Kallmann syndrome: Difference between revisions
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'''Kallmann syndrome''' ('''KS''') is a [[hereditary|genetic]] disorder that prevents a person from starting or fully completing [[puberty]]. |
'''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]] or a [[hyposmia|reduced sense of 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, etal |title=Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment. |journal=Nat Rev Endocrinol. |volume= 11|issue=Jul 21 |pages= 547–64|year=2015 |pmid=26194704 |doi=10.1038/nrendo.2015.112}}</ref> |
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If left untreated people with Kallmann syndrome will have poorly defined [[secondary sexual characteristics]], show signs of [[hypogonadism]], almost invariably be [[infertile]] and be 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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<!-- Cause and diagnosis --> |
<!-- Cause and diagnosis --> |
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The underlying cause is a failure in the correct production |
The underlying cause is a failure in the correct production or activity of [[GnRH]] [[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 --> |
<!-- Treatment --> |
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Treatment for both males and females is normally required life long. [[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. |
Treatment for both males and females is normally required life long. [[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=Eur J Endocrinol. |volume=170 |issue=6 |pages=R229-39 |year=2014 |pmid=24836550 |doi=10.1530/EJE-13-0894}}</ref> |
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<!-- Epidemiology and history --> |
<!-- Epidemiology and history --> |
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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 |author=Laitinen EM1, 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 J Rare Dis.|volume=6:41 |issue=Jun 17 |pages= 41|year=2011 |pmid= |doi=10.1186/1750-1172-6-41}}</ref> |
The condition is more commonly diagnosed in males than in females.<ref name="pmid:28476224">{{cite journal |author=Lima Amato LG, Latronico AC, Gontijo Silveira LF |title=Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism |journal=Endocrinol Metab Clin North Am |volume=46 |issue=2 |pages=283–303 |year=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 |author=Laitinen EM1, 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 J Rare Dis.|volume=6:41 |issue=Jun 17 |pages= 41|year=2011 |pmid= |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>{{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>{{WhoNamedIt|synd|2549}}</ref> The link between anosmia and hypogonadism had already been noted by the 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> |
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== Signs and symptoms == |
== Signs and symptoms == |
Revision as of 20:22, 15 February 2018
![]() | This article may require copy editing for grammar, punctuation and spelling. (February 2018) |
Kallmann syndrome | |
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Video explanation | |
Specialty | Endocrinology |
Kallmann syndrome (KS) is a 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 total lack of sense of smell or a reduced sense of sense of smell.[1][2][3]
If left untreated people with Kallmann syndrome will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably be infertile and be at increased risk of developing osteoporosis.[1] A range of other physical symptoms affecting the face, hands and skeletal system can also occur.[2]
The underlying cause is a failure in the correct production or activity of GnRH 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.[3]
Treatment for both males and females is normally required life long. 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.[4]
The condition is more commonly diagnosed in males than in females.[5]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.[6] Kallmann syndrome was first described by name in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist.[7][8] The link between anosmia and hypogonadism had already been noted by the Spanish doctor Aureliano Maestre de San Juan in 1856.[9]
Signs and symptoms
It is normally difficult to distinguish a case of KS / HH from a straightforward constitutional delay of puberty. However, if puberty has not started by either age 14 (girls) or 15 (boys) and one or more of the non-reproductie features mentioned belowe is present then a referral to reproductive endocrinologist might be advisable.[10][1][5]
The features of Kallmann syndrome (KS) and other forms of hypogonadotropic hypogonadism (HH) can be split into two different categories; "reproductive" and "non reproductive".[3][11][4][12][2]
Reproductive features
- Failure to start or fully complete puberty in both men and women.[1]
- Lack of testicle development in men (size < 4 ml, whereas the normal range is between 12 and 25 ml).[1]
- Primary amenorrhoea (failure to start menstruation).[5]
- Poorly defined secondary sexual characteristics in both men and women.[2]
- Micropenis in 5-10% of male cases.[1]
- Cryptorchidism (undescended testicles) at birth.[1]
- Low levels of the gonadotropins LH and FSH.[2]
- Hypogonadism due to low levels of testosterone in men or oestrogen / progesterone in females.[2]
- Infertility.[1]
Non-reproductive features
- 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.[2]
- Cleft palate, hare lip or other midline cranio-facial defects.[3]
- Neural hearing impairment[2]
- Absence of one of the kidneys (unilateral renal agenesis)[2]
- Skeletal defects including split hand/foot (ectrodactyly), shortened middle finger (metacarpal)[2] or scoliosis[13]
- Manual synkinesis (mirror movements of hands)[2]
- Missing teeth (hypodontia)[2]
- Poor balance or coordination due to cerebral ataxia.[5]
- Eye defects such as coloboma or ptosis.[11]
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.[2][5]
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 such as a pituitary tumour. This will lead to a fall in testosterone or oestrogen levels and infertility.[13][14]
Functional hypothalamic amenorrhoea is seen in females where the HPG axis is suppressed in response to physical or psychological stress or malnutrition. It is reversible with the removal of the stressor.[1]
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.[5][3]
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.[15]
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 & 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.[3]
Osteoporosis
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.[16] 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.
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.[13]
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.[17]
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 disease states.[18]
Some people with severe osteoporosis might be prescribed bisphosphonates to preserve bone mass in addition to hormone replacement therapy.[19]
Genetics
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/5d/The_genetic_and_molecular_basis_of_idiopathic_hypogonadotropic_hypogonadism.jpg/350px-The_genetic_and_molecular_basis_of_idiopathic_hypogonadotropic_hypogonadism.jpg)
To date at least twenty five 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. 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.[20][21]
The number of genes known to cause cases of KS / CHH is still increasing.[12] In addition it is thought that some cases of KS / CHH are caused by two separate gene defects occurring at the same time.[5]
Table of known genes responsible for cases of Kallmann syndrome and other forms of hypogonadotropic hypogonadism. Listed are the estimated prevalence of cases caused by the specific gene, additional associated symptoms and the form of inheritance.[5][2]Between 35-45% of cases of KS / CHH have an unknown genetic cause.[22]
Prevalence (%) | OMIM | Name | Gene | Locus | Clinical features | Syndromes Associated | Inheritance pattern |
---|---|---|---|---|---|---|---|
5[5], 5-10[2] | Template:OMIM2 | ANOS1 (KAL1) | ANOS1 | Xp22.3 | Anosmia. Bimanual synkinesis. Renal agenesis. | x-linked | |
10[5][2] | Template:OMIM2 | KAL2 | FGFR1 | 8p11.23 | Cleft lip and / or cleft palate. Septo-optic dysplasia. Skeletal anomomalies. Bimanual synkinesis. Hand / foot malformations such as ectrodactyly. Combined pituitary hormone deficiency. | Hartsfield syndrome | Autosomal dominant |
6-16[5], 5-10[2] | Template:OMIM2 | GNRHR | GNRHR | 4q13.2 | Autosomal recessive | ||
6[5], 5-10[2] | Template:OMIM2 | CHD7 | CHD7 | 8q12.2 | Congenital hearing loss. Semicircular canal hypoplasia. | CHARGE syndrome | Autosomal dominant |
3-6[5], <2[2] | Template:OMIM2 | KAL4 | PROK2 | 3p13 | Autosomal recessive | ||
3-6[5], 5[2] | Template:OMIM2 | KAL3 | PROKR2 | 20p12.3 | Combined pituitary hormone deficiency. | Morning Glory syndrome | Autosomal recessive |
3[5], 2-5[2] | Template:OMIM2 | IL17RD | IL17RD | 3p14.3 | Congenital hearing loss. | Autosomal recessive | |
2[5], 2-5[2] | Template:OMIM2 | SOX10 | SOX10 | 22q13.1 | Congenital hearing loss. | Waardenburg syndrome | Autosomal dominant |
2[5], <2[2] | Template:OMIM2 | KISS1 | KiSS-1 | 1q32.1 | Autosomal recessive | ||
2[5], <2[2] | Template:OMIM2 | KISS1R (GPR54) | GPR54 | 19p13.3 | Autosomal recessive | ||
<2[2] | Template:OMIM2 | FGF8 | FGF8 | 10q24.32 | Cleft lip and / or cleft palate. Skeletal anomomolies. Bimanual synkinesis. Combined pituitary hormone deficiency. | Autosomal dominant | |
<2[5], 1 report[2] | Template:OMIM2 | FGF17 | FGF17 | 8p21.3 | Dandy-Walker syndrome | Autosomal dominant | |
<2[5] | Template:OMIM2 | LEP | LEP | 7q32.1 | Early onset of morbid obesity. | Autosomal recessive | |
<2[5] | Template:OMIM2 | LEPR | LEPR | 1p31.3 | Early onset of morbid obesity. | Autosomal recessive | |
<2[5] | Template:OMIM2 | PCSK1 | PCSK1 | 5q15 | Early onset of morbid obesity. | Autosomal recessive | |
Rare[5], 1 report[2] | Template:OMIM2 | FEZF1 | FEZF1 | 7q31.32 | Autosomal recessive | ||
Rare[5], 1 report[2] | Template:OMIM2 | CCDC141 | CCDC141 | 2q31.2 | Unknown | ||
Rare[5], <2[2] | Template:OMIM2 | SEMA3A | SEMA3A | 7q21.11 | Autosomal dominant | ||
1 report[2] | Template:OMIM2 | SEMA3E | SEMA3E | 7q21.11 | CHARGE syndrome | Autosomal dominant | |
Rare[5] | Template:OMIM2 | SEMA7A | SEMA7A | 15q24.1 | Autosomal dominant | ||
Rare[5], <2[2] | Template:OMIM2 | HS6ST1 | HS6ST1 | 2q14.3 | Cleft lip and / or cleft palate. Skeletal anomalies. | Autosomal dominant | |
Rare[5], 1 report[2] | Template:OMIM2 | WDR11 | WDR11 | 10q26.12 | Combined pituitary hormone deficiency. | Autosomal dominant | |
Rare[5] | Template:OMIM2 | NELF (NSMF) | NELF | 9q34.3 | Autosomal dominant | ||
Rare[5] | Template:OMIM2 | IGSF10 | IGSF10 | 3q24 | Autosomal dominant | ||
Rare[5], <2[2] | Template:OMIM2 | GNRH1 | GNRH1 | 8p21.2 | Autosomal recessive | ||
Rare[5], <2[2] | Template:OMIM2 | TAC3 | TAC3 | 12q3 | Autosomal recessive | ||
Rare[5], 5[2] | Template:OMIM2 | TACR3 | TACR3 | 4q24 | Autosomal recessive | ||
Rare[5] | Template:OMIM2 | OTUD4 | OTUD4 | 4q31.21 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
Rare[5] | Template:OMIM2 | RNF216 | RNF216 | 7p22.1 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
Rare[5] | Template:OMIM2 | PNPLA6 | PNPLA6 | 19p13.2 | Cerebellar ataxia. | Gordon Holmes syndrome | Autosomal recessive |
1 report[2] | Template:OMIM2 | AXL | AXL | 19q13.2 | Unknown | ||
Rare[5] | Template:OMIM2 | DMXL2 | DMXL2 | 15q21.2 | Polyendocrine deficiencies and polyneuropathy. | Autosomal recessive | |
Rare[5] | Template:OMIM2 | NR0B1 (DAX1) | NR0B1 | Xp21.2 | Adrenal hypoplasia. | x-linked | |
1 report[2] | Template:OMIM2 | DUSP6 | DUSP6 | 12q21.33 | Autosomal dominant | ||
1 report[2] | Template:OMIM2 | POLR3B | POLR3B | 12q23.3 | Autosomal recessive | ||
1 report[2] | Template:OMIM2 | SPRY4 | SPRY4 | 5q31.3 | Autosomal dominant | ||
1 report[2] | Template:OMIM2 | FLRT3 | FLRT3 | 20p12.1 | Autosomal dominant | ||
1 report[2] | Template:OMIM2 | SRA1 | SRA1 | 19q13.33 | Unknown | ||
Rare[5] | Template:OMIM2 | HESX1 | HESX1 | 3p14.3 | Septo-optic dysplasia. Combined pituitary hormone deficiency. | Autosomal recessive and dominant |
Pathophysiology
![](http://upload.wikimedia.org/wikipedia/commons/thumb/3/31/Flow_diagram_showing_normal_hormonal_control_of_puberty.gif/350px-Flow_diagram_showing_normal_hormonal_control_of_puberty.gif)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/51/Diagram_showing_the_disruption_of_the_hormonal_pathways_of_puberty_due_to_the_failure_of_GnRH_release_seen_in_KS_and_HH.gif/350px-Diagram_showing_the_disruption_of_the_hormonal_pathways_of_puberty_due_to_the_failure_of_GnRH_release_seen_in_KS_and_HH.gif)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/c/ce/GNRH1_structure.png/220px-GNRH1_structure.png)
(from PDB: 1YY1)
The underlying cause of Kallmann syndrome or other forms of hypogonadotropic hypogonadism is a failure in the correct action of the hypothalamic hormone GnRH. This failure in GnRH activity can either be due to the absence of the GnRH releasing neurones inside the hypothalamus or the inability of the hypothalamus to release GnRH in the correct pulsatile manner to ensure LH and FSH release from the pituitary.[12][22] 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.
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 totally different etiology.[23] 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).
In the first 10 weeks of normal embryonic development the GnRH releasing neurones migrate from their original source in the nasal region and end up inside the hypothalamus. These neurones originate in an area of the developing head, called the olfactory placode, that will give rise to the nose; 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 neurones towards the brain.[24]
Diagnosis
The diagnosis is often one of exclusion found during the workup of delayed puberty.[25][26][27]
One of the biggest challenges in the diagnosis of KS and other forms of CHH is the ability to distinguish between a normal constitutional delay of puberty or a case of KS / CHH[28][4][29]
Post natal diagnosis of KS / CHH before the age of 6 months is sometimes possible. 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.[30]
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.[31]
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.[32]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/8/8f/Tanner_scale-male.png/220px-Tanner_scale-male.png)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/0/0c/Tanner_scale-female.svg/220px-Tanner_scale-female.svg.png)
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).[2]
- 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.
Lab tests
- Early morning hormonal testing including FSH, 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.
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.
Treatment
![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/18/Kallmann_treatment_methods.jpg/220px-Kallmann_treatment_methods.jpg)
For both males and females the initial aim for treatment is the development of the secondary sexual characteristics normally seen at puberty.[2][33][26][27][34] 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.[3] In males testosterone replacement therapy is required for the maintenance of normal muscle mass.[2]
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 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.[3]
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.[2][3]
- 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.[2]
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.[3][4]Nasal testosterone delivery methods have been developed but their use in KS / CHH treatment has not been formally evaluated.[2]
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 along with possible fertility induction at the same time.[3]
For females hormone replacement involves the use of oestrogen and progesterone. In females oestrogen only is used first in tablet or gel form in order to maximise breast development before a combination of oestrogen and progesterone is used.[3][2]Cyclical progesterone is normally required used to help keep the endometrium (lining of the uterus healthy).[2]
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.[3]
In females monitoring normally consists of measurement of oestrogen, FSH, LH, inhibin B and anti-Müllerian hormone (AMH).[3]
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.[3]
Fertility treatments
Gonadotropin therapy can be used in both male and female patients in order to achieve fertility for some people.[3][2]
Pulsatile GnRH therapy can also be used to induce fertility, especially in females but its use is limited to a few specialist treatment centres.[2]
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 (hCG, FSH, 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.[35]
In females with KS / CHH infertility is primarily due to the lack of 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 to allow for natural conception.[35]
Prognosis
Reversal of symptoms have been reported in between 10% to 22% of cases.[36][2]
Reversal cases have been seen in cases of 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.[37]
Epidemiology
The epidemiology of Kallmann's is not well understood. Individual studies include a 1986 report reviewing medical records in the Sardinian army found a prevalence of 1 in 86,000 men[38] and a 2011 report from Finland found a prevalence of 1:30,000 for males and 1:125,000 for females.[39]
It occurs about 4 times more often in males than females. However, in familial cases it is only 2.5 time more common in males.[38][39]
History
![](http://upload.wikimedia.org/wikipedia/commons/thumb/9/9b/Franz_J._Kallmann.jpg/220px-Franz_J._Kallmann.jpg)
Kallmann syndrome was first described by name in a paper published in 1944 by Franz Josef Kallmann, a German-American geneticist.[40][41] The link between anosmia and hypogonadism had already been noted by the Spanish doctor Aureliano Maestre de San Juan in 1856.[9] In the 1950s De Morsier and Gauthier reported the partial or complete absence of the olfactory bulb in the brains of men with hypogonadism.[42][11]
Society and culture
Terminology
The terminology used when describing cases of HH can vary, other terms used to describe the condition include:
- GnRH deficiency
- congenital hypogonadotropic hypogonadism (CHH)[43]
- 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 conditions such as Kallmann syndrome and CHH in certain cases.[44][45]
References
- ^ a b c d e f g h i "Kallmann syndrome". Genetics Home Reference. US Library of Medicine. National Institutes for Health. Genetic and Rare Diseases Information. June 26, 2016. Retrieved December 17, 2017.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc Balasubramanian R, Crowley WF Jr (2017). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency". SourceGeneReviews® [Internet]. PMID 20301509.
- ^ a b c d e f g h i j k l m n o p q r s Boehm U, Bouloux PM, Dattani MT, et al. (2015). "Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism-pathogenesis, diagnosis and treatment". Nat Rev Endocrinol. 11 (Jul 21): 547–64. doi:10.1038/nrendo.2015.112. PMID 26194704.
- ^ a b c d Dunkel L, Quinton R (2014). "Transition in endocrinology: induction of puberty". Eur J Endocrinol. 170 (6): R229-39. doi:10.1530/EJE-13-0894. PMID 24836550.
- ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am Lima Amato LG, Latronico AC, Gontijo Silveira LF (2017). "Molecular and Genetic Aspects of Congenital Isolated Hypogonadotropic Hypogonadism". Endocrinol Metab Clin North Am. 46 (2): 283–303. doi:10.1016/j.ecl.2017.01.010. PMID 28476224.
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: CS1 maint: multiple names: authors list (link) - ^ Laitinen EM1, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T. (2011). "Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland". Orphanet J Rare Dis. 6:41 (Jun 17): 41. doi:10.1186/1750-1172-6-41.
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: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Kallmann FJ, Schönfeld WA, Barrera SE (1943–1944). "The genetic aspects of primary eunuchoidism". Am J Ment Defic. 48: 203–236.
- ^ synd/2549 at Who Named It?
- ^ a b Maestre de San Juan, Aureliano (1856). "Teratolagia: falta total de los nervios olfactorios con anosmia en un individuo en quien existia una atrofia congenita de los testiculos y miembro viril". El Siglo Médico. 3: 211–221.
- ^ McCabe MJ, Bancalari RE, Dattani MT (2014). "Diagnosis and evaluation of hypogonadism". Pediatr Endocrinol Rev. 11 (Feb): Suppl 2:214–29. PMID 24683946.
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: CS1 maint: multiple names: authors list (link) - ^ a b c Soo-Hyun Kim (2015). "Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome: Past, Present, and Future". Endocrinol Metab (Seoul). 30 (4): 456–466. doi:10.3803/EnM.2015.30.4.456. PMID 4722398.
- ^ a b c Mitchell AL, Dwyer A, Pitteloud N, Quinton R (2011). "Genetic basis and variable phenotypic expression of Kallmann syndrome: towards a unifying theory". Trends Endocrinol. Metab. 22 (7): 249–58. PMID 21511493.
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: CS1 maint: multiple names: authors list (link) - ^ a b c "Kallmann syndrome". Rare Diseases. National Organisation for Rare Disorders (NORD). 2012. Retrieved December 16, 2017.
- ^ "Kallmann syndrome". National Institutes for Health. US Library of Medicine. Genetics Home Reference. December 2017. Retrieved December 17, 2017.
- ^ Sperling, Mark (2014). Pediatric Endocrinology E-Book. Elsevier Health Sciences. p. 136. ISBN 9781455759736.
- ^ Guo CY, Jones TH, Eastell R (1997). "Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover". J Clin Endocrinol Metab. 82 (2): 658–65. PMID 9024272.
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: CS1 maint: multiple names: authors list (link) - ^ Laitinen EM, Hero M, Vaaralahti K, Tommiska J, Raivio T (2012). "Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism". Int J Androl. 35 (4): 534–40. doi:10.1111/j.1365-2605.2011.01237.x. PMID 22248317.
- ^ Wimalawansa SJ, Razzaque DMS, Al-Daghri NM (2017). "Calcium and Vitamin D in Human Health: Hype or Real?". J Steroid Biochem Mol Biol. Dec 16. doi:10.1016/j.jsbmb.2017.12.009. PMID 29258769.
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: CS1 maint: multiple names: authors list (link) - ^ Golds G, Houdek D, Arnason T (2017). "Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health". Int J Endocrinol. : (2017:4602129). doi:10.1155/2017/4602129. PMID 5376477.
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: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ Layman L. (2013). "Clinical Testing for Kallmann Syndrome". J Clin Endocrinol Metab. 98 (5): 1860–1862. doi:10.1210/jc.2013-1624. PMC 3644595. PMID 23650337.
- ^ Valdes-Socin H, Rubio Almanza M, Tomé Fernández-Ladreda M, Debray FG, Bours V, Beckers A (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Front Endocrinol (Lausanne). 5 (109). doi:10.3389/fendo.2014.00109. PMC 4088923.
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: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ a b Vezzoli V, Duminuco P, Bassi I, Guizzardi F, Persani L, Bonomi M (2016). "The complex genetic basis of congenital hypogonadotropic hypogonadism". Minerva Endocrinol. 41 (2): 223–39. PMID 26934720.
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: CS1 maint: multiple names: authors list (link) - ^ Au MG1, Crowley WF Jr, Buck CL. (2011). "Genetic counseling for isolated GnRH deficiency". Mol Cell Endocrinol. 346 (1–2): 102–9. doi:10.1016/j.mce.2011.05.041. PMC 3185214. PMID 21664415.
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: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link) - ^ Teixeira L, Guimiot F, Dodé C, Fallet-Bianco C, Millar RP, Delezoide AL, Hardelin JP (2010). "Defective migration of neuroendocrine GnRH cells in human arrhinencephalic conditions". J Clin Invest. 120 (10): 3668–72. doi:10.1172/JCI43699. PMC 2947242. PMID 20940512.
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: CS1 maint: multiple names: authors list (link) - ^ Lee, Peter A.; Houk, Christopher P. (August 13, 2012). "The Smallest Kid in School: Evaluating Delayed Puberty". Medscape Pediatrics.
- ^ a b Oxford Endocrinology Library. Testosterone Deficiency in Men. 2008. ISBN 978-0199545131 Editor: Hugh Jones. Chapter 9. Puberty & Fertility.
- ^ a b Male Hypogonadism. Friedrich Jockenhovel. Uni-Med Science. 2004. ISBN 3-89599-748-X. Chapter 3. Diagnostic work up of hypogonadism.
- ^ Pitteloud N. (2012). "Managing delayed or altered puberty in boys". BMJ. 345 (Dec 3): e7913. doi:10.1136/bmj.e7913. PMID 23207503.
- ^ Young J (2012). "Approach to the Male Patient with Congenital Hypogonadotropic Hypogonadism". J Clin Endocrinol Metab. 97 (3): 707–718. doi:10.1210/jc.2011-1664. PMID 22392951.
- ^ Dwyer AA, Jayasena CN, Quinton R (2016). "Congenital hypogonadotropic hypogonadism: implications of absent mini-puberty". Minerva Endocrinol. 41 (2): 188–95. PMID 27213784.
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: CS1 maint: multiple names: authors list (link) - ^ Bry-Gauillard H, et al. (May 2010). "Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics". Ann. Endocrinol. 71 (3). Paris: 158–162. doi:10.1016/j.ando.2010.02.024. PMID 20363464.
- ^ Quinton R. (2005). "Adolescent development: advice in ABC of adolescence is potentially misleading". BMJ. 330 (7494: Apr 2): 789. doi:10.1136/bmj.330.7494.789. PMC 555895. PMID 15802728.
- ^ Bouvattier C; et al. (2011). "Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism". Nat Rev Endocrinol. 18, 8 (3): 172–82. PMID 22009162.
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(help) - ^ Han TS, Bouloux PM (2010). "What is the optimal therapy for young males with hypogonadotropic hypogonadism?". Clin Endocrinol. 72 (6): 731–7. doi:10.1111/j.1365-2265.2009.03746.x. PMID 19912242.
- ^ a b Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, Young J (2018). "GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing". Eur J Endocrinol. doi:10.1530/EJE-17-0749. PMID 29330225.
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: CS1 maint: multiple names: authors list (link) - ^ Sidhoum VF, Chan YM, Lippincott MF, et al. (2013). "Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System". J. Clin. Endocrinol. Metab. 99: 861–70. doi:10.1210/jc.2013-2809. PMC 3942233. PMID 24423288.
- ^ Dwyer AA, Raivio T, Pitteloud N (2016). "MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism". Eur J Endocrinol. 174 (6): R267-74. doi:10.1530/EJE-15-1033. PMID 26792935.
- ^ a b Tritos, Nicholas A (October 10, 2016). "Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism: Background, Pathophysiology, Epidemiology". eMedicine.
- ^ a b Balasubramanian, Ravikumar; Crowley, William F. (March 2, 2017). "Isolated Gonadotropin-Releasing Hormone (GnRH) Deficiency". GeneReviews. University of Washington, Seattle.
- ^ Kallmann FJ, Schönfeld WA, Barrera SE (1943–1944). "The genetic aspects of primary eunuchoidism". Am J Ment Defic. 48: 203–236.
- ^ synd/2549 at Who Named It?
- ^ De Morsier,G Gauthier, G (1963). "[OLFACTO-GENITAL DYSPLASIA]". Pathol Biol (11): 1267–72. PMID 14099201.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - ^ Valdes-Socin H, Almanza MR, Fernández-Ladreda T, et al. (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes". Frontiers in Endocrinology. 5: 109. doi:10.3389/fendo.2014.00109.
{{cite journal}}
: CS1 maint: unflagged free DOI (link) - ^ Skorupskaite K, George JT, Anderson RA (2014). "The kisspeptin-GnRH pathway in human reproductive health and disease". Hum Reprod Update. 20 (4): 485–500. doi:10.1093/humupd/dmu009. PMC 4063702. PMID 24615662.
- ^ Jyothis T. George; Stephanie B. Seminara. "Kisspeptin and the Hypothalamic Control of Reproduction: Lessons from the Human". Endocrinology. 153 (11): 5130–5136. doi:10.1210/en.2012-1429. PMC 3473216. PMID 23015291.
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External links
- National Organisation for Rare Diseases page on Kallmann syndrome.
- European network for GnRH deficiency conditions. Information for patients, clinicians & researchers
- Rare Disease UK video on Kallmann syndrome.
- Man, 33, seeks puberty, the case of Lawrence Koomson, a physician who was treated for the condition as filmed in the documentary. (BBC)
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