Definition

Kallmann syndrome is a rare genetic disorder characterized by delayed or absent puberty and an impaired sense of smell. This syndrome occurs when the body does not produce enough gonadotropin-releasing hormone (GnRH). It is a form of hypogonadotropic hypogonadism, a condition resulting from insufficient GnRH production necessary for sexual development. Normally, this hormone is produced in the brain and is called the hypothalamus.

The function of GnRH is to stimulate the testes in males and the ovaries in females, enabling them to produce sex hormones. In addition, there is a disruption in the development of specific nerves in the brain that signal the hypothalamus. Without these nerves, the hypothalamus cannot stimulate the pituitary gland, which also produces and releases sex hormones.

In Kallmann syndrome, the hypothalamus fails to produce the necessary surge of GnRH during fetal development, infancy, and puberty. This surge triggers the release of male and female sex hormones from the testes and ovaries, leading to the development of sperm and eggs. Without adequate hormone production, a child will not enter puberty and may experience fertility issues. Later in life, special treatments may be necessary for those who wish to have children.

Patients also have an impaired sense of smell, ranging from reduced ability (hyposmia) to complete absence (anosmia). The olfactory nerves fail to develop properly during fetal development. Many patients are unaware of their inability to detect odors until the issue is discovered during a medical examination. However, some patients with hormonal abnormalities like Kallmann syndrome have normal olfactory function, a condition known as normosmic idiopathic hypogonadotropic hypogonadism (nIHHH).

Causes

Kallmann syndrome is a genetic condition caused by mutations in various genes. These genetic changes prevent the genes from functioning correctly. While not all mutations that cause Kallmann syndrome have been identified, researchers have found several genes and their inheritance patterns within families.

Mutations in more than 20 genes have been associated with Kallmann syndrome. The most commonly mutated genes include ANOS1, CHD7, FGF8, FGFR1, PROK2, and PROKR2. Patients may sometimes have mutations in more than one of these genes.

• Autosomal Recessive

Some gene mutations must be inherited from both parents (autosomal recessive). Both parents are carriers of the mutated gene but do not exhibit disease symptoms in this type.

• Autosomal Dominant

In this condition, only one parent, the mother or father, passes the mutated gene to the child.

• X-linked

In this condition, females are carriers of the mutated gene, and males manifest the disease. The mutated gene can be passed from mother to son. Either parent can pass the mutation to a daughter, who will be a carrier, and her sons may develop Kallmann syndrome.

Risk Factor

Kallmann syndrome is a congenital disorder more common in males than females, with an estimated incidence of 1 in 30,000 males and 1 in 120,000 females. A person is more likely to develop this syndrome if one or both parents are carriers of the mutated gene.

Symptoms

The primary symptom of Kallmann syndrome is delayed or absent puberty. Puberty issues occur alongside olfactory disturbances, a condition present from birth but often unnoticed until puberty is delayed.

Various signs and symptoms in children and adolescents with Kallmann syndrome include:

• Undescended or partially descended testicles (cryptorchidism)
• Small penis size (micropenis)
• Lack of facial hair growth and voice changes in males
• Menstrual irregularities and underdeveloped breasts in females
• Low sex drive in males
• Absence of growth spurts (periods of rapid height and weight gain)
• Facial abnormalities such as cleft lip or palate
• Hearing impairment
• Color blindness
• Abnormal eye movements
• Abnormal dental development
• Unilateral renal agenesis (failure of one kidney to develop)
• Shortened bones in fingers or toes
• Short stature in some cases
• Impaired sense of smell (hyposmia/anosmia)
• Low energy or weakness
• Mood changes
• Poor balance
• Scoliosis (curved spine)
• Bimanual synkinesis (mirrored hand movements, making activities requiring different hand movements difficult)

Diagnosis

Diagnosis typically begins with a medical interview with the parents or caregivers. Parents often notice their child has not entered puberty and consult a doctor. After asking about puberty and olfactory issues, symptoms observed by the child and parents, and the child's and family's medical history, the doctor will perform a physical examination.

The physical examination will relate to delayed puberty and olfactory disturbances. If signs indicate possible Kallmann syndrome, additional tests may include:

• Blood tests to evaluate hormone levels from the pituitary gland
• Olfactory function tests to assess the child's sense of smell
• MRI scans to visualize the hypothalamus, pituitary gland, and nasal structures for any abnormalities
• Genetic testing to identify specific genetic mutations

Management

Treatment for Kallmann syndrome involves hormone replacement therapy, with specific medications and dosages tailored to each patient's needs. The initial focus of treatment is to induce puberty and normalize hormone levels. Subsequent therapy may aim to induce fertility. Other medications can help maintain bone health, as hormone deficiencies affect bone density and strength. Patients and families receive counseling on fertility issues.

Hormone replacement therapy options depend on the patient's specific issues and may include:

• Testosterone injections, skin patches, or gels for males
• Estrogen and progesterone pills or skin patches for females
• GnRH injections

Complications

Various congenital heart defects have been reported in some children with Kallmann syndrome, along with bone thinning or osteoporosis. Skeletal development abnormalities may also occur and can be present at birth. Fertility issues are another complication, and without treatment, patients may become infertile. Hearing loss can also occur as a complication of the syndrome.

Prevention

There is no way to prevent Kallmann syndrome if you carry the genetic mutation. However, you can consider genetic screening before starting a family if you or your partner has a family history of genetic disorders. In some cases, doctors may recommend prenatal testing to determine if the fetus is at risk of congenital disorders.

When to See a Doctor?

If your child has not shown signs of puberty while peers have begun, it is advisable to consult a doctor. The doctor can conduct necessary tests and discuss treatment options with you.

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