Sex Development & Maturation

Kallmann syndrome and other CHH syndromes

The first mention of the condition came in 1856 when a paper was published by Aureliano Maestre de San Juan highlighted an autopsy report on a patient with undeveloped sex organs and absent olfactory lobes (the part of the brain concerned with sense of smell). In Spanish speaking parts of the world the condition is still called after him.

Kallmann syndrome was first introduced in a paper published in 1944 by Franz Josef Kallmann, a German American geneticist who described 3 families with members with absent puberty, and no sense of smell.

In 1954 de Morsier published a paper on 14 cases of anosmia (lack of sense of smell) and absent puberty and proved the neuro-pathological basis of the condition.

These multiple contributions led to several different names being given to the same syndrome, depending on what part of the world you are in:

  • de Morsier’s Syndrome II;
  • Morsier-Gauthier Syndrome;
  • Kallmann-de Morsier Syndrome;
  • Maestre-Kallmann-de Morsier Syndrome;
  • Maestre de San Juan-Kallmann Syndrome;
  • Maestre de San Juan-Kallmann-de Morsier Syndrome.

Nowadays, the syndromic nomenclature is mostly replaced by its pathophysiological background that is the absence of pubertal hormones of the pituitary gland, called hypogonadotropic hypogonadism.

Congenital Hypogonadotropic Hypogonadism (CHH) is a developmental disorder caused by gonadotropin-releasing hormone (GnRH) deficiency leading to a lack of production of sex hormones (testosterone in males and oestrogens in females). It is classically divided into two main subgroups: the Kallmann Syndrome (KS) characterised by the association with anosmia or hyposmia and the normoosmic CHH (nCHH) without the absence of sense of smell. Most CHH cases are diagnosed at the time of puberty due to lack of sexual development, but CHH may also be suspected in infancy in males with cryptorchidism, micropenis or associated non reproductive signs such as the midline defects (palate and dental defects).

Characteristically, untreated adult males usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility due to low concentration of testosterone. Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development due to lack of oestrogens. The clinical variability at presentation generally depends upon the degree of GnRH dysfunction.

However, CHH is multifaceted disease with variable presentation that can be present in several syndromic contexts. Abnormalities frequently associated with CHH can also affect the development of central nervous system or kidneys or limbs or sensory organs (smell, hearing, eyes).

The standard forms of medical intervention involve sex hormone replacement therapy, and this is usually tailored to the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining adequate circulating levels of sex hormones. Subsequently, gonadotropin treatment is generally required for fertility induction in both sexes and achieving pregnancy. Unfortunately, several hormone preparations effective in the treatment of the CHH patients do not have the clinical indication for puberty induction.

No treatments exist so far for many of the CHH-associated phenotypes such as neurological manifestations (eg, anosmia or bimanual synkinesia) or renal agenesis. Other phenotypes such as cleft lip and/or palate, hearing loss or various skeletal defects require surgical and/or specialist intervention early in life.

CHH is not a life-threatening disease but generates several comorbidities and severely affects quality and expectancy of life in case of inappropriate or retarded treatment. Diagnostic delay of CHH leads to the eunuchoid habitus, and psychological consequences of growth and puberty retardation are usually relevant. With hormonal replacement, pubertal feminization or virilization can occur in all patients. Fertility, when desired, is achieved in most cases but delay in cryptorchidism treatment has a poor fertility outcome in males.

The country codes at the end of the pdf’s indicate the language of the document!

(Source references: NIH/GARD, Orphanet, HYPOHH, Wikipedia, DSD Life, Kallmann Syndrome Links and Help, GNRH)

Information on the rare disease

Educational Materials

Medical certificate in can be found here.

Videos on YouTube in english:

Patient organizations / Social Networking websites

United Kingdom:



  • The Pituitary Foundation- Irish Contact Point: E-Mail




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