text:
A-level Mathematics/OCR/D1/Node Graphs/Spanning Trees

In this module we will introduce the concept of the spanning tree, the minimum spanning tree, and some methods of finding minimum spanning trees.

Firstly, we must say what we mean by a tree. A tree is a graph where there is exactly one path between any pair of vertices. This means that a tree is connected, i.e. there exists at least one path between each pair of points.

A tree is the most efficient way of connecting a set of vertices, in the sense that if we have a tree then every edge is necessary, as if we remove any edge, then the graph is no longer connected. Also all trees on a graph with n vertices have exactly n - 1 edges.

If we have a connected graph G then another graph H is a spanning tree of G, if it is a tree with the same vertices as G, and all the edges of H are edges of G.

Finally, we will introduce the concept of a minimum spanning tree. For this to make sense, we must consider graphs called networks. A network is a graph where each edge has a weight. The weight can be the length of the edge, or the distance between the two points, or it could represent the difficulty of going between the points, or the cost. In any case, the weight is a number. It will usually be positive (or non-negative, with zero a possibility), but the maths is the same if we allow negative numbers. As it is each edge of the graph that will be assigned a distance, rather than the pairs of vertices themselves, no distance is assigned for pairs of vertices not joined by an edge.

Given a graph G with distances assigned to its edges, then a minimum spanning tree, H, is a spanning tree of G, where the sum of the weights of the edges are the lowest possible. There may be more than one minimum spanning tree. For a trivial example, any spanning tree of a graph G, with all weights 1, will be a minimum spanning tree, with the relevant sum equal to n-1, where n is the number of vertices of the original graph.

Kruskal's algorithm
Kruskal's algorithm is one way of finding a minimum spanning tree for a network G. We start with  a graph H consisting of all the vertices of G, but with no edges. Then we follow the following instructions:

 * 1) Consider the set E of edges in G, that will connect the end points when added to H
 * 2) Find the member of E with the lowest weight. If there are more than one such member, pick any one.
 * 3) Add this edge to H
 * 4) If H is not connected, then go back to step 1. Otherwise, H is a minimum spanning tree of G.

Example

Above is the diagram (figure 1) for a graph, for which a spanning tree will be constructed using Kruskal's algorithm. Each edge is given a weighting. The lines are dotted, as the edges of the spanning tree will be indicated with solid lines.

Below are figures 2 to 5, which indicate the stages of the construction of a spanning tree.

In figure 2, we add an edge of weight 2, as that is the edge of lowest weight. For figure 3 there are two options, both of weight 3, that could have been added. Note that the edge added is not connected to the first edge. This is allowed under this algorithm, but not Prim's algorithm, described below. In figure 4 the other edge of weight 3 is added. Finally, in figure 5 we add an edge of weight 6, out of two allowable. There are edges of lower weight, such as that of weight 4, but these all join edges we have already been connected. The final spanning tree is given below in figure 6, with the other edges in the original graph, and their weights, not given. The total weight is 2+3+3+6 = 14.

Prim's algorithm
Prim's algorithm is an alternative way of finding a minimum spanning tree for a network G. Again, we start with a graph H, consisting of all the vertices of G, but with no edges. Then we follow the following instructions:

 * 1) Pick any vertex v in the graph
 * 2) Make it the only member of a set S
 * 3) Consider the set E of edges joining one member of S to a vertex not in S.
 * 4) Find the member of E with the lowest weight. If there are more than one such member, pick any one.
 * 5) Add this edge to H, and the add the vertex not in S, to S.
 * 6) If H is not connected, then go back to step 3. Otherwise, H is a minimum spanning tree of G.

Example

Above is figure 7, which is the same as figure 1, the graph used for the example for Kruskal's algorithm. We will construct a different spanning tree, although as is guaranteed, the total weight will be the same. The first step is to choose a vertex to start with. This will be the top most vertex. Below are figures 8 to 11, the stages in the construction of a spanning tree.

At the start, only the top vertex is in S. The edges with lowest weight between S, and other vertices are those with weight 6, so in figure 8 one is chosen, thus adding the middle right vertex to S.  In figure 9 the edge of weight 2 is added, adding the bottom right vertex to S.  In figure 10, one of the edges of weight 3 is added, the other not having a vertex in S on either end. This edge is then added in figure 11. This is now allowed, as the middle left vertex was added to S in figure 10. The final spanning tree is given below in figure 12. The total weight is again 2+3+3+6=14, although the actual spanning tree is different from that for Krustal's algorithm.

Matrix representation
An alternative way of finding minimum spanning trees is when the graph we are interested in is in matrix form. A matrix in this case is simply a table of numbers, the numbers corresponding to the weights of the edges. For example, below is table 1, the matrix form of the graph we have been using in our examples, along with figure 13, the familiar graphical representation:

The vertices are given numbers 1 to 5, with 1 the top vertex, 2 and 3 the middle-left and middle-right vertices, and 4 and 5 the bottom-left and bottom-right. The row and column headings correspond to these numbers, and the other numbers are the weights of the appropriate edges. For example, the number 8 in row 1, column 2, is the weight, 8, of the edge between vertices 2 and 3. Note that there is symmetry in the matrix, in that, for example, row 2, column 1 is also 8. This is because the edge between 1 and 2, say, is also the edge between 2 and 1. Also, there is no edge between a vertex and itself, so row 1, column 1, row 2 column 2, etc., are all empty.

Using this form we can apply Prim's algorithm to find a minimum spanning tree. We will start with vertex 4, making that the only member of S. To denote this, we write it in bold, and will for other members of S later. You can use any method you want to indicate members of S, such as cicling. Below is table 2, with vertex 4 marked as a member of S.

Now, we must pick the next edge. This will have one vertex in S, and one not in S. These correspond to the numbers in row 4 (the one in bold), where it doesn't cross column 4 (also in bold). This gives the numbers 6, 3, 5 and 7, the lowest of which is 3, which corresponds to row 4, colunn 2, so the edge between vertices 4 and 2. We thus add this to our tree, and 2 to S. Below is table 3, with both 2 and 4, the members of S, in bold.

Now, the edges to select from correspond to numbers in rows 2 and 4 (those in bold), but not in columns 2 and 4. This gives the numbers 8, 3, 4, 6, 5 and 7. The lowest is 3, corresponding to an edge between vertices 2 and 3. Thus we add 3 to S, and this edge to our tree. Below is table 4, with 3 now in bold.

Now, we have the numbers 8, 4, 6, 2, 5 and 7. The lowest is 2, which corresponds to the edge between vertices 3 to 5. We thus add this edge to our tree, and vertex 5 to S. In table 5, this vertex is added to S, and thus in bold.

Here, the numbers are 8, 6, 6 and 9. There are thus two possible edges, between 1 and either 3 or 4. The previous edges were between 4 and 2, 2 and 3, and 3 and 5. Below are figure 14 and 15, images of the spanning trees formed by choosing one of the two edges. Figure 14 has the edge between vertices 1 and 3, and figure 15 that between 1 and 4.

Note that these are the spanning trees generated by Prim's algorithm, and Krustal's algorithm, respectively. Also note that when finding the lowest number, we only considered the case where the member of S is the row, and the non-member is the column. This leaves out the possibility that the member of S is the column, and the non-member is the row. However, as we have discussed, each edge is listed twice, and our way of considering elements includes each edge once. For example, if 1 is in S, and 2 not, then we include the edge between them as row 1, column 2, but not as row 2, column 1.

Node Graphs/Spanning Trees


text:
Cookbook:Beurre Blanc

Traditionally, a beurre blanc consists of nearly equal parts white wine and good white wine vinegar reduced dramatically with shallot, held in emulsion with quite a lot of butter. Once the basic technique has been mastered, don't be afraid to experiment with new ingredients. Many modern variations exist employing any number of herbs and flavorings.

The sauce, whose name means "white butter," traces its roots to the French cuisine of the Loire Valley, and would be conventionally served with river fish, like trout or pike.

Correctly prepared, a basic beurre blanc should be creamy and tangy with a good savory component, pairing well with lean meats, particularly fish. I recommend it highly with a nice preparation of pan-seared halibut, seasoned simply with salt and pepper. What follows is a recipe for a simple, semi-traditional beurre blanc.

Ingredients

 * 1 cup of good white wine (dry aromatic white, preferably French, such as Pouilly-Fumé)
 * 1 lemon, juiced
 * 1–2 shallots, minced
 * 1 Tbsp heavy cream (optional and non-traditional)
 * 10–12 Tbsp unsalted butter, very cold and in cubes or lumps
 * Salt
 * White pepper

Procedure

 * 1) Place the white wine in a non-reactive saucepan with the lemon juice and chopped shallots.
 * 2) Cook this mixture until reduced to about 2 tablespoons, and don't be shy about letting it boil—it will not adversely affect the sauce. Once reduced, the shallot should still be fairly moist. If you're looking at a dry pan, there's a good chance your sauce won't hold.
 * 3) Reduce heat to low flame. If you want to increase the holding power of your sauce, add the heavy cream at this juncture, but every authority on traditional French preparation would disapprove.
 * 4) Begin to add cubes of the cold butter while whisking vigorously. From a technical standpoint, the sauce should stay under 200°F (95°C), so do some of the whisking off the flame. Whisk in 1 or 2 cubes and add more, and continue until you've added all the butter.
 * 5) Season with salt and white pepper, and serve immediately. The sauce can be held in a vacuum container, such a Thermos, but this is not recommended for long periods of time.

Notes, tips, and variations

 * American chefs may try to enhance the presentation of the sauce by straining the shallot out before plating, but the French know better. If the shallot has been sufficiently chopped it has no deleterious effect on the texture of the finished product.
 * You must use a non-reactive saucepan (i.e. stainless steel, ceramic, enamel, etc.) because the sauce contains acidic components.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Cookbook:Beurre Blanc


text:
Talk:LaTeX/Importing Graphics

Graphics storage
should be under Windows (XP) with a double dot to work properly: --Escalator (discuss • contribs) 15:57, 5 March 2012 (UTC)

 * I do not use Windows so I can't check, but aren't you working with an 'images' folder located in the parent folder, hence the double points? --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Sam2p - a better graphics file converter than ImageMagic
I have struggled for some time with ImageMagic to get correct bounding-boxes in .eps graphics files (converted from .jpg, .png, .pdf format).

Generally speaking I found it unsatisfactory, so I searched for an alternative and finally found Sam2p (see http://www.inf.bme.hu/~pts/sam2p/). After using it for some months I was so impressed by its quality that I have come to use it exclusively instead of ImageMagic.

Like ImageMagic, Sam2P is a commandline program and Open Source. It is more recent than ImageMagic however and seems to boast a number of improvements over ImageMagic (other than finding bounding boxes) which are listed on its website. Highly recommended.

 * Link and recommendations added by someone. --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Bug in file extension in graphicx package
Adding a figure with in this format : [filename.eps] produces an error : "Unknown graphics extension .eps".

However removing the extension from the parameter solves the problem.

So, the correct format : [filename].

 * Yes, seems to be a bug for .eps files, but I'm not sure. Anyway, it works flawlessly without extension. This detail has been added to the chapter. --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

eps - what about using pdflatex
indeed, ".eps" extension is not needed in modern implementations of (la)tex, at least not in tetex. An extra advantage is that if you also have a pdf-version of the picture, then it will automatically be picked up, instead of eps-version, when you run pdflatex

In the list of software producing EPS graphics, it is worth mentioning IDL, Matlab and Mathematica, used by many scientists.

At least since version 2010.20288-1, pdflatex natively handles EPS files by converting them to pdf.

-- Karper (discuss • contribs) 20:38, 27 January 2011 (UTC)

 * I updated the part about EPS support for pdflatex. I do not know enough about IDL, Matlab not Mathematica, but feel free to contribute! --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Creating vector graphics natively in LaTeX
LaTeX has some primitive line drawing functions in the picture environment that can be used to create graphics. Although it's quite simple and probably not so useful anymore, an extension of it called Portable Graphics Format (PGF) and TikZ is really useful and amazingly extensible. I think it should be placed after Inkscape. (I just saw that there is an entire page called Creating Graphics, so this should definitely go into that page) --Cengique (talk) 18:37, 10 March 2009 (UTC)
 * The whole section of creating graphics should be moved to the chapter about this subject. I'm no native English speaker so I prefer someone else doing it.--Sanderd17 (talk) 14:09, 23 January 2010 (UTC)

 * I moved the TikZ stuff to its dedicated chapter. I've put some references to the 'Creating Graphics' part. --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Examples do not work
Examples on this page do not work. LaTex keeps complaining Cannot determine size of graohic, or, no bounding box.

None of the given examples actually do something usefull. This page is a waste of time.
 * You do have to place the pictures with the exact same name (LaTeX is capital sensitive) in a directory where LaTeX searches (in jou directory where the .tex file is is a good option). Also be sure you have a good format. You may have renamed a .gif image to a .jpg but that doesn't make it readable for LaTeX.--Sanderd17 (talk) 14:06, 23 January 2010 (UTC)

Draft document option
LaTeX/Importing_Graphics In this subsection there is said that the default is draft. But when you compile your doc without draft, the figures are included and with draft only the name is shown. Am I wrong if I say the default isn't draft but final?--Sanderd17 (talk) 16:19, 20 January 2010 (UTC)

 * Fixed by someone. --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Images as Figures
The images as figures section sounded like two guys having an editting war. I think that both people had a point; images are not figures, definately, but the figures page (http://en.wikibooks.org/wiki/LaTeX/Floats,_Figures_and_Captions#Figures) jumps straight into more complex figure usage. I thought that a bare-minimum example was needed, so provided two; one that's almost completely useless, and a slightly longer one which provides a basic 'all you need' example for using figures and images. I think this is a much better way to present the concept than pushing people towards a more advanced topic, as most people who come looking for how to insert images are most likely looking for a figure & image example to copy/paste into their documents. The above comment was added by 130.209.6.40 at 19:13:23 2010-07-08
 * Yeah, this book needs more cross-referencing, and as is evident on the main page, many chapters are far from finished. Anyway, good edit, if you find any similar problems in other chapters feel free to correct them. Tomato86 (talk) 20:54, 8 July 2010 (UTC)

 * I worked out duplicates and cross-referencing for this chapter (as well as for lots of chapters actually). I removed the wrapfig example, replacing it by a link to the Figure chapter. --Ambrevar (discuss • contribs) 12:41, 13 January 2013 (UTC)

Process LaTeX article that use png or jpg image files to eps ones ...
I have created with some days of effort this script in order to convert a LaTeX using jpg files to one using eps. All is done automatic. The new source folder is ready to be compiled using latex instead of pdflatex. I did this for my self use in order to save many effort, specially looking for the included images through a complex images folder tree and calculating for each one its final dimension in "cm" in order to be converted to eps and able to be used for proffesional publication or by editors.

Process latex article%20JPG%202%20EPS%20Automatic

It is released with GPL licence.

If this is not the better place to this free tool, please tell me where to publish it in case it is usefull.

Regards. --Gengiskanhg (discuss • contribs) 21:01, 10 May 2011 (UTC)

Error in "trim" documentation
The article describes syntax for the trim option to \includegraphics as "trim=t l b r". I believe it should be "trim=l b r t". I am using pdflatex v. 3.1415926-1.40.11 (TeX Live 2010). --144.02.110.145 (discuss) 03:36, 11 May 2012 (UTC)
 * Hi, I just checked the grfguide.pdf from CTAN and it seems you are right. This has been changed yesterday by an anonymous user, it originally was as you say. I undid this change. Thanks. -- XonqNopp Tk 05:54, 11 May 2012 (UTC)
 * (Please remember to sign your posts on talk pages with ~ Thanks.)

 * After the rewrite, the trim option is no longer mentioned at all... Pipping (discuss • contribs) 11:14, 17 April 2017 (UTC)

Rewrite needed
As many other pages/chapters in this wikibook, much of the information is old and partially obsolete. A user of todays LaTeX doesn; t have to think about most of the stuff that is said as relevant. Starting a rewrite now. --Johannes Bo (discuss • contribs) 10:13, 16 October 2016 (UTC)

 * One thing that should be changed when someone re-writes this: There's a contradiction about preferred formats. Up near the top (sxn entitled "Raster graphics vs. vector graphics") it says, "you should always prefer PDF or EPS to PNG or JPG."  Further down (sxn entitled "Compiling with pdflatex"), it says that JPG is "the best choice if you want to insert photos", and PNG is "the best choice for diagrams", while PDF is "not recommended" for some types of images.  I suspect also that some readers will be confused by the distinction in the discussion of "Supported image formats" between "latex" and "pdflatex", especially since on some installations they may be the same program.  (On our Linux installation of TeXLive 2016, both 'latex' and 'pdflatex' are symbolic links to 'pdftex'.)  Finally, xe(la)tex and other "*tex"s should probably be mentioned--I thought XeLaTeX had some limitations, although I can't find anything to that effect now.  BTW, I would write some of this, but I don't consider myself knowledgeable enough. Mcswell (discuss • contribs) 20:08, 4 February 2017 (UTC)

 * True,  and   run the very same program, but in different modes. So there is a cear distiction (altough the user doesn't notice it with pdflatex and a modern setup as all eps file are converted in the backround). In  -mode, you cannot have jpg or png or pdf, it really just supports eps files. XeLaTeX works a bit different at the low level, so it supports (almost?) all formats.

 * Same is true for the image format. If you take a picture and it is saved as jpg, there is no point to convert it in any other format. Creating a diagram/scheme with paint or any other software, i would choose png over jpg any time, but i would much more appreciate if the thing i have done would be saved in a vector format, so it is scalable. --Johannes Bo (discuss • contribs) 07:32, 5 February 2017 (UTC)

trim
you forgot "trim=l b r t". it is important.

title: Talk:LaTeX/Importing Graphics


text:
Online OsiriX Documentation/How to Increase Thick Slab

This file explains how to increase the thick slab mode limitation of 90 imags, however volume rendering via thick slab anything past 90 images is unstable. It works well with mean and MIP. (make sure you follow the two columns on each page, before going to the next of the three pages.)

---

---

OsiriX オンライン解説文書/OsiriX入門_シック・スラブのモード設定値を増やす


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User talk:Mpaulsondds

Copyright problem with Image:2-thickslab.jpg
--Derbeth talk 00:34, 10 December 2005 (UTC)

Image copyright problems
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User talk:212.219.90.99

Please do not make entries with useless content. If you continue to do so, you may be banned from editing. Kellen T 00:55, 10 December 2005 (UTC)

title: User talk:212.219.90.99


text:
Handbook of Genetic Counseling/Russell Silver Syndrome

Russell Silver Syndrome

Introduction

 * Introductions
 * What do you understand about why you are coming to genetics?
 * What specific questions would you like to have answered today?
 * Outline what will happen in session:
 * Take medical and family history
 * Doctor will perform physical exam
 * Discussion and answer further questions

Obtain Medical History

 * Thorough pregnancy history
 * History of maternal hypertension
 * Teratogenic exposures
 * Intrauterine infections

Obtain Family History

 * Birth weights and heights of parents and siblings

Genetics

 * Etiology is widely variable
 * 10% of patients have maternal UPD of chromosome 7
 * autosomal dominant and autosomal recessive forms have also been seen
 * some evidence for AD gene located on long arm of chromosome 17

Clinical Features

 * Growth and Feeding
 * IUGR with weight less than 3SD below mean for gestational age
 * Birth length also diminished
 * Normal head circumference
 * Usually difficult to feed
 * GERD and delayed gastic empting are prevelent GI disorders
 * Normal growth velocity
 * Remain small into adulthood
 * Most do not have growth hormone deficiency
 * Development and Behavior
 * Normal IQ
 * Early gross motor delay
 * Mild hypotonia
 * Many patients have learning disabilities
 * Craniofacial
 * Dental anomalies common including microdontia
 * Micrognathia is common
 * Can cause secondary cleft palate
 * Musculoskeletal
 * Limb length asymmetry
 * No cancer related to asymmetry has been reported
 * Genitourinary
 * Cryptorchidisim
 * Hypospadias
 * Occasional renal anomalies

Diagnosis

 * Minimal diagnostic criteria includes
 * IUGR
 * Postnatal growth retardation
 * Normal head circumference
 * Triangular face
 * Fifth finger clinodactyly
 * Normal psychomotor development
 * Supportive criteria
 * Short arm length
 * Limb length asymmetry
 * Cryptorchidism
 * Hypotonia
 * Normal intelligence
 * Diagnostic Testing
 * Microsatellite analysis of chromosome 7

Differential Diagnosis

 * Any condition that can include IUGR
 * Many chromosomal disorders
 * Deletion distal arm chromosome 15
 * MR, microcephaly, non triangular face
 * Chromosome breakage syndromes
 * Fanconi anemia, Nijmegen immunodeficiency syndrome, and Bloom syndrome
 * Tend to have microcephaly
 * Fetal Alcohol syndrome
 * X-linked short stature with skin pigmentation
 * 3-M syndrome
 * skeletal changes, no triangular face

Surveillance and Treatment

 * growth hormone for those with deficiency
 * early intervention for learning disabilities
 * evaluation and treatment limb asymmetry depending on severity
 * lift in shoe during growth
 * bone lengthening when growth is finished
 * epiphysiodesis

Psychosocial Issues

 * How have you been dealing with this?
 * How would having this diagnosis change care?
 * What other ways will having this diagnosis be beneficial?
 * Have you had any trouble with insurance?
 * Are you considering having other children?
 * Have you had all your questions answered?

Resources

 * Association for Children with Russell-Silver Syndrome, Inc.
 * 22 Hoyt St.
 * Madison, NJ 07940
 * Phone: (201) 377-4531
 * Fax: (201) 822-2715

 * Russell-Silver Support Group (MAGIC Foundation)
 * 1327 N Harlem Ave.
 * Oak Park, IL 60302
 * (313) 586-8038
 * (800) 3-MAGIC-3
 * email: slantana@awol.com
 * website: http://www.nettap.com/~magic/

 * National Organization for Rare Disorders, Inc. (NORD)
 * P.O. Box 8923
 * New Fairfield, CT 06812-8923
 * (203) 746-6481
 * TDD: (203) 746-6481
 * Email: orphan@nord-rdb.com


text:
Handbook of Genetic Counseling/Sanfilippo syndrome

Sanfilippo syndrome

Other names: Mucopolysacchardosis III, Type A, B, C, and D

 * So, it is a syndrome in which the large saccharides are not broken down properly in the lysosomes. It's a lysosomal storage deficiency.

Characteristics

 * Most common of the MPS diseases
 * Normal to fast growth 1-3 years. Slow growth after that.
 * Slow development by 1-3 years then deterioration
 * Short stature
 * Hearing loss
 * Poor gait
 * Poor speech
 * Poor behavior
 * Synophrys (joined eyebrows)
 * Mild cardiac involvement
 * Clear corneas
 * Sleep disturbances
 * Upper respiratory tract infections
 * Many die of pneumonia (10-20 years)

Genetics

 * Autosomal recessive in all types
 * Sanfilippo A = defect in heparan N-sulfatase
 * Sanfilippo B = deficiency in N-acetyl-alpha-delta glucosaminidase
 * Sanfilippo C = deficiency of acetyl-CoA: alpha-glucosaminide-N-acetyltransferase
 * Sanfilippo D = deficiency of N-acetyl-alpha-delta glucosaminide-6-sulfatase

Diagnosis

 * By clinical features mentioned above (same for all four types except type D)
 * Overactivity
 * Destructive tendencies
 * Weakness in all extremities
 * Presence of excess heparan sulfate in the urine

Resources

 * National MPS Society
 * 102 Aspen Drive

 * Downingtown, PA 19335
 * (610) 942-0100
 * http://mpssociety.org/index.htm


text:
Handbook of Genetic Counseling/Scheie Syndrome

Scheie Syndrome

Contracting

 * Medical update
 * Physical exam
 * Answer any new questions

Medical Update

 * How are your hands?
 * Carpal tunnel repair… any complications?
 * Current medications
 * Current activities at school
 * How's the replacement therapy going?
 * How's your vision currently?

Scheie Syndrome

 * Definition: It is a mucopolysaccharidoses Type I disease. This means the body has trouble breaking down the large molecules in the lysosomes. Instead of breaking them down completely, they kick out only partially degraded molecules = storage occurs as well. So there is an increase of stuff in the lysosomes causing a build up in various parts of the body
 * Incidence
 * 1/500,000 births
 * Characteristics
 * Broad mouth and fill lips
 * Clouding of corneas/visual impairment
 * Aortic valve defects
 * Hairy body
 * Hernias are common
 * Carpal tunnel syndrome
 * Joint limitation leading to claw hand.
 * Normal life span
 * Genetics
 * Autosomal recessive
 * Chromosome 4p16 has a defect = the alph-L-iduronidase gene

Recommendations

 * Ophthgamology
 * Cardiology
 * Physical Therapy
 * Occupational Therapy

Treatment

 * Bone marrow transplants -experimental
 * Fetal tissue transplants - experimental
 * Enzyme replacement - experimental (When lysosomal storage diseases were discovered, hopes were raised that they could be treated by enzyme substitution. When exogenous lysosomal enzymes are injected into the patient, this enzyme can eventually be taken up by enzyme-deficient cells. This uptake is regulated by certain receptors on the cell surface. Different tissue have different receptors. It is therefore necessary to change the natural enzyme to enable uptake in the tissue of interest. If properly designed, the missing enzyme could be injected regularly like the diabetic subject injects insulin. In many in vitro studies with the purified active enzyme added to the media of enzyme-deficient fibroblasts, the lysosomal substrate accumulation was corrected, but in vivo treatment has been hampered through the problem of producing the sufficient quantity of enzymes, immunological problems, and that the substituted enzyme does not pass the blood-brain barrier.
 * Since it can be expected that enzymes supplied from the outside do not pass the blood brain barrier, suitable candidates for enzyme replacement are disorders without neurological involvement (e.g. Maroteaux Lamy, Morquio B, Fabry, late onset Pompe disease).

Resources

 * Human Genetic Disease, in Layman's Terms
 * http://mcrcr2.med.nyu.edu/murphp01/lysosome/hgd5.htm

 * National MPS Society
 * www.mpssociety.org
 * 17 Kraemer Street Hicksville, NY 11801 (516) 432-1797


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User:Einsteinbock

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text: User:Einsteinbock/User Page

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User talk:Einsteinbock

Wikibooks:Image copyright
Can you set license of Image:Albert-einstein.jpg? --User:Derbeth talk 19:23, 11 December 2005 (UTC)

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text: User:Einsteinbock/Assignments

title: User:Einsteinbock/Assignments


text: User:Einsteinbock/Assignment Archives

title: User:Einsteinbock/Assignment Archives


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User:Einsteinbock/Catholicism

Open for Modification

title: User:Einsteinbock/Catholicism


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User:Einsteinbock/Education

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User:J.Steinbock~enwikibooks/Deleted Archives

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User:J.Steinbock~enwikibooks/Discussion Archives

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Handbook of Genetic Counseling/Seizure Medications

Seizure Medications

Contracting

 * Introductions and small talk
 * Confirm referring physician
 * Assess understanding of the reason for the referral to genetics
 * How much information has your physician given you about the possible effects of taking seizure medications while pregnant?
 * Despite the increased risk of problems, there is a greater than 90% chance that the baby will be just fine
 * Control of seizures is important because they may cause injury to you or the fetus
 * Stillbirths or miscarriages are more common for women who have epilepsy, occurring in 1.7 percent of pregnancies (about three times the amount in the general population)
 * There is a small increase in mortality rates during the first year of life for children of mothers with epilepsy. That risk is only about 0.6 percent, but is higher if seizures are not well controlled. (increased risks probably related to periods where the fetus does not get enough oxygen due to changes in the circulation of blood in the uterus and placenta during seizures)
 * What concerns or questions do you have that you would like to discuss today?
 * Outline session agenda
 * Medical and family history questions
 * Some of the possible effects that anticonvulsants can have on the pregnancy
 * Options available to you
 * Discussion of concerns and questions

Elicit Medical History

 * Confirm LMP: __________
 * EDC: __________
 * Today's gestational age: __________
 * Have you had an ultrasound?
 * Date of ultrasound: __________
 * Results of ultrasound: __________
 * How has the pregnancy been going so far?
 * Have you had any seizures during your pregnancy
 * What medications are you taking?
 * Amount and frequency of each.
 * When did you start taking each?
 * At what age did you begin having seizures?
 * What type of seizures do you typically have?
 * Any complications other than the seizures? Infections, colds, exposures etc.

Elicit Family History
(3 generations)
 * Anyone else with seizures?
 * Anyone had: multiple SAB, SB, early deaths or babies that required surgery as infants?
 * Anyone born with birth defects such as cleft lip or palate, spina bifida, or heart problems
 * MR/LD
 * Has anyone in family had cancer (dx. <50) or chronic illnesses (heart disease, diabetes)

Discuss possible side effects of taking anticonvulsants during pregnancy

 * Stress importance of taking medicines- to keep you healthy and therefore the baby healthy
 * Although it's very important for you to take these medications, sometimes seizure medications can have some effects on a developing baby
 * There appears to be an increased risk of Stillbirth correlated with carbamazepine or valproic acid intake during first 6 weeks (2-5% risk of causing stillbirth)
 * All pregnancies are at a 3-5% risk of birth defects or mental retardation
 * Women who take anticonvulsants are at a 2-3 times increased risk for some specific problems (consensus seems to be about 7-10%)
 * This doesn't mean that the baby will be born with a problem, it just means that we know that based on your special circumstances, your pregnancy is at an increased risk
 * Some of the things that we sometimes see in children who have been exposed to seizure medications during pregnancy include:
 * Subtle changes in the facial features of the baby
 * such as the shape of the eyes and nose
 * usually so subtle features that you might not even recognize them
 * Sometimes we see changes in the length of the fingers (slightly shortened) and the fingernails may be small
 * But sometimes children can be born with more apparent changes such as a cleft lip/palate or spina bifida
 * Occasionally we see kids who have some delays in development (usually ranging from borderline normal intelligence to mild mental retardation)
 * Heart defects have been reported in infants of a group of women who were treated with a number of different anticonvulsants (RR of 2.2, 1.4-3.5)
 * RR of other birth defects when the group of meds was considered together was 2.5 (1.5-2.4) for oral clefts and 2.5 (1.2-5.0) for urinary tract anomalies
 * But this was for the group of meds considered together and not for individual meds
 * Some children who have been exposed to anticonvulsants during pregnancy have several of these features and some have none
 * Just based on your history I can't tell you whether or not your baby will have some or none of these features
 * However, we can offer you a level II ultrasound that can often determine if the there is a major birth defect

Options

 * Level II ultrasound -- performed at 18 -20 weeks
 * Done by an experienced technician
 * Can detect many of the birth defects for which your fetus is at increased risk
 * Developing organs will be looked at in detail
 * Can often detect abnormalities in the formation of the limbs, spine, heart, and brain
 * U/S is good to make us suspicious of some birth defects but it can't tell us everything
 * We won't know if there is mental deficiency by u/s
 * Also, u/s is dependent upon cooperation of the baby. Sometimes we just can't get a great view and may not be able to see everything we are looking for
 * But it can usually provide some reassurance to see that organs and body parts have formed properly
 * MSAFP at about 16-18 weeks is optimal
 * Screening performed on a sample of your blood
 * Can provide an indication that a fetus may be at a higher or lower risk than the general population to have an ONTD, but it will not tell us for certain if there is a neural tube defect
 * Detects about 80-90% of ONTD's (so it can miss some)
 * Blood test can also look at other markers in the blood and determine if there may be an increased risk for two chromosomal abnormalities (for which you are not at an increased risk for based on your history of seizures and medications)
 * Amniocentesis at about 15-18 weeks
 * Can detect about 95-98% of open neural tube defects (when test both AFP and AchE)
 * Procedural risk for miscarriage of 1 in 200
 * Although you are not at an increased risk for other specific types of birth defects caused by changes in the chromosomes or hereditary material, amnio can also look at the chromosomes and determine if there is a chromosome abnormality with high accuracy

Other medications

 * Studies of women have shown that neither other medication you are taking (Zoloft and Zantac) cause an increase in birth defects when compared to what would be expected in the general population. However, high levels of Zantac are found in breastmilk and it is recommended that a woman who is taking Zantac not breast-feed

Psychosocial Considerations

 * Guilt over doing something that may cause birth defects
 * Catch 22 (don't want to hurt the fetus, but need to make sure that mom is healthy because if mom were having seizures that too would put the fetus at risk)
 * Are there other health concerns or circumstances that would make this a difficult pregnancy
 * Assess support system and coping strategies

Follow-up

 * Questions?
 * Registry for patients taking anticonvulsants…
 * Do you plan to breast feed the baby?
 * Provide information about Epilepsy foundation at 1-800-EFA-1000 or www.efa.org

Carbitrol, Epitol, Tegretol (Carbamazepine) Facts

 * Anticonvulsant and mood stabilizer
 * Clearance increases during pregnancy so doses may need adjustment
 * Series of 125 infants exposed, 17 (12%) had congenital anomalies
 * Several other reports show a 2-3 times as great of risk for birth defects as in the general population (this is similar to reports of children born to women treated with other anticonvulsants)
 * Study with controls who had trivial exposure to ethanol
 * Found malformations in 18% of babies exposed to Carbitrol during pregnancy
 * Hypoplastic fingernails, short nose, long philtrum, upslanting palpebral fissures, distal digital hypoplasia and microcephaly
 * But major birth defects not increased
 * 20% of exposed were found to have developmental delay (5 of 25 offspring)
 * problems with the design though
 * may be confounded by SES status or parental IQ
 * used only one standard deviation as the cut off rather than two
 * Other studies fail to show any significant effects of prenatal exposure on head size, IQ, or neurologic function
 * Incidence of spina bifida
 * When data from 22 published studies was pooled, a relative risk of 14 was calculated
 * Questions about adequacy of data because many of 21 published studies that were used reported 0-1 cases
 * Nested case control study showed odds ration of 6.0 for NTD's but not statistically significant, but is suggestive of a relationship
 * May therefore be a risk and the risk is generally quoted at 1 in 200 to 1 in 100 (up to 10 times the risk for general population which is about 1 in 1,000)
 * Folate supplements often recommended because carbamazepine is folic acid antagonist
 * When in combination with other anticonvulsant drugs especially valproic acid, higher frequencies of birth defects have been observed
 * Considered "probably safe" to consume while breastfeeding

Topamax (Topiramate) Facts

 * Mechanism of action unknown --Appears to block the spread of seizures rather than raise the seizure threshold
 * Not well studied in humans
 * Most studies have been done on mice, rats, and rabbits
 * developmental toxicity shown at all doses tested (lowest 20% of human dose)
 * Show craniofacial malformations most commonly such as cleft lip and palate
 * Caused limb reduction anomalies in rats at 10 times human dose
 * Delays in physical development seen when used during late pregnancy and lactation in rats
 * Skeletal abnormalities at 6 times the human dose in rabbits (maternal toxic dose)
 * Intrauterine death in 2 times the human dose (maternal toxic dose)
 * 8 exposed pregnancies
 * 5 chose to terminate
 * 3 infants were normal
 * Case report (abstract) one woman only on topamax throughout gestation (700mg) had infant with prenatal onset growth deficiency and multiple minor anomalies (5th nail hypoplasia, generalized hirsutism, third fontanelle, short nose and anteverted nares)

Zoloft (Setraline) Facts

 * SSRI antidepressant
 * Studies in rats and rabbits
 * 20 times the dose in pregnant rats and rabbits produced NO INCREASE in birth defects
 * Neonatal survival was decreased at maternal doses of 5 times higher than recommended in humans
 * Report of 147 women followed prospectively
 * Comparable incidence of malformations to that found in unexposed controls
 * Offspring of 112 women in another study
 * Babies DID NOT have an increase in birth defects compared to control population
 * Admission to a special care nursery were associated with late pregnancy exposure
 * Case report of infant with withdrawal symptoms
 * Agitation, poor feeding, constant crying, insomnia
 * Intense for 48 hours then subsided
 * Nystagmus reported in another infant and resolved after 72 hours
 * Zoloft is excreted in breast milk, along with active metabolite
 * Studies suggest that there is minimal transfer of active drug to the infant though

Zantac (Ranitidine) facts

 * Histamine H2 antagonist used for peptic ulcer disease
 * No increase in birth defects or fetal toxicity in rats or rabbits
 * Frequency of major malformations NOT increased among children of 142 women taking various H2 receptor antagonists
 * No increase in incidence of birth defects in 330 infants exposed to Zantac during first trimester
 * Cohort study with 176 infants showed rate of birth defects NO greater than expected
 * Not recommended during breast feeding because may accumulate in breast milk up to 6-12% of maternal daily dose


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User:Dweekly

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User talk:24.4.88.246

This is probably user:dweekly David Weekly being lazy and forgetting to log in.

title: User talk:24.4.88.246


text:
Handbook of Genetic Counseling/Septo-optic dysplasia

Septo-optic dysplasia

Introduction and Contracting

 * What is your understanding about why you were referred to genetics?
 * What are your main concerns for _______?
 * Do you have any questions for us today?
 * Outline the session:
 * Want to first take a family medical history
 * Then make sure the medical information I have is correct
 * We will discuss the information we obtain with Dr. Doktour
 * Then we will answer all your questions and explain what we believe might be the cause of the problems ____ has experienced

Pedigree

 * Learning difficulties or mental retardation
 * Birth defects
 * Seizures
 * Eye problems
 * Problems with growth
 * Infertility
 * History of pregnancy losses
 * Anyone died at a young age or unexpectedly
 * Chronic health problem
 * Anything that seems to be running in your family

Take medical history
(follow form)
 * Explain how mosaic turner syndrome was ruled out as an explanation for her short stature and absent periods

Introduce septo-optic dysplasia also called SOD

 * A rare disorder where some of the structures in the middle of the brain don't form properly
 * This can lead to changes in the way they function and a number of symptoms and characteristic findings
 * A number of findings on ______'s MRI suggested that she might have septo-optic dysplasia
 * Septo refers to the center structure of the brain
 * The septum pellucidum is a membrane that separates one of the fluid filled spaces in the brain (show picture)
 * This membrane is missing in ________.
 * The pituitary gland is also located in the center of the brain and does not seem to be functioning properly in _____.
 * The term optic refers to the optic nerve, which is what carries the messages from the eyes to the brain
 * ______'s optic nerves are underdeveloped and small
 * Dysplasia means that these structures are not formed properly

Symptoms of SOD

 * The problems that can occur in individuals with SOD vary and can range from mild or serious
 * A person with SOD can have a combination of any number of symptoms or characteristics
 * Eye problems
 * If the optic nerve is small or not developed properly will have fewer connections to the brain and can therefore have poor vision
 * This is called optic nerve hypoplasia (ONH)
 * Vision doesn't usually decrease over time though
 * Most with ONH also have unusual eye movements where the eyes move around and don't focus well (nystagmus)
 * Brain Structure and Function
 * Septum pellucidum missing (agenesis)
 * Some have an abnormal corpus callosum which is the group of nerve fibers connecting the brain
 * Other structural changes (larger than usual fluid filled cavities (ventricles), and fluid filled sacs in the ventricles (cysts) )
 * Sometimes changes in structure alter function and sometimes there is no brain function affected
 * Can be mildly to severely affected and cause developmental delays and cognitive problems
 * Some also have seizures
 * Pituitary Gland
 * Found in middle of brain and is master control gland
 * Makes important chemicals (hormones) which direct other glands in other parts of body to make other hormones
 * These other hormones are needed for things such as proper growth of body, energy control, sexual development

GH (growth hormone)

 * About 6:10 children with ONH don't make enough growth hormone
 * Can be treated with growth hormone shots
 * GH also necessary after growth is complete to maintain bone strength and normal metabolism

Thyroid hormone can be lacking in kids with ONH/SOD

 * Pituitary releases signal TSH to tell thyroid gland in neck to make thyroxin
 * Thyroxin necessary for growth and metabolism
 * Without enough can cause: poor growth, weight gain, slowing of mental function, feeling cold, irregular periods, dry skin, brittle nails, hair loss
 * Can be replaced with pills taken every day

Gonadotropins (FSH and LH)

 * Signal the ovaries and testes to produce sex hormones
 * Without sex hormones sexual development may be delayed

Cortisol

 * Made by adrenal glands above the kidneys
 * ACTH from pituitary tells adrenal gland to make cortisol
 * Increased amounts of cortisol needed when injured or sick
 * If pituitary doesn't work right in telling adrenal glands to make more than may need to take cortisol pills daily

ADH (anti-diuretic hormone)

 * Keeps water in the body by controlling amount of urine
 * Without enough may lose too much water
 * Feel thirsty, dry mouth, but urinates a lot
 * May become dehydrated and have problems (called diabetes insipidus or water diabetes)
 * Treatment available

Prolactin

 * May have high prolactin
 * Leads to no known health problems
 * Used to test how pituitary is functioning

Services

 * Children may need many tests and services
 * Often followed by Ophthalmology, Endocrinology and Neurology
 * Need early intervention
 * May need IEP in school
 * Services may include PT, OT, speech therapy depending on child's needs
 * Special needs for those with severe vision problems

Etiology of SOD

 * Exact cause of SOD is not known
 * Probably due to a combination of genetic and environmental influences early in gestation at about 6 wks gestation
 * Usually thought to be sporadic meaning that it is not something that was inherited
 * Cases have been reported where it appears to be autosomal recessive (presence of two copies of altered copies of a gene)
 * Mutations were in homeodomain of HESX1 gene
 * Found similar phenotype in mice that were mutant for homologous gene Hesx1
 * Also identified heterozygous mutations in HESX1 that correlated with milder pituitary phenotypes

Recurrence Risks

 * Dependent on whether it is a sporadic case or a mutation is present
 * Few documented reports of affected siblings
 * Testing was available on a research basis for the HESX1 gene as of first part of Nov. 2001, but we would need to contact the researcher to see if they are still searching for mutations (researcher is in UK).

Psychosocial considerations

 * May be a lot of new information and it is not simple
 * We have some written information that you can read through if you would like
 * May regret not having diagnosis earlier
 * May feel that more could have been done if it was diagnosed earlier
 * What are plans for her in the future
 * Will she live at home or in a group home
 * Is she connected with anyone who can help her with a job placement when school is done

Patient resources/references

 * Focus Families - parent support
 * www.focusfamilies.org

 * The Magic Foundation for Children's Growth
 * www.magicfoundation.org/sodp.html

 * Hormone Abnormalities in SOD: A Reference Guide
 * Mary J. Sarrantonio, MD, pediatric endocrinologist

 * Optic Nerve Hypoplasia: A Guide for Parents
 * Francine Ratner Kaufman, MD
 * Neal Kaufman, MD
 * Mark Borchert, MD

 * National Institute of Neurological Disorders and Stroke
 * www.ninds.nih.bov/health_and_medical/disorders/septo-optic.html

References in primary literature

 * Hellstrom A, et al. Children with septo-optic dysplasia - how to improve and sharpen the diagnosis. Hormone Research vol. 53 Suppl 1: 19-25 (2000).
 * Ouvrier R and Billson F. Optic nerve hypoplasia: a review. Journal of Child Neurology. Vol 1, no. 3 : 181-188. (1986).
 * Dattani M L, et al. Molecular genetics of septo-optic dysplasia. Hormone Research. Vol 53 Suppl 1: 26-33. (2000).


text:
Handbook of Genetic Counseling/Short Chain Acyl-CoA Dehydrogenase (SCAD)

Short Chain Acyl-CoA Dehydrogenase (SCAD)

General Information

 * a disorder of lipid metabolism characterized by a defect in the oxidation of short-chain fatty acids resulting in neurologic and gastrointestinal manifestations
 * SCAD is one of four enzymes in the mitochondria responsible for the breakdown of short-chain (C4-C6) fatty acids to 2-carbon fragments (acetyl-CoA) in the beta oxidation pathway
 * homozygous patients are unable to mobilize large fat stores and are thus at risk for becoming hypoglycemic when stressed (i.e., during infection or fasting) during which time the long and medium acyl-CoA dehydrogenases are unable to compensate for the lack of SCAD
 * gene map locus: 12q22-qter
 * autosomal recessive inheritance

Diagnosis

 * diagnosis is difficult because patients do not consistently excrete characteristic metabolites
 * it is necessary to collect and analyze several urine and plasma specimens in patients with neurologic abnormalities that suggest this disorder
 * deficiency of SCAD activity in leukocytes and cultured skin fibroblasts
 * prenatally, a deficiency of SCAD activity in cultured chorionic villi or amniocytes can be detected

Clinical Evaluation

 * two distinct clinical phenotypes have been identified :
 * one type observed in infants with acute acidosis and muscle weakness (generalized)
 * one type observed in middle-aged patients with chronic myopathy (localized to skeletal muscles)
 * cases with neonatal onset have a variable phenotype
 * includes metabolic acidosis, failure to thrive, developmental delay, seizures and myopathy
 * no episodes of nonketotic hypoglycemia (characteristic of medium-chain and long-chain acyl dehydrogenase deficiencies)

Infantile type

 * metabolic: neonatal acidosis, low-normal plasma total carnitine, highly esterified
 * GI: poor feeding, vomiting, failure to thrive
 * muscle: progressive skeletal muscle weakness, hypotonia
 * neurological: developmental delay
 * laboratory results: generalized SCAD deficiency, ethylmalonate urinary excretion, low normal highly esterified muscle carnitine

Adult type

 * muscle: lipid-storage myopathy
 * lab results: skeletal muscle carnitine low, deficiency of skeletal muscle mitochondrial short-chain acyl-CoA (butyryl-CoA)

Support Groups

 * James William Lazzaro Foundation
 * 4493 Liberty Road
 * South Euclid, OH 44121
 * Contact Person: Jamie Lazzaro
 * Phone: (502) 254-2209
 * Email: info@jwlsite.com
 * Website: www.jwlsite.com

 * FOD(Fatty Oxidation Disorders)Family Support Group
 * 2041 Tomahawk
 * Okemos, MI 48864
 * Contact Person: Deb Lee Gould, MEd
 * Phone: (517) 381-1940
 * Email: deb@fodsupport.org
 * Website: www.fodsupport.org


text:
Handbook of Genetic Counseling/Short Stature

Short Stature

Considerations for Short Stature

 * Abnormally short stature may result form a primary abnormality of skeletal organization, growth, or development (skeletal dysplasia - metabolic or single-gene), or from extraosseous defect (nutrition, teratogen, endocrine, psychosocial, or cytogenetic).
 * The use of growth curves with attention to ethnic and family background will help identify the patient with pathologic short stature.
 * The initial step in the clinical evaluation of short stature is to determine whether the body is proportionate or disproportionate. (Proportionate growth suggests an extraosseous defect, while disproportionate growth suggests a skeletal dysplasia.) Precise body measurements, such as upper to lower-limb-segment ratios, sitting height, arm span, and hand and foot measurements are diagnostically useful.
 * The next step is to determine whether the growth deficiency was of prenatal or postnatal onset. (Prenatal onset suggests a fetal environment insult or genetic defect, while a postnatal onset suggests chronic disease, endocrine disorder, or psychosocial issues.)
 * A family height history should be discussed and parental heights should be measured. A pregnancy history should be taken and teratogen exposure should be discussed. Cytogenetic studies, including a karyotype should be done. Skeletal films of the hand will determine bone age. Growth hormone assays and thyroid studies should be coordinated through endocrinology.

Considerations for Failure to Thrive

 * The term failure to thrive is used for children and infants who, without superficially evident cause, fail to gain and often lose weight.
 * Most instances of FTT result from psychosocial circumstances which adversely affect the child's intake, absorption, or utilization of food (including emotional deprivation, physical neglect or abuse, and withholding food).
 * FTT may be related to a physical handicap, such as cerebral palsy or cleft palate.
 * FTT may also result from obscure organic abnormalities or overt diseases in which growth failure occurs.
 * Hospitalization for study and treatment allows for quantification of factors controlling the net caloric intake (food intake, vomiting, and stools) and for observation of the child's interactions with the family. This hospitalization frequently leads to dramatic improvement of weight gain and provides evidence that the environmental factors are the cause.
 * Making a growth chart and developmental flow sheet flow sheet may identify the point in time where the child began to fail to thrive. If the child's growth has been steady, just below the expected level (if the child is following their own growth curve), then diagnoses like constitutional short stature, hypopituitarism, or chromosomal abnormality may be considered.
 * If the medical history and physical examination suggest disturbances in any particular organ systems, then diagnostic study should be pursued. This could begin with routine screening tests, like blood counts and urinalyses.


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Handbook of Genetic Counseling/Sickle Cell Anemia

Sickle Cell Anemia

Introduction

 * Determine what the patient already knows about sickle cell
 * Assess what concerns the patient wants to address today

What is sickle cell disease?

 * inherited blood disorder affecting the oxygen carrying part of the blood cells called hemoglobin
 * hemoglobin in sickle cell anemia forms a "sickle" or banana shape
 * normal hemoglobin is called hemoglobin A
 * sickle cell hemoglobin is called hemoglobin S
 * this shape causes it to be broken down in the liver leading to not enough blood cells
 * people with sickle cell disease experience pain, damage to organs, and sometimes early death
 * this is due to sickle shaped blood cells blocking tiny blood vessels
 * this leads to prevention of blood flow to certain areas of the body

Diagnosis

 * diagnosis is made by a blood test called hemoglobin electrophoresis
 * those with mostly hemoglobin S have sickle cell disease
 * those with only hemoglobin A do not have sickle cell disease
 * those with both hemoglobin A and hemoglobin S are heterozygote carriers and have sickle cell trait
 * this means they are carriers of the sickle cell gene
 * they generally do not have any health problems but can pass the gene to their children
 * this test requires 3cc of blood in a red-capped EDTA tube
 * prenatal testing is also available
 * in Ohio children are now tested for sickle cell as part of the newborn screening program

Symptoms

 * chronic hemolytic anemia - may lead to reduction in energy and cause growth retardation
 * Vaso-occlusion - blockage of small blood vessels that may lead to pain and tissue damage.
 * Splenic sequestration - increase in spleen size due to storage of red blood cells
 * Organ failure - may result from insufficient blood flow later in life
 * other problems may arise such as neurological effects, stroke, chronic eye disease, renal disease, and leg ulcers

Treatment

 * mainly symptomatic
 * drugs such as hydroxyurea are used to increase fetal hemoglobin
 * vasodilators and lubricants used to prevent microvascular blockage with very little success

Inheritance

 * Sickle cell disease is inherited in an autosomal recessive fashion
 * people with sickle cell disease have two copies of the mutated gene
 * people with sickle cell trait have one normal gene and one mutated gene
 * Parents who both have sickle cell trait will have a 25% chance of having a child with sickle cell disease, a 50% chance of having a child with sickle cell trait, and a 25% chance of having a normal child who is not a carrier
 * If one parent has sickle cell disease and one parent has sickle cell trait, they have a 50% chance of having a child with sickle cell disease but the child will have sickle cell trait.
 * If one parent has sickle cell disease and the other parent is normal the child will have sickle cell trait but 0% chance of having sickle cell disease.

Clarification: In order for a child to have sickle cell disease both parents must have at least one copy of the abnormal sickle cell gene, or in other words both parents must have sickle cell trait for the child to have sickle cell disease.

Population Genetics

 * African-Americans: 1/12 are carriers
 * 1/400-600 children are born with sickle cell disease
 * People of Hispanic, Greek, Italian, Arabic, and Asian Indian also have high carrier rates

Psychosocial Issues

 * Guilt over passing on trait to children
 * people with sickle cell trait may be treated as though they are sick despite having no symptoms
 * people with sickle cell trait may also be more worried about their health despite having no symptoms
 * worry over reproductive decisions

Resources

 * CHMC Cincinnati Comprehensive Sickle Cell Center
 * 513-636-4541
 * 333 Burnett Avenue
 * Cincinnati, OH 45229

 * The Ohio Sickle Cell Affected Families Association, Inc.
 * 141 Tishman Street
 * Columbus, OH 43228

614-272-1516
 * National Association for Sickle Cell Disease, Inc.
 * 3345 Wilshire Blvd., Suite 1106
 * Los Angeles, CA 90010-1880
 * 213-736-5455
 * 800-524-7802


text:
Handbook of Genetic Counseling/Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz Syndrome

Contracting

 * Make small talk and establish rapport with the family.
 * Elicit the family's concerns. What issues would you like to discuss today?
 * Briefly outline the topics to be covered during the visit.

Eliciting Interim History

 * Interim Family History:
 * Have there been any new births, deaths, or diagnoses in the family?
 * Is there any consanguinity in the family?

Genetic Etiology

 * Autosomal recessive inheritance
 * Caused by a deficiency of the enzyme 7DHCR, the final enzymatic step in the cholesterol biogenesis pathway.
 * Molecular Genetics
 * The gene encoding 7DHCR is located at 11q12-13, and is named DHCR7.
 * 19 different mutations have been reported (including 13 missense, 5 frameshift, and 1 nonsense mutation).
 * Milder phenotypes can be seen if the mutation renders the enzyme partially active.
 * The mechanism leading to the manifestations seen appears to be the result of a deficiency in cholesterol.
 * Cholesterol is a critical component of myelin and other CNS proteins
 * Cholesterol is also a precursor to the sex steroids, estrogen and testosterone, thus hypocholesterolemia results in a deficiency of these hormones.
 * The derangement of sterol composition in the cell membranes may result in abnormal cell-to-cell interactions in the developing embryo. (? Explains polydactyly and cleft palate and growth deficiency seen in some??)
 * Penetrance:
 * 100% penetrant with variable expressivity

Recurrence Risks

 * The risk of recurrence is 25%

Incidence

 * The incidence is estimated to be 1:40,000- 1:60,000
 * The carrier frequency is approximately 1:122
 * More common in people of European background, and has been seen rarely in those of African American and Asian descent.
 * There is an excess of males diagnosed with Smith-Lemli-Opitz syndrome (bias of ascertainment as a result of hypogenetalism seen in boys).

Diagnostic Criteria and Clinical Features

 * Diagnosis is usually made based on the recognition of a constellation of characteristic clinical features, with diagnostic confirmation based on measurement of elevated 7DHC in plasma or other tissues.
 * The cardinal features include:
 * Prenatal growth deficiency with subsequent failure to thrive
 * Developmental delay/ mental retardation (moderate to severe)
 * Poor muscle tone (hypotonia)
 * Characteristic facies (change with age and are difficult to recognize in adulthood)
 * Microcephaly with narrow bifrontal diameter
 * Ptosis (50%)
 * Down-slanting palpebral fissures
 * Short nose with depressed nasal bridge, with anteverted nares
 * Low set and posteriorly rotated ears
 * Retrognathia
 * Cleft palate (37-52%)
 * Cardiac defects (36-38%)
 * AV canal defects, and total anomalous pulmonary venous return defects
 * Gastrointestinal anomalies (25%)
 * Pyloric stenosis, malrotation, Hirschsprung disease
 * Polydactyly
 * Cutaneous 2-3 toe syndactyly (90%)
 * Genital abnormalities (70%)
 * Hypospadias, cryptorchidism, micropenis, hypoplastic scrotum, and microutethra.
 * Upper tract anomalies (57%) include hydronephrosis, renal cystic dysplasia, renal duplication, renal agenesis, and reflux.

Occasional Abnormalities

 * Seizures
 * Demyelination in the cerebral hemispheres, cranial nerves, and peripheral nerves.
 * Cataracts
 * Dislocation of the hip

Natural History

 * Congenital onset
 * Many are born in breech presentation
 * Stillbirth and early neonatal death are not uncommon
 * Feeding difficulty and vomiting, hypotonia, and irritable behavior with shrill screaming have been frequently reported problems in infancy
 * Of those who survive, 20% die within the first year.
 * Death is commonly related to pneumonia
 * The degree of mental deficiency is usually moderate to severe (adults described had IQ's in the 20's).

Testing

 * Diagnostic:
 * Increased 7DHC levels in blood or other tissues
 * Clinical evaluation
 * Prenatal:
 * Measurement of elevated 7DHC in amniotic fluid or chorionic villi
 * Carrier testing:
 * Not currently available
 * Differences of 7DHC in heterozygotes is indistinguishable from homozygotes (normal).
 * With the discovery of the gene, it is hoped that mutation analysis will assist in heterozygote identification.

Surveillance, Management, and Treatment Options

 * Growth and Feeding:
 * Adequate caloric intake should be ensured.
 * Consideration should be given to cholesterol supplementation to improve weight gain.
 * Oral-motor training with OT to help patient take food orally
 * G-tube to assist in feeding if oral intake is not adequate
 * Development and behavior
 * EI, special education programs, and therapies to enhance the developmental potential of the patient.
 * Supervised setting for adults (group home) - improved behavior and development has been noted in patients receiving cholesterol supplementation
 * Craniofacial
 * Cleft palate repair at age 12-18 months
 * Ophthalmologic
 * If there is a suggestion of visual compromise from ptosis, cataracts, or any other abnormality, referral to an ophthalmologist is recommended.
 * Cardiovascular
 * Specific to malformation identified
 * Special consideration should be given in those cases where prognosis is poor.
 * Gastrointestinal
 * Surgical referral and standard treatment for each specific condition
 * Genitourinary
 * Ultrasound of urinary tract at diagnosis
 * Treatment is dependent upon the condition identified
 * Repair of hypospadias
 * Observe boys with cryptorchidism to see if spontaneous descent occurs
 * Determine chromosomal sex if ambiguous genitalia is present.
 * Musculoskeletal
 * Simple excision of supernumerary digits
 * Skin
 * Cholesterol treatment has been reported to cause a decrease in photosensitivity and skin rashes.
 * Limit length of sun exposure to avoid sun photosensitivity

Differential Diagnosis

 * Chromosomal abnormalities including Trisomy 18 (Growth deficiency, cleft palate, and DD) and Trisomy 13 (Growth retardation, polydactyly, and DD)
 * Noonan syndrome (short stature, DD, cardiac defects, cryptorchidism)

Support Groups

 * Smith-Lemli-Opitz/RSH Foundation
 * P.O. Box 212
 * Georgetown, MA 01833
 * (978) 352-5885
 * Contact person: Cynthia Gold
 * email: info@smithlemliopitz.org
 * http://www.smithlemliopitz.org


text:
Handbook of Genetic Counseling/Sotos Syndrome

Sotos Syndrome

Introduction

 * Overgrowth syndrome
 * etiology still uncertain although researchers in Japan found a gene that may be the cause of Sotos syndrome in a large number of individuals with classical Sotos syndrome (published paper in 2002)
 * usually sporadic
 * <2% show autosomal dominant inheritance (4 of 200 families, but facial gestalt is different)

Incidence

 * Unknown slightly less common than Beckwith-Wiedemann with prevalence of 1 in 13,700 births

Diagnosis

 * Diagnosis is clinical
 * 4 core features (must have at least 3 of the 4 to really make a diagnosis)
 * First 3 features are relative to general population so setting a cutoff is not always clear
 * rapid early growth pre and postnatal
 * advanced bone age
 * developmental delay
 * characteristic facial appearance specific to Sotos syndrome
 * alters in childhood and adolescence
 * in newborn period (macrocephaly, high bossed forehead, dolichocephaly, high palate, appearance suggestive of hypertelorism)
 * face lengthens, jaw becomes more prominent, dolichocephaly (tall narrow skull) and frontal bossing (prominent forehead) become more obvious
 * delay in growth of hair which is often thin "appearance of receding hairline"
 * midchildhood downslant to palpebral fissures, wear and discoloration of teeth, tendency for a rosy coloration of cheeks, chin, and nasal tip.
 * All 4 core features are present in at least 75% of true cases of Sotos syndrome and <20% of other specific and nonspecific overgrowth patterns

At birth

 * Often the presence of a high arched palate, poor suck, and low muscle tone which often produce feeding problems
 * Jaundice occurs frequently.

Molecular Genetics and Genetic Testing

 * Gene mutation found in a number of Japanese patients with Sotos syndrome
 * Located at 5q35 gene named NSD-1
 * Lab in Chicago and Germany are doing clinical testing
 * Details found at http://www.genes.uchicago.edu/clinic/SotosTest.html
 * FISH analysis for NSD1 deletion detection. Mutation analysis is currently being validated for clinical use; please check back on availability.
 * No lab listed on GeneClinics doing research testing presently, but lab in UK may be doing research testing
 * FISH - 12 days and cost is $325
 * NSD1 encodes 2,696 amino acids and may interact with nuclear receptors (NRs)
 * expressed in the fetal and adult brain, kidney, skeletal muscle, spleen, and the thymus, and faintly in the lung.
 * Among 42 SS patients examined, we detected 4 (10 %) de novo point mutations in NSD1
 * In addition, FISH analysis using BAC clones flanking the 5q35 breakpoint revealed submicroscopic deletions involving the entire NSD1 gene in 20 (67%) of 30 patients whose chromosomes were available (Nat Genet 30:365-366, 2002)
 * http://caroll.vjf.cnrs.fr/cancergene/CG1830.html discusses the NSD1 protein

Neuroradiological findings

 * Ventricular abnormalities (prominence of trigone, prominent occipital horns, ventriculomegaly)
 * Midline defects and absence or hypoplasia of corpus collosum

Growth and Feeding

 * Feeding problems common in neonatal period
 * Most LGA (most evident in length and in head circumference)
 * Height and head circumference most significantly larger and run parallel to growth curve but sig. above 97th centile
 * Excess growth mostly in limbs rather than trunk
 * Girls in UK population were an average of 6.2 cm above calculated target height based on parental heights, but were within usual height range
 * Boys height less predictable and greater tendency for increased adult stature

Development, learning, behavior

 * Almost all have developmental delay and cognitive impairment (may be selection bias because this is used as diagnostic criteria)
 * Behavioral problems common
 * Poor concentration and ADHD common
 * Difficulty with social interactions results in tendency to associate with younger children and social isolation later in life
 * Reliance on routines common in many children
 * May have impetuous behavior
 * Poor sleep patterns common
 * Unusual anxiety and subsequent phobias commonly reported

Neurological

 * Hypotonia usually present from birth but improves during childhood
 * Poor coordination and delayed motor skills primarily gross motor (swimming is sport many succeed in)
 * Febrile convulsions in almost 50%
 * Almost half with febrile seizure will go on to have nonfebrile seizures
 * Seizures managed same as in other children/adults

Immune system

 * Infections very common in early childhood
 * Recurrent OM and potential conductive hearing loss
 * Urinary tract infections in up to 20% (caused by structural abnormalities and reflux usually)

Eye problems

 * poorly documented
 * Refractive errors and strabismus (less common, glaucoma and syntagmas reported)
 * Regular evaluations

Dental abnormalities (common)

 * Early teeth eruption (54%)
 * Excessive wear and discoloration
 * Teeth may be crooked due to changes in craniofacial structure and many require orthodontic work

Heart problems
(thought to be rare)
 * Overt congenital heart disease is thought to be rare may be up to 10%
 * Most common are ASD, VSD, PDA
 * Routine echo not necessary

Malignant tumors
(rare, but may occur in approximately 2-4% of individuals with Sotos syndrome)
 * Embryonal tumors
 * Neuroblastoma
 * Mephroblastoma
 * Hepatoblastoma
 * Age of onset is wide and no clear benefit from surveillance

Musculoskeletal

 * Hypotonia, large size, joint laxity can cause complications
 * Foot deformities (~50%)
 * Flat feet common
 * Kyphoscoliosis

GI

 * Tendency for severe constipation in over 10%

Main Psychosocial Considerations

 * Intellectual, social, and emotional maturity may evolve on widely different timetables
 * How is school going? (confirm that she is in 4th grade and ask specifically about math and language skills)
 * Does she have a new IEP since last visit?
 * Is she getting the help you would like her to?
 * Math tutoring and speech therapy?
 * How is attention and behavior?
 * Assess social relationships (is she being teased or socially isolated)
 * Any changes in the family?
 * Confirm number of siblings

Differential Diagnosis

 * Number of other generalized overgrowth syndromes
 * Sotos syndrome is distinguished from others by presence of developmental delay and characteristic facial features.
 * Other overgrowth syndromes have other commonly associated characteristics that also aid in distinction

Patient resources

 * Soto Syndrome Support Association
 * http://www.well.com/user/sssa/ -- website is very updated and contains good accurate information
 * Three Danada Square East, #235
 * Wheaton, IL 60187


text:
Arabic/TasksArticles

Articles Needed:

-Guide on how to use the hamza

title: Arabic/TasksArticles


text:
Handbook of Genetic Counseling/Spinal Muscular Atrophy (SMA1)

Spinal Muscular Atrophy (SMA1)

SMA is the number one genetic killer of children under the age of 2

Introduction

 * Establish rapport with small talk and introduce myself
 * Assess the concerns of the family and what they hope to learn today
 * Ascertain the level of understanding of SMA
 * Briefly discuss the topics to be discussed during the appointment
 * Ask if anyone has any questions

Definition

 * Spinal muscular atrophy (SMA) is a group of inherited neuromuscular diseases that attack motor neurons, which control the movement of voluntary muscles. This disease causes anterior horn cells (lower motor neurons) in the base of the brain and spinal cord to gradually disintegrate.

Types of SMA

 * Prior to the availability of molecular diagnosis, SMA was classified into subgroups. These subgroup classifications are useful for prognosis and management.
 * Infantile progressive spinal muscular atrophy (SMA 1)
 * Intermediate SMA (SMA 2)
 * Juvenile SMA (SMA 3)
 * Adult SMA (SMA 4)
 * These forms differ in the age of onset, the severity, the progression rate, and in the adult form, the muscles affected.

Etiology

 * Mode of inheritance:
 * SMA is an autosomal recessive disorder
 * Chromosome location:
 * Chromosomal locus 5q11-q13
 * Molecular Genetics:
 * SMN (survival motor neuron) has been identified as the primary SMA-determining gene
 * The SMN gene is very complex, containing repetitive sequences, pseudogenes, deletions and inverted duplications
 * 2 copies exist: the telomeric copy (SMNT ) and the centromeric copy (SMNC)
 * These only differ by a few nucleotides
 * Unaffected individuals have 2 copies arranged in tandem on each chromosome 5 (centromeric and telomeric)
 * A defect in both copies of the SMNT gene causes SMA
 * Individuals with SMA are either:
 * Homozygous for a deletion of exon 7 of the SMNT gene (95% of cases) or
 * Compound heterozygotes for a deletion of exon 7 of the SMNT gene and a subtle intragenic mutation of SMN T (5% of cases)
 * Abnormal protein product is produced by mutant SMN T
 * Normal gene products are thought to play a role in splicing; it has been shown to be necessary for pre-mRNA splicing

Incidence

 * One study suggests that SMA occurs at a frequency of ~4: 100,000
 * 1:40-1:80 are carriers for SMA

Clinical Features (general for all types of SMA)

 * Progressive degeneration and loss of the lower motor neurons (anterior horn cells) in the spinal cord and sometimes in the brainstem nuclei.
 * Results in muscle weakness and atrophy
 * The onset varies from before birth until adulthood
 * The weakness is symmetric and progressive
 * Contractures, usually mild
 * Anterior horn cell involvement, apparent due to tongue fasciculations and absent deep tendon reflexes
 * Respiratory failure
 * Variable cranial nerve involvement: opthalmoplegia, facial diplegia

Additional Specific SMA1Clinical Features

 * Lack of motor development
 * Infants with the gravest prognosis have sucking and swallowing difficulty
 * Face muscles are completely spared
 * Ocular and diaphragmatic muscles are involved late in the disease
 * The heart is normal
 * Intellect is normal
 * Prognosis depends primarily upon respiratory function

Risk Assessment

 * ~98% of parents of an affected child are carriers, and ~2% are not carriers, thus the mutation was de novo
 * The risk of occurrence/recurrence for parents who are both carriers is 25%, while the risk of having an unaffected carrier child is 50%.

Age of Onset, natural history and life span

 * The age of onset for SMA1 is before 6 months
 * The lifespan is two years or less

Testing

 * Diagnostic: A direct DNA analysis to detect a homozygous deletion of exon 7 of SMNT is used to confirm a clinical diagnosis.
 * This test has one limitation, it does not detect intragenic mutations
 * If only one deletion SMNT is present, this does not confirm a clinical diagnosis but supports a clinical diagnosis.
 * Carrier: Dosage testing for carrier detection. This PCR test determines the # of exon 7 containing SMNT gene copies that are present in an individual.
 * Both technical and interpretation limitations for this test
 * Some carriers have 2 SMNT gene copies on one chromosome
 * Some carriers have one normal allele and a subtle mutation
 * de novo mutations occur in 2% of SMA patients, meaning that only one parent is a carrier
 * Prenatal: this test is possible for fetuses at a 25% risk when the disease causing SMN mutations in both parents is known
 * Analysis of fetal DNA obtained via CVS or amnio
 * If the SMNT gene is normal, two other tests are available:
 * Neurophysiologic studies-electromyography (EMG). This reveals devervation and diminished motor potential amplitude.
 * Muscle biopsy- reveals evidence of devervation with no other structural abnormalities.

Management

 * Physical therapy and occupational therapy to promote and maintain motor skills
 * Monitoring of respiratory function, ventilatory support (usually not used for SMA1 patients)
 * SMA1 patients that aren't sucking or swallowing well may need a gastrostomy (g-tube)

Differential Diagnosis

 * SMA1 is considered in the differential diagnosis of the "floppy child
 * Prader-Willi syndrome
 * Pompe's disease (when cardiomegaly is present)
 * Congenital myotonic dystrophy
 * Congenital muscular dystrophy

Psychosocial Issues

 * The parents,grandparents and immediate family have an impending death (patients with SMA1) and are typically having a difficult time dealing with the severity of the disease.
 * Counselors should encourage parents to discuss their feelings and concerns.
 * As this disease is very draining on the parents,grandparents and immediate family, the counselor should check on the support network available to the family.

Web References

 * GENE CLINICS


text:
Handbook of Genetic Counseling/Spontaneous Pregnancy Loss and X-chromosome Inactivation

Spontaneous Pregnancy Loss and X-chromosome Inactivation

General Information about Pregnancy Loss

 * Common problem
 * Approximately 50% of all conceptions spontaneously lost
 * Often occurs before pregnancy is diagnosed
 * Miscarriage occurs in 20% of confirmed pregnancies
 * Recurrent pregnancy loss affects 1 in 100 (1%) of couples who wish to have children
 * Potential causes of pregnancy loss
 * Most miscarriages due to sporadic chromosome abnormalities
 * About 50% of women experiencing recurrent pregnancy loss of "non-genetic" explanation
 * Anatomical problems of female reproductive tract
 * Infectious diseases
 * Hormonal problems
 * About 20% of women with recurrent pregnancy loss may have a mutation on their X-chromosome causing skewed X-inactivation
 * Many couples have no explanation for their recurrent pregnancy loss

Skewed X-Chromosome Inactivation (SXCI)

 * Pattern of X-inactivation weighted heavily toward one chromosome
 * Would expect random inactivation to inactivate each chromosome about 50% of the time
 * Highly skewed is defined as >90% of cells with same active X-chromosome
 * May be caused by mutation in an essential gene on one X-chromosome that causes the chromosome to be selected against by the body
 * Mutation probably causes the cells that express it to have a growth disadvantage
 * The gene must be essential so that cells die when it doesn't function properly
 * Usually causes no health problems in females
 * If other X-chromosome also has an X-linked recessive mutation, female will be a manifesting carrier
 * Have seen women with Duchenne muscular dystrophy, Lesch-Nyhan, and hemophilia that are as severely affected as men
 * Mutation on active X-chromosome can be new mutation inherited from father's sperm or mutation that affects her father also
 * Mutation that causes skewed X-inactivation inherited from mother's side
 * May be family history of pregnancy loss on mothers side affecting male conceptions
 * Studies show consistently more females in families with skewed X-inactivation than males
 * Mutation lethal in males who don't have second X-chromosome to compensate
 * Females with SXCI have 32% risk to lose pregnancy compared to 15% risk in general population
 * In families with SXCI, females who inherit their mother's inactive X will inactivate the same X chromosome

X-Chromosome Inactivation Study (X-CIS)

 * Coordinated by Dr. Eric Hoffman at Children's National Medical Center In Washington, DC and Dr. Allen Hogge at Magee-Women's Hospital in Pittsburgh
 * Will conduct linkage studies on families that show heritable highly skewed XCI and have enough members for significant LOD score
 * Participation requirements (Must have one of the following)
 * Women who have had more than 1 miscarriage
 * Women with at least one spontaneous abortion of a male conceptus
 * Manifesting carriers of X-linked recessive disorders or asymptomatic carriers of X-linked dominant disorders
 * Females with X-chromosome rearrangements, including X-autosome translocations, deletions, duplications, inversions
 * Sample requirements
 * Send 7-10 ml blood in 2 purple top (EDTA) tubes at room temperature
 * Send overnight mail
 * Cost of blood draw and shipping covered by research lab
 * Lab will supply kits including vacutainers upon request
 * When sending blood, include pedigree, completed intake form, and any pertinent clinical information
 * Requires signed consent form for each participant
 * Results take 3–5 weeks
 * Linkage studies will be done on families of females with highly skewed XCI in more than two generations

Contact information

 * Phone: 866-252-4460
 * Email: xcis@cnmcresearch.org
 * Web: http://www.cnmresearch.org/xcis/
 * Send samples to:
 * Attention: Melissa Thouin
 * CRI/Center III
 * Children's National Medical Center
 * 111 Michigan Avenue, NW
 * Washington, DC 20010


text:
Handbook of Genetic Counseling/Stickler Syndrome

Stickler Syndrome

Contracting

 * What is your understanding of why your doctor referred you to see us?
 * Do you have any questions or concerns?
 * You are probably already familiar with Stickler syndrome since you have it yourself, but your doctor probably just wanted to make sure you understand the chance for your child to have it as well as the potential for a child to have different characteristics or symptoms than you.
 * We also may have the ability to do prenatal testing to see if your fetus has Stickler syndrome.
 * Is this something you are interested in?
 * Establish an agenda: Obtain medical and family history to determine if there are any other risks that we might want to talk about, answer any questions you might have about Stickler syndrome, discuss risks

Elicit Family History

 * Are there any other members of the family who have a diagnosis if Stickler syndrome
 * Any family members with cleft palate, recurrent ear infections, nearsightedness, blindness, cataracts, glaucoma, astigmatism, early-onset arthritis, hyperextendable joints, joint replacements in the 30-40s, joint stiffness, hearing impairment (high-tone?), mitral valve prolapse, or a flattened midface
 * Anyone die young or unexpectedly
 * Anyone with Mental retardation/learning difficulties
 * Birth defects (heart defects, CL/CP, spina bifida)
 * Chronic illnesses such as diabetes or heart disease
 * Anyone with cancer diagnosed at a young age (before 50)

Stickler Syndrome (a.k.a. hereditary artho-ophthalmopathy)

 * A connective tissue disorder that can affect the ocular (eyes), craniofacial (formation of facial structures), audiologic (hearing), cardiovascular (heart), and skeletal systems.
 * Connective tissue (CT) is the most plentiful protein in the body and acts as support tissue. CT can allow for elastic stretching and tightening, especially in the muscles.
 * Prevalence: 1/7500 - 1/10,000 - often goes undiagnosed in individuals with mild symptoms
 * Affects both sexes

Clinical Description

 * Symptoms vary from patient to patient, even within the same family)
 * Patients do not usually have all the symptoms!!
 * Features include:
 * Ophthalmologic
 * Congenital or early-onset cataracts.
 * Myopia (non-progressive, detectable in newborn period) - can lead to retinal detachment, which can result in blindness.
 * Glaucoma
 * Vitreal anomalies (gel that fills the eye).
 * Type 1 characterized by a persistence of a vestigial vitreous gel in the retrolental space and is bordered by a folded membrane, present at birth.
 * Type 2 is much less common, and is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity, have milder ocular findings.
 * Types of vitreal fluid anomalies breed true within families.
 * Craniofacial
 * Midface hypoplasia
 * Depressed nasal bridge (in childhood)
 * Anteverted nares (upturned nose)
 * Bifid uvula, submucous cleft, or cleft palate
 * Robin sequence (micrognathia, cleft palate, and glossoptosis)
 * Audiologic
 * Hearing impairment (40%) - degree of impairment (typically high one) is variable and may be progressive.
 * Sensorineural hearing loss (common)
 * Conductive hearing loss can also be seen.
 * Skeletal (problems tend to worsen with age)
 * Short stature as compared to unaffected siblings
 * Marfanoid body habitus without tall stature
 * Hypermobility
 * Joint laxity (becomes less prominent with age)
 * Mild spondyloepiphyseal dysplasia
 * Precocious osteoarthritis - joint pain in childhood may signify the onset, can be a major complication in adulthood.
 * Scoliosis
 * Mitral Valve Prolapse (45-50%) - occurs when the heart valve shuts and then protrudes into the next chamber.
 * Possible learning difficulties due to sight and hearing problems/

Diagnosis

 * Clinical diagnosis
 * At present, no consensus minimal clinical diagnostic criteria exist.
 * A point system was developed to aid in the diagnosis by Rose et al. 2000.
 * Molecular testing not reliable for making the diagnosis, only confirmatory.

Management

 * Eye
 * Ophthalmology evaluation - at least annual starting in infancy.
 * -Prescribe corrective lenses as early as possible
 * -Prophylactic laser photocoagulation of vitreoretinopathy.
 * Surgery as needed to remove cataracts or repair detachments.
 * Avoid activities such as contact sports which may lead to retinal detachment.
 * Patients should be aware of symptoms associated with retinal detachment.
 * Hearing Loss
 * Baseline audiogram.
 * Hearing can be progressive, so follow-up evals are recommended.
 * Arthropy
 * Full skeletal eval including x-rays for mild spondyloepiphyseal dysplasia.
 * Treatment is symptomatic with anti-inflammatory meds.
 * Possible avoidance of high-impact activities.
 * Cleft palate
 * Deal with growth and feeding issues - bottle feed baby in seated position, use special bottles, frequent weight checks.
 * Otolaryngology/craniofacial eval
 * Test hearing regularly
 * Treat otitis media aggressively, possibly PE tubes
 * Cleft palate surgery ~9 months
 * Eventual speech therapy.
 * Mitral valve prolapse
 * Screening for MVP with ECHO
 * If MVP exists, need antibiotic prophylaxis for certain surgical procedures.

Genetics

 * Autosomal dominant inheritance
 * Recurrence risk is 50% for each child of an affected parent.
 * Prevalence of new gene mutations unknown
 * Disease causing mutations in genes COL2A1, COL11A1, and COL11A2, but some families are not linked to any of these loci.
 * COL2A1 gene (cause in 75% of families)
 * Typically have type 1 vitreous anomaly and a high risk for retinal detachment, normal hearing or mild SNHL, and early-onset arthritis.
 * COL11A1
 * Typically have type 2 vitreous anomaly and more severe hearing loss
 * COL11A2
 * Causes "anocular" Stickler syn because protein is not expressed in the eye -a.k.a oto-spondylo-megaepiphyseal dysplasia (OSMED).

Molecular Testing
Matrix DNA Diagnostics Laboratory New Orleans, LA
 * Clinical testing available for COL2A1 and COL11A1
 * Tulane University Health Sciences Center
 * Contact: Charlene Crain, MBA, BSMT (ASCP)
 * email:ccrain@tulane.edu phone: (504) 988-7706 fax: (504) 988-7704
 * Methodology: Direct DNA
 * Research testing may be available for COL11A2 and mutations in unknown loci
 * Geneclinics

Pregnancy and Testing

 * Option of prenatal testing exists for fetuses at 50% risk for Stickler syndrome if a mutation in COL2A1 or COL11A1 has been identified in the affected parent
 * molecular testing performed either on sample from chorionic villus sampling (CVS) at about 10-12 weeks' gestation or amniocentesis at 16-18 weeks' gestation.
 * Alternatively, or in conjunction with molecular genetic testing, ultrasound can be performed at 19-20 weeks gestation to detect cleft palate,
 * HOWEVER not all individuals with Stickler have cleft palate and cleft palates is difficult to detect on ultrasound
 * Detection somewhat dependent on position of the fetus

Psychosocial Counseling

 * Discuss patient experience with Stickler syndrome and perceived burden
 * Discuss unaffected husband/partner's comfort-level with the diagnosis.
 * Assess whether they are concerned about having a child with Stickler syndrome?
 * Assess patient support systems.
 * Address potential feelings of guilt.
 * Assess whether she would like information about online support group

Resources

 * Parent and Infant Group (Craniofacial)
 * Contact Tricia Bender for more information

 * Stickler Involved People
 * 15 Angeline
 * Augusta, KS 67010
 * www.sticklers.org

 * Stickler Syndrome Support Group
 * PO Box 371
 * Walton-on-Thames
 * Surrey KT12 2YS
 * www.stickler.org.uk