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Kallmann Syndrome

Congenital Hypogonadotropic Hypogonadism with Anosmia

Kallmann syndrome is a rare genetic condition and a form of hypogonadotropic hypogonadism.


Presentation

Kallmann syndrome presents with the following features:

Respiratory: Lack of migration of olfactory neurons from olfactory epithelium leads to complete anosmia. Breathing is rarely affected.

Systemic: Delayed female puberty and secondary sexual characteristics are the chief complaints in Kallmann syndrome.

Urogenital: Delayed menarche and amenorrhea are common presentations of Kallmann syndrome in females and may lead to failure to conceive.

Musculoskeletal: Due to decreased sex hormones which play an important role in bone thickening, growth and muscle mass gain, the bones are usually of decreased density hence easily fractured. Recurring fractures may be a frequent presenting complaint, especially in females. The patients are also usually under weight

Complications

Complications commonly include the following:

Facial deformities: Of these, cleft lip and palate are the most prevalent. This is usually due to faulty migration of neural crest cells during embryonic development.
Auditory defects: In some cases neural hearing defects may also occur. These are rare but occurrence is also due to incomplete or improper migration of the cells of the first pharyngeal pouch.
Renal defects: Anosmin-1 is normally produced by the brain, mesonephros and metanephros. KS may accompany renal agenesis in which the symptoms will be more severe due to complete loss of Anosmin-1. Agenesis if present could be unilateral or bilateral, greatly increasing the mortality rate.
Bone defects: Osteoporosis due to decreased bone density may also be found.

Mortality 

Patients who do not have congenital heart disease or other neurologic manifestations concomitantly with Kallmann syndrome seem to live longer than those who do.

Male Hypogonadism
  • Male hypogonadism is characterized by impaired testicular function, which can affect spermatogenesis and/or testosterone synthesis.[dnatesting.uchicago.edu]
  • Genetic aspects in male hypogonadism. Rec. Prog. Horm. Res. 17: 53 (1961). PubMed Google Scholar National Research Council Committee on Vision. Procedures for Testing Color Vision, p. 9. National Academy Press, Washington, D.C. (1981).[doi.org]
  • You may be born with male hypogonadism, or it can develop later in life, often from injury or infection. The effects — and what you can do about them — depend on the cause and at what point in your life male hypogonadism occurs.[mayoclinic.org]
  • Swerdloff , Emerging medication for the treatment of male hypogonadism , Expert Opinion on Emerging Drugs , 10.1080/14728214.2016.1226799 , 21 , 3 , (255-266) , (2016) . Colleen M. Makey, Michael D. McClean, Lewis E. Braverman, Elizabeth N.[doi.org]
  • Gary Golds, Devon Houdek and Terra Arnason , Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health , International Journal of Endocrinology , 10.1155/2017/4602129 , 2017 , (1-15[doi.org]
Delayed Female Puberty
  • Systemic: Delayed female puberty and secondary sexual characteristics are the chief complaints in Kallmann syndrome.[symptoma.com]
Heat Intolerance
  • Last year, he developed clinical symptoms of hyperthyroidism with a fast heartbeat, heat intolerance and weight loss. Blood examinations revealed low levels of FSH, LH, and testosterone.[ncbi.nlm.nih.gov]
Anosmia
  • Hypogonadism with anosmia (disorder) Kallman syndrome Kallman's syndrome Familial hypogonadism with anosmia GnRH deficiency Hypogonadism with anosmia edit English Kallmann syndrome A form of hypogonadotropic hypogonadism which is also accompanied by a[wikidata.org]
  • He had no clinical signs of hypogonadism or anosmia.[ncbi.nlm.nih.gov]
  • RESULTS: The objective smell test showed anosmia in all six of the patients. However, the subjective test revealed anosmia in five patients and hyposmia in one patient. Brain MRI showed olfactory bulb aplasia in all six cases.[ncbi.nlm.nih.gov]
  • Complete anosmia may therefore be associated with gonadotropin deficiency that is only partial; the presence of anosmia does not predict the need for gonadotropin therapy to attain fertility.[ncbi.nlm.nih.gov]
  • Abstract Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. A previously unreported association of Kallmann syndrome and choanal atresia in a family is reported.[ncbi.nlm.nih.gov]
Hyposmia
  • OBJECTIVE: Kallmann syndrome (KS) is a genetic disorder with the distinctive features of hyposmia or anosmia and hypogonadotropic hypogonadism.[ncbi.nlm.nih.gov]
  • Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit.[ncbi.nlm.nih.gov]
  • Associated findings were hyposmia, high pitched voice, absence of puncta and smooth philtrum. Hormonal assay showed hypogonadotropic hypogonadism. He has normal male karyotype. Ultrasonography revealed no renal abnormalities.[ncbi.nlm.nih.gov]
  • Abstract Kallmann syndrome (KS) is a developmental disease characterized by the association of isolated hypogonadotropic hypogonadism and anosmia/hyposmia. We report an unusual presentation of two females with KS and empty sella.[ncbi.nlm.nih.gov]
  • RATIONAL: Kallmann syndrome (KS) is a genetic gonadotropin-releasing hormone deficiency associated with hyposmia or anosmia and characterized by various modes of inheritance.[ncbi.nlm.nih.gov]
Amenorrhea
  • These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases.[ncbi.nlm.nih.gov]
  • The patient reported also amenorrhea caused by primary HH. A diagnostic work-up using double-checked Sniffin' Sticks test and 6-items olfactory test confirmed serious hyposmia and identified the presence of KS.[ncbi.nlm.nih.gov]
  • Urogenital: Delayed menarche and amenorrhea are common presentations of Kallmann syndrome in females and may lead to failure to conceive.[symptoma.com]
  • […] symptoms including: failure to go through puberty no sense of smell (anosmia) or very weak ability to smell (hyposmia) undescended testes (cryptorchidism) in males a small penis ( microphallus ) in males menstruation never starts in women (called primary amenorrhea[rarediseases.about.com]
  • Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development.[orpha.net]
Primary Amenorrhea
  • These females, aged at 20 and 29-year-old, presented primary amenorrhea with prepubertal estradiol and low gonadotropin levels. No other significant clinical signs were observed. Empty sella was observed on MRI in both cases.[ncbi.nlm.nih.gov]
  • amenorrhea) simultaneous movement of both hands (called bimanual synkinesis) affects about one-fifth of males with the disorder There are other symptoms that occur less often, such as being born with only one kidney or having osteoporosis (weak bones[rarediseases.about.com]
  • Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development.[orpha.net]
  • Females with KS usually present with primary amenorrhea or infertility. Mutations in at least two genes have been shown to be associated with KS.[genedx.com]
Delayed Menarche
  • Urogenital: Delayed menarche and amenorrhea are common presentations of Kallmann syndrome in females and may lead to failure to conceive.[symptoma.com]

Workup

A complete work up is necessary before establishing a diagnosis of Kallmann syndrome. This includes the following:

Imaging

X-rays of upper and lower limbs show decreased bone mass and density indicating a probable underlying hormone deficiency. CT scans may indicate delayed bone age.

Hormone evaluation

For narrowing down the underline cause between probable suspects like hypothalamus, pituitary gland and the gonads themselves, hormone evaluation is vital.

Physical examination

A thorough physical examination may reveal micropenis and lack of pubic hair in males and incomplete breast enlargement in females. CT scans may reveal testicular agenesis or cryptorchidism in males and abnormally small ovaries and an immature uterine tract in females.

Delayed Bone Age
  • CT scans may indicate delayed bone age. Hormone evaluation For narrowing down the underline cause between probable suspects like hypothalamus, pituitary gland and the gonads themselves, hormone evaluation is vital.[symptoma.com]
Testosterone Decreased
  • As testosterone decreases, some men may experience symptoms similar to those of menopause in women.[mayoclinic.org]

Treatment

The treatment plan includes genetic counselling of affected individuals and the family involved, explaining the disease and the accompanying problems they may face. The second step is hormone replacement therapy which, studies show, has been observed to be beneficial [7]. Complications such as facial deformities may be corrected by surgical means.

Prognosis

The disease is present at birth with progressively evident features. Initially there is agenesis of ovaries in females and testes in males with accompanying hypogenesis of external genitalia. As the individual grows, there is marked increase in height and stature due to delayed closure of epiphyseal plates.

Puberty is late in onset and secondary sexual characteristics are poorly defined, for example, lack of facial and axillary hair, enlargement of larynx and deepening of voice, heavier bone structure and increased muscle mass due to lack of testosterone in males and lack of breast enlargement, growth of axillary and pubic hair, widening of hips and increased subcutaneous fat deposition due to decreased estrogen in females.

As the age progresses, more serious effects are seen like erectile dysfunction and oligospermia in males and amenorrhea and infertility in females.

Etiology

Mutations in various genes play a vital role in the development of Kallmann syndrome, and as the gene in question varies, so does the pattern of inheritance [1] [2] [3] [4] [5].

KAL1 

The first causative gene is the KAL1 gene on locus Xp22.3 which encodes the synthesis of Anosmin-1 which is a neural cell adhesion molecule. This molecule is necessary for the embryonic migration of two chief factors: olfactory neurons and GnRH synthesizing neurons. A mutation in KAL1 results in incomplete migration of olfactory neurons from the olfactory bulbs to the hypothalamus, a defect which leads to slight or usually, complete loss of smell. The external and internal nares as well as the rest of the anatomical structure of the nasal cavity are normal but a lack of sensory neurons cause significant anosmia in both affected males and females.

The second factor promoted by Anosmin-1 is the migration of GnRH synthesizing neurons to the hypothalamus. A mutation in KAL1 causes a migratory defect causing decreased or in severe cases, absent production of GnRH, which in return presents as hypogonadism, late onset of puberty, diminished libido and infertility. KAL1 mutations are inherited by an X-linked recessive pattern, thus affecting males more.

KAL2 

The second mutation that may cause Kallmann syndrome (KAL2) occurs in the Fibroblast Growth Factor Receptor 1 (FGFR1) gene on chromosome 8. The pattern of inheritance is autosomal dominant. This presentation is rare, evident in only 10% of cases.

KAL3 

Another extremely uncommon autosomal dominant form of Kallmann syndrome (KAL3) is a result of mutations in the Prokineticin receptor-2 gene (PROK2). However, a slight variation in symptoms has been observed in this form.

Others 

Defects in some other ligands like TAC3, LEP, GnRH1 etc have also been indicated in the pathogenesis of Kallmann syndrome.

Epidemiology

Kallmann syndrome is a rare genetic disorder which shows a predisposition in male children affecting 1:8000 males and 1:40.000 females. In strictly familial Kallmann syndrome, the male-to-female ratio is 2.5:1.

Sex distribution
Age distribution

Pathophysiology

A decrease in GnRH from the hypothalamus causes diminished synthesis and release of Luteinising hormone and Follicle stimulating hormone from the pituitary gland. A decrease in these hormones cause delayed onset of puberty, small non-functional gonads leading to decreased levels of sex hormones, lack of secondary sexual characters, prolonged and sometimes abnormal growth, decreased bone density and muscle mass. Affected patients are infertile [6].

Prevention

Kallmann syndrome is the result of a genetic defect. To prevent mutations, life style changes may be advised such as avoidance of harmful radiation, exposure to radioactive substances and in the case of pregnant females, safeguarding against teratogens.

Summary

Kallmann syndrome is a congenital disease associated with complete absence or partial decrement of Gonadotropin releasing hormone (GnRH) from the hypothalamus. This isolated GnRH deficiency results in hypogonadism and consequent infertility.

Major symptoms also include partial or complete anosmia. The anosmia is due to a defect in the development of olfactory bulbs leading to progressive decrease in perception of smell. This disease, although present from birth, may not be evident at first but can be suspected in the case of abnormally small genitalia, as observed in male infants.

Patient Information

Definition 

Kallmann syndrome is a genetic disease which results in loss of smell, delayed puberty, bone and muscle weakness and infertility.

Types

Kallmann syndrome is of 3 major types of which the first one, known as KAL1, is the most common. It is inherited from parent to son, having a chance of 1 in 4 children of being affected.

Prevention

As the defect lies in the mutated genes, prevention is essential. Protecting and safeguarding oneself from harmful radiation, radioactive substances, high exposure to ultra violet light and toxic chemicals can prevent the occurrence of Kallmann syndrome.

KS and pregnancy

Special care should be taken by pregnant women to avoid mutations occurring in the fetus. Some drugs like tetracyclines, aminoglycosides, etc should be avoided as well as alcohol intake, exposure to radiation and other toxic substances.

Treatment

The disease itself can be managed with symptomatic treatment. Hormone therapy is initiated to treat the delayed, and often incomplete, attaining of puberty. Administration of sex hormones can reverse the infertility in both males and females, leading to successful conception. Vitamins may be given to strengthen bones and muscles.

Summary

Kallmann syndrome is treatable but not curable. This disease occurs at birth and persists for life. Male infants are especially vulnerable to it. However, its negative effects may be reversed or at least significantly improved by regular treatment and counselling.

References

Article

  1. Dode C, Levilliers J, Dupont JM, et al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nat Genet. Apr 2003;33(4):463-5
  2. Monnier C, Dode C, Fabre L, et al. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling-activity. Hum Mol Genet. Sep 29 2008
  3. Canto P, Munguía P, Söderlund D, et al. Genetic analysis in patients with Kallmann syndrome: coexistance of mutations in prokineticin receptor 2 and KAL1. J Androl. Aug 21 2008
  4. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. Oct 23 2003;349(17):1614-27
  5. Trarbach EB, Silveira LG, Latronico AC. Genetic insights into human isolated gonadotropin deficiency. Pituitary. 2007;10(4):381-91
  6. Layman LC. The molecular basis of human hypogonadotropic hypogonadism. Mol Genet Metab. Oct 1999;68(2):191-9
  7. Hoffman AR, Crowley WF Jr. Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. Nov 11 1982;307(20):1237-41

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Last updated: 2018-06-22 07:09