Tuesday, July 29, 2008

Recommendations for dental problems with SDS by Dr. Michael Glogauer:

Recommendations for dental problems with SDS by Dr. Michael Glogauer:

1. Visit your dentist at least every 6 months and more frequently (every 3 months) if oral problems have developed.
2. Discuss home topical fluoride treatments to prevent dental decay.
3. Monitor gums and oral tissues for inflammation and infections (red puffy tissue that bleeds easily) which indicate early periodontal diseases associated with neutropenia.
4. Provide your dentist with Dr. Glogauer’s research paper so that s/he understands the oral problems associated with SDS. (I have the full-text PDF of the paper, if you need it)


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Notes: Q&A Hem notes

There was a Q&A with Dr. S and Dr. H after their talks. These are my notes from that Q&A session.

I have written down “del 7q is serous” here was mention of del 20q and how it is not as serious as the other clonal abnormalities.

A question came up of using dedicated donors when our SDS kids need transfusions of red cells and platelets. Here is what I wrote down from their answers:

Dedicated donors: DO NOT USE FAMILY DONORS! Relatives as donors increase the risk of graft rejection post transplant.

Donor drive donors have been shown to have a higher risk of infection—volunteer donors are best. When people are *forced* to donate blood products, say because of a co-worker doing a drive, they feel as if they have to give –and will go with infections, etc…..

Random pooled platelets? Or Pherised (sp) platelets to minimize donor exposure? This is becoming less of an issue with newer techniques. Data doesn’t necessarily support this.

Female bone marrow donors—pregnancy (number of) makes a difference—more antigens— if all things are the same in two donors except one is male and one is female w/ pregnancies, they would choose the male.

HLA Loci are located on Chromosome 6. Parents are unlikely to be a match (less than 1-2% chance that parents would be an HLA match for their children)

Growth hormone studies. There are no studies showing increased risk. Talked about the possibility that high doses might have increased risk, but that there really are no studies. There is no data on GH in SDS. Dr. Durie weighed in and said that SDS is a chondrodysplasia meaning that growth plates do not behave themselves & may result in premature fusion of the growth plates (if GH used) no real data, of course & he said that he was very conservative…if the SDS patient was TRULY GH deficient, then he may try it.

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp notes: BMT

I wrote down a few things he said that were not on his slides…… just thought I’d share for those interested.

There are 7-8 million people in registry (US) and there are more in Europe. (This is up from the stats in 2006!!! Interesting)

He has a bit on the slides about the regimen…but not with numbers—he said they used this regimen on 50 patients in Cinci (I believe they were all Fanconi’s patients who have the same toxicity issues as SDSers) and they have used it on the 7 SDSers he reports on the slides.

The aplastic anemia patients did better than the MDS and Leukemia patients. The one adult with Leukemia is currently going through transplant again there in Cinci.

The regimen in Cinci begins 3 weeks before transplant—they start the Campath then. (this is on the slides)

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

SDS Article:Myocardial function in patients with Shwachman-Diamond syndrome: Aspects to consider before stem cell transplantation.

Myocardial function in patients with Shwachman-Diamond syndrome: Aspects to consider before stem cell transplantation.
Toiviainen-Salo S, Pitkänen O, Holmström M, Koikkalainen J, Lötjönen J, Lauerma K, Taskinen M, Savilahti E, Smallhorn J, Mäkitie O, Kivistö S.Helsinki Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland.
BACKGROUND: Early studies have suggested increased risk of fatal cardiac complications in infants with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome. Patients undergoing stem cell transplantation (STC) have appeared susceptible to organ toxicity, including cardiac involvement. PROCEDURE: This study assessed anatomical and functional features of the heart in SDS. Eight patients (mean age 24.1 years, range 7-37 years, seven males) with SDS and confirmed SBDS mutations were prospectively assessed for cardiac anatomy, myocardial wall properties, and systolic and diastolic function. The study protocol included conventional echocardiography (n = 8) complemented by exercise Tissue-Doppler echocardiography (n = 7), and by MRI (n = 6). RESULTS: No abnormalities in cardiac anatomy or function were observed in baseline clinical assessment, EKG, or conventional echocardiographic and MRI measurements. Myocardial structure and left ventricular (LV) mass were normal. The maximum isovolumic acceleration (IVA) value during exercise in Tissue-Doppler was significantly lower (P < p =" 0.02)" p =" 0.008)">

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

camp notes: more hematology

These were from a talk by Dr. S..... she gave handouts later. She said the studies are limited.

Evaluation of low blood counts
r/o other treatable causes of low blood counts

anemia-- blood loss, antibodies, erythropoietin levels
neutropenia - infections or medication

G-CSF increases neutrophils and not all patients respond. Indications for using G-CSF:
neutropenia with persistent or serious bacterial infections or fungal infections
neutropenia w/ history of recurrent bacterial/fungal infections, gingivitis or mouth sores
some centers recommend G-CSF prophylactically for persistently low neutrophil counts (<200-500)
need to weigh potential risks
G-CSF potential side effects:
bone pain
enlarged spleen (associated with chronic use)
?osteopenia (seeing it in SCN patients-not sure if it is the underlying disease or from G-CSF)
Anectdotally- kidney problems
Bone marrow exam with cytogenetics should be done prior to initiating therapy with G-CSF. No causal relationship between cytokine therapy and leukemia has been demonstrated to date, but can;t rule it out, either.

Leukemia patients have used G-CSF to get through chemotherapy and have not seen an adverse effect. Not sure if you can extrapolate this to SDS population.

Supportive care for Anemia
Transfusion
Indications for transfusion: symptomatic anemia, fatigue, exercise intolerance, rapid heart rate and breath rate, poor growth

Rough guide: transfuse when hemoglobin is <8 -- this varies from patient to patient.

Risks of transfusion
allosensitizatization: patient develops antibodies against transfused red cells or platelets such that transfused cells are rapidly destroyed (makes transplant harder)
iron overload secondary to red cell transfusion (also makes transplant more difficult) (can use chelating agents)
transfusion reaction
infection (blood borne)
high body iron stores puts you at risk for transplant complications.

supportive care for thrombocytopenia

Indications for transfusion: symptomatic, bleeding, bruising and prophylaxis prior to surgery
20,000 is usually uses, but studies show 5,000-10,000 can be okay. Must consider the patient....for instance, a toddler who is always bonking his head.....transfusion would possibly be considered at a different number.

must also check Vit K levels....low vit K levels with low platelets can cause worse problems. Also, liver function can be a cause of bleeding problems.

Risks of platelet transfusions-- infections

For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp notes Dr. S BMT talk/Suggested monitoring of bone marrow failurees:

Dr. S and Dr. H both gave talks on BMT topics. Dr. H had handouts and I don’t think Dr. S did—she did get her hematology 101 or hematology basics handouts to us….. these are my notes from her talks…. If she had hand outs and I missed them….could someone send me a copy?



Here are my notes from her talk on BMT:



One of the questions she had up on the board was: when should transplant be considered?



Donor selection



First choice: HLA matched sibling who does not have SDS.
Be sure to check CBC for siblings. This is particularly difficult in patients without SBDS mutations. This is important! Must look for even subtle changes in CBC or marrow in sibling donors.


Basic principles of HSCT

Cytoreduction (conditioning)
immunosuppression (prevent graft rejection)
myeloablation (make room for new stem cells)
anti leukemic effect (kill minimal residual disease)


Conditioning—this is done by using chemotherapy with or without radiation (TBI) (TBI= total body irradiation)


Acute complications of allogeneic SCT

Immunologic
Endocrine issues are particularly important for children
Increased risk of solid tumors


Reduced Intensity Regimens

Advantage: reduced toxicity of conditioning regimen
Potential problems: not myeloablative (at least not in non-SDS patients)so there is a theoretical risk that premalignant host marrow cells might persist. It might actually be sufficient, but marrow might have SDS marrow left so SDS cells left could cause problems (Dr. Harris addressed this in his talk—not on his handouts--)


Timing of transplant

Factors increasing transplant associated risks
active or occult infections
organ dysfunction
leukemia (need to identify patients at high risk for leukemia)
Age: as patients get older, more side effects/transplant related risks increase
Risk of “preemptive transplant”

Cannot predict whether any individual patient will eventually need a transplant


Transplant planning

HLA matching—get plans in place—it can take up to 6 months to find a donor.
If you have a rare HLA type—start early


Suggested Clinical Monitoring of Bone Marrow Failure

If blood counts are stable (in the normal/mildly low range)and clonal cytogenetics are absent: blood counts every 3-4 months and Bone marrow with cytogenetics every year
Clinical management if new cytogenetic clone is detected or blood counts are falling or rising: counts every 1-2 months, BMB with cytogenetics, then every one-six months, have plans for possible transplant in place. If everything then remains stable, may be able to back off of such frequent monitoring, but the clinical course will determine this.


Dr. S felt that it is important to use a study protocol so that they can learn from the experience. There in Seattle, they are using a new protocol called protocol 2256 using Treosulfan. Treosulfan has been used in SDS patients in Europe. The contact for the Seattle (she flashed this fast) is : lburrough@fhcrc.org


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp notes: Celularity

On Dr. S’s handout I wrote this from her talk:



“Why do we do both BMB and BMA? A looks at individual cells—and we cannot estimate cellularity from the aspirate.” “Interpretation of cellularity needs to be made with caution. It depends on where you sample. “



For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp notes: SDS behavioral, social and learning issues

Great talk by Dr. Kerr.

She said that our SDS kids need to have neuropsych evals and to be sure that is what we got….because many psychologists are limited to achievement testing. There are actually colleges who now offer special services….look on the websites for more info (the particular colleges—she did not list them) She gave handouts for her talk, so my notes are short on this one. SDS kids need to be taught specific learning strategies when they have problems… When I get home, I can type in more from the handout—very interesting stuff…I believe the handout said there was a bit more of ADHD in SDS…..


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Notes: Skeletal and Dental

Skeletal abnormalities—most have them or can develop them. Dysplasia means something that does not form properly. Chondrodysplasia refers to the Metaphyses.



Metaphyseal dysplasia is found in 44-77%
Delayed bone maturation found in up to 100%
Rib +/- thoracic cage abnormalities f found in 32-52%
One study of 15 patients with SDS and SBDS mutations found that skeletal dysplasia was present in all patients & there was no correlation between severity of PI or blood counts
Secondary ossification centers have delayed appearance—they are normal and are just delayed/slow in developing. There is normalization with age.




Metaphyses/Growth Plates



· Widening and irregularity in ribs—this also occurs in Vit D deficiency and Rickets

· There can be progressive metaphyseal irregularity and sclerosis

· Those listed above do not cause pain or problems (Metaphyseal Dysplasia)



SDS patients also often have Osteopenia and wormian bones. These are not a secondary thing due to deficiencies. Careful radiographic follow-up of all patients is warranted. Osteopenia is likely due to low bone turnover…i.e. the bone making cells not doing their job fast enough. Appearance of the gestational mice in the lab with SDS showed normal skeletons—the only difference was the size.



Oral Study Results --SDS patients had more tooth decay and also had more mouth sores than the non-SDS patients in the study. They don’t know if there is anything that can be done to fight osteoporosis. It is primary to the condition. Other things need to be ruled out—just to be sure. Check for hypothyroid and hypoparathyroid. Vit K2 Co factor……


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Notes: SDS Genetics

Dr. Rommens gave some wonderful talks. As we all know, SDS is autosomal recessive. She went into the inheritance patterns of SDS, etc. The SBDS mutations (when someone had them) are in all the cells of the body. (Constitutional make up of all cells)



I took a lot of notes…… but am only putting in the *important stuff* . SBDS is 1/10th the size of the average gene (I thought this was interesting) There is an SBDS Pseudogene that we all have….yes, everyone has a copy of the SBDS pseudogene. The pseudogene (the SBDS P) has very little functioning protein and is very unstable.



To the best of their knowledge, carriers of SBDS (heterozygous/one gene copy) are unaffected
More than ½ of the SDS patients have the common mutations on exon 2
2 common mutations and 38 known rare mutations now
SDS exists all over the world and some changes are unique to the various populations (again, most have common 2 mutations on exon 2 >50%)
Small number of families with SDS disease and no identified mutations
Families without clinical picture of SDS disease with both hematological and pancreatic dysfunction (at least) do not have mutations in SBDS
One dilemma in SDS is that they do not know the impact of the genetic changes
SBDS is expressed in almost all tissues and they don’t; know why some don’t show symptoms (i.e. variability in disease)
SBDS is highly conserved in all organisms except for bacteria


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Notes: Hematology

The Hematology session (formerly called Hematology 101)

Some of the talks gave handouts—this was one of them….so I only have a few notes. Once I get home, I will try to add more to this.

Must interpret cellularity in context with the CBC
If the CBC is normal and there is low cellularity, it may be a sampling error
Young children should be quite cellular
Be sure that the marrow is read by those who work with children’s bone marrows…..


There was talk of clones, etc……. can’t draw pictures in email! LOL


CGH is a new genetics test like FISH that paints chromosomes various colors. We were told it is in the research stages—but know one person who has had it done.

MDS/Myelodysplastic syndrome is a highly contested area in IBMFS

People with IBMFS have abnormal marrows and may look like MDS marrows. MDS diagnosis is more complicated in SDS. Adult hem/oncs would say definite MDS…but in SDS it could be normal.

Hypo cellular marrow—mild decrease—wait and watch. The functional test is the blood counts. Over time, if cellularity is dropping and if counts also drop……it is premature to go to transplant with just low cellularity and normal counts.

Notes from Hematology break o0ut session:

I asked about kids without mutations that have been called SDS-like….when looking at the marrow, can you tell they have an inherited bone marrow failure syndrome? Could normal kids have some abnormalities in their marrow.

Yes, normal kids could have something pop up, and that is why repeat marrows are done. i..e if you have an abnormality (mild) in one our of five marrows, then it would be okay for a normal person to have it—but when you have a child who has abnormalities in every marrow, it is a clue to diagnosis.

He explained that of the kids with inherited marrow failure syndromes, 50% are diagnosed…. The other 50% don’t fall into the *named* IBMFS….but they know they have a BMFS because more than one child/person in the family has it

It can be autosomal recessive like SDS or autosomal dominant like SCN or sex linked recessive like DC (only males & skips a generation)

Looking at the marrow, you may not be able to tell that a person has an IBMFS…..

If you have one cell out of 20 with a chromosomal abnormality, it can be considered to be normal. If you have 2 out of twenty, it is a clone. FISH 4% of monosomy 7 is *okay* (tried to paraphrase what he was saying. It is not normal to have 4%, but continued follow up is needed. He went on to explain that sometimes cells can be together and sludge, etc…so that is why follow up is needed.

We talked about iron stores…and there are types of iron stores that you don’t want—especially ringed sideroblasts.

CBC is a late spot for leukemia or MDS. Cannot use CBC in BMFS—must do bone marrow biopsies.

Abnormal clones—even with normal counts must be followed closely with more frequent marrows.


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Sunshine Notes: Gastro, nutrition and SDS--notes from day one

This talk was about the exocrine pancreas, growth and nutrition

In SDS, there are too few Acinar cell- there is fatty replacement.

He gave the definitions of PI and PS

PI (pancreatic insufficient) – needs enzymes

PS(pancreatic sufficient) – mild to moderate pancreatic disease still capable of digesting food.

At diagnosis, 95% of SDS patients are PI ~50% become pancreatic sufficient over the first 4-5 years although starch digestion is still affected.

Monitoring the pancreas. Stool fat losses-72 hr test or the fecal elastase 1 testing, though there are no normal values established in SDS. Testing of blood enzymes (trypsinogen and amylase)

Pancreatic stimulation test has false positive results in 25% & is the most inaccurate--- in the US they don’t collect properly……… us the wrong hormone in the US in particular.

Pancreas testing should be done annually for the first 4-5 years, then if pancreatic function seems to be improved. If not PS by 4-5 years, then it is not likely the SDS patient will become PS

SDS patients may be functioning at 2-3 % of pancreatic function & not need enzymes

Most SDS patients have low serum trypsinogen and those with high serum trypsinogen or normal serum trypsinogen are PS.Growth and nutrition

Malnutrition and FTT are not a problem once feeding properly (enzymes, too) Short stature is the problem. Pushing feeding doesn’t improve the short stature. 80% are lower than the 50th percentile and many are in the 50th percentile. There was a 6’3” patient recently diagnosed….diagnosis came late because of his exceptional growth. So….SDS patients CAN BE TALL. INTERESTING…….. I think this was an interesting point because of comments made about Sean being in the 50th percentile in the past…. VERY validating for those of us with kids who are growing well. I also thought it was interesting that they said growth in SDS children is normal once the enzymes are started/ malabsorption is corrected…. SDS kids tend to grow normally……

Summary—prior to diagnosis FTT and malnutrition, but after diagnosis, these are not a problem SDS patients grow at proper rate once nutritional status improves.


LIVER

Enlarged liver can be the first clue to a SDS diagnosis. There can be fat in the liver cells. This is usually seen in people with obesity problems—(fat in liver). This seems to go away along with the elevated biochemical tests (liver enzymes). No intervention is usually necessary—Dr. Durie said to keep an eye on it if it is mildly elevated/mildly abnormal.

Fatty changes in the pancreas are not unique to SDS.

Trypsinogen is a precursor to trypsin. Amylase and lipase are not well developed at birth –even in normal kids.


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Camp Sunshine Notes:notes from day one-Dr. Durie SDS Clinical DIagnosis

I typed up all the notes I took at the doctor sessions at Camp......I am not a doctor.....and these are just my notes....consult your physician before trying or changing treatment!

We had some interesting talks today! First, Dr. Durie went over the clinical diagnosis of SDS and how it is established, etc. It is difficult to diagnose because there is no one single test and many organs can be affected. There is variability in presentation from person to person. There have been some patients who have had a large liver and that was the single thing that alerted doctors to start looking.



Requirements for diagnosis:



1) exclude other diagnoses

2) exocrine pancreatic insufficiency

3) bone marrow dysfunction



there are many conditions that are like SDS—disorders of the pancreas, various other hematological abnormalities and other growth disorders.



Pancreatic disorders:



CF 95%

SDS 3-5 %

Johanson Bizzard <1%

Pancreatic hypoplasia/dysplasia <1%

Isolated enzyme deficiency <1%



Dr. Durie shared that in all of his many years of practice, he has only diagnosed one case of Johansson Blizzard and 50-60 cases of SDS. Just to give an idea of how rare the other causes of pancreatic insufficiency/ pancreatic disorders are.



The bone marrow problems in SDS are not always easy to detect. Neutropenia can jump up and down.



Skeletal abnormalities.



The main skeletal abnormalities in SDS are:

1) abnormal Metaphyses

2) rib cage abnormalities

3) delayed bone age

4) progressive deformities

5) osteoporosis

6) pathological fractures



skeletal problems may not be present at infancy but manifest at a later age. Short stature is part of SDS not from the malnutrition or malabsorption. Malnutrition is corrected with enzymes and proper feeding. i.e. SDS folks have short stature by nature. Not all SDS people have a growth problem. In fact, SDS patients can absolutely have normal growth. They have recently diagnosed a patient with SDS who is 6’3”—SDS had been overlooked because the patient was so tall and his growth was so normal.



Mutations are found in ~90% of patients. There may be another gene responsible… SDS is a clinical diagnosis—not going to find mutations in everyone and/or don’t always pick up the mutations on the gene.



Obligatory for diagnosis: Exocrine pancreatic dysfunction, bone marrow dysfunction



Common: short stature, skeletal abnormalities, hepatic, behavior



He also mentioned something I thought was interesting (especially since Joseph is in an eczema flare) – a skin rash is common and it is like an allergic eczema rash.



Other things I noted from his talk:

in SDS weight is usually proportional to height—pushing feeding doesn’t make them grow more.
Bone age delay—at puberty bones have longer to grow



Part of SDS


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America

Saturday, July 12, 2008

Genetics 101

A friend sent this link to me a few months ago. It is a great place to get a basic understanding of genetics. Genetics 101


For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America