Link to a recent paper mentioned in a earlier blog. This is the full paper.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?doi=10.1172/JCI29884
This paper represents recent work from researchers / doctors from the UK and USA about the inheritance of Kallmann syndrome and Hypogonadotrophic Hypogonadism.
In the past inheritance was thought due to be a defect in a single gene. This may now not be the case. It appears that the cause may be a combination of gene defects. To date there have been 7 different genes identified that lead to Kallmann syndrome or HH.
While this may not have an effect on the treatment of Kallmann syndrome at the moment but it might lead to a better chance of earlier diagnosis in the future.
Thursday, February 08, 2007
Friday, January 19, 2007
Current views on the genetics of Kallmann Syndrome and
Hypogonadotrophic Hypogonadism.
In the past Kallmann Syndrome (KS) and Hypogonadotrophic Hypogonadism (HH) were thought to be caused by single gene defects.
To date there have been 7 different genes on 7 different chromosomes that have been implicated in causing either or both KS or HH.
It has been recognised that different people with the same detectable gene defect for KS or HH show different symptoms. Even within family groups with the same inherited gene defect there is a variation in symptoms seen.
Recent evidence presented by researchers from Boston, USA (Dr Nelly Pitteloud)and Newcastle, UK (Dr Richard Quinton) has presented a new method to explain the inheritance of KS and HH.
It is proposed that some KS and HH cases are caused by a combination of gene defects on two different genes at the same time. This digenic inheritance of two separate gene defects would help to explain the range of symptoms seen in KS and HH cases. Mild or more severe symptoms would depend on what 2 genes are involved and the type of defect in each of the genes.
This has implications for the prediction of inheritance of KS and HH. On a single gene model it was fairly straight forward to give a 0%, 25%, 50% or 100% chance of passing on a gene defect. With 2 genes involved the situation becomes more complex and it becomes increasingly difficult to predict the chances of passing on KS or HH.
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The 7 genes currently thought to cause KS or HH:
FGFR-1 (8p 12) Fibronectin growth factor receptor.
NELF (9q 34.3) Nasal embryonic GnRH factor.
KAL-1 (Xp 22.32) Anosmin
PROK2 (3p 21.1) Prokineticin (G protein 73)
PROKR2 (20p 12.3) Prokineticin receptor
GNRHR (4q 21.2) GnRH receptor
GPR54 (19p 13.3) G-protein 54 receptor (also called KISS-2 receptor)
Abstract from a paper due to be published in February's issue of The Journal of Clinical Investigation:
http://www.jci.org/
ENDOCRINOLOGY :
The more mutations the worse the disease in idiopathic hypogonadotropic hypogonadism:
Idiopathic hypogonadotropic hypogonadism (IHH) is an inherited genetic disorder that results in impaired sexual development due to a deficiency in a sex hormone known as GnRH. Although individuals are thought to inherit IHH by having just one gene defect (in any one of a number of genes), not all the evidence supports this hypothesis, for example, not all family members with a given gene defect have the same symptoms.
In a study that appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Nelly Pitteloud and colleagues from Massachusetts General Hospital in Boston show that in two separate families with distinct forms of IHH (Kallmann syndrome and normosmic IHH, respectively) different combinations of several gene defects result in different disease symptoms. In the first family, the individual with the most severe phenotype had mutations in two different genes (FGFR1 and NELF). By contrast, his parents and siblings with only one or other of the mutations exhibited less severe disease. Similarly, in the second family, the most severely affected individual had 2 mutations in her GNRHR genes and 1 mutation in her FGFR1 gene, whereas the less severely affected family members did not have all 3 genetic mutations.
This study indicates that IHH is not caused by a defect in a single gene, something that has implications for the genetic counseling of IHH.
TITLE: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
AUTHOR CONTACT:
Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-1830; Fax: (617) 726-5357; E-mail: .
http://www.jci.org/
ENDOCRINOLOGY :
The more mutations the worse the disease in idiopathic hypogonadotropic hypogonadism:
Idiopathic hypogonadotropic hypogonadism (IHH) is an inherited genetic disorder that results in impaired sexual development due to a deficiency in a sex hormone known as GnRH. Although individuals are thought to inherit IHH by having just one gene defect (in any one of a number of genes), not all the evidence supports this hypothesis, for example, not all family members with a given gene defect have the same symptoms.
In a study that appears online on January 18 in advance of publication in the February print issue of the Journal of Clinical Investigation, Nelly Pitteloud and colleagues from Massachusetts General Hospital in Boston show that in two separate families with distinct forms of IHH (Kallmann syndrome and normosmic IHH, respectively) different combinations of several gene defects result in different disease symptoms. In the first family, the individual with the most severe phenotype had mutations in two different genes (FGFR1 and NELF). By contrast, his parents and siblings with only one or other of the mutations exhibited less severe disease. Similarly, in the second family, the most severely affected individual had 2 mutations in her GNRHR genes and 1 mutation in her FGFR1 gene, whereas the less severely affected family members did not have all 3 genetic mutations.
This study indicates that IHH is not caused by a defect in a single gene, something that has implications for the genetic counseling of IHH.
TITLE: Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism
AUTHOR CONTACT:
Nelly Pitteloud
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 724-1830; Fax: (617) 726-5357; E-mail: .
Saturday, April 15, 2006
A personal story from a Kallmann syndrome patient in the UK:
I was born on the 18th January 1978, along with my sister, one of twins 11 weeks early. We were kept on the special care baby ward for three months until we were big enough to be allowed home. However I still needed to gain some weight, as I needed surgery to correct my harelip. I gained the weight quite quickly thanks to my uncles who insisted on feeding me more than required. I had the corrective surgery and was allowed home.
About a year later I was diagnosed as having epilepsy and deafness I have around 75% hearing in my right ear and around 10-15% in my left. At 2 years old I had a fit that was severe enough to stop both my heart and my lungs completely. Luckily I survived anyway the severity of the fit was enough that I was put onto phenobarbital and phenytoin.
I stayed on these drugs until my early teens when the doctors thought it best to wean me off them. The side effects were pretty drastic, some days I would forget who I was and where I lived and on occasion would have the whole street out looking for me. There even a few incidents of violent outbursts on my behalf, which anyone who knows me would agree that, that is about as far away from me as you can get. Anyway this landed me in the offices of a child psychologist, who as I was only 10 years old, did not give me enough credit to think I didn't know I was being observed through that big two way mirror. They could not find anything psychologically wrong with me nor could they explain my outbursts of violent behaviour. I would say it was probably due to the large dosage of barbiturates being thrown down my neck, but what would I know.
Anyway as I started approaching my teens I was noticing that I wasn't changing like the rest of my friends my age this puzzled me and I remember being taken to the doctors by my mum who was told "oh he's just a late developer". Secondary school was a nightmare as I was constantly bullied because the other lads my age knew I was different. I used to forget my PE kit on purpose in an attempt to not have to change or shower with the rest of the lads. However there would be the odd time where a spare kit my size would be found and I would be forced to participate. Detentions were common for me as forgetting your kit was a punishable offence
I didn't really mind as it meant less bullying in one respect but my schoolwork did suffer. Meanwhile the doctors were just fobbing mum off with the same excuse. So I left school and went to the local agricultural college where I did my animal care and veterinary nursing diploma. I went on to do a further two animal care related courses. All this time and still puberty was determined not to show. I put this to the back of my mind and just carried on with life I became quite depressed.
As time went on I turned to drink and one night during a heart to heart with a close friend's mum I told her. The very next day she marched me off to the doctors determined to sort it out. My GP, admittedly out of his depth referred me to the endocrinologist at our local hospital he put me onto the testosterone injections. He did not tell me why or even perform any other tests apart from x-raying my wrists. I figured best not to question his ways of doing things he must know what he's doing. It was only when my twin sister saw the same doctor and he told he that she could not have kids and that she was too young to be trying anyway that alarm bells started ringing (we were twenty at that point) so a friend of mine started doing a bit of research.
We came across the HYPOHH site online so I rang Mark Saunders spoke to him, wow what an awesome relief. He advised me to get a second opinion ASAP so when I went to the HYPOHH conference in Birmingham of that year I did just that. I went up at the Bristol Royal Infirmary. They explained everything and they were great. I had several MRI scans and ultrasound scans. It was discovered that I had un-descended testes so an operation was arranged to have them removed. I had a prosthesis put in place I figured life would now take on some form of normality.
My care was handed over to my GP. However the prosthesis did not fall into its correct place and caused me a great deal of pain for two years. I tried all sorts of drugs and even acupuncture. In the end I decided the best thing to do was to have them removed. It was around this time that I discovered the Yahoo group and I discovered that in fact everything was not as it should be, again I had been grossly mistreated.
So I eventually plucked up the courage to change my GP and demanded a referral back to an endocrinologist (a different one this time). I saw him last month and the appointment went better than I ever could have imagined. I finally found a doctor that listens to me and takes my point of view. I never thought I would find one. Everything is now under control and for the first time in my life. I am looking forward to the future and it's all thanks to this group, the HYPOHH site and a few good friends.
I wanted to write this for two reasons
1) To thank everyone for there help and support and prompting
2) To make anyone stuck in a similar predicament see there is a light at the end of the tunnel.
Help is available all you need do is ask
Many thanks Paul C.
I was born on the 18th January 1978, along with my sister, one of twins 11 weeks early. We were kept on the special care baby ward for three months until we were big enough to be allowed home. However I still needed to gain some weight, as I needed surgery to correct my harelip. I gained the weight quite quickly thanks to my uncles who insisted on feeding me more than required. I had the corrective surgery and was allowed home.
About a year later I was diagnosed as having epilepsy and deafness I have around 75% hearing in my right ear and around 10-15% in my left. At 2 years old I had a fit that was severe enough to stop both my heart and my lungs completely. Luckily I survived anyway the severity of the fit was enough that I was put onto phenobarbital and phenytoin.
I stayed on these drugs until my early teens when the doctors thought it best to wean me off them. The side effects were pretty drastic, some days I would forget who I was and where I lived and on occasion would have the whole street out looking for me. There even a few incidents of violent outbursts on my behalf, which anyone who knows me would agree that, that is about as far away from me as you can get. Anyway this landed me in the offices of a child psychologist, who as I was only 10 years old, did not give me enough credit to think I didn't know I was being observed through that big two way mirror. They could not find anything psychologically wrong with me nor could they explain my outbursts of violent behaviour. I would say it was probably due to the large dosage of barbiturates being thrown down my neck, but what would I know.
Anyway as I started approaching my teens I was noticing that I wasn't changing like the rest of my friends my age this puzzled me and I remember being taken to the doctors by my mum who was told "oh he's just a late developer". Secondary school was a nightmare as I was constantly bullied because the other lads my age knew I was different. I used to forget my PE kit on purpose in an attempt to not have to change or shower with the rest of the lads. However there would be the odd time where a spare kit my size would be found and I would be forced to participate. Detentions were common for me as forgetting your kit was a punishable offence
I didn't really mind as it meant less bullying in one respect but my schoolwork did suffer. Meanwhile the doctors were just fobbing mum off with the same excuse. So I left school and went to the local agricultural college where I did my animal care and veterinary nursing diploma. I went on to do a further two animal care related courses. All this time and still puberty was determined not to show. I put this to the back of my mind and just carried on with life I became quite depressed.
As time went on I turned to drink and one night during a heart to heart with a close friend's mum I told her. The very next day she marched me off to the doctors determined to sort it out. My GP, admittedly out of his depth referred me to the endocrinologist at our local hospital he put me onto the testosterone injections. He did not tell me why or even perform any other tests apart from x-raying my wrists. I figured best not to question his ways of doing things he must know what he's doing. It was only when my twin sister saw the same doctor and he told he that she could not have kids and that she was too young to be trying anyway that alarm bells started ringing (we were twenty at that point) so a friend of mine started doing a bit of research.
We came across the HYPOHH site online so I rang Mark Saunders spoke to him, wow what an awesome relief. He advised me to get a second opinion ASAP so when I went to the HYPOHH conference in Birmingham of that year I did just that. I went up at the Bristol Royal Infirmary. They explained everything and they were great. I had several MRI scans and ultrasound scans. It was discovered that I had un-descended testes so an operation was arranged to have them removed. I had a prosthesis put in place I figured life would now take on some form of normality.
My care was handed over to my GP. However the prosthesis did not fall into its correct place and caused me a great deal of pain for two years. I tried all sorts of drugs and even acupuncture. In the end I decided the best thing to do was to have them removed. It was around this time that I discovered the Yahoo group and I discovered that in fact everything was not as it should be, again I had been grossly mistreated.
So I eventually plucked up the courage to change my GP and demanded a referral back to an endocrinologist (a different one this time). I saw him last month and the appointment went better than I ever could have imagined. I finally found a doctor that listens to me and takes my point of view. I never thought I would find one. Everything is now under control and for the first time in my life. I am looking forward to the future and it's all thanks to this group, the HYPOHH site and a few good friends.
I wanted to write this for two reasons
1) To thank everyone for there help and support and prompting
2) To make anyone stuck in a similar predicament see there is a light at the end of the tunnel.
Help is available all you need do is ask
Many thanks Paul C.
Wednesday, March 15, 2006
Kallmann Syndrome is a rare enough condition without having trouble finding information on the internet because of spelling...
The German / American scientist who published the landmark paper on this syndrome in 1944 was Franz Kallmann.
The correct notation is now Kallmann Syndrome, rather than Kallmann's Syndrome. It was recently agreed that all the personal notation associated with disease names would be dropped, so for instance Down's syndrome is now Down syndrome and Klinefelter's is now Klinefelter syndrome.
The German / American scientist who published the landmark paper on this syndrome in 1944 was Franz Kallmann.
The correct notation is now Kallmann Syndrome, rather than Kallmann's Syndrome. It was recently agreed that all the personal notation associated with disease names would be dropped, so for instance Down's syndrome is now Down syndrome and Klinefelter's is now Klinefelter syndrome.
Wednesday, February 15, 2006
The first medical paper to use the name Kallmann syndrome was published in 1944 in the unfortunately titled magazine "American Journal of Mental Deficiency".
It was first thought that Kallmann Syndrome was linked to a marked level of mental incompetence. This is NOT the case.
The fact that the few people in the first paper had Kallmann syndrome and mental problems was a coincidence and not a direct result of having Kallmann syndrome.
There is no link between intelligence, mental awareness and having Kallmann syndrome.
It was first thought that Kallmann Syndrome was linked to a marked level of mental incompetence. This is NOT the case.
The fact that the few people in the first paper had Kallmann syndrome and mental problems was a coincidence and not a direct result of having Kallmann syndrome.
There is no link between intelligence, mental awareness and having Kallmann syndrome.
Sunday, January 15, 2006
Kallmann Syndrome and the closely related hypogonadotrophic hypogonadism are genetic conditions.
However unlike a lot of other genetic conditions its route cause is still not fully understood.
At present there are 4 different genes that are known to cause this condition, and there may well be more out there. It has been estimated that these 4 genes only account for about 30% of all cases.
The lack of complete understanding of the genetic cause of Kallmann Syndrome prevents an effective, reliable screening test from being developed.
If any person with Kallmann Syndrome is going through fertility treatment they should be aware that there is a chance of passing the condition on but it is impossible to give an assessment of the risk.
However unlike a lot of other genetic conditions its route cause is still not fully understood.
At present there are 4 different genes that are known to cause this condition, and there may well be more out there. It has been estimated that these 4 genes only account for about 30% of all cases.
The lack of complete understanding of the genetic cause of Kallmann Syndrome prevents an effective, reliable screening test from being developed.
If any person with Kallmann Syndrome is going through fertility treatment they should be aware that there is a chance of passing the condition on but it is impossible to give an assessment of the risk.
Friday, October 14, 2005
Kallmann's Syndrome is not a very well known condition, even in the medical community.
The actual incidence is difficult to know for certain but estimates are in the range of 1 in 10,000 for men and 1 in 50,000 for women.
On one hand it is a very mild condition to have, there is no change in life expectancy and no pain associated with having the condition. The only big thing to watch out for is the increased risk of developing osteoporosis, or "brittle bones" due to the low levels of circulating sex hormones. The lack of sense of smell may get noticed from time to time and may cause a few embarrassing or awkward situations during life.
However the psychological damage of not going through puberty at the same time as you peer group, or even not all, can be immense. Just how damaging will depend from individual to individual and will be affected by age of diagnosis / treatment, knowledge of the condition and family & friends.
There are two aspects of not going through puberty that have to be considered. One is the feeling of being physically different from the people around you and the other is the fact that you will be infertile without treatment. Each of these may be more important than the other depending if you are male or female or at what stage of life you are at.
The actual incidence is difficult to know for certain but estimates are in the range of 1 in 10,000 for men and 1 in 50,000 for women.
On one hand it is a very mild condition to have, there is no change in life expectancy and no pain associated with having the condition. The only big thing to watch out for is the increased risk of developing osteoporosis, or "brittle bones" due to the low levels of circulating sex hormones. The lack of sense of smell may get noticed from time to time and may cause a few embarrassing or awkward situations during life.
However the psychological damage of not going through puberty at the same time as you peer group, or even not all, can be immense. Just how damaging will depend from individual to individual and will be affected by age of diagnosis / treatment, knowledge of the condition and family & friends.
There are two aspects of not going through puberty that have to be considered. One is the feeling of being physically different from the people around you and the other is the fact that you will be infertile without treatment. Each of these may be more important than the other depending if you are male or female or at what stage of life you are at.
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