Kallmann Syndrome

Kallmann syndrome (KS), also called olfacto-genital syndrome, is a genetic condition that causes hypogonadotropic hypogonadism due to decreased secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus. Both sexes can be affected, although the incidence is much higher in males. The lack of sex hormones results in impaired pubertal development. Characteristically, there is an associated absence or decreased sense of smell (hyposmia or anosmia), which helps differentiate KS from other conditions. The diagnosis is made by hormone levels in blood and brain imaging showing the absence of olfactory structures. Genetic testing may assist in establishing a definite diagnosis. Treatment consists of hormone replacement therapy.

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  • Incidence: males >> females (4:1):
    • Males: 1 in 30,000
    • Females: 1 in 120,000


  • More than 20 genes have been identified as associated with the development of Kallman syndrome (KS):
    • Most common genes affected are ANOS1, FGFR1, FGF8, CHD7, PROK2, and PROKR2.
    • Only in 30% of cases does genetic testing reveal a mutation in 1 of the known genes.
  • Inheritance pattern and penetrance varies: 
    • Depends on the gene mutation involved
    • May be X-linked recessive, autosomal dominant, or autosomal recessive
    • 10%–14% of cases due to ANOS1 mutation: 
      • X-linked recessive inheritance 
      • Most severe form of KS


The genes listed above are involved in the migration of olfactory neurons and neurons involved in gonadotropin-releasing hormone (GnRH) production to their proper functional place in the brain during development.

  • Olfactory neuron migration to the olfactory bulb is needed for the sense of smell.
  • GnRH neuron migration to the hypothalamus is necessary for proper hormone release:
    • GnRH controls the production of sex hormones needed for sexual development. 
    • Essential for the normal functioning of testes and ovaries
  • Mutations in the genes listed above → defective migration of GnRH-releasing neurons and olfactory neurons → ↓ synthesis of GnRH in the hypothalamus and failure of olfactory bulb development → ↓ sex hormone production and hyposmia or anosmia (decreased/absent sense of smell)

Clinical Presentation

The clinical presentation is highly variable due to the different gene mutations and penetrance levels. However, all individuals with KS show abnormal sexual development and hyposmia or anosmia.

Sexual development and fertility

  • Delayed or absent onset of sexual development and maturation
  • Lack of a pubertal growth spurt 
  • Infertility
  • Decreased libido
  • Male patients: small or undescended testes, micropenis, absent facial and body hair growth, and no deepening of the voice in puberty
  • Female patients: absent breast development, absent axillary hair, and primary amenorrhea
  • Pubic hair can be normal in both sexes because pubic hair is controlled by androgens from the adrenal gland.

Other congenital anomalies

  • Hyposmia or anosmia (reduced or absent sense of smell)
  • Cleft lip and/or cleft palate
  • Hearing loss
  • Syndactyly (webbing or fusion of toes and fingers)
  • Unilateral renal agenesis (missing kidney)
  • Dental agenesis
  • Bimanual synkinesis (the contralateral hand involuntarily mirrors the movement of the other)

Associated conditions

  • Sleep disorders
  • Eating disorders
  • Osteoporosis in adulthood


  • History and clinical examination
  • Labs (serum):
    • ↓ GnRH levels
    • ↓ Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels
    • ↓ Testosterone levels in males
    • ↓ Estradiol levels in females
  • Genetic testing of known genes 
  • Imaging: Brain magnetic resonance imaging (MRI) shows normal hypothalamus and pituitary glands, but the absence of an olfactory bulb.
Brain MRI findings in Kallmann syndrome

Brain MRI findings in KS
Magnetic resonance imaging (MRI) of 3 male patients with KS (b)-(d). Image (a) shows normal structures in a healthy control. The red arrows indicate olfactory bulbs. Images (b), (c), and (d) show the lack of the bilateral olfactory bulb, the olfactory tract, and the sulcus (squares), respectively.

Image: “Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate” by Xu H, Niu Y, Wang T, Liu S, Xu H, Wang S, Liu J, Ye Z – BioMed research international (2015). License: CC BY 3.0.


  • Hormone replacement therapy: 
    • Needed to initiate sexual development in puberty with lifelong maintenance required for most 
    • Men: testosterone intramuscularly (IM) or topically:
      • Oral testosterone should be avoided due to possible hepatotoxicity.
      • Approximately 10% of men may eventually be able to discontinue therapy and have adequate gonadal function.
    • Women: estrogen therapy initially, with later addition of progestin to prevent endometrial hyperplasia
    • Fertility treatment if desired
  • Bone scan to monitor for signs of osteoporosis
  • Renal ultrasound or computed tomography (CT) scan to evaluate for kidney anomalies
  • Auditory exam to screen for hearing loss

Differential Diagnosis

  • Normosmic idiopathic hypogonadotropic hypogonadism (normosmic IHH): genetic condition that causes hypogonadotropic hypogonadism due to isolated GnRH deficiency. Males and females are affected. Puberty is delayed in both sexes due to the lack of sex hormones. In contrast to KS, patients with normosmic IHH have a normal sense of smell and non-reproductive anomalies are typically absent. Genetic testing confirms the diagnosis. Treatment consists of hormone replacement therapy.
  • Klinefelter syndrome: a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype (47,XXY). Klinefelter syndrome is associated with hypergonadotropic hypogonadism and is the most common cause of congenital hypogonadism. Individuals present as tall, phenotypic men, with small testes, decreased body hair, gynecomastia, and infertility. Luteinizing hormone (LH) and FSH levels are elevated in Klinefelter syndrome. Genetic testing confirms diagnosis. Treatment consists of lifelong testosterone replacement therapy. 
  • Prader-Willi syndrome (PWS): a genetic condition due to idiopathic loss of function in certain genes. Hypogonadism and delayed puberty are seen. Individuals present with hypotonia and feeding difficulties as neonates and chronic overeating and obesity in childhood. Individuals with PWS may also have cognitive disabilities. Olfaction is not affected. Genetic testing helps in diagnosis. Hormone replacement is a part of management but other treatments are available based on symptoms, as well. 
  • Constitutional delay of growth and puberty (CDGP): not a disorder but a variant of normal growth. Constitutional delay of growth and puberty is the most common cause of delayed puberty and short stature. Both adrenal function and gonadal function are delayed, usually leading to the absence of pubic hair. The physical development of individuals with CDGP often catches up in later years. 


  1. Pitteloud, N., Crowley Jr, W.F., & Balasubramanian, R. (2019). Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism). UpToDate. Retrieved December 17, 2020, from https://www.uptodate.com/contents/isolated-gonadotropin-releasing-hormone-deficiency-idiopathic-hypogonadotropic-hypogonadism?sectionName=GENETICS&topicRef=5814&anchor=H372819954&source=see_link#H2
  2. MedlinePlus Genetics. (2020). Kallman syndrome. MedlinePlus. https://medlineplus.gov/genetics/condition/kallmann-syndrome/
  3. Grumbach MM. (2005). A window of opportunity: The diagnosis of gonadotropin deficiency in the male infant. The Journal of clinical endocrinology and metabolism. 90(5),3122–7.
  4. Chelaghma, N., Rajkanna, J., Trotman, J., Fuller, G., Elsey, T., Park, S. M., & Oyibo, S. O. (2018). Normosmic idiopathic hypogonadotrophic hypogonadism due to a rare KISS1R gene mutation. Endocrinology, diabetes & metabolism case reports, 2018(1). https://doi.org/10.1530/EDM-18-0028

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