Kallmann syndrome

A genetic condition characterized by delayed or absent puberty and an impaired sense of smell

Kallmann syndrome
Synonyms	Kallmann's hereditary anosmia, Hypogonadotropic hypogonadism with anosmia
Pronounce
Field	Endocrinology, Medical genetics
Symptoms	Absent or delayed puberty, infertility, inability to smell, small testes or ovaries, delayed or absent secondary sexual characteristics
Complications	Osteoporosis, psychological impact due to delayed puberty or infertility
Onset	Present at birth
Duration	Lifelong
Types	X-linked, autosomal dominant, and autosomal recessive forms
Causes	Mutations in genes such as KAL1, FGFR1, PROKR2, and others affecting GnRH neuron migration
Risks	Family history of the syndrome; genetic mutations
Diagnosis	Physical examination, MRI of the brain, hormonal blood tests, olfactory testing, genetic testing
Differential diagnosis	Constitutional delay of growth and puberty, other forms of hypogonadotropic hypogonadism
Prevention	None
Treatment	Hormone replacement therapy, gonadotropin therapy, assisted reproductive technology for fertility
Medication	Testosterone (in males), estrogen and progesterone (in females), GnRH or gonadotropin injections
Prognosis	Generally good with appropriate hormone therapy; fertility may be restored in some cases
Frequency	1:30,000 males, 1:125,000 females
Deaths	Rare, not typically life-threatening

Shows the effect of the interruption of GnRH hormone release from the hypothalamus and the subsequent inability of the testes and ovaries to function correctly at puberty as seen in cases of KS/HH. In most cases of KS/HH the testes and ovaries are able to function correctly, but fail to do so because they have not had the correct hormonal signals.

Kallmann syndrome is a rare genetic disorder that is characterized by a combination of hypogonadotropic hypogonadism and anosmia or hyposmia. It is a form of hypogonadotropic hypogonadism where the production of gonadotropin-releasing hormone (GnRH) is deficient, leading to a lack of sexual development and a diminished or absent sense of smell.

Pathophysiology

Kallmann syndrome is caused by a failure in the development of the olfactory bulbs and the migration of GnRH-producing neurons during embryonic development. This results in the absence or underdevelopment of the olfactory bulbs and a deficiency in GnRH, which is crucial for the stimulation of the pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are essential for the normal function of the gonads and the onset of puberty.

Genetics

Kallmann syndrome can be inherited in an X-linked recessive, autosomal dominant, or autosomal recessive manner. Several genes have been implicated in the condition, including:

• KAL1 on the X chromosome, which is responsible for the X-linked form of the disorder.
• FGFR1 (also known as KAL2), which can cause an autosomal dominant form.
• PROKR2 and PROK2, which are associated with autosomal recessive forms.

Clinical Features

The primary clinical features of Kallmann syndrome include:

• Delayed or absent puberty
• Anosmia or hyposmia (reduced or absent sense of smell)
• Infertility due to hypogonadism

Additional features may include:

• Cleft lip or palate
• Hearing loss
• Renal agenesis (absence of one kidney)
• Mirror movements (bimanual synkinesis)

Diagnosis

Diagnosis of Kallmann syndrome is based on clinical evaluation, family history, and laboratory tests. Key diagnostic criteria include:

• Low levels of sex steroids (testosterone in males, estrogen in females)
• Low or normal levels of LH and FSH
• MRI imaging may reveal underdeveloped or absent olfactory bulbs
• Genetic testing can confirm mutations in known associated genes

Treatment

Treatment for Kallmann syndrome focuses on hormone replacement therapy to induce and maintain secondary sexual characteristics and fertility. Options include:

• Testosterone replacement therapy for males
• Estrogen and progesterone therapy for females
• Pulsatile GnRH therapy or gonadotropin injections to stimulate fertility

Prognosis

With appropriate treatment, individuals with Kallmann syndrome can achieve normal sexual development and fertility. However, the sense of smell typically does not improve with treatment.

Gallery

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  Franz J. Kallmann, circa 1950

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  The structure of GNRH1

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  Singer Jimmy Scott (r), whose unusual voice was due to Kallman syndrome

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  Testosterone gel sachets, Testosterone undecanoate injection (Nebido), Human chorionic gonadotropin (hCG) injection, Menotropin injection (hMG).

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  Tanner scale-female

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  The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism

Related pages

• Hypogonadotropic hypogonadism
• Anosmia
• Gonadotropin-releasing hormone
• Luteinizing hormone
• Follicle-stimulating hormone

External links

Classification	ICD-10: E23.0 OMIM: 308700 MeSH: D017436 DiseasesDB: 7091
External resources	eMedicine: med/1216

• National Organisation for Rare Diseases page on Kallmann syndrome.

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