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20. What are the genes implicated in the development and migration of both olfac-
    tory and GnRH neurons?
    The genes responsible for the development and migration of olfactory and
    GnRH neurons include KAL1, FGF8, FGFR1, PROK2, PROKR2, NELF,
    CHD7, HS6ST1, WDR11, and SEMA3A.


21. What are the genes implicated only in GnRH secretion?

The genes implicated in GnRH secretion include LEP, LEPR, KISS1/KISS1R,

TAC3, TACR3, and PCSK1. Therefore, inactivating mutations of these genes

results in congenital isolated hypogonadotropic hypogonadism (normosmic).

22. What is anosmin?

Anosmin is a 680-amino-acid protein which is coded by KAL1 gene present on

short arm of X chromosome. Anosmin is involved in growth, development, prolif-

eration, and migration of olfactory and GnRH neurons to their appropriate

destination.

23. Why is anosmia associated with Kallmann syndrome?

During embryogenesis, olfactory neurons and GnRH neurons share a common

origin at olfactory placode. These neuronal fibers migrate together through

cribriform plate to the olfactory bulb where olfactory fibers terminate, while

GnRH neurons continue to migrate to the arcuate nucleus of hypothalamus.

Congenital isolated hypogonadotropic hypogonadism

Anosmia/Hyposmia

Genetic evaluation

Mutation

present

No mutation

identified

• KAL 1 Idiopathic


• FGFR 1


• FGF 8


• PROK 2


• PROKR2


• CHD 7


• NELF

Kallmann syndrome Normosmic Hypo-Hypo

• FGFR 1


• FGF8


• PROK2


• PROKR2


• CHD7


• NELF
  
  
  • Lep
  
  
  • LepR
  
  
  • KISSR
  
  
  • TAC3
  
  
  • TACR3
  
  
  • GnRHR
  
  
  
  

Idiopathic

No mutation

identified

Mutation

in GnRH

secretion/action

Mutation in genes

involved in

development &

migration of GnRH &

olfactory neurons

Genetic evaluation

Normosmia

Fig. 7.6 Etiology of congenital isolated hypogonadotropic hypogonadism

7 Delayed Puberty