Kallmann Syndrome



  • Kallmann syndrome (KS) is hypogonadotropic hypogonadism caused by deficient gonadotropin-releasing hormone (GnRH).
  • Patients present with incomplete or absent puberty, infertility, and anosmia.
  • Both familial and sporadic forms, with a range of genetic defects reflected in various modes of inheritance that display some phenotypic variability
  • It is distinct from other forms of idiopathic hypogonadotropic hypogonadism, which have a different pathogenesis and do not present with anosmia.



  • Prevalent sex: male > female (4:1)
  • Overall incidence varies from 1:10,000 to 1:86,000.
  • Men: 10/100,000 per year; women: 2/100,000 per year

Etiology and Pathophysiology

In the developing embryo, the olfactory placodes represent ectodermal tissue that will develop to produce certain distinct types of neuronal tissue, including both olfactory neurons and GnRH-secreting neurons. During the 6th embryonic week of development, certain accessory neurons from the olfactory placode will migrate to the forebrain, induce the development of olfactory bulbs, and help guide the GnRH-secreting neurons to the medial hypothalamus. KS results from a disruption of this process, leading to a poorly developed olfactory system, an absence of GnRH-secreting neurons in the hypothalamus, and loss of FSH and LH production.


  • Most cases due to sporadic mutations
  • Genes involved: KAL1, FGFR1, CHD7, FGF8, PROKR2, and PROK2 (1)[C]
  • 25–30% of cases due to known forms of familial inheritance are as follows:
    • X-linked recessive form: 14% of inherited cases
      • Mutation in KAL1 gene (Xp 22.3) that codes for anosmin-1, an extracellular matrix protein that functions like an adhesion molecule
      • Unique phenotypic findings: synkinesia (up to 80% of patients), renal agenesis (up to 30% of patients)
      • Female carriers are phenotypically normal.
      • Sensorineural hearing loss
    • Autosomal dominant form: ~10% of inherited cases
      • Mutation in FGFR1 gene (short arm chromosome 8) that codes for receptor protein
      • Unique phenotypic findings: cleft palate or high-arched palate (up to 30% of patients)

Risk Factors

  • Family history is a significant risk factor.
  • No identified risk factors for the sporadic form of this syndrome

Commonly Associated Conditions

Genetic overlap between KS and other midline defects include, but are not limited to, septo-optic dysplasia and holoprosencephaly (2)[C].

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