What is Kallmann syndrome?

Kallmann syndrome combines an impaired sense of smell with a hormonal disorder that delays or prevents puberty.

The hormonal disorder 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 of certain hormones 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 syndrome. 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.

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 (nIHH).

Causes of Kallmann syndrome

Kallmann syndrome and nIHH 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 nIHH 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 nIHH.

Signs and symptoms of Kallmann syndrome

The main symptom of Kallmann syndrome or nIHH 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.

Other characteristics may also be present in children and adolescents with Kallmann syndrome or nIHH. 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

Testing and diagnosis of 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 nIHH, 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