medical literature. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Most of the time, people with Kallmann syndrome resulting from an ANOS1 gene mutation inherit the mutation from their mothers, who carry a single altered copy of the gene in each cell (and generally do not have any signs or symptoms of the condition). Other people have Kallmann syndrome as a result of a new mutation in the ANOS1 gene.

When Kallmann syndrome results from mutations in other genes, it often has an autosomal dominant pattern of inheritance, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from an affected mother or father. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

In several families, Kallmann syndrome has shown an autosomal recessive pattern of inheritance. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Kallmann syndrome symptoms

Kallmann syndrome is not a life-threatening condition. The main features are delayed or absent signs of puberty, and absent or diminished sense of smell (anosmia or hyposmia, respectively).

Males with Kallmann syndrome may have signs of the condition at birth, such as undescended testes or a smaller than average penis. However, most cases are diagnosed at the time of puberty due to lack of sexual development. Males usually have no growth of facial or body hair, and decreased growth of pubic hair and genitals. They also have a delayed pubertal growth spurt in comparison to their peers. If not treated, adult males may have decreased bone density and muscle mass; decreased testicular volume; erectile dysfunction; low sex drive; and infertility.

Females with Kallmann syndrome usually have absent breast development, an attenuated growth spurt, decreased pubic hair growth, and no initiation of menses (primary amenorrhea). However, some females partially undergo puberty with the beginning of breast development that fails to progress. Very occasionally, affected females have onset of menses at an appropriate age, but it stops after a few cycles.

In both males and females, development of pubic hair can be normal because it is controlled by secretion of androgens from the adrenal glands, which are not affected by the condition. Almost all untreated people with Kallmann syndrome are infertile, but fertility can be restored in those that respond to certain treatments.

Other characteristics may also be present in children and adolescents with Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism. These can include:

• Undescended, or partially descended, testicles
• Small penile size
• Facial defects, such as cleft lip or palate
• Short fingers or toes, especially the fourth finger
• Development of only one kidney
• Hearing loss
• Color blindness
• Abnormal eye movements
• Abnormal development of the teeth
• Mirror hand movements (bimanual synkinesis), in which the movements of one hand are mirrored by the movements of the other

Kallmann syndrome can have a wide variety of additional signs and symptoms. These include a failure of one kidney to develop (unilateral renal agenesis), abnormalities of bones in the fingers or toes, a cleft lip with or without an opening in the roof of the mouth (a cleft palate), abnormal eye movements, hearing loss, and abnormalities of tooth development. Some affected individuals have a feature called bimanual synkinesis, in which the movements of one hand are mirrored by the other hand. Bimanual synkinesis can make it difficult to do tasks that require the hands to move separately, such as playing a musical instrument.

Kallmann syndrome diagnosis

The diagnosis of Kallmann syndrome may be suspected with evidence of lack of sexual maturation or hypogonadism, and evidence of incomplete sexual maturity by Tanner staging. Tanner staging is an established method used by endocrinologists worldwide to evaluate the maturation of the primary and secondary sexual characteristics ¹²⁾.

The diagnosis of Kallmann syndrome additionally relies on hormone evaluation, as well as evaluation of the sense of smell (olfactory function testing). Analysis of the olfactory bulbs by MRI can be useful, especially in young children. Genetic testing can also be used to diagnose the condition by identifying a disease-causing mutation in one of the genes responsible for Kallmann syndrome.

Your doctor will usually begin with a physical exam and with questions about any symptoms you may have noticed, especially those having to do with delayed puberty and impairments to the sense of smell. Because this is an inherited condition, the doctor may also ask about relatives who have experienced delayed puberty or problems with fertility.

If signs indicate the possibility of Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism, additional tests may include:

• Blood tests looking specifically at hormone levels in the peripheral veins that originate from the pituitary gland
• Magnetic resonance imaging (MRI) of the hypothalamus, pituitary gland and nose to look for anatomical abnormalities
• Molecular genetic testing to look for specific gene mutations

Kallmann syndrome life expectancy

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism survive long term if they do not have associated conditions such as congenital heart disease or neurologic manifestations.

Adrenocortical insufficiency is fatal unless recognized and treated. Thyroid function must also be assessed. In patients who do not receive adequate gonadal steroid replacement, hypogonadal osteoporosis may develop insidiously.

Kallmann syndrome treatment

The standard forms of medical treatment involve hormone replacement therapies and this is usually tailored the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining normal hormonal levels. Subsequently, treatment may also be need for inducing fertility for achieving pregnancy.

In males, puberty is usually initiated using testosterone therapy and various formulations of testosterone are currently available for this purpose. The most commonly used modes of treatment include testosterone injections given intramuscularly every 2 or 3 weeks depending on the particular injection) or topical testosterone formulations (patches, gels, liquids etc). Once puberty is initiated, testosterone therapy is continued to maintain secondary sex characteristics as well as to normalize biochemical testosterone levels in the blood. When fertility is desired, gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) can be administered to stimulate testicular growth and initiate sperm production (spermatogenesis). Typically, sperm is rarely seen in the semen analysis until testicular volume reaches at least 8 mL. In most isolated GnRH deficiency individuals without a history of cryptorchidism (undescended testes), sperm function is usually normal and conception can occur even with relatively low sperm counts.

In females, estrogen and progestin therapy is used to induce the secondary sex characteristics, whereas gonadotropins or pulsatile GnRH therapy can be utilized to stimulate production of mature egg cells (folliculogenesis). If spontaneous pregnancy fails to occur despite normal folliculogenesis, in vitro fertilization may be considered with conception rates reported to be approximately 30% per ovulatory cycle.

In addition to treating hypogonadism, potential deterioration in bone health that may have resulted from periods of low circulating sex hormones should be addressed. Depending on the history (the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors [e.g., glucocorticoid excess, smoking) and bone mineral density measurement, measurement, specific treatment for decreased bone mass should be considered.

Finally, it is really important to be reminded that since ~10-15 % of male patients studied in a referral isolated GnRH deficiency clinical center have been noted to have reversal of their hypogonadism, isolated GnRH deficiency patients must be evaluated serially for evidence of this reversibility. Features indicative of reversal include: testicular volume growth despite being on testosterone therapy and normalization of testosterone levels without adequate hormone replacement.

Follow-up care

When medication is needed to supplement hormone production, periodic follow-up tests are needed to ensure that the treatment continues to work effectively. Dosage levels and the combination of medications may need to be adjusted over time.