Kallmann syndrome; hypogonadotropic hypogonadism & anosmia

Epidemiology

• occurs in males
• often familial

Pathology

• absence of GnRH-producing cells in the hypothalamus
• developmental abnormality of the olfactory placode
• GnRH cells that arise in the olfactory placode fail to migrate to the hypothalamus
• impaired axonal extension of olfactory neurons towards the forebrain
• absence or hypoplasia of the olfactory bulbs & tracts
• in some cases, midline cranial anomalies (cleft lip/palate & imperfect fusion) are present & anosmia may be absent or inconspicuous
• renal agenesis, selective tooth agenesis, & bimanual synkinesis in some cases (not type 3)

Genetics

• associated with defects in KAL1 gene (type 1)
• associated with defects in FGFR1 (type 2)
• associated with defects in PROKR2 (type 3)
• associated with defects in PROK2 (type 4)
• associated with defects in CHD7 (type 5)
• associated with defects in FGF8 (type 6)

Clinical manifestations

• sexual infantilism
• testes are prepubertal
• anosmia or hyposmia (80%)
• midline defects that may be present
  • cleft lip or palate
  • color blindness
  • cryptorchidism
  • skeletal abnormalities

Laboratory

• decreased serum LH & FSH
  • other pituitary hormones are normal
• decreased serum testosterone

Radiology

• magnetic resonance imaging (MRI) of the head is normal

Management

• androgen replacement
• GnRH or gonadotropin therapy
  • necessary for restoration of fertility
  • patients may be unresponsive to 1st single dose of GnRH, but repeated stimulation leads to normal LH & FSH response

More general terms

• genetic syndrome (multisystem disorder)
• developmental disorder syndrome (multisystem disorder)

Additional terms

• anosmia
• Anosmin-1; kallmann syndrome protein; Adhesion molecule-like X-linked (KAL1, ADMLX, KAL, KALIG1)

Database

• OMIM: https://mirror.omim.org/entry/147950
• OMIM: https://mirror.omim.org/entry/308700
• OMIM: https://mirror.omim.org/entry/244200
• OMIM: https://mirror.omim.org/entry/308750
• OMIM: https://mirror.omim.org/entry/612370
• OMIM: https://mirror.omim.org/entry/612702