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| {{Infobox medical condition (new) | | {{Short description|A genetic condition characterized by delayed or absent puberty and an impaired sense of smell}} |
| | name = Kallmann syndrome
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| | synonyms = Kallmann's hereditary anosmia
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| | caption = Video explanation
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| | pronounce =
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| | field = [[Endocrinology]]
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| | symptoms = Absent or delayed [[puberty]], [[infertility]], [[anosmia|inability to smell]]
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| | complications = [[Osteoporosis]]
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| | onset = [[Congenital|Present at birth]]
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| | duration = Life long
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| | types =
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| | causes =
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| | risks =
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| | diagnosis =
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| | differential =
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| | prevention =
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| | treatment = [[Hormone replacement therapy]] [[Gonadotropin]] therapy
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| | medication =
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| | prognosis =
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| | frequency = 1:30,000 (males), 1:125,000 (females)
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| | deaths =
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| <!-- Definition and symptoms -->
| | '''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. |
| '''Kallmann syndrome''' ('''KS''') is a [[hereditary|genetic]] disorder that prevents a person from starting or fully completing [[puberty]]. Kallmann syndrome is a form of a group of conditions termed [[hypogonadotropic hypogonadism]]. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a [[anosmia|total lack of sense of smell]] (anosmia) or a [[hyposmia|reduced sense of smell]].<ref name="US Library of Medicine Genetics Home Reference"/><ref name="pmid:20301509"/><ref name="pmid:26194704">{{cite journal | vauthors = Boehm U, Bouloux PM, Dattani MT, de Roux N, Dodé C, Dunkel L, Dwyer AA, Giacobini P, Hardelin JP, Juul A, Maghnie M, Pitteloud N, Prevot V, Raivio T, Tena-Sempere M, Quinton R, Young J | title = Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatment | journal = Nature Reviews. Endocrinology | volume = 11 | issue = 9 | pages = 547–64 | date = September 2015 | pmid = 26194704 | doi = 10.1038/nrendo.2015.112 | doi-access = free }}</ref> If left untreated, people will have poorly defined [[secondary sexual characteristics]], show signs of [[hypogonadism]], almost invariably are [[infertile]] and are at increased risk of developing [[osteoporosis]].<ref name="US Library of Medicine Genetics Home Reference"/> A range of other physical symptoms affecting the face, hands and skeletal system can also occur.<ref name="pmid:20301509"/> | |
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| <youtube>
| | ==Pathophysiology== |
| title='''{{PAGENAME}}'''
| | 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. |
| movie_url=http://www.youtube.com/v/sv4_YTU9V9E
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| embed_source_url=http://www.youtube.com/v/sv4_YTU9V9E
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| </youtube>
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| <!-- Cause and diagnosis -->
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| The underlying cause is a failure in the correct production or activity of [[GnRH|gonadotropin-releasing hormone]] by the [[hypothalamus]]. This results in low levels of the sex hormones [[testosterone]] in males or [[oestrogen]] and [[progesterone]] in females. Diagnosis normally occurs during teenage years when puberty fails to start.<ref name="pmid:26194704"/>
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| <!-- Treatment -->
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| Lifelong treatment for all sexes is normally required. [[Hormone replacement therapy]] (HRT) is the major form of treatment with the aim to replace the missing testosterone or oestrogen and progesterone. Specialised fertility treatments are also available.<ref name="pmid:24836550">{{cite journal | vauthors = Dunkel L, Quinton R | title = Transition in endocrinology: induction of puberty | journal = European Journal of Endocrinology | volume = 170 | issue = 6 | pages = R229–39 | date = June 2014 | pmid = 24836550 | doi = 10.1530/EJE-13-0894 | doi-access = free }}</ref>
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| <!-- Epidemiology and history -->
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| The condition is more commonly diagnosed in males than in females.<ref name="pmid:28476224">{{cite journal | vauthors = Lima Amato LG, Latronico AC, Gontijo Silveira LF | title = Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism | journal = Endocrinology and Metabolism Clinics of North America | volume = 46 | issue = 2 | pages = 283–303 | date = June 2017 | pmid = 28476224 | doi = 10.1016/j.ecl.2017.01.010 }}</ref> A 2011 study of the Finnish population produced an estimated incidence of 1 in 48,000 people overall, with 1 in 30,000 for males and 1 in 125,000 for females.<ref name="pmid: 21682876">{{cite journal | vauthors = Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T | title = Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland | journal = Orphanet Journal of Rare Diseases | volume = 6 | issue = Jun 17 | pages = 41 | date = June 2011 | pmid = 21682876| pmc = 3143089 | doi = 10.1186/1750-1172-6-41 }}</ref> Kallmann syndrome was first described by name in a paper published in 1944 by [[Franz Josef Kallmann]], a [[Germany|German]]-[[United States|American]] [[geneticist]].<ref name="ReferenceA">{{cite journal |vauthors=Kallmann FJ, Schönfeld WA, Barrera SE |title=The genetic aspects of primary eunuchoidism. |journal=Am J Ment Defic |volume=48 |pages=203–236 |year=1943–1944}}</ref><ref name="WhoNamedIt|synd|2549">{{WhoNamedIt|synd|2549}}</ref> The link between anosmia and hypogonadism had already been noted by Spanish doctor [[Aureliano Maestre de San Juan]] in 1856.<ref name="Maestre">{{cite journal|last=Maestre de San Juan|first=Aureliano|title=Teratolagia: falta total de los nervios olfactorios con anosmia en un individuo en quien existia una atrofia congenita de los testiculos y miembro viril.|journal=El Siglo Médico|year=1856|volume=3|pages=211–221}}</ref><ref name="Kim_2005"/>
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| == Signs and symptoms ==
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| [[File:19 year old Kallmann syndrome patient, pre-diagnosis.jpg|thumb|right|upright|19 year old with Kallmann syndrome before diagnosis and treatment]]
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| [[File:Jimmy_Scott.jpg|thumb|Singer [[Jimmy Scott]] (r), whose unusual voice was due to Kallman syndrome]]
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| It is normally difficult to distinguish a case of Kallmann syndrome (KS)/hypogonadotropic hypogonadism (HH) from a straightforward constitutional delay of [[puberty]]. However, if puberty has not started by either age 14 (girls) or 15 (boys) years and one or more of the non-reproductive features mentioned below is present, then a referral to [[reproductive endocrinologist]] might be advisable.<ref name="pmid:24683946">{{cite journal | vauthors = McCabe MJ, Bancalari RE, Dattani MT | title = Diagnosis and evaluation of hypogonadism | journal = Pediatric Endocrinology Reviews | volume = 11 Suppl 2 | issue = Feb | pages = 214–29 | date = February 2014 | pmid = 24683946 | doi = }}</ref><ref name="US Library of Medicine Genetics Home Reference">{{cite web|url=https://ghr.nlm.nih.gov/condition/kallmann-syndrome |title=Kallmann syndrome |date=June 26, 2016 |website=Genetics Home Reference. US Library of Medicine |publisher=National Institutes for Health. Genetic and Rare Diseases Information |access-date=December 17, 2017}}</ref><ref name="pmid:28476224"/>
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| The features of KS and other forms of HH can be split into two different categories; "reproductive" and "non-reproductive".<ref name="pmid:26194704"/><ref name="Kim_2005">{{cite journal | vauthors = Kim SH | title = Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future | journal = Endocrinology and Metabolism | volume = 30 | issue = 4 | pages = 456–66 | date = December 2015 | pmid = 26790381 | pmc = 4722398 | doi = 10.3803/EnM.2015.30.4.456 }}</ref><ref name="pmid:24836550"/><ref name="pmid21511493">{{cite journal | vauthors = Mitchell AL, Dwyer A, Pitteloud N, Quinton R | title = Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory | journal = Trends in Endocrinology and Metabolism | volume = 22 | issue = 7 | pages = 249–58 | date = July 2011 | pmid = 21511493 | doi = 10.1016/j.tem.2011.03.002 }}</ref><ref name="pmid:20301509">{{cite journal | vauthors = Balasubramanian R, Crowley WF Jr | title = Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency | journal = SourceGeneReviews | volume = | issue = | year = 2017 | pmid = 20301509 | doi = }}</ref>
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| ===Reproductive features===
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| * Failure to start or fully complete puberty.<ref name="US Library of Medicine Genetics Home Reference"/>
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| * Lack of testicle development in men (size < 4 ml, whereas the normal range is between 12 and 25 ml).<ref name="US Library of Medicine Genetics Home Reference"/>
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| * Primary [[amenorrhoea]] (failure to start [[menstruation]]).<ref name="pmid:28476224"/>
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| * Poorly defined secondary sexual characteristics.<ref name="pmid:20301509"/>
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| * Micropenis in 5-10% of male cases.<ref name="US Library of Medicine Genetics Home Reference"/>
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| * [[Cryptorchidism]] (undescended testicles) at birth.<ref name="US Library of Medicine Genetics Home Reference"/>
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| * Low levels of the [[gonadotropins]] [[Luteinizing hormone|LH]] and [[Follicle-stimulating hormone|FSH]].<ref name="pmid:20301509"/>
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| * [[Hypogonadism]] due to low levels of [[testosterone]] in men or [[oestrogen]]/[[progesterone]] in women.<ref name="pmid:20301509"/>
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| * [[Infertility]].<ref name="US Library of Medicine Genetics Home Reference"/>
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| ===Non-reproductive features===
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| * Total lack of sense of smell ([[anosmia]]) or markedly reduced sense of smell (hyposmia). This is the defining feature of Kallmann syndrome; it is not seen in other cases of HH. Approximately 50% of HH cases occur with anosmia and can be termed as Kallmann syndrome.<ref name="pmid:20301509"/>
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| * [[Cleft palate]], [[Cleft palate|cleft lip]] or other midline cranio-facial defects.<ref name="pmid:26194704"/>
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| * Neural hearing impairment<ref name="pmid:20301509"/>
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| * Absence of one of the kidneys (unilateral renal agenesis)<ref name="pmid:20301509"/>
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| * Skeletal defects including split hand/foot ([[ectrodactyly]]), shortened middle finger (metacarpal)<ref name="pmid:20301509"/> or [[scoliosis]]<ref name="National Organisation for Rare Disorders (NORD)">{{cite web|url=https://rarediseases.org/rare-diseases/kallmann-syndrome |title=Kallmann syndrome |date=2012 |website=Rare Diseases |publisher= National Organisation for Rare Disorders (NORD)|access-date=December 16, 2017 |quote=}}</ref>
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| * Manual [[synkinesis]] (mirror movements of hands)<ref name="pmid:20301509"/>
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| * Missing teeth (hypodontia)<ref name="pmid:20301509"/>
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| * Poor balance or coordination due to [[cerebral ataxia]].<ref name="pmid:28476224"/>
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| * Eye defects such as [[coloboma]] or [[ptosis (eyelid)|ptosis]].<ref name="Kim_2005"/>
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| * Increased incidence of color-blindness <ref>{{cite journal | vauthors = Chopra R, Chander A, Jacob JJ | title = The eye as a window to rare endocrine disorders | journal = Indian Journal of Endocrinology and Metabolism | volume = 16 | issue = 3 | pages = 331–8 | date = May 2012 | pmid = 22629495 | pmc = 3354836 | doi = 10.4103/2230-8210.95659 }}</ref><ref>{{cite book|title=Colour Vision Deficiencies IX|last=Jaffe|first=M. J.|last2=Sherins|first2=R. J.|last3 = de Monasterio|first3 = F.M. | name-list-format = vanc |date=1989|publisher=Springer | location = Dordrecht|isbn=9789401077156|series=Documenta Ophthalmologica Proceedings Series|pages=201–207|doi=10.1007/978-94-009-2695-0_24}}</ref>
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| The exact genetic nature of each particular case of KS/HH will determine which, if any, of the non-reproductive features will occur. The severity of the symptoms will also vary from case to case. Even family members will not show the same range or severity of symptoms.<ref name="pmid:20301509"/><ref name="pmid:28476224"/>
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| KS/HH is most often present from birth but adult onset versions are found in both males and females. The [[hypothalamic-pituitary-gonadal axis]] (HPG axis) functions normally at birth and well into adult life, giving normal puberty and normal reproductive function. The HPG axis then either fails totally or is reduced to a very low level of GnRH release in adult life with no obvious cause (e.g. a pituitary tumour). This will lead to a fall in testosterone or oestrogen levels and infertility.<ref name="National Organisation for Rare Disorders (NORD)"/><ref name="NIH Genetics Home Reference">{{cite web|title=Kallmann syndrome|url=https://ghr.nlm.nih.gov/condition/kallmann-syndrome|website=National Institutes for Health. US Library of Medicine. Genetics Home Reference|access-date=December 17, 2017|date=December 2017}}</ref>
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| Functional hypothalamic amenorrhoea is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition but is reversible with the removal of the stressor.<ref name="US Library of Medicine Genetics Home Reference"/>
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| Some cases of KS/HH appear to reverse during adult life where the HPG axis resumes its normal function and GnRH, LH, and FSH levels return to normal levels. This occurs in an estimated 10 to 22% of people, primarily normosmic CHH cases rather than KS cases and only found in people who have undergone some form of testosterone replacement therapy. It is only normally discovered when testicular volume increases while on testosterone treatment alone and testosterone levels return to normal when treatment is stopped. This type of KS/HH rarely occurs in cases where males have had a history of un-descended testes.<ref name="pmid:28476224"/><ref name="pmid:26194704"/>
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| Affected individuals with KS and other forms of HH are almost invariably born with normal sexual differentiation; i.e., they are physically male or female. This is due to the human chorionic gonadotrophin (hCG) produced by [[placenta]] at approximately 12 to 20 weeks [[gestation]] (pregnancy) which is normally unaffected by having KS or CHH.<ref>{{cite book |last=Sperling |first=Mark |date=2014 |title=Pediatric Endocrinology E-Book |publisher=Elsevier Health Sciences |page=136 |isbn=9781455759736}}</ref>
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| People with KS/HH lack the surge of GnRH, LH, and FSH that normally occurs between birth and six months of age. This surge is particularly important in infant boys as it helps with testicular descent into the scrotum. The surge of GnRH/LH/FSH in non KS/HH children gives detectable levels of testosterone in boys and oestrogen and progesterone in girls. The lack of this surge can sometimes be used as a diagnostic tool if KS/HH is suspected in a newborn boy, but is not normally distinct enough for diagnosis in girls.<ref name="pmid:26194704"/>
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| ===Osteoporosis===
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| One possible side effect of having KS/CHH is the increased risk of developing secondary [[osteoporosis]] or [[osteopenia]]. Oestrogen (females) or testosterone (males) is essential for maintaining [[bone density]].<ref name="pmid9024272">{{cite journal | vauthors = Guo CY, Jones TH, Eastell R | title = Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 2 | pages = 658–65 | date = February 1997 | pmid = 9024272 | doi = 10.1210/jc.82.2.658 | doi-access = free }}</ref> Deficiency in either testosterone or oestrogen can increase the rate of [[bone resorption]] while at the same time slowing down the rate of [[bone formation]]. Overall this can lead to weakened, fragile bones which have a higher tendency to fracture.
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| Even a short time with low oestrogen or testosterone, as in cases of delayed diagnosis of KS/CHH can lead to an increased risk of developing osteoporosis but other risk factors, such as smoking are involved so the risk of developing it will vary from person to person. Bone density scans are recommended to monitor the bone mineral density.<ref name="National Organisation for Rare Disorders (NORD)"/>
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| The bone density scan is known as a [[dual energy X-ray absorptiometry]] scan (DEXA or DXA scan). It is a simple test, taking less than 15 minutes to perform. It involves taking a specialised [[X-ray]] picture of the spine and hips and measuring the bone mineral density and comparing the result to the average value for a young healthy adult in the general population.<ref name="pmid22248317">{{cite journal | vauthors = Laitinen EM, Hero M, Vaaralahti K, Tommiska J, Raivio T | title = Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism | journal = International Journal of Andrology | volume = 35 | issue = 4 | pages = 534–40 | date = August 2012 | pmid = 22248317 | doi = 10.1111/j.1365-2605.2011.01237.x }}</ref>
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| Adequate [[calcium]] levels and, probably, more importantly, [[vitamin D]] levels are essential for healthy bone density. Some people with KS/CHH will have their levels checked and may be prescribed extra vitamin D tablets or injections to try to prevent the condition getting worse. The role of vitamin D for general overall health is under close scrutiny at the moment with some researchers claiming vitamin D deficiency is prevalent in many populations and can be linked to other diseases.<ref name="pmid:29258769">{{cite journal | vauthors = Wimalawansa SJ, Razzaque DM, Al-Daghri NM | title = Calcium and Vitamin D in Human Health: Hype or Real? | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = Dec 16 | issue = | pages = 4–14 | date = December 2017 | pmid = 29258769 | doi = 10.1016/j.jsbmb.2017.12.009 }}</ref>
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| Some people with severe osteoporosis might be prescribed [[bisphosphonates]] to preserve bone mass, in addition to hormone replacement therapy.<ref name="pmid:28408926">{{cite journal | vauthors = Langeron P, Routier G, Empereur-Buisson R | title = [Compression of the terminal aorta by retroperitoneal fibrosis] | journal = Mémoires de l'Académie de Chirurgie | volume = 95 | issue = 14 | pages = 427–30 | year = 1969| pmid = 5376477}}</ref>
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| ==Genetics== | | ==Genetics== |
| {{See|Genetics of GnRH deficiency conditions.}}
| | 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: |
| [[File:The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism.jpg|thumb|upright=1.6|The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism]] | | * '''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. |
| To date at least 25 different genes have been implicated in causing Kallmann syndrome or other forms of hypogonadotropic hypogonadism through a disruption in the production or activity of GnRH (37). These genes involved cover all forms of [[inheritance]] and no one gene defect has been shown to be common to all cases which makes genetic testing and inheritance prediction difficult.<ref name="pmid:23650337">{{cite journal | vauthors = Layman LC | title = Clinical genetic testing for Kallmann syndrome | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 98 | issue = 5 | pages = 1860–2 | date = May 2013 | pmid = 23650337 | pmc = 3644595 | doi = 10.1210/jc.2013-1624 }}</ref><ref name="pmid:25071724">{{cite journal | vauthors = Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A | title = Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes | journal = Frontiers in Endocrinology | volume = 5 | issue = 109 | pages = 109 | year = 2014 | pmid = 25071724 | pmc = 4088923 | doi = 10.3389/fendo.2014.00109 }}</ref>
| | * '''PROKR2''' and '''PROK2''', which are associated with autosomal recessive forms. |
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| The number of genes known to cause cases of KS/CHH is still increasing.<ref name="pmid21511493"/> In addition it is thought that some cases of KS/CHH are caused by two separate gene defects occurring at the same time.<ref name="pmid:28476224"/>
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| Individual gene defects can be associated with specific symptoms which can help in identifying which genes to test for.<ref name="pmid:28476224"/><ref name="pmid:20301509"/> Between 35-45% of cases of KS/CHH have an unknown genetic cause.<ref name="pmid:26934720">{{cite journal | vauthors = Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M | title = The complex genetic basis of congenital hypogonadotropic hypogonadism | journal = Minerva Endocrinologica | volume = 41 | issue = 2 | pages = 223–39 | date = June 2016 | pmid = 26934720 | doi = }}</ref>
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| The [[KAL1|ANOS1]] gene defect (previously known as KAL-1) was the first one discovered and the one most commonly tested for. It causes the [[x-linked]] form of Kallmann syndrome and is associated with the additional symptoms of [[anosmia]], bimanual [[synkinesis]] and [[renal agenesis]]. This defect is thought to be responsible for between 5 and 10% of all Kallmann syndrome/CHH cases.<ref name="pmid:28476224"/><ref name="pmid:20301509"/>
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| ==Pathophysiology== | | ==Clinical Features== |
| [[File:Flow diagram showing normal hormonal control of puberty.gif|thumb|upright=1.6|Shows the normal hormonal control of puberty from the hypothalamus down to the testes or ovaries and their negative feedback mechanisms. The negative feedback control allows just the right amount of hormone to be released according to the needs of the body at that time.]]
| | The primary clinical features of Kallmann syndrome include: |
| [[File:Diagram showing the disruption of the hormonal pathways of puberty due to the failure of GnRH release seen in KS and HH.gif|thumb|upright=1.6|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.]]
| | * Delayed or absent puberty |
| [[File:GNRH1 structure.png|thumb|The structure of GNRH1<br />(from {{PDB|1YY1}})]]
| | * Anosmia or hyposmia (reduced or absent sense of smell) |
| The underlying cause of Kallmann syndrome or other forms of hypogonadotropic hypogonadism is a failure in the correct action of the hypothalamic hormone [[GnRH]]. The term isolated GnRH deficiency (IGD) has increasingly been used to describe this group of conditions as it highlights the primary cause of these conditions and distinguishes them from other conditions such as [[Klinefelter syndrome]] or [[Turner syndrome]] which share some similar symptoms but have a different etiology.<ref name="pmid:21664415">{{cite journal | vauthors = Au MG, Crowley WF, Buck CL | title = Genetic counseling for isolated GnRH deficiency | journal = Molecular and Cellular Endocrinology | volume = 346 | issue = 1–2 | pages = 102–9 | date = October 2011 | pmid = 21664415 | pmc = 3185214 | doi = 10.1016/j.mce.2011.05.041 }}</ref> The term hypogonadism describes a low level of circulating [[sex hormones]]; [[testosterone]] in males and [[oestrogen]] and [[progesterone]] in females. Hypogonadism can occur through a number of different mechanisms. The use of the term hypogonadotropic relates to the fact that the hypogonadism found in HH is caused by a disruption in the production of the [[gonadotropin]] hormones normally released by the [[anterior pituitary gland]] known as [[luteinising hormone]] (LH) and [[follicle stimulating hormone]] (FSH).<ref name="pmid21511493" /><ref name="pmid:26934720"/> Failure in GnRH activity can otherwise be due to the absence of the GnRH releasing neurons inside the hypothalamus. HH can occur as an isolated condition with just the LH and FSH production being affected or it can occur in combined pituitary deficiency conditions.
| | * Infertility due to hypogonadism |
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| In the first 10 weeks of normal embryonic development, the GnRH releasing neurons migrate from their original source in the nasal region and end up inside the hypothalamus. These neurons originate in an area of the developing head, the [[olfactory placode]], that will give rise to the olfactory epithelium; they then pass through the [[cribriform plate]], along with the fibres of the olfactory nerves, and into the [[rostral forebrain]]. From there they migrate to what will become the hypothalamus. Any problems with the development of the olfactory nerve fibres will prevent the progression of the GnRH releasing neurons towards the brain.<ref name="pmid:20940512">{{cite journal | vauthors = Teixeira L, Guimiot F, Dodé C, Fallet-Bianco C, Millar RP, Delezoide AL, Hardelin JP | title = Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions | journal = The Journal of Clinical Investigation | volume = 120 | issue = 10 | pages = 3668–72 | date = October 2010 | pmid = 20940512 | pmc = 2947242 | doi = 10.1172/JCI43699 }}</ref>
| | Additional features may include: |
| | * Cleft lip or palate |
| | * Hearing loss |
| | * Renal agenesis (absence of one kidney) |
| | * Mirror movements (bimanual synkinesis) |
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| ==Diagnosis== | | ==Diagnosis== |
| Diagnosing KS and other forms of CHH is complicated by the difficulties in distinguishing between a normal constitutional delay of puberty or a case of KS/CHH.<ref name="pmid:23207503">{{cite journal | vauthors = Pitteloud N | title = Managing delayed or altered puberty in boys | journal = BMJ | volume = 345 | issue = Dec 3 | pages = e7913 | date = December 2012 | pmid = 23207503 | doi = 10.1136/bmj.e7913 }}</ref><ref name="pmid:24836550" /><ref name="pmid22392951">{{cite journal | vauthors = Young J | title = Approach to the male patient with congenital hypogonadotropic hypogonadism | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 97 | issue = 3 | pages = 707–18 | date = March 2012 | pmid = 22392951 | doi = 10.1210/jc.2011-1664 | doi-access = free }}</ref> The diagnosis is often one of exclusion found during the workup of [[delayed puberty]].<ref name="Peter A. Lee 2012">{{cite web|url=http://www.medscape.com/viewarticle/768564|title=The Smallest Kid in School: Evaluating Delayed Puberty|last1=Lee|first1=Peter A.|last2=Houk|first2=Christopher P.|date=August 13, 2012|work=Medscape Pediatrics|name-list-format=vanc}}</ref><ref name="Oxford Endocrinology Library 2008">{{cite book|title=Testosterone Deficiency in Men|year=2008|isbn=978-0199545131|editor-last=Jones|editor-first=Hugh|series=Oxford Endocrinology Library|chapter=Chapter 9: Puberty & Fertility|name-list-format=vanc}}</ref><ref name="Male Hypogonadism 2004">{{cite book|title=Male Hypogonadism|last=Jockenhovel|first=Friedrich|date=2004|publisher=Uni-Med Science|isbn=978-3-89599-748-8|chapter=Chapter 3: Diagnostic work up of hypogonadism|name-list-format=vanc}}</ref>
| | 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) |
| In males, the use of age appropriate levels of testosterone can help to distinguish between a case of KS/CHH from a case of delayed puberty. If no puberty is apparent, especially no testicular development, then a review by a reproductive endocrinologist may be appropriate. If puberty is not apparent by the age of 16 then the person should be referred for endocrinological review.<ref name="pmid:15802728">{{cite journal | vauthors = Quinton R | title = Adolescent development: advice in ABC of adolescence is potentially misleading | journal = BMJ | volume = 330 | issue = 7494 | pages = 789; author reply 789 | date = April 2005 | pmid = 15802728 | pmc = 555895 | doi = 10.1136/bmj.330.7494.789 }}</ref> Post natal diagnosis of KS/CHH before the age of 6 months is sometimes possible as the normal post natal hormonal surge of gonadotropins along with testosterone or oestrogen is absent in babies with KS/CHH. This lack of detectable hormones in the blood can be used as a diagnostic indicator, especially in male infants.<ref name="pmid:27213784">{{cite journal|vauthors=Dwyer AA, Jayasena CN, Quinton R|date=June 2016|title=Congenital hypogonadotropic hypogonadism: implications of absent mini-puberty|journal=Minerva Endocrinologica|volume=41|issue=2|pages=188–95|doi=|pmid=27213784}}</ref>
| | * Low or normal levels of LH and FSH |
| | | * MRI imaging may reveal underdeveloped or absent olfactory bulbs |
| In females, diagnosis is sometimes further delayed as other causes of [[amenorrhoea]] normally have to be investigated first before a case of KS/CHH is considered.<ref name="pmid20363464">{{cite journal|vauthors=Bry-Gauillard H, Trabado S, Bouligand J, Sarfati J, Francou B, Salenave S, Chanson P, Brailly-Tabard S, Guiochon-Mantel A, Young J|date=May 2010|title=Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics|journal=Annales d'Endocrinologie|volume=71|issue=3|pages=158–62|doi=10.1016/j.ando.2010.02.024|pmid=20363464}}</ref>
| | * Genetic testing can confirm mutations in known associated genes |
| [[File:Tanner scale-female.svg|thumb|Tanner scale-female]]
| |
| Diagnosis of KS/CHH normal involves a range of clinical, biochemical and radiological tests to exclude other conditions that can cause similar symptoms.
| |
| | |
| === Clinical tests ===
| |
| | |
| *Comparing height to standard growth charts. | |
| *Determining the [[Tanner stage]] of sexual development. (Males with KS/CHH are normally at stage I or II with genitalia, females at stage I with breast development and both males and females at stage III with pubic hair development).<ref name="pmid:20301509"/>
| |
| *Checking for micropenis and undescended testes ([[cryptorchidism]]) in males.
| |
| *Measuring testicular volume.
| |
| *Checking for breast development and age at [[menarche]] in females.
| |
| *Checking sense of smell using odorant panel or [[University of Pennsylvania Smell Identification Test]] (UPSIT)
| |
| *Checking for hearing impairment. | |
| *Checking for missing teeth or presence of [[cleft lip]] and/or [[cleft palate]].
| |
| *Checking for pigmentation of skin and hair.
| |
| *Checking for mirror movements of the hands or signs of [[neurodevelopmental delay]].
| |
| <ref name="pmid:26194704"/><ref name="pmid:20301509"/>
| |
| | |
| === Lab tests ===
| |
| | |
| *Early morning hormonal testing including [[Follicle-stimulating hormone|FSH]], [[Luteinizing hormone|LH]], [[testosterone]], [[oestrogen]] and [[prolactin]].
| |
| *GnRH and/or hCG stimulation test to determine activity of [[hypothalamus]] and [[pituitary]]. | |
| *Sperm test
| |
| *[[Liver function]], [[renal function]] and [[inflammation marker]] testing.
| |
| *[[Karyotype]] to check for chromosomal abnormalities.
| |
| <ref name="pmid:26194704"/><ref name="pmid:20301509"/>
| |
| | |
| === Medical imaging ===
| |
| *Performing wrist [[x-ray]] to determine bone age.
| |
| *Brain [[MRI]] to rule out any structural abnormalities in the [[hypothalamus]] or [[pituitary]] and to check for presence of [[olfactory bulbs]].
| |
| *Ultrasound of kidneys to rule out unilateral [[renal agenesis]]. | |
| *Bone density scan ([[DXA]]) to check for [[osteoporosis]] or [[osteopenia]].
| |
| <ref name="pmid:26194704"/><ref name="pmid:20301509"/>
| |
|
| |
|
| ==Treatment== | | ==Treatment== |
| [[File:Kallmann treatment methods.jpg|thumb|Testosterone gel sachets, Testosterone undecanoate injection (Nebido), Human chorionic gonadotropin (hCG) injection, Menotropin injection (hMG).]]
| | Treatment for Kallmann syndrome focuses on hormone replacement therapy to induce and maintain secondary sexual characteristics and fertility. Options include: |
| For both males and females, the initial aim for treatment is the development of the [[secondary sexual characteristics]] normally seen at puberty.<ref name="pmid:20301509"/><ref name="pmid22009162">{{cite journal | vauthors = Bouvattier C, Maione L, Bouligand J, Dodé C, Guiochon-Mantel A, Young J | title = Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism | journal = Nature Reviews. Endocrinology | volume = 8 | issue = 3 | pages = 172–82 | date = October 2011 | pmid = 22009162 | doi = 10.1038/nrendo.2011.164 }}</ref><ref name="Oxford Endocrinology Library 2008"/><ref name="Male Hypogonadism 2004"/><ref name="pmid19912242">{{cite journal | vauthors = Han TS, Bouloux PM | title = What is the optimal therapy for young males with hypogonadotropic hypogonadism? | journal = Clinical Endocrinology | volume = 72 | issue = 6 | pages = 731–7 | date = June 2010 | pmid = 19912242 | doi = 10.1111/j.1365-2265.2009.03746.x }}</ref> Once this has been achieved, continued [[hormone replacement therapy]] is required for both males and females to maintain sexual function, bone health, [[libido]] and general wellbeing.<ref name="pmid:26194704"/> In males, testosterone replacement therapy is required for the maintenance of normal muscle mass.<ref name="pmid:20301509"/>
| | * [[Testosterone]] replacement therapy for males |
| | | * [[Estrogen]] and [[progesterone]] therapy for females |
| Early treatment is sometimes required for male infants with suspected KS/CHH to correct un-descended testes and [[micropenis]] if present with the use or surgery or [[gonadotropin]] or [[Dihydrotestosterone|DHT]] treatment. Females with KS/CHH normally do not require any treatment before the age of adolescence. Currently, no treatments exist for the lack of sense of smell, mirror movement of the hands or the absence of one kidney.<ref name="pmid:26194704"/>
| | * Pulsatile GnRH therapy or gonadotropin injections to stimulate fertility |
| | |
| Treatment for both males and females with KS/CHH normally consists of one of three options which can be used for both hormone replacement therapy and/or fertility treatment.<ref name="pmid:20301509"/><ref name="pmid:26194704"/>
| |
| | |
| *Sex hormone replacement (testosterone or oestrogen & progesterone). | |
| *Gonadotropin therapy (medications that replicate the activity of FSH and LH).
| |
| *GnRH pulsatile therapy.
| |
| | |
| ===Hormone replacement therapy===
| |
| The method and dose of treatment will vary depending on the individual being treated. Initial treatment is normally made with lower doses in younger patients in order to develop the secondary sexual characteristics before adult doses are reached.<ref name="pmid:20301509"/>
| |
| | |
| For males with KS/CHH the types of testosterone delivery include daily patches, daily gel use, daily capsules, sub cutaneous or intramuscular injections or six-monthly implants. Different formulations of testosterone are used to ensure both the [[anabolic]] and [[androgenic]] effects of testosterone are achieved.<ref name="pmid:26194704"/><ref name="pmid:24836550"/> [[Nasal administration|Nasal]] testosterone delivery methods have been developed but their use in KS/CHH treatment has not been formally evaluated.<ref name="pmid:20301509"/>
| |
| | |
| Gonadotropin therapy, in the form of [[human chorionic gonadotropin]] (hCG) injections, with or without the use of FSH, can also be used in male patients to induce secondary sexual characteristic development alongside possible fertility induction.<ref name="pmid:26194704"/>
| |
| | |
| For females, hormone replacement involves the use of oestrogen and progesterone. Firstly, oestrogen is used in tablet or gel form in order to maximise breast development, then a combination of oestrogen and progesterone is used.<ref name="pmid:26194704"/><ref name="pmid:20301509"/> Cyclical progesterone is normally required to help keep the [[endometrium]] (lining of the [[uterus]]) healthy.<ref name="pmid:20301509"/>
| |
| | |
| In males, the monitoring of treatment normally requires the measurement of serum testosterone, [[inhibin B]], [[haematocrit]] and [[prostate-specific antigen]] (PSA). If injections are used, trough levels are taken to ensure an adequate level of testosterone is achieved throughout the injection cycle.<ref name="pmid:26194704"/>
| |
| | |
| In females monitoring normally consists of measurement of oestrogen, FSH, LH, [[inhibin B]] and [[anti-Müllerian hormone]] (AMH).<ref name="pmid:26194704"/>
| |
| | |
| Standard hormone replacement therapy will not normally induce fertility in either males or females, with no testicular growth in males. Early treatment as adolescents can help with psychological well being of people with KS/CHH.<ref name="pmid:26194704"/>
| |
| | |
| ===Fertility treatments===
| |
| Gonadotropin therapy can be used in both male and female patients in order to achieve fertility for some people.<ref name="pmid:26194704"/><ref name="pmid:20301509"/>
| |
| | |
| Pulsatile GnRH therapy can also be used to induce fertility, especially in females, but its use is limited to a few specialist treatment centres.<ref name="pmid:20301509"/> | |
| | |
| In males with KS/CHH, infertility is primarily due the lack of [[sperm]] production within the [[testes]]. Sperm production can be achieved through either the use of GnRH administered via a micro infusion pump or through the use of gonadotropin injections ([[Human chorionic gonadotropin|hCG]], FSH, [[Human menopausal gonadotrophin|hMG]]). The time taken to achieve adequate sperm production for natural conception will vary from person to person. If the pre-treatment testes are very small and there has been a history of undescended testes it might take longer to achieve sperm production. In these cases, [[assisted reproductive technology]], such as sperm retrieval using [[testicular sperm extraction]] (TESE) and/or [[intracytoplasmic sperm injection]] (ICSI), might be required.<ref name="pmid:29330225">{{cite journal | vauthors = Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, Young J | title = GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing | journal = European Journal of Endocrinology | volume = 178 | issue = 3 | pages = R55–R80 | date = March 2018 | pmid = 29330225 | doi = 10.1530/EJE-17-0749 | doi-access = free }}</ref>
| |
| | |
| In females with KS/CHH, infertility is primarily due to the lack of [[Cellular differentiation|maturation]] of eggs located within the [[ovaries]]. Ovulation induction can be achieved either with pulsatile GnRH therapy or alternatively with gonadotropin injections (hCG, FSH, hMG) given at set intervals to trigger the maturation and release of the egg for natural conception.<ref name="pmid:29330225"/>
| |
|
| |
|
| ==Prognosis== | | ==Prognosis== |
| Reversal of symptoms have been reported in between 10% to 22% of cases.<ref name="pmid">{{cite journal | vauthors = Sidhoum VF, Chan YM, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, Dwyer A, Pitteloud N, Hayes FJ, Hall JE, Martin KA, Boepple PA, Seminara SB | title = Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 99 | issue = 3 | pages = 861–70 | date = March 2014 | pmid = 24423288 | pmc = 3942233 | doi = 10.1210/jc.2013-2809 }}</ref><ref name="pmid:20301509"/>
| | 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. |
| | |
| Reversal cases have been seen in both KS and normosmic CHH but appear to be less common in cases of KS (where the sense of smell is also affected). Reversal is not always permanent and the precise genetic causes are not yet fully understood.<ref name="pmid:26792935">{{cite journal | vauthors = Dwyer AA, Raivio T, Pitteloud N | title = MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism | journal = European Journal of Endocrinology | volume = 174 | issue = 6 | pages = R267–74 | date = June 2016 | pmid = 26792935 | doi = 10.1530/EJE-15-1033 | doi-access = free }}</ref>
| |
| | |
| ==Epidemiology==
| |
| The epidemiology of Kallmann syndrome is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army which found a prevalence of 1 in 86,000 men<ref name=Tritos>{{cite journal|last1=Tritos|first1=Nicholas A|title=Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism: Background, Pathophysiology, Epidemiology|url=https://emedicine.medscape.com/article/122824-overview#a6|publisher=eMedicine|date=October 10, 2016}}</ref> and a 2011 report from Finland which found a prevalence of 1:30,000 for males and 1:125,000 for females.<ref name=GeneReviews>{{cite book|last1=Balasubramanian|first1=Ravikumar|last2=Crowley|first2=William F. | name-list-format = vanc |title=GeneReviews|date=March 2, 2017|publisher=University of Washington, Seattle|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1334/|chapter=Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency}}</ref>
| |
| | |
| Kallmann syndrome occurs about 4 times more often in males than females, but is only 2.5 times more common among males in familial cases.<ref name=Tritos/><ref name=GeneReviews/>
| |
| | |
| ==History==
| |
| [[File:Franz J. Kallmann.jpg|thumb|[[Franz Josef Kallmann|Franz J. Kallmann]], circa 1950]]
| |
| | |
| Kallmann syndrome was first described by name in a paper published in 1944 by [[Franz Josef Kallmann]], a [[Germany|German]]-[[United States|American]] [[geneticist]].<ref name="ReferenceA"/><ref name="WhoNamedIt|synd|2549"/> The link between anosmia and hypogonadism had already been noted by the Spanish doctor [[Aureliano Maestre de San Juan]] in 1856.<ref name="Maestre"/> In the 1950s, [[De Morsier]] and Gauthier reported the partial or complete absence of the [[olfactory bulb]] in the brains of men with hypogonadism.<ref name="pmid:14099201">{{cite journal | vauthors = De Morsier G, Gauthier G | journal = Pathologie et Biologie | volume = 11 | pages = 1267–72 | date = November 1963 | pmid = 14099201 | doi = | title = [Olfacto-Genital Dysplasia] }}</ref><ref name="Kim_2005"/>
| |
| | |
| ==Terminology==
| |
| The terminology used when describing cases of HH vary and can include:
| |
| | |
| *[[GnRH deficiency]]
| |
| *[[congenital hypogonadotropic hypogonadism]] (CHH)<ref>{{cite journal | vauthors = Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A | title = Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes | journal = Frontiers in Endocrinology | volume = 5 | pages = 109 | date = 2014 | pmid = 25071724 | doi = 10.3389/fendo.2014.00109 | pmc=4088923}}</ref>
| |
| *idiopathic/[[isolated hypogonadotropic hypogonadism]] (IHH)
| |
| *normosmic hypogonadotropic hypogonadism (nHH)
| |
| *hypothalamic hypogonadism
| |
| *olfacto-genital syndrome
| |
| | |
| ==Research==
| |
| | |
| [[Kisspeptin]] is a protein that regulates the release of GnRH from the hypothalamus, which in turn regulates the release of LH and, to a lesser extent, FSH from the anterior pituitary gland. Kisspeptin and its associated receptor [[KISS1R]] are known to be involved in the regulation of puberty. Studies have shown there is potential for kisspeptin to be used in the diagnosis and treatment of certain cases of Kallmann syndrome and CHH.<ref name="pmid:24615662">{{cite journal | vauthors = Skorupskaite K, George JT, Anderson RA | title = The kisspeptin-GnRH pathway in human reproductive health and disease | journal = Human Reproduction Update | volume = 20 | issue = 4 | pages = 485–500 | year = 2014 | pmid = 24615662 | pmc = 4063702 | doi = 10.1093/humupd/dmu009 }}</ref><ref name="PMC3473216">{{cite journal | vauthors = George JT, Seminara SB | title = Kisspeptin and the hypothalamic control of reproduction: lessons from the human | journal = Endocrinology | volume = 153 | issue = 11 | pages = 5130–6 | date = November 2012 | pmid = 23015291 | pmc = 3473216 | doi = 10.1210/en.2012-1429 }}</ref>
| |
| | |
| == References ==
| |
| {{Reflist|32em}}
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| | |
| == External links ==
| |
| {{Medical resources
| |
| | DiseasesDB = 7091
| |
| | ICD10 = {{ICD10|E|23|0|e|20}}
| |
| | ICD9 = {{ICD9|253.4}}
| |
| | ICDO =
| |
| | OMIM = 308700
| |
| | OMIM_mult = {{OMIM2|147950}} {{OMIM2|244200}} {{OMIM2|138850}} {{OMIM2|607002}} {{OMIM2|146110}} {{OMIM2|136350}} {{OMIM2|615271}} {{OMIM2|615270}} {{OMIM2|614880}} {{OMIM2|1527600}} {{OMIM2|162330}} {{OMIM2|164160}} {{OMIM2|608137}} {{OMIM2|608892}} {{OMIM2|300473}} {{OMIM2|603286}} {{OMIM2|613301}} {{OMIM2|604808}} {{OMIM2|603725}} {{OMIM2|606807}} {{OMIM2|602748}}{{OMIM2|607984}}
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| | eMedicineSubj = med
| |
| | eMedicineTopic = 1216
| |
| | eMedicine_mult = {{eMedicine2|med|1342}}
| |
| | MeshID = D017436}}
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| | |
| *[https://rarediseases.org/rare-diseases/kallmann-syndrome/ National Organisation for Rare Diseases page on Kallmann syndrome.]
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| {{Endocrine pathology}}
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| {{Receptor deficiencies}}
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| {{X-linked disorders}}
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|
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| {{Authority control}}
| | ==Related pages== |
| | * [[Hypogonadotropic hypogonadism]] |
| | * [[Anosmia]] |
| | * [[Gonadotropin-releasing hormone]] |
| | * [[Luteinizing hormone]] |
| | * [[Follicle-stimulating hormone]] |
|
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|
| [[Category:Hypothalamus disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Syndromes affecting the endocrine system]] | | [[Category:Endocrine diseases]] |
| [[Category:Cell surface receptor deficiencies]]
| | [[Category:Rare diseases]] |
| [[Category:Pituitary disorders]]
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| [[Category:Rare syndromes]] | |
