Unfortunately some are all very different with the monitoring.  However, I have commonly heard the majority use the figures 10-50nmol as the range.  

I have posted below an e-mail that I sent to Gary Warne before Christmas.  He replies and then we have a sort of e-mail discussion.  Within that he mentions not letting 17 OHP levels go below 10nmol.  That would tally with the figure above.  He however uses 40nmol as the top end figure.  Perhaps he is just more precise with his control boundaries are concerned.  I would be happy with  the 10-50nmol being used so long as Ashley did not spend too much time in the top end of the range.  I look at all his records and some have come back 20-ish nmol and the consultant has noted "Perfect" on the results.  Is that because it is the middle ranges to be 20-30?  Here is the e-mail anyway.  It has a few intereresting things within for others to note:

My Original Letter to Gary Warne:

Dear Sir,

My sons was born with SWCAH in 1992 in the UK.  We emigrated to New Zealand when he turned 18 months and since then the quality of his care has deteriorated.  Earlier this year I had on line connection and so was able to be put in touch with Support groups.  At the time my son's 17 OHP  levels had extended to 426* nmol/L and he was wildly out of control.  They had cut back his dose by 2.50mg which was a substantial cut back of 20% from 15mg per day.  Then inadequate follow up after such.  We went back three months after that cut back and no bloods aware taken.  My son had grown considerably, slimmed down and was looking more athletic and less podgy.  He had adult under arm BO and we mentioned this to his Paediatrician.  he does not specialize in CAH and said it was normal an come back six months as he said our son was doing really well.  At the six months check his 17 OHP was 336nmol/L showing that he had escaped quite badly.  I understand what the normal ranges to be as my sons health care as been so neglected I took it upon my self to learn about which blood tests are done and what they should read and why they are done.  The only one they have been doing the past 2 years I note was 17 OHP with a renin run 18 months prior to his levels escaping wildly.  At the point of the 336nmol/L blood tests result, they stepped his dose back up to 15mg per day only.  There are only two doses available with the 5mg pill and so they are trying to tune him with these increments whenever they go up and down any.  In this his treatment has been very crude.  When things were apparently wrong and I educated myself, I also went to my GP's and gathered all the data sent to him from when we arrived in NZ.  To my horror I discovered that at the age of 4 yrs, my sons meds (HCT) were raised by 50% from 10mg per day to 15mg per day.  A blood tests done four days after an adrenal crisis had come back understandably reading 336nmol/L and his dose was raised to  5mg AM and 10mg PM .  At the time we were in the middle of moving from one city to the next and all records where transferred to another hospital and for three years although I mentioned to the consultant that my son was not growing correctly, he did nothing.  I note that he was religious with tests though, never any less than three monthly and a battery of tests such as ACTH, 27 OHP, Renin, Electrolytes, Androstenedione , Testosterone etc.  However, he never altered the dose back down to a more sufficient dose (not even 12.50mg per day) so that my son could grow normally.  Some years later he retired and another Paediatrician (the current one) took over and he was very good at first and must have noted the over treatment after a bone age came back three yrs immature of my son chronological age. 

The meds were dropped back to 12.50mg at that point but testing like I said became very poor.  Only 17 OHP and lack of renin or any other.  It is all here on my sons notes.  As a consequence he nigh on hit puberty this year and had to be put on dex (00.25mg) to stomp on the adrenals and make the regress.  He was on that a month and no one ran a renin as I was aware that HCT has some mineral corticosteroid properties that supplement his Florinef in retaining sodium whereas the dex dose not and I felt that they needed to run that to make sure that whilst he was on dex that they could make sure he was receiving adequate amounts of Florinef.  They did not,  though they did one a month after and his renin was high at 18nmol/L.  They have never had to alter the 100mcg that he was on otherwise and the renin results have always been ok apart from crisis.  As you can imagine I am quite worried now.  We lost three years growth  and then this recent turn of events and I am really writing to ask which tests are still regularly being done for these children that are simply a must and cannot be compromised on.   I need to complain about his healthcare and be able to fairly state which they must run and why.  I always perceived them all important as some reading of some complement others and give you the whole picture of what is happening for the child.  Before having on line connection, I just had your book and basically that was the level to which I was educated.  Now I have educated myself, I find it almost unbearable to have my sons treatment this way knowing why these tests are important, and have this Hospital cutting back financially where their regard is. 

I await your response and would be very grateful of your input as I know that you are Internationally recognised and if I have some recommendations from yourself of how things should be up to date then I can be better able to negotiate what is "a waste of time" where tests are concerned and what are absolutely essential and how often they need to be done.  Thank you so much in advance,

Your sincerely,

Anne Jefferies

From: Garry Warne

To: ROOANNE

Sent: Friday, November 23, 2001 3:27 PM

Subject: Re: Congenital Adrenal Hyperplasia

Dear Mrs Jeffries,

Thanks for your enquiry. Certainly these levels of 17OHP are very high and the bone is very advanced as a result of increased androgen levels. You asked about our routines, so here they are. We carry out blood and 24h urine tests every 3 months, combined with clinical assessment. What we try to achieve at our hospital is a 9:00 am serum 17OHP level (with blood collected before the first daily dose of medication) of less than 30 nmol/L and the plasma renin should be within the normal range. We also measure 24 hour urinary pregnanetriol which is the urinary metabolite of 17OHP. We aim for the pregnanetriol to be somewhere near the normal rage for age. In addition, we monitor height, weight, blood pressure, degree of skin pigmentation, testicular size and stage of pubic hair development. The medication most commonly precribed for our patients is hydrocortisone and giving it three times a day is best if control is a problem. The usual dose range, related to body surface area, is 15-20 mg/sq. metre/day but some need much more than this. Fludrocortisone doses are usually around 0.1-0.2 mg daily. We don't use dexamethasone at all in growing children.

If you are in the North Island you should try to see Dr Wayne Cutfield at the Starship Children's Hospital in Auckland. There is no paediatric endocrinologist in the South Island which is a bit of a problem.

Best wishes,

Garry Warne

At 09:50 AM 23-11-01 +1300, you wrote:

Assoc. Prof. Garry L. Warne

Program Director

Royal Children's Hospital International

Senior Endocrinologist,

Dept of Endocrinology and Diabetes

Principal Fellow

Department of Paediatrics

University of Melbourne

Royal Children's Hospital

Parkville Victoria 3052

AUSTRALIA

Fax +61-3-9347 7763

Tel +61-3-9345 5951

----- Original Message -----

From: Garry Warne

To: ROOANNE

Sent: Friday, November 23, 2001 4:56 PM

Subject: Re: Congenital Adrenal Hyperplasia

*At 04:24 PM 23-11-01 +1300, you wrote:

Sir,
Thank you for your speedy response :)
 
Do you use suspension there in Aussie or have 1mg HCT pills?*

HIS RESPONSE:
No we use 4 mg and 20 mg tablets. You don't need to fiddle too much to achieve exact doses. Changes in 2 mg steps are adequate. We would usually make changes of about 20-30% per day if we were going to change at all.

 

 

*If not what is the lowest dose of HCT you can obtain ?  When you raise or decrease to tune a dose to a child what is the typical  amount you would go up or down to find one that is suitable?
Would you raise each dose in the day or just one or two?* 

 

HIS RESPONSE:
We would probably raise the morning and evening dose and leave the afternoon one the same.

*What is the typical % is what I am trying to decipher would be best to increase in small children to allow for good normal growth?  My sons doctor scripted us:
5mg
3mg
7mg
=15mg*

HIS RESPONSE:
I think that 5, 2.5 and 7.5 would be fine, as would 5 mg three times a day.

 

 

*Which was unattainable splitting 5mg tablets which are the lowest available in NZ.  this is most frustrating but I have a pill splitter and split the pills to 1,25mg and then I juggle to get nearest to the dose he has scripted at present.  I have also started a different dosing regime as I am up in the early hours with a small baby anyway.   Suspension is not subsidized here in New Zealand and is only available by claiming a special circumstances allowance which we were not granted.   
So I am currently giving him:
3mg - 3am
6.75mg-7am
5mg-3.15pm when he comes in from school
=15mg
I read that this emulates the circadian rhythms and actually now that I have switched to this dosing he seems to look over dosed slightly so I think he may need dropping down.  We have bloods done on the 29th November so I will note his 17OHP.*

HIS RESPONSE:
I don't know anyone else who wakes up at 3 am to give it! It should not be necessary to do this. He just needs more steroid overall. I would probably increase him to 20 mg and re-test in 3 weeks to assess the effect, then go up or down from there. You need to ask your doctor if your son is entering true puberty now: in other words, does he have testicular enlargement?

 

(You should note here that THIS particular Endo along with many other's would not advocate waking at 3am to dose a child.  The abstract that we were discussing had only been published in October 2001)

 

 

*I understand the normal ranges to be between 10-50.  How much before 10 would you let them go before you assume he needs a reduction and what % would you cut back is needed.  I just want to ensure that any dose alterations up or down in future are typical with what you yourself would do since I know you specialized for years. *

HIS RESPONSE:
Don't go below a 17OHP of 10nmol/L at all. It's unnecessary.

 

*I give the Florinef at 7am (100mcg---0.1mg) with the early morning dose.   Is that the best time to give this?* 

HIS RESPONSE:
It doesn't matter when you give Florinef because it is a long acting drug. Once daily is fine

 

                                                     *******

(Could I just make an observation here.  Yes Florinef is a long acting drug.  However, it is just the same as dex in that when first given the levels are high.  Eventually it reaches a half life and then decreases thereafter in the blood serum.  I feel that given "anytime" would be the wrong thing to do. 

Too much in one place leaves you short or low in another within that 24 hour period.  That is why we spread the dose 50mcg, 25mcg and 25mcg.  I felt that after reading the abstract about it enhancing hydrocrotisone in treating CAH that we needed to dose it that way.  Not high at one end of the day and low at another.  i felt also thataldosterone would b playing an important role normally at night as since we are not drinking fluids, that we would need to retain more.  It would stop you running to the loo all night and becoming very dehydrated.  I think really that they need to measure the aldosterone with the circadian rythms also to really study ho this should be dosed in these kids.)

 

                                                 *******

 

Back to the e-mail:

 

*Also if I am dosing at 3am, would that affect the morning blood tests?  We decided to use this dosing regime so that we could utilize GH between him going to bed at 8pm and the 3am dose.  Since he has lost height I am not comfortable giving a large dose at night when cortisol is not required until 2-3am. *

 

HIS RESPONSE:
It's a bit over the top I think. I understand why you are doing it but it would be far better if you could establish a relationship with a doctor you could trust and let him/her make the decisions.

 

 *I have lost a lot of faith and trust in the doctors here since all this happened and want to survey other CAH experts to correlate what has happened and what is exactly "normal" for these children.  Would you say that with the extreme over and under suppression that we have had that that is "typical" of "normal" of what should happen with a child these days with CAH? *

HIS RESPONSE:
No it's not typical. However some kids can be difficult to control and that's why some elder statesmen of endocrinology are advocating removal of the adrenals.  It would in fact help some children and your son could be one like that. After removing the adrenals, the source of androgen is gone (until the testes swing into action at puberty  and hormone replacement is much more straightforward. Apart from the risk associated with surgery, the risk to life and health in a salt waster is not altered.

 *Thanks very much for your e-mail, and thanking advance for your response.*

HIS RESPONSE:
It's a pleasure. Where are you located in NZ?
Garry Warne

 

*My Final Comment back:

Yes we are in New Zealand and are part of the Support group here,which I am not deriving much support from presently.  I feel that I am going quite mad with it all actually.  it's like they think because I would like them to follow the correct protocol where testing is concerned that I am being fussy.  Its very frustrating.  I DO want to trust them, it was far easier for me as a parent when I could relax.  after he was born and I got over th initial shock, I relaxed to the degree that he was just a normal child and I had four other children and he just blended in as the others as no more special.  Now that we are having problems and I see all these discrepancies in his medical file and the troubles lately, I am worried about his final height potential.  We are relatively short (5' 2"  & 5' 6") so really I just want him to achive as good a final height as they can squeeze out of him then he is not self conscious as an adult.  Thank you for your time.  You are most kind.  I will let you know how that dosing regime goes! 

Kind Regards

 

 Anne Jefferies*

 

My Summary:
I have come to the conclusion that ALL  doctors are different in the way that they monitor and treat children---even the ones doing so for up to 30 years.  That is why we need to ONE International standard for ALL testing in CAH.  ONE International basic standard for treatment in CAH.  Anything that deviates from those standards need's to be having the fully informed consent of the parent OR the child if they are old enough to understand why they need the different treatment. 

Monitoring:

Once every three months AT THE LEAST.  Should the child's bloods be out of the ranges for 17 OHP and this should correlate with other bloods taken at the same time such as androstenedione or testosterone, then the bloods should be monthly.  This is for not just under but over suppression ALSO.  I think that there should be a broad range of tests done to confirm the 17 OHP results atleast EVERY three months.  These should be 17 OHP, Androstenedione, Testosterone, Renin, ACTH, Cortisol.

The androgens will be taken to confirm any under suppression that has been occuring.  The cortisol and will help confirm over suppression.  It should be taken BEFORE meds are taken for that reason.  The test would therfore need to be done BEFORE the usual morning dose is taken to avoid 17 OHP levels elevating and confusing the results.  If the child is upset with blood draws and can do urine tests then these should be done to check for the same hormones.  The 17 OHP that is too low, that being under 10nmol, or too high, that being above 50nmol and  confirmed with the other tests drawn with it should be repeated four weeks from the tests results being received.  If the results come back consistently over or under then this is good enough reason to consider cropping the dose back or raising this according to over or under suppression.  

X-RAYS

Should be done 12 monthly from the age of one year old.  If diagnosed late then done AT diagnosis and then every twelve months thereafter.  IF the child is overly exposed to androgens in ANY of that 12 month period for any length of time enough to cause symptoms not normally present except within puberty, then they should have an extra X-RAY.  If they failt to grow over two blood tests (three monthly) then an extra X-RAY should be considered to check the bone age.  If the results are vurtually unchanged then this is enough to cut or raise the dose in my opinion.  Especially so if the child shows outward signs of over suppression such as puffy face or emotional changes.

TREATMENT (BASIC):

I feel that it technically does not matter which corticosteroid is used to treat the child as long as it is doing what it should do.  I think that if your child is able to, they should ALL go in for 24 hour profiling occasionally if there is some difficulty tuning the meds and the child has had growth problems in BOTH directions.  As long as the doctor treating is familiar with the type of drug he is controlling the child with and doses it as it should be, fine.  However, ANY drug that is newly introduced I feel really needs to be having the express permission of the parent.  Any treatment method that deviates such as surgery also.  Full counselling should be given to girls parents BEFORE they are asked what they would like for their daughters.  This should include ALL information currently available on the surgery and what is known regarding the long term results of such surgery in adult women with CAH.  It should be encouraged for this to be fully informed consent and left to the child where this matter is concerned.   Should the child have physical ill health due to surgeries not being performed then this should be reassessed and discussed and ALL options thoroughly gone over.  What can be done at that particular stage, i.e. making an opening to help with any reflux taking place.  Even then couselling should be offered for the parents and the child right into adoloescence all the same even after any surgery has been done.  The child should be fully informed of why surgery was done and why when they are old enough to understand.  Doctors should not take any stance whatsoever in one direction or the other where sugery is concerned.  They should ensure full counselling first and then listen to the parents cue's from there. 

Studies need to be done in the following:

***The circadian rythyms of aldosterone. Therapy should be changed to conform to this when the studies have been done.

***Different potencies of different steroids and where they are best to be taken and why to avoid side effects.   We know about Hydrocortisone now.  We now need the same done with Dex and Pred or any others used in the treatment of such.

***The effects of over and under suppression on behaviour and learning.

***The effects of Physical activity that exceds normal exhertion upon cortisol and aldosterone levels and 17 OHP levels in healthy and then CAH individuals to compare the differences.

 

DRUGS:

I feel that all children should be treated with tablets after the age where they are weaned ideally.  Any suspension should be made by a local pharmacists as opposed to being manufactured and transported to the pharmacy.  The ingredients of which should be basic and no additives,flavorings or colours.  Tablets should be provided in the following does in all countries and fully subsidized:

Hydrocortisone:

1mg,5mg.10mg,20mg

The 1mg pill can be split to as small as 0.25mg if necessary.  This can be dissolved for small babies and fed with food or drink.

A sustained release 1mg Hydrocortisone tablet to give last thing at night that does not release it's contents for several hours.  if given for example at 10pm, it does not release its content until 4 hours later.  (Do ya think that they can do this anyone? )

***Prednisone and Dex should also be made as above and supplied in Paediatric doses of the equivalencies above.***

Florinef will need to be supplied in smaller doses so that the treatment can be spread out over the day IF the studies done on the circadian rythyms of aldosterone production in normal healthy individuals recommend that it should be dosed like this.

I think I have covered most everything here.  We need someone to basically take what has written for treatment and monitoring and do something with it.  Too much of the problem is that no one really goes into depth.  perhaps if we supply a body like The magic Foundation with such and have it approved by an Internationally recognised Doctor who treats CAH, we will be half way to having an International Standard in both treatment and monitoring atleast BASICALLY.  As for the drugs, we really need the above doses in the long run.  Bear in mind that these are what the kids need as basic requirement before the doctors can start controlling the condtion better.  To my mind as I have said before, the treatment has been around some 60yrs.  It is a very poor world that we live in when a child can be suffering side effects and under dosed symptoms of corticosteroids in this condition.  Especially with all the scientific achievements that have been and are made very year that goes by.  It is hard to believe really when we are seeing new innovative drugs being developed and cures for condtions all the time and nothing being done about the drugs that have been around for so long now and saving childrens lives.  They ARE saving lives but sometimes there are costs incurred for these children when they are not monitored correctly.  Every effort should be made to therefore get the above brought about.  When manufacturers do not take the initiative to make such, the Doctors are in effect limited by their standards of treatment and what they can script.  So technically our childrens well beings are in the hands of the manufacturers in effect and the buck stops with them and the bodies that are responsible for getting meds approved for treatment in children with these drugs.

To adequately treat a child with this condition the manufacturers really play a vital part in improving things for the future.   Side-effects of these drugs are not pleasant.  Short term OR long term.  Why is this and why are all the other above matters not being addressed for these and other children dependant on such medication for basic every day life?

When you next go to collect your script, ask your pharmacists who supplied your childs pills.  Please contact the manufacturer and explain all of the above.  Send them information and take a part in getting some way towards educating these people.