OVERVIEW

What is Kallmann Syndrome?

Kallmann Syndrome was first reported by American scholar Kallmann in 1944 and has since been named after him.

The main characteristic is that due to abnormalities during congenital development, the "upstream commanders" (pituitary and hypothalamus) of the gonads (testes or ovaries) are dysfunctional, leading to a lack of "incentives" for the gonads—deficiency in gonadotropin-releasing hormone and gonadotropins. This results in secondary hypogonadism and congenital anosmia or hyposmia, hence it is also called congenital hypogonadotropic hypogonadism with anosmia.

Most male patients often seek medical attention for cryptorchidism or micropenis, while female patients typically do so for underdeveloped breasts or primary amenorrhea. Symptoms of hyposmia or anosmia are usually discovered through further medical history inquiries and related olfactory function tests.

Is Kallmann Syndrome Common?

Kallmann Syndrome is more prevalent in males, with a significantly higher incidence rate than in females. The male prevalence is about 1 in 8,000, while the female prevalence is about 1 in 40,000, resulting in a male-to-female ratio of 5:1.

SYMPTOMS

What are the common manifestations of Kallmann syndrome?

• Hypogonadism:

• Male patients exhibit a small penis, small testicular volume (less than 4 mL), absence of spermatogenesis or cryptorchidism, lack of secondary sexual characteristics during puberty, minimal or no facial and body hair growth, absence of significant muscle development, and no deepening of the voice.

• Female patients present with primary amenorrhea, underdeveloped breasts, absence of axillary hair, and immature internal and external genitalia. However, both sexes may develop some pubic hair due to typically normal adrenarche (the adrenal glands produce small amounts of androgens and estrogens).

• Anosmia or hyposmia.

• Delayed bone age: Due to sex hormone deficiency, delayed epiphyseal closure results in a tall, slender stature, with an arm span exceeding height by more than 5 cm (this sign indicates delayed long bone epiphyseal closure caused by hypogonadism during puberty).
  May be accompanied by midline cranial abnormalities (cleft lip, cleft palate, and incomplete fusion), dental agenesis (tooth hypoplasia), vision problems (color blindness or optic atrophy), hearing abnormalities (sensorineural deafness), mirror movements (synkinesis), unilateral renal dysplasia, musculoskeletal deformities, abnormal eye movements, or cardiac defects.

What are the common manifestations of Kallmann syndrome in newborns?

• Male infants may present with a small penis and/or cryptorchidism.

• Female newborns lack obvious abnormalities that provide diagnostic clues.

What are the common manifestations of Kallmann syndrome in children?

Some pediatric patients may exhibit hyposmia or anosmia, or have congenital anomalies such as cleft lip/palate or syndactyly.

What are the common manifestations of Kallmann syndrome during puberty?

Male and female patients show varying degrees of delayed sexual maturation and growth spurts (commonly referred to as "shooting up" in height).

What are the common manifestations of Kallmann syndrome in adult patients?

Some patients may experience entirely normal puberty but develop hypogonadotropic hypogonadism later in adulthood, leading to sexual dysfunction and infertility.

CAUSES

What is the cause of Kallmann syndrome?

For the human body, the secretion of gonadotropins (primarily follicle-stimulating hormone and luteinizing hormone) by the pituitary gland is a crucial foundation and prerequisite for the reproductive function and sexual development of the gonads (testes in males, ovaries in females).

However, the secretion of pituitary gonadotropins relies on gonadotropin-releasing hormone (GnRH) produced by the hypothalamus as a necessary condition.

To use an analogy, the hypothalamus acts as the top leader, the pituitary as the middle management, and the gonads as the lower-level workers: without instructions from the top leader, middle management lacks incentives, and the workers lose motivation, leading to inactivity.

In this scenario, none of the levels fulfill their respective responsibilities, and the core of the disease lies in the problem with the "top leader."

Hypothalamic GnRH primarily originates from the nasal region and is closely linked to the olfactory system during embryonic development.

The main pathogenesis of Kallmann syndrome may involve gene mutations affecting the migration of hypothalamic GnRH neurons and the formation of the olfactory bulb and tract, leading to defective GnRH secretion and olfactory nerve atrophy, resulting in Kallmann syndrome.

In summary, Kallmann syndrome is caused by gene mutations and is essentially a genetic disorder.

Who is commonly affected by Kallmann syndrome?

Kallmann syndrome is more prevalent in males, with a significantly higher incidence rate than in females, at a ratio of 5:1.

Is Kallmann syndrome contagious?

Kallmann syndrome is not contagious; it is a congenital genetic disorder.

Is Kallmann syndrome hereditary?

Kallmann syndrome is hereditary, with 1/3 of cases being familial inheritance and 2/3 being sporadic occurrences. It follows three inheritance patterns: X-linked recessive, autosomal dominant, and autosomal recessive.

DIAGNOSIS

How is Kallmann Syndrome Diagnosed?

When diagnosing Kallmann syndrome, doctors rely on clinical manifestations, physical characteristics, hormone tests, genetic testing, and MRI of the hypothalamic-pituitary region. The diagnosis requires meeting the following criteria:

• Males: Bone age >12 years or biological age ≥18 years without the development of secondary sexual characteristics and testicular enlargement, with low testosterone levels ≤3.47 nmol/L (100 ng/dL) and low or "normal" gonadotropin (FSH and LH) levels.

• Females: No development of secondary sexual characteristics or onset of menstruation by age 14, with low estradiol levels and low or "normal" gonadotropin (FSH and LH) levels.

If the above conditions are present and no clear underlying cause is identified, Kallmann syndrome should be considered.

The diagnosis requires ruling out other conditions that cause low gonadotropin levels, such as pituitary hypoplasia or chromosomal abnormalities.

If thyroid axis function, adrenal axis function, growth hormone axis function, and prolactin levels are normal, MRI of the sella turcica shows no hypothalamic or pituitary structural abnormalities, and karyotype analysis is normal, conditions like hypopituitarism, pituitary hypoplasia, or chromosomal abnormalities can be excluded. Combined with underdeveloped or absent olfactory bulbs and tracts, a clinical diagnosis of Kallmann syndrome can be made.

If there are no olfactory issues, normosmic idiopathic hypogonadotropic hypogonadism (nIHH) should be considered.

What Tests Are Needed for Kallmann Syndrome?

Generally, the following tests are required: hormone testing, human chorionic gonadotropin (hCG) stimulation test, gonadotropin-releasing hormone (GnRH) stimulation test, semen analysis, karyotype analysis, olfactory function testing, imaging studies, and genetic testing.

• Hormone testing: Low levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and estradiol.

• hCG stimulation test: Shows a significant increase in testosterone or estradiol levels.

• GnRH stimulation test: Reveals delayed LH secretion and absent LH pulses, indicating hypothalamic dysfunction.

• Semen analysis in male patients: Azoospermia (no sperm).

• Karyotype analysis: Normal.

• Imaging studies: Delayed bone age and underdeveloped or absent olfactory bulbs and sulci on brain MRI.

• Olfactory function testing: Absent or reduced function.

• Genetic testing: May identify pathogenic mutations.

Which Conditions Can Kallmann Syndrome Be Confused With?

Due to overlapping symptoms and test results, Kallmann syndrome may be confused with delayed puberty or secondary hypogonadism.

• Delayed puberty: A family history, anosmia/hyposmia, and/or associated congenital anomalies (e.g., cleft lip/palate, syndactyly) suggest Kallmann syndrome. Genetic testing can help differentiate the two.

• Secondary hypogonadism: For Kallmann syndrome presenting after puberty, differentiation from secondary hypogonadism is necessary.
  Neurological symptoms (e.g., headaches, visual disturbances), deficiencies in other pituitary hormones (e.g., TSH, ACTH), or imaging findings of pituitary/brain lesions support secondary hypogonadism. Genetic testing can also aid in differentiation.

TREATMENT

Which department should I visit for Kallmann syndrome?

Endocrinology.

Can Kallmann syndrome resolve on its own?

Kallmann syndrome cannot resolve on its own. Most patients require lifelong treatment. Currently, a small number of male patients have reportedly experienced reversal of the condition after treatment, meaning they can produce normal testosterone levels without continued therapy.

How is Kallmann syndrome treated?

Treatment options for Kallmann syndrome primarily include sex hormones (androgens, estrogens), human gonadotropins, and gonadotropin-releasing hormone (GnRH).

The goals of treatment are to promote secondary sexual characteristics, establish and maintain normal bone and muscle growth, and restore fertility. There is no effective treatment for anosmia (loss of smell).

Current common treatment approaches:

• Sex hormone replacement therapy:

• For prepubertal females, exogenous estrogen is used to initiate secondary sexual development.
  Initial treatment involves estrogen alone to maximize breast development and promote uterine and endometrial growth. Progesterone (e.g., progesterone) is eventually added to prevent endometrial hyperplasia.
  However, progesterone should not be added too early before complete breast development to avoid underdeveloped breasts.

• The timing of estrogen use should be determined by a doctor. Starting estrogen too early may lead to premature epiphyseal closure (resulting in short stature) or irregular menstrual bleeding.

• For adolescent males, the primary goal is secondary sexual development, which can be achieved with testosterone therapy.

• Human gonadotropin and GnRH therapy:

• This treatment aims to restore fertility and induce ovulation in females. It is an effective alternative, with exogenous GnRH pulsatile administration yielding the best results.

• To induce normal spermatogenesis in males, three methods are available: human chorionic gonadotropin (hCG) therapy, combined hCG and human menopausal gonadotropin (HMG) therapy, and GnRH pulsatile therapy.

• Specific medication protocols should follow the treating physician's guidance.

Can Kallmann syndrome be completely cured? How long does treatment take?

Current data indicate that a small number of male patients may experience reversal of the condition after treatment, meaning they can produce normal testosterone levels without continued therapy. However, most patients do not achieve reversal and require lifelong treatment, as the condition cannot be completely cured.

DIET & LIFESTYLE

Does Kallmann Syndrome Affect Fertility?

Without treatment, Kallmann syndrome prevents fertility. Through ovulation induction and spermatogenesis therapy, approximately 95% of patients successfully achieve ovulation and sperm production, significantly improving fertility success rates.

PREVENTION

Can Kallmann Syndrome Be Prevented?

For those with a family history of Kallmann syndrome, genetic counseling before pregnancy may help reduce the risk of the disease.

How Can Kallmann Syndrome Patients Prevent Other Diseases?

Early diagnosis and proper treatment of Kallmann syndrome are crucial for improving prognosis and preventing complications:

• Treatment before puberty in male patients can promote the development of secondary sexual characteristics, increase testicular volume, and enable sperm production.

• For female patients, it can induce ovulation and achieve pregnancy. Treatment after puberty is less effective, and the later it starts, the poorer the results.