Growth Hormone in Shwachman-Diamond Syndrome

I cut and pasted from the eMedicine article. Such a shame that medical professionals still cannot SPELL the disease. SIGH.


Growth hormone has been used to treat children with Schwachman-Diamond syndrome who have growth hormone deficiency. The initial response is good; however, long-term therapy with growth hormone is unsuccessful.

It comes from the eMedicine article on SDS found here: http://www.emedicine.com/ped/topic2060.htm

The reference is gives is: Marseglia GL, Bozzola M, Marchi A, et al. Response to long-term hGH therapy in two children with Schwachman- Diamond syndrome associated with GH deficiency. Horm Res. 1998;50(1):42-5




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

Shwachman-Diamond Syndrome Registry

You can contact the SDS registry for info on how to register. Melissa Alvendia malvendi@fhcrc.org Questionnaires are available, but the website is not up and running yet. It will hopefully be on-line soon. They also have pamphlets in PDF…but the margins are off when they are printed. They are working on getting all the supporting organizations a flyer that is easier to print. I just got an email about the flyer last night—so hopefully it will be soon.

The website for the registry will be located at www.SDSRegistry.org



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

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane.

Apoptosis. 2008 Nov 14.

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane.
Watanabe KI, Ambekar C, Wang H, Ciccolini A, Schimmer AD, Dror Y.

Shwachman-Diamond syndrome (SDS) is an inherited disorder characterized by reduced cellularity in the bone marrow and exocrine pancreas. Most patients have mutations in the SBDS gene, whose functions are unknown. We previously showed that cells deficient in the SBDS protein are characterized by accelerated apoptosis and Fas hypersensitivity, suggesting that the protein might play an important role in Fas-mediated apoptosis. To study the mechanism of Fas hypersensitivity, we compared shRNA-mediated SBDS-knockdown HeLa cells and SDS marrow CD34+ cells for their sensitivity to several groups of apoptosis inducers. Marked hypersensitivity was noticed in response to Fas stimulation, but not to tumor necrosis factor-alpha, DNA-damaging agents, transcription inhibition or protein synthesis inhibition. To identify the Fas signaling factors that cause hypersensitivity, we analyzed the expression of the pathway's proteins. We found that Fas accumulated at the plasma membrane in SBDS-knockdown cells with corresponding expression of Fas transcript 1, the main Fas transcript which contains both the transmembrane domain and the death domain. However, the total levels of Fas protein and mRNA were comparable to controls, and Fas internalization occurred normally. Expression of FADD, caspase-8 and -3 were not elevated and the pathway inhibitors: ERK, c-FLIP and XIAP were not decreased. These results suggest that SBDS loss results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by Fas ligand.


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

Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A.

I have the full-text of this one-- very interesting article!

Blood Cells Mol Dis. 2008 Nov 15.

Depletion of the Shwachman-Diamond syndrome gene product, SBDS, leads to growth inhibition and increased expression of OPG and VEGF-A.
Nihrane A, Sezgin G, Dsilva S, Dellorusso P, Yamamoto K, Ellis SR, Liu JM.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by bone marrow failure and leukemia predisposition, pancreatic exocrine dysfunction, and skeletal abnormalities, manifesting as skeletal dysplasia and osteoporosis. Mutations in SBDS have been shown to cause SDS, but the function of the SBDS gene product is unclear. Accelerated angiogenesis has recently been described in bone marrow cells from SDS patients. To clarify the unknown function of SBDS, we performed experiments analyzing the cellular effects of depleting SBDS by RNA interference. The growth of HeLa cells constitutively depleted of SBDS was markedly hindered when compared to cells stably transfected with siRNA against an irrelevant control gene. Similarly, growth of HeLa cells induced to express siRNA against SBDS was specifically inhibited. Inducible SBDS knockdown was associated with modestly increased levels of apoptosis, suggesting a partial contribution of this process to growth inhibition. By microarray analysis of knockdown cells, we found marked differences in expression of genes in multiple pathways, and we chose to examine a selected subset more closely using quantitative PCR arrays. In constitutive and inducible SBDS-depleted HeLa cell clones, we found 3- to 6-fold elevated mRNA levels of osteoprotegerin (OPG or TNFRSF11B) and vascular endothelial growth factor-A (VEGF-A). We confirmed significant overexpression of both secreted proteins by ELISA from supernatants of SBDS-depleted HeLa cells. Osteoprotegerin and VEGF-A are known to have diverse effects on osteoclast differentiation, angiogenesis, and monocyte/macrophage migration, all processes that may be aberrant in SDS, and we propose that overexpression of these factors may contribute to its pathology.

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

Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome.

Br J Haematol. 2008 Nov 11.
Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome.

Crescenzi B, La Starza R, Sambani C, Parcharidou A, Pierini V, Nofrini V, Brandimarte L, Matteucci C, Aversa F, Martelli MF, Mecucci C.

Summary SBDS/7q11 gene mutations underlie the congenital Shwachman Diamond syndrome (SDS), characterized by bone marrow failure and high risk of haematological malignancies. In two cases of SDS with bone marrow failure and isolated del(20q) interphase fluorescence in situ hybridization (I-FISH) found no abnormalities in FHIT/3p14.2, IKZF1/7p13, D7S486/7q31, PTEN/10q23.3, WT1/11p13, ATM/11q23, D13S25/13q14, TP53/17p13, NF1/17q11, SMAD2/18q21, RUNX1/21q22. Fluorescence immunophenotype combined with I-FISH found del(20q) in a totipotent haematopoietic stem cell (CD34(+), CD133(+)) and downstream myelocyte (CD33(+), CD14(+), CD13(+)), erythrocyte (Glycophorin A(+)) and lymphocyte lineages (CD19(+), CD20(+), CD3(+), CD7(+)). These findings and clinical follow-ups confirm the benign course of SDS with isolated del(20q).


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

Fecal fat

here are a few good links for information on fecal fat tests and results:
http://www.medhelp.org/perl6/gastro/archive/2847.html

http://pediatrics.aappublications.org/cgi/content/abstract/46/5/690

This site has pediatric reference ranges:

http://www.aruplab.com/guides/ug/tests/0020386.jsp



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

Shwachman-Diamond Syndrome Information

This site has information on SDS including the common cytogenetic findings in SDS, telomeres, and information on P53 protein overexpression. http://atlasgeneticsoncology.org/Kprones/ShwachmanID10058.html




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

GREAT UK SDS video

Thank you to all who made this video possible-- the camera crews, the doctors who spoke and Jules who jumped out of the airplane! Great awareness video!

Iron Deficiency Anemia - Iron Stores

Great site about Iron Deficiency Anemia. Also has info on iron stores in the marrow along with pictures.

http://www.med-ed.virginia.edu/courses/path/innes/rcd/iron.cfm

Shwachman-Diamond Syndrome on Mystery Diagnosis

Part one:



Part two:

Bone Scans

Here are a few articles that will be helpful in understanding bone scans:

http://www.lifesteps.com/gm/Atoz/ency/bone_nuclear_medicine_scan.jsp


http://www.webmd.com/a-to-z-guides/bone-scan

Bone scans detect inflammation, cancer and new bone growth......



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

Iron Testing

DrGreene Content

The "Iron Test" FailsMany children in the United States get a simple screening blood test to check for iron deficiency – but the test doesn't work! The test does identify anemia (not enough red blood cells) by measuring either the hemoglobin level (hgb) or the hematocrit (hct). But parents are often told that if the test is low, the child needs more iron – or that if the test is normal, the child's iron level is fine. Because getting enough iron is so important to normal development, the screening test is required by many Medicaid insurance programs. All children must have the test to qualify to get food in the Supplemental Nutrition Program for Women, Infants, and Children. But the test had not been checked for accuracy in the last twenty years. According to a study in the February 2005 Pediatrics, the test fails to identify most kids with iron deficiency. It's true that kids with iron deficiency are more likely to be anemic than other kids, but the correlation is not strong enough to make the test useful. The test is wrong more often than it is right. More than two thirds of the children with a low hgb or hct have normal iron levels. They are anemic for other reasons, such as a recent viral illness or genetic trait. More disturbingly, more than two thirds of the children who are truly iron deficient will have a normal screening test. We routinely fail to identify children whose iron levels are low enough to affect their intelligence. We need better tests. In the meantime, it's important to be sure that toddlers have diets that are rich in iron or take a multivitamin with iron.
Alan Greene MD FAAPOrginally published: February 25, 2005

from this link: http://www.drgreene.com/21_1881.html



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

p53 Protein

p53 protein overexpression in Shwachman-Diamond syndrome / In reply
Archives of Pathology & Laboratory Medicine, Oct 2002 by Dror, Yigal, Elghetany, M Tarek, Alter, Blanche P

To the Editor.-We read with great interest the paper of Drs Elghetany and Alter in the April 2002 issue of the ARCHIVES.1 Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystemic disorder characterized by varying degrees of marrow failure and a high propensity for malignant myeloid transformation into myelodysplastic syndromes (MDS) and acute myeloid leukemia.2-4 The authors found p53 overexpression in bone marrow biopsies from 9 patients with SDS. None of the bone marrow biopsies from patients with acquired aplastic anemia or acquired cytopenias and none of those from individuals in the control group had overexpression of p53 protein. Very interestingly, p53 overexpression in patients with SDS was comparable to p53 results in 46 bone marrow specimens from patients with refractory anemia. Refractory anemia is a subtype of MDS.
Although neither the method for selecting patients nor the clinical phenotype of the patients was specified in the paper, the authors' work is important and furthers our understanding of the relationship between SDS and MDS. Myelodysplastic syndrome is a preleukemic, stem cell disease with peripheral blood cytopenia, ineffective hematopoiesis, and varying degrees of bone marrow cellularity and dysplasia. Shwachman-Diamond syndrome meets many of these criteria2: it is a stem cell disorder with peripheral cytopenia, ineffective hematopoiesis,5,6 and varying degrees of bone marrow cellularity, and it carries a significantly increased risk of leukemia.2-4 In addition, scattered mild dysplastic changes in the erythroid, myeloid, and megakaryocytic precursors are commonly seen on careful examination of bone marrow biopsies of patients with SDS2 and are part of the syndrome. Further, the close relationship between SDS and MDS is reflected by similar defects in marrow stromal support of normal hematopoiesis,5 increased apoptosis mediated through the Fas pathway,6 a high frequency of clonal marrow cytogenetic abnormalities,2 and as the authors showed also by a prevalence of p53 protein overexpression that is similar to that in patients with refractory anemia.1 Therefore, SDS seems to be a myelodysplastic disorder from its inception. We therefore consider SDS to be refractory anemia 2 or refractory cytopenia according to the CCC (category-cytology-- cytogenetics) classification of childhood MDS.7 When we refer to malignant myeloid transformation in SDS, we mean stages beyond refractory anemia, namely refractory cytopenia with cytogenetic abnormality, refractory anemia with ring sideroblasts, refractory anemia with dysplasia, refractory cytopenia with excess blasts, or leukemia.
We have recently analyzed bone marrow mononuclear cells from 11 patients with SDS (2 had a clonal marrow cytogenetic abnormality), and we did not find mutations in exons 2 through 11 of the p53 gene.2 Therefore, p53 protein overexpression in SDS can result from either upregulation of the functional p53 gene (as the authors postulated) or posttranslational modification of the protein, rendering it more stable than the wild type protein, which normally cannot be detected.
YIGAL DROR, MD
Marrow Failure and Myelodysplasia Programme
Division of Hematology/ Oncology
The Hospital for Sick Children and the University of Toronto
Toronto, Ontario, Canada M5G 1X8
1. Elghetany MT, Alter BP. p53 Protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126:452-455.
2. Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30:659-669.
3. Mack DR, Forstner GG, Wilschanik M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:15931602.
4. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br] Haematol. 1996;94: 279-284.
5. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999;94:3048-3054.
6. Dror Y, Freedman MH. Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood. 2001;97:3011-3016.
7. Mandel K, Dror Y, Poon A, Freedman MH. Practical classification of pediatric MDS. J Pediatr Hematol Oncol. 2002;24:343-352.
In Reply.-We thank Dr Dror for his comments in support of our recent article.1 Our patients were unselected, and included all of those whose samples were available between November 1999 and November 2000. None of the patients with Shwachman-Diamond syndrome (SDS) had cytogenetic clones, and their bone marrow morphology did not show significant dysplastic features. Thus, p53 overexpression was the hallmark of the similarity between SDS and refractory anemia (RA). Dr Dror raises the interesting question regarding the relationship between this syndrome and RA. Although we agree with Dr Dror that SDS shares common features with RA, it may not be appropriate to classify all patients with this syndrome as having RA at the time of diagnosis. Other bone marrow failure syndromes, such as Fanconi anemia and Diamond-Blackfan anemia, share some features with RA as well.2,3 We are concerned that labeling SDS as RA may prompt an aggressive mode of treatment that may not be supported by data other than these similarities. Moreover, there are some indications that myelodysplastic syndromes evolving from an inherited bone marrow disease may not have the same biological behavior as primary myelodysplastic syndromes in children.4 Longterm prospective studies and the continued search for an underlying molecular defect for SDS should shed some light on this rare disease and its relationship to RA.



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

Medications that Cause Neutropenia

Here is a link to a site that lists medications that can cause neutropenia:

http://www.globalrph.com/neutropenia.htm



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

Types of Eczema

Types of Eczema (Dermatitis)
Allergic contact eczema (dermatitis): a red, itchy, weepy reaction where the skin has come into contact with a substance that the immune system recognizes as foreign, such as poison ivy or certain preservatives in creams and lotions

Atopic dermatitis: a chronic skin disease characterized by itchy, inflamed skin

Contact eczema: a localized reaction that includes redness, itching, and burning where the skin has come into contact with an allergen (an allergy-causing substance) or with an irritant such as an acid, a cleaning agent, or other chemical

Dyshidrotic eczema: irritation of the skin on the palms of hands and soles of the feet characterized by clear, deep blisters that itch and burn

Neurodermatitis: scaly patches of the skin on the head, lower legs, wrists, or forearms caused by a localized itch (such as an insect bite) that become intensely irritated when scratched

Nummular eczema: coin-shaped patches of irritated skin-most common on the arms, back, buttocks, and lower legs-that may be crusted, scaling, and extremely itchy

Seborrheic eczema: yellowish, oily, scaly patches of skin on the scalp, face, and occasionally other parts of the body

Stasis dermatitis: a skin irritation on the lower legs, generally related to circulatory problems


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

Eczema - atopic dermatitis

Merck Atopic Dermatitis Article

Great info and pictures with this article. Includes causes and treatment.


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

Merck Neutropenia Article

Merck Neutropenia Article

Great article on Neutropenia, causes and degrees. Talks about inflammation of response (when ANC is below 200, inflammation response can be gone). Very detailed!


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