What are the other Names for this Condition? (Also known as/Synonyms)

• Anosmic Idiopathic Hypogonadotropic Hypogonadism
• Hypogonadotropic Hypogonadism-Anosmia Syndrome
• Olfacto-Genital Pathological Sequence

What is Kallmann Syndrome? (Definition/Background Information)

• Kallmann Syndrome (KS) is a condition that causes hypogonadotropic hypogonadism (HH) and an impaired sense of smell. HH affects the production of the hormones needed for sexual development. It is present from birth and is due to deficiency of gonadotropin-releasing hormone (GnRH)
• Kallmann Syndrome is often diagnosed at puberty due to lack of sexual development. It 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

(Source: Kallmann Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Kallmann Syndrome? (Age and Sex Distribution)

• Kallmann Syndrome is a rare, congenital disorder. The presentation of symptoms may occur in childhood or adolescence
• Both males and females may be affected. However, the condition is 5 times more frequent in men (1:8,000) than women (1:40,000)
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Kallmann Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Kallmann Syndrome is an inherited condition
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Kallmann Syndrome? (Etiology)

• In most cases, Kallmann Syndrome develops sporadically during embryonic development
• In some cases, however, the condition may be caused by mutations in KAL1, FGFR1, PROKR2, CHD7 or FGF8 genes, and can be inherited
• KAL1 gene mutations causing Kallmann Syndrome 1 are inherited in an X-linked recessive manner
• Mutations in FGFR1, PROKR2, PROK2, CHD7 or FGF8 genes (causing Kallmann Syndrome types 2, 3, 4, 5 and 6, respectively) are typically inherited in an autosomal dominant manner
• PROKR2 and PROK2 can also be inherited in an autosomal recessive manner

Autosomal recessive mode of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

Autosomal dominant pattern of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

X-linked recessive mode of inheritance: The gene associated with this condition 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 occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

What are the Signs and Symptoms of Kallmann Syndrome?

The signs and symptoms of Kallmann Syndrome may be reproductive and/or non-reproductive.

Reproductive signs and symptoms of Kallmann Syndrome in males:

• Undescended testes 
• Smaller than average penis
• No facial or body hair
• Decreased growth of pubic hair and genitals. 
• 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.

Reproductive signs and symptoms of Kallmann Syndrome in females:

• Absent breast development
• An attenuated growth spurt
• Decreased pubic hair growth
• 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

Some people with KS have any of various non-reproductive features. These may include:

• Cleft lip and palate
• Renal agenesis (one kidney does not develop)
• Hearing impairment
• Dental abnormalities
• Eye movement abnormalities
• Poor balance
• Scoliosis (curvature of the spine)
• Synkinesis of the hands, in which the movements of one hand are mirrored by the other hand

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of the cases:

• Anosmia
• Anterior hypopituitarism 
• Decreased fertility
• Decreased testicular size
• Delayed puberty
• Erectile abnormalities
• Hypogonadotrophic hypogonadism 
• Hyposmia 
• Hypothalamic gonadotropin-releasing hormone deficiency 
• Micropenis

Frequently present symptoms in 30-79% of the cases:

• Abnormality of the voice
• Breast hypoplasia
• Cryptorchidism

Occasionally present symptoms in 5-29% of the cases:

• Abnormality of cardiovascular system morphology 
• Abnormality of color vision
• Ataxia 
• Bimanual synkinesia
• Cleft palate 
• Delayed skeletal maturation
• Dysarthria
• Dyspareunia
• Facial asymmetry
• Gait disturbance
• Gynecomastia 
• Ichthyosis 
• Muscle weakness
• Muscular hypotonia 
• Nystagmus
• Obesity
• Paraplegia
• Pes cavus 
• Pes planus           
• Primary amenorrhea 
• Ptosis
• Recurrent fractures
• Reduced number of teeth
• Renal agenesis
• Seizures
• Sensorineural hearing impairment 
• Skeletal dysplasia
• Tremor 
• Visual impairment

Additional signs and symptoms of Kallmann Syndrome may include:

• Azoospermia
• Eunuchoid habitus 
• High palate
• Leydig cell insensitivity to gonadotropin 
• Olfactory lobe agenesis

(Source: Kallmann Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Kallmann Syndrome Diagnosed?

The diagnosis of Kallmann Syndrome is made based on information from the following:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• The Tanner staging method is an established standard endocrinological method for evaluation of sexual maturity (both primary and secondary sexual development)
• Olfactory function testing
• Laboratory tests
• Imaging studies, which may include MRI of the olfactory bulbs
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Kallmann Syndrome?

The complications of Kallmann Syndrome may include:

• Without treatment, low sex drive and infertility in males
• Without treatment, lack or cessation of menses in females
• Deafness
• Breathing problems and abnormal heart function, if scoliosis is present

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Kallmann Syndrome Treated?

Kallmann Syndrome is generally treated by supplementation of hormones to aid in pubertal development and to improve fertility.

Treatment for Kallmann Syndrome in males:

• Testosterone esters
• Human chorionic gonadotropin injections with or without follicle stimulating hormone

Treatment for Kallmann Syndrome in females:

• Estrogen therapy
• Progestin therapy
• Pulsatile gonadotropin-releasing hormone (GnRH) treatment

How can Kallmann Syndrome be Prevented?

Currently, Kallmann Syndrome may not be preventable, since it is a congenital or genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy, if the condition runs in the family
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Kallmann Syndrome? (Outcomes/Resolutions)

• The prognosis of Kallmann Syndrome is good, since it is not a life-threatening condition
• Most affected individuals are able to achieve fertility
• However, males with cryptorchidism have a poor outcome in terms of achieving normal sexual performance and fertility

Additional and Relevant Useful Information for Kallmann Syndrome:

• Kallmann Syndrome was formerly referred to as Dysplasia Olfactogenitalis of De Morsier

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/