text:
MATLAB Programming/Psychtoolbox/Example Code/xsearch

function output = xsearch3

% generic visual search architecture % started 12/06/2005 % current 12/06/2005 % Todd S. Horowitz

global screenRect MainWindow

% this bit should make the code windows/macos9 portable if strcmp(computer, 'PCWIN') warning off MATLAB:DeprecatedLogicalAPI; end

% get parameter input (optional) prompt = {'subject''s initials', 'practice trials', 'experimental trials', 'set sizes'}; defaults = {'xxx', '5', '50', '[4 8 16]'}; answer = inputdlg(prompt, 'Experimental Setup Information', 1, defaults);

% now decode answer [subject, pTrials, xTrials, setsizes] = deal(answer{:}); pTrials = str2num(pTrials); xTrials = str2num(xTrials); setsizes = str2num(setsizes);

% other major variables formatString = '%s, %d, %d, %d, %d, %d, %d, %d, %d \n'; % this is for data output % saved variables: subject, block, trial, target, setSize, timeoutFlag, wrongKeyFlag, err, RT keys = [KbName()  KbName('a')]; % response key assignments dataFileName = 'xsearch3Data'; jitter = 10; % coordinates of stimuli will vary by up to this much in their grid cells

if exist(dataFileName, 'file') == 0 dataFile = fopen(dataFileName, 'a'); count = fprintf(dataFile, '%s \n', 'subject, block, trial, target, setSize, timeoutFlag, wrongKeyFlag, err, RT'); fclose('all'); end

% set the state of the random number generator to some random value (based on the clock) tau = clock; rand('state',sum(100*tau)); state=rand('state'); seedFileName = ['pptxSeed-', subject]; save (seedFileName, 'tau');

% basic setup stuff screens = Screen('Screens'); MainScreen = max(screens); % video setup

% this sets up a display which is the size of the current monitor % the color is 8 bits, the lowest color resolution, this is for speed and compactness % if you're using images, you might want to change bitDepth to 32 % on MacOS9, you can also specify a screenRect smaller than the actual monitor

bitDepth = 8; MainWindow = screen(0, 'OpenWindow', [], [], bitDepth); hz = round(screen(MainWindow, 'FrameRate')) HideCursor;

% define rects screenRect = screen(0, 'Rect'); objectSize=40; objectRect = [0 0 objectSize objectSize]; % this is the size of the individual items stimulusRect = [0 0 500 500]; % this is an area smaller than the full screen in which to present stimuli fieldRect = CenterRect(stimulusRect, screenRect); % define coordinate system

cellX = 100; cellY = cellX; % these are the cells of the imaginary stimulus matrix nColumns = 5; nRows = 5; columns = ((1:nColumns) - .5) * cellX; rows = ((1:nRows) - .5) * cellY; [X, Y] = meshgrid(columns, rows); % this is the coordinate system for the stimuli, relative to stimulusRect nPositions = nColumns * nRows; nSetSizes = length(setsizes); maxWait = 5; % allow 5 seconds for response fixationDuration = 30; % this is in refreshes

% now set colors dacBits = ScreenDacBits(MainWindow); white = WhiteIndex(MainWindow); black = BlackIndex(MainWindow); midGray = round((white+black)/2); if round(midGray)==white midGray=black; end darkGray = (midGray+black)/2; lightGray = (midGray+white)/2; red = 1; blue = 2; green = 3; clut = screen(MainWindow, 'GetClut'); clut (red + 1, :) = [255 0 0]; clut (blue + 1, :) = [0 0 255]; clut (green + 1, :) = [0 255 0]; if dacBits == 10 clut = clut*1024/256; end LoadClut(MainWindow, clut);

screen(MainWindow, 'FillRect', midGray); screen(MainWindow, 'TextFont', 'Skia'); screen(MainWindow, 'TextSize', 24);

% more offscreen windows backgroundColor = midGray; stimulus = screen(MainWindow, 'OpenOffscreenWindow', midGray, stimulusRect);

% make stimuli % here I'm drawing the stimuli, but one can also use alphanumeric characters or import jpegs itemColor = black; stroke = 10; topRect = [0 0 objectSize stroke]; bottomRect = [0 objectSize - stroke objectSize, objectSize]; hCrossRect = [0 (objectSize - stroke)/2 objectSize (objectSize + stroke)/2]; vCrossRect = [(objectSize - stroke)/2 0 (objectSize + stroke)/2 objectSize]; leftRect = [0 0 stroke, objectSize]; rightRect = [objectSize - stroke 0 objectSize objectSize];

t(1) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(t(1), 'FillRect', itemColor, topRect); screen(t(1), 'FillRect', itemColor, vCrossRect); t(2) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(t(2), 'FillRect', itemColor, rightRect); screen(t(2), 'FillRect', itemColor, hCrossRect); t(3) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(t(3), 'FillRect', itemColor, bottomRect); screen(t(3), 'FillRect', itemColor, vCrossRect); t(4) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(t(4), 'FillRect', itemColor, leftRect); screen(t(4), 'FillRect', itemColor, hCrossRect);

d(1) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(d(1), 'FillRect', itemColor, leftRect); screen(d(1), 'FillRect', itemColor, bottomRect); d(2) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(d(2), 'FillRect', itemColor, leftRect); screen(d(2), 'FillRect', itemColor, topRect); d(3) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(d(3), 'FillRect', itemColor, rightRect); screen(d(3), 'FillRect', itemColor, topRect); d(4) = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(d(4), 'FillRect', itemColor, rightRect); screen(d(4), 'FillRect', itemColor, bottomRect);

fixation = screen(MainWindow, 'OpenOffscreenWindow', backgroundColor, objectRect); screen(fixation, 'FillRect', itemColor, vCrossRect); screen(fixation, 'FillRect', itemColor, hCrossRect); fixationRect = CenterRect(objectRect,screenRect);

screen(MainWindow, 'FillRect', backgroundColor); % this blanks the screen instructionString = { 'Your task is to look for a T in the display'; 'If you see a T, press the "quote" key with your right hand.' 'If you are sure that there is no T in the display, press the "a" key with your left hand.'; 'Please respond as quickly and accurately as possible.'; ['There will be ', num2str(pTrials), ' practice trials followed by ', num2str(xTrials), ' experimental trials.']; }; CenterCellText(MainWindow, instructionString); SitnWait; % block routine

for block = 1:2 if block == 1 blockMessage = 'Practice '; nTrials = pTrials; else blockMessage = 'Experimental '; nTrials = xTrials; end

nTrialString = num2str(nTrials); screen(MainWindow, 'FillRect', midGray); message = [' Press any key to begin ', nTrialString, ' ', blockMessage, 'trials']; CenterText(message); SitnWait; % trial routine for trial = 1:nTrials screen(MainWindow, 'FillRect', backgroundColor); %start with a blank screen screen(stimulus, 'FillRect', backgroundColor); %start with a blank screen % now select trial properties target = randi(2); % 1 = target present, 2 = target absent setSize = setsizes(randi(nSetSizes)); positionIndex = randperm(nPositions); % randomize order of stimulus placement selectItem = mod(randperm(setSize ) - 1, 4) + 1; % this ensures that distractor types will be distributed evenly % put stimuli onto stimulus screen for i = 1:setSize if target == 1 & i == 1 item = t(selectItem(1)); else item = d(selectItem(i)); end dx = round(randi(jitter) - jitter/2); dy = round(randi(jitter) - jitter/2); itemRect = CenterRectOnPoint(objectRect, X(positionIndex(i)) + dx, Y(positionIndex(i)) + dy); screen('CopyWindow', item, stimulus, objectRect, itemRect); end % present fixation cross screen('CopyWindow', fixation, MainWindow, objectRect, fixationRect); screen(MainWindow, 'WaitBlanking', fixationDuration); % synch to the vertical refresh for fixationDuration refreshes % now copy display to screen in one fell swoop screen('CopyWindow', stimulus, MainWindow, stimulusRect, fieldRect); % now wait for a response initTime = GetSecs; response = []; while isempty(response)&(GetSecs - initTime) < maxWait [keyIsDown, KbTime, keyCode] = KbCheck; if keyIsDown response = find(keyCode); response = response(1); responseTime = KbTime; end end if isempty(response) timeoutFlag = 1; err = 1; feedback = 'Time out!'; RT = 0; else timeoutFlag = 0; responseKey = find(keys == response); wrongKeyFlag = 0; RT = round((responseTime - initTime) * 1000); % RT in ms			if isempty(responseKey) err = 1; feedback = 'Wrong Key! Use "a" for "no" and "quote" for "yes"!'; wrongKeyFlag = 1; elseif responseKey == target err = 0; feedback = 'Correct!'; else err = 1; feedback = 'Wrong!'; end end % save trial data % note that you should open and close the file every time you write to it, otherwise you may lose data in crashes dataFile = fopen(dataFileName, 'a'); fprintf(dataFile, formatString, subject, block, trial, target, setSize, timeoutFlag, wrongKeyFlag, err, RT); fclose(dataFile); screen(MainWindow, 'FillRect', midGray); CenterText([feedback, ' - RT = ', num2str(RT), ' ms']); WaitSecs(1); end % trial loop end % block loop

% clean up and go home

screen(MainWindow, 'FillRect', midGray); CenterText('Thank you for participating'); SitnWait; clear screen;

function SitnWait

FlushEvents('keyDown'); GetChar;

function CenterText (message, xoffset, yoffset, color, window) % print a text string centered on the screen % syntax [newX, newY] = CenterText (message, [xoffset], [yoffset], [color], [window]) % if you want the text offset from center, use xoffset and yoffset % if window is not specified, prints to MainWindow, which must be a global in the calling function % 2/23/2000 accepts color option % 4/23/2002 can now print to offscreen windows

global screenX global screenY global MainWindow

switch nargin case 1 xoffset=0; yoffset=0; color = []; window = MainWindow; case 2 yoffset=0; color = []; window = MainWindow; case 3 color = []; window = MainWindow; case 4 window = MainWindow; end

windowRect = screen(window, 'Rect'); width = screen(window, 'TextWidth', message); screen(window, 'DrawText', message, ((windowRect(3)/2)-(width/2))+xoffset, (windowRect(4)/2)+yoffset, color);

function CenterCellText(window, messages, spacing, color)

% prints a cell array of text strings centered on the screen % syntax [newX, newY] = CenterCellText(window, messages, [spacing], [color]) % messages is a cell array of lines of text % spacing governs the distance between lines of text, in pixels % default spacing is 20 pixels % added color option 1/17/2003; only does one color for the whole thing % fixed number of options bug 01/24/2003

defaultSpacing = 30; switch nargin case 0 error('CenterCellText requires at least two arguments!'); case 1 error('CenterCellText requires at least two arguments!'); case 2 spacing = defaultSpacing; color = []; case 3 color = []; end

lines = length (messages);

% find the middle line middleLine = round(lines/2);

yOffset = spacing*((1:lines)-middleLine); for y = 1:lines CenterText(messages{y}, 0, yOffset(y), color, window); end


text:
Handbook of Genetic Counseling/Marfan Syndrome

Marfan Syndrome

Introduction and contracting

 * What is your understanding of why you were referred to genetics
 * What are your main concerns
 * Explain that they are there to determine if they might have a genetic condition called Marfan syndrome and give overview of Marfan

Outline session

 * I will begin by taking a family history
 * Our resident _____ will take a medical history
 * She and Dr. Doktour will perform a physical examination
 * We will then discuss whether or not we believe a diagnosis can be made or if there are other tests that need to be performed
 * If a diagnosis is made we will discuss Marfan syndrome in more detail
 * We will also answer any questions you have

Overview of Marfan syndrome

 * A heritable disorder of the connective tissue that affects many organ systems, including the skeleton, lungs, eyes, heart and blood vessels.
 * The condition affects both men and women of any race or ethnic group
 * occurs in 1-2 people per every 10, 000

Symptoms of Marfan syndrome

 * high degree of clinical variability
 * ocular findings: myopia, displacement of the lens, retinal detachment, glaucoma, early cataract formation
 * skeletal findings: bone overgrowth, joint laxity, long extremities, pectus excavatum or carinatum, scoliosis, high arched palate, positive wrist and thumb signs, reduced upper to lower segment, arm span to height ratio >1.05, flat feet
 * cardiovascular findings: dilatation of the aorta, aortic dissection, mitral valve prolapse, triscupsid valve prolapse, enlargement of the pulmonary artery
 * other systems involved: pulmonary, skin, nervous

Diagnosis of Marfan

 * Diagnosis is made clinically (see diagnostic criteria below for details)
 * based on family history and the observation of characteristic findings in multiple organ systems
 * no family history? 2 major criteria and 1 minor (3 systems)
 * with a family history? 1 major and 1 minor (2 systems)
 * sometimes we're very confident in the diagnosis (and sometimes sure of a negative diagnosis), sometimes we're just not sure and we may follow a person for a while, sometimes we think there may be another diagnosis
 * What will a diagnosis mean
 * predisposition for aortic rupture and other heart problems so must have cardiology exams for echocardiograms (monitor aortic root growth - beta-blockers may be prescribed)
 * orthopedist exams (for early detection of scoliosis and pectus)
 * yearly ophthalmology exams (due to various eye problems that can often be treated with corrective lenses, but sometimes require surgery)
 * potential for complications during pregnancy (rapid progression of aortic root enlargement) must be closely monitored
 * 50% chance that future children will inherit Marfan syndrome

Age of Onset, natural history, and life span

 * Some signs of the syndrome are present at birth
 * The serious vascular complications may develop at any time from fetal life through old age and are the chief cause of death in these individuals
 * The use of b-adrenergic blockers has been associated with a decrease in aortic dilatation and thus increased life
 * The mean age for survival for men = 43 and women = 46
 * However, with appropriate management, individuals are reportedly living until their 70's.

Genetics

 * Autosomal dominant inheritance
 * 75% have an affected parent
 * 25% due to new mutations
 * The disrupted gene is FBN1 - codes for Fibrillin (a protein constituent of connective tissue).
 * Located at 15p21
 * Molecular genetics
 * >100 mutations leading to abnormal splicing of the mRNA have been reported
 * The gene is >110 kb and is composed of 65 exons
 * A common motif is the epidermal growth factor (EGF) like domain. This domain occurs 47 times
 * Each EGF domain contains 6 conserved cysteine residues that from 3 disulfide bonds
 * 43 of the EGF domains contain a consensus sequence for calcium binding which facilitates inter and intramolecular interactions
 * Mutations in any of the conserved calcium binding sequences or the conserved cysteine residues lead to classical Marfan syndrome
 * The syndrome is fully penetrant, although the manifestations can vary considerably

Recurrence Risks

 * If parent affected 50% chance future children will also be affected
 * If parent of affected child is not affected then they have a much smaller chance of having another affected child (rare cases of germline and somatic mosaicism)

Genetic Testing
(available, but often not used)
 * Because FBN1 mutations have been detected in individuals with other fibrillinopathies, the presence of a mutation doesn't by itself confirm the diagnosis.
 * Mutations have not been detected in at least 25% of subjects with Marfan syndrome.
 * There exists the possibility that the Marfan syndrome phenotype may be produced by mutations in at least one other gene, for this reason, a definitive DNA-based test is not available
 * molecular genetic testing for mutations in the fibrillin-1 (FBN1) gene on chromosome locus 15q21.1
 * direct mutation screen cumbersome and inefficient due to large size
 * up to 70% show positive results
 * mutation is not identified in large number of individuals with Marfan syndrome
 * If a specific mutation is known within a family, that specific mutation can be tested individuals suspected to be affected
 * many mutations in FBN1 cause phenotype different from Marfan syndrome
 * mutational screening available on research basis
 * Linkage analysis
 * Markers are highly informative and are within the FBN1 gene
 * Nearly completely informative
 * Not available if only one affected individual in family
 * Although usually informative caution needed because locus heterogeneity not definitively excluded
 * Protein based methods
 * Being explored
 * Further research needed to determine specificity
 * Immunofluorescence studies of extracellular microfibrils with fibrillin antibodies are available as diagnostic aids

Prenatal Testing

 * Available using linkage analysis if linkage has been established in affected family members
 * Or using mutational analysis when disease-causing mutation has been identified
 * Ultrasound exam in first two trimesters cannot detect manifestations of Marfan

Geneotype-Phenotype Correlations

 * Few and none are definitive
 * Those with most severe and rapid termed "neonatal Marfan syndrome" have alterations in center of gene exons 24-32 (but not all with severe form have identified mutations and others with mutations in this region have classic or mild variants of Marfan)
 * In general mutations causing in-frame gain or loss of coding sequence associated with more severe disease
 * Premature termination result in rapid degradation of transcripts associated with mild conditions that fail to meet diagnostic criteria
 * Individuals with mutation preventing C-terminal propeptide processing had only skeletal manifestations
 * Amino acid substitution may have functional or not have functional importance

Diagnostic Criteria

 * Diganosis can be made clinically if: 2 organ systems are involved in the presence of an affected first degree relative
 * Or, involvement of the skeleton and two or more organ systems is required, as well as the presence of at least one major criterion
 * Note: skeletal system qualifies as a major criterion only if at least four major manifestations are present

Clinical Features (major and minor criteria)

 * Skeletal (can develop in young children and progress during periods of rapid growth)
 * Major criteria for diagnosis:
 * Pectus carinatum (protruding sternum in convex shape)
 * Pectus excavatum requiring surgery (congenital condition in which the sternum is abnormally depressed caused by overgrowth of ribs pushing the sternum in)
 * Scoliosis (mild to severe and progressive may require bracing or surgery)
 * Reduced extension at the elbows (<170°)
 * Pes planus (flatfoot)
 * Protrusio acetabuli (pertaining to the hip bone socket where acetabulum abnormally deep and shows accelerated erosion)
 * Reduced upper to lower segment ratio
 * Wrist sign: thumb overlaps the distal phalanx of the fifth digit when grasping the contralateral wrist (due to bone overgrowth and joint laxity)
 * Thumb sign: entire nail of the thumb projects beyond the ulnar border of the hand when the hand is clenched without assistance.
 * Minor criteria:
 * Pectus excavatum of moderate severity
 * Joint hypermobility
 * High arched palate with crowded teeth
 * Specific facies: dolicocephaly, malar hypoplasia, retrognathia, down slanting palpebral fissures, deep set eyes, palate can be highly arched
 * Dolichostenomelia (extremities are disproportionately long for the size of the trunk)
 * Arachnodactyly (spider fingers long and thin)
 * Major criteria:
 * Ectopia lentis (displacement of the lens of the eye in 60% of affected and it is a hallmark feature)
 * Minor critieria:
 * Flat cornea
 * Increased axial length of globe
 * Hypoplastic iris or hypoplastic ciliary muscle
 * Major Criteria:
 * Dilitation of the ascending aorta w/ or w/o aortic regurgitation, involving the sinuses of Valsalva
 * Dissection of the ascending aorta
 * Minor criteria:
 * Mitral valve prolapse w/ or w/o mitral valve regurgitation
 * Dilatation of the main pulmonary artery, in the absence of valvular or peripheral pulmonic stenosis before the age of 40
 * Calcification of the mital annulus before age 40
 * Dilatation or dissection of the descending thoracis or abdominal aorta before age 50.
 * Minor criteria:
 * Spontaneous pneumothorax (air in the pleural cavity)
 * Apical blebs
 * Minor criteria:
 * Striae atrophicae (stretch marks)
 * Recurrent or incisional hernia
 * Major criteria:
 * Lumbosacral dural ectasia by CT or MRI

Management/Treatment

 * Growth
 * All individuals should be measured periodically
 * Prepubertal girls can have height reduction by taking high-dose estrogen therapy combined with progesterone to prevent endometrial hyperplasia
 * Development
 * Physical therapy is of value in promoting motor skill development
 * Psychosocial family counseling
 * Musculoskeletal
 * Delays in gross motor development caused by joint hypermobility can be ameliorated with PT and orthopedic braces (as needed)
 * Treatment of scoliosis and kyphosis depending on the severity of the curvature
 * Pectus excavatum or carinatum may need to be repaired to prevent cardiac or pulmonary compromise
 * Cardiovascular
 * Follow with a cardiologist
 * Echocardiogram required at frequent intervals
 * b-Adrenergic blaockade has been demonstrated to slow progression of the aortic root dilatation by decreasing the stress on the aortic wall and the tunica media.
 * Graft replacement surgery if necessary
 * Most adults with Marfan syndrome will eventually need replacement of the dilated aortic root (5% operative risk) and leaking aortic valve.
 * If mitral valve prolapse is diagnosed, standard prophylaxis against bacterial endocarditis is recommended for all dental procedures.
 * Limit physical activities such as contact sports (football, basketball, hockey, volleyball, boxing, wrestling, etc.)
 * Ophthalmologic:
 * Myopia most common treated with corrective lenses
 * Adequate optical correction must be prescribed and worn
 * Assessments of refraction must be performed
 * Amblyopia must be treated aggressively
 * Lens removal for optical reasons is not recommended (the cataract of Marfan syndrome is a true indication for lens extraction)
 * When ectopia lentis is progressive and leads to complications such as iritis, glaucoma etc. the lens may need to be removed.
 * Because individuals are prone to retinal detachment, they should avoid contact sports
 * Neurologic
 * Orthostatic headache resulting from cerebrospinal fluid leakage is often transient. Treat with bed rest or corticosteroids
 * Respiratory
 * Spontaneous pneumothorax is treated by evacuation of the intrapleural air and restoration of the negative pleural pressure by insertion of a drainage test tube.

Differential

 * Many of the skeletal features common in general population
 * Other disorders caused by FBN1 mutations
 * MASS phenotype - mitral valve prolapse, borderline and nonprogressive aortic enlargement, nonspecific skin and skeletal features
 * Mitral valve prolapse syndrome - MVP with or without skeletal features
 * Predominant aortic aneurysm with other subdiagnostic features of Marfan
 * Predominant or isolated skeletal features of Marfan
 * Dominant ectopia lentis - lens dislocation with skeletal features
 * Familial ectopia lentis - associates eye and skeletal features (prolonged follow-up to differentiate it from Marfan)
 * Shprintzen-Goldberg syndrome - skeletal and heart findings with craniosynostosis and neurodevelopmental abnormalities (this is likely a genetically heterogeneous condition)
 * Other connective tissue disorders share some overlap (Ehlers-Danlos syndrome, fragile X, Stickler syndrome) Should be easily distinguished by other features though

Patient Resources

 * National Marfan Foundation
 * 22 Manhasset Avenue
 * Port Washington, NY 11050
 * phone: 1-800-8-MARFAN
 * http://www.marfan.org
 * mailto:staff@marfan.org

 * Canadian Marfan Association
 * 1-905-826-3223
 * http://www.marfan.ca

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


text:
Handbook of Genetic Counseling/Maternal Serum Triple Screen

Maternal Serum Triple Screen

Introduction

 * Acknowledge any prior contact
 * Ask them what they know already about why they are here and what they hope to get out of the session
 * Address any immediate concerns or indicate that they will be addressed later during the discussion
 * Reassure them that this is not a diagnostic test so it can't tell us if there is a problem with the fetus or not. A triple screen is performed to pick out a smaller group of pregnancies that are at an increased risk for specific birth defects and to offer diagnostic testing.
 * The majority of women with a positive screen will have babies without birth defects
 * This does not mean the test was wrong because all it was supposed to do is pick out fetuses at higher risk and allow us to offer diagnostic testing.

Obtain Medical and Family History

 * It is helpful for me to know some information about your medical history as well as your family history to determine if there are any health problems that may run in the family. (Make sure all the following information was correct on the test report before the visit or while taking the history because it can change the results drastically.)
 * Gestational age - marker levels change throughout pregnancy and inaccurate dates are a common reason for a false positive
 * Maternal weight - with increased blood volume, the markers will be diluted in the serum and lower their concentrations
 * Maternal race - African American women typically have a 10-15% higher [AFP], but a lower incidence of NTD's
 * Maternal age - the detection rate and false positive rate for Down syndrome will both be higher in women over age 35
 * Diabetic status - Insulin-dependent diabetics have an increased risk of NTD's, but lower [AFP]
 * number of fetuses - increases marker levels

General Information about Triple Screen

 * A triple screen is a blood test that is routinely offered to women under age 35 where amniocentesis is not recommended.
 * It is performed between 14-22 weeks gestation (It is most accurate when performed between 16-18 weeks)
 * A negative or normal screening result does not ensure that a child will not have a birth defect
 * As mentioned before, a positive result is not a diagnosis of an abnormality. It only indicates that a person has a high enough risk to warrant further testing.
 * It is easy to get confused when discussing the triple screen because there is a lot of information so please interrupt me and ask questions as they come up or let me know if something is unclear.

What a Positive Test Means

 * A positive test can tell whether you are at an increased risk for any of 3 disorders, but it can't tell you whether or not the fetus is actually affected
 * Open Neural Tube Defects
 * Give spina bifida as an example (where the spinal cord didn't form properly and nervous tissue is exposed)
 * Can cause motor impairments along with other health concerns
 * Does not detect all types of NTDs
 * If at high risk mention anencephaly so they can be prepared (where the brain is not formed properly and it is exposed) They may survive to term but die shortly after.
 * Explain whether their test showed that they were at increased risk or reassure them that their risk is not increased above the general population risk
 * Trisomy 18 and Trisomy 21
 * Explain chromosomes
 * When there is an extra chromosome it is called trisomy
 * Extra genetic material can cause problems in growth and development
 * There are a few relatively common trisomies, but the triple screen can detect only two of these
 * Explain the features and prognosis of trisomy 18 and Down syndrome
 * Explain whether or not their test showed they are at an increased risk for these

How Does Screening Work

 * Products made by the fetus and placenta can be detected in the mother's blood during pregnancy.
 * Levels of these products, referred to as markers, change throughout pregnancy
 * Increased or decreased levels of these markers can be correlated to an increased risk of any of the three types of problems that were discussed previously.
 * Triple screen measures three markers
 * AFP (alpha-fetoprotein --made in the liver and GI tract of the fetus) It is excreted into fetal urine, thus amniotic fluid, then transferred across placenta into maternal blood it increases during 2nd trimester
 * hCG (human chorionic gonadotropin - made by the placenta peaks at 10 weeks and falls from there) Pregnancy hormone tested for in pregnancy tests. Important marker for Down syndrome (increased)
 * uE3 (unconjugated estriol) - made by the fetus, placenta, and mother it increases throughout pregnancy-- found in both pregnant and nonpregnant women, but at different levels)

Risk Assessment

 * When the levels of the three markers are determined they are compared to the general population of pregnant women
 * The computer takes all factors into account, such as age of the mother and gestational age, to calculate a number (MoM - multiple of the median) that allows us to readily see if the levels are higher or lower than expected
 * A value that is 1 means that particular marker is present at expected levels
 * However most women do not receive 1's for all three markers and a little variation is common
 * It is not bad for the fetus to make different amounts of these proteins, but it is concerning if there are particular patterns to the levels of these three markers.
 * A value of 2 indicates that the levels are twice the average expected amount
 * A value of ½ indicates that the levels are half the average expected amount
 * When risks are determined, all three numbers are looked at together to look for a pattern that may indicate an increased risk for the three specific abnormalities we mentioned already

Interpreting What Your Results Mean

 * screen positive tests for singletons of non-diabetic mothers

ONTD

 * Only one marker is used to screen for ONTDs.
 * Positive screen if MSAFP is greater than or equal to 2.5 MoM
 * This indicates an unspecified increased risk of having a child with an ONTD
 * (The population incidence is 1 or 2 per every 1000 fetuses)

Trisomy 18

 * All three markers tend to be lower than expected, but uE3 is the most sensitive marker for trisomy 18.
 * The computer program takes your age related risks of having a child with trisomy 18 and calculates a new risk based on all the information
 * Your age related risk is _______________________
 * Your calculated new risk is _____________________ which means that the chance your fetus does not have trisomy 18 is ____________
 * The test is considered to be a positive screen if your new risk is greater than or equal to 1 in 100

Down syndrome

 * Markers tend to show the pattern in the chart above, but the most important predictive marker is hCG and it tends to be present in higher levels when the fetus has Down syndrome (reason unknown)
 * The computer program takes your age related risks of having a child with Down syndrome and calculates a new risk based on all the information
 * Your age related risk is ______30_________________
 * Your calculated new risk is _____________________ which means that the chance your fetus does not have Down syndrome is ____________
 * The test is considered to be a positive screen if your new risk is greater than or equal to 1 in 270 (approximate risk in women age 35 of having a fetus with Down syndrome at time of amnio)

Reasons for a Screen Positive Result

 * ONTD -- Other conditions can be associated with an elevated MSAFP

ONTD

 * Normal variant
 * Underestimated gestational age
 * Multiple pregnancy
 * Abdominal wall defect (gastroschisis or omphalocele)
 * Feto-maternal bleeding
 * Fetal demise
 * Other birth defects
 * Increased risk for 3rd trimester complications

Trisomy 18

 * Trisomy 18
 * Normal variant
 * Inaccurate dating (uE3 levels most predictive)
 * Another chromosome abnormality
 * Fetal demise
 * Steroid sulfatase deficiency (X-liked icthyosis) common reason if estriol is undetectable

Down Syndrome

 * Down Syndrome
 * Normal Variant
 * Gestational age (if GA off by more than 10 days should recalculate)
 * Multiple pregnancy
 * Another chromosomal abnormality
 * Triploidy
 * Increased risk of third trimester complications (if hCG > 2.5 she should be monitored more closely)

ONTDs

 * Offer ultrasound -
 * confirm gestational age (MSAFP increases throughout this time in pregnancy and the g.a. may just be underestimated)
 * rule out anencephaly, ONTD, fetal demise, multiple gestation
 * If nothing is found on ultrasound and dates are correct
 * 2.0-2.9 MoM, g.a. <18 wks repeat serum AFP
 * >3 MoM, or g.a. > 18 wks offer amnio (measures AFP 90-96% accurate and can also measure Acetylcholinesterase level which detects 99% of ONTD) also detects chromosomal abnormalities
 * If the cause of the elevation is still not identified and AFP was greater than 3.0 MoM, serial ultrasounds and antenatal testing should be considered (watch for pre-eclampsia)

Trisomy 18

 * Offer ultrasound
 * Confirm gestational age - off by >10 days call and get a recalculation (uE3 most important increases with gestational age)
 * Explain what they look for that might provide clues as to whether the fetus is affected (not diagnostic though so it cannot tell us for sure whether or not the fetus has trisomy 18)
 * Offer amniocentesis
 * diagnostic testing that will accurately determine if the fetus has trisomy 18 with greater than 99% accuracy
 * risks of miscarriage 0.5 % above baseline
 * also detects various other chromosomal abnormalities
 * If hCG is <2.5 MoM and cause is not identified, a third trimester ultrasound for growth should be considered and patient monitored for pre-eclampsia

Down syndrome

 * Offer ultrasound
 * Confirm gestational age
 * if off by 10 days or more and drawn before 15 weeks than repeat at 15-18 wks
 * if off by 10 days of more and drawn at or after 15 wks than recalculate the DS risk using corrected age
 * Explain other things they will look for on the ultrasound that may be signs of Down syndrome
 * Signs are found on ultrasound in about 2/3 of fetuses with Down syndrome
 * Whether or not signs are found ultrasound cannot confirm for certain whether or not the fetus is affected.
 * Offer amniocentesis (diagnostic testing that will tell us whether the fetus has Down syndrome with >99% accuracy and also detects other chromosomal abnormalities
 * If hCG is <2.5 MoM and cause is not identified, a third trimester ultrasound for growth should be considered and patient monitored for pre-eclampsia

Triple Screen Sensitivity

 * Focus on their results
 * These statistics are for the population and don't really affect their results
 * They may be confused about this though so address it if there are questions
 * Detection rate
 * Given the fetus is affected detection rate is the chance that it will be picked up and have a positive screen.
 * NOT ALL AFFECTED FETUSES ARE PICKED UP ON TRIPLE SCREEN
 * False positive
 * Chance of having an unaffected fetus and obtaining a positive screen out of all unaffected pregnancies
 * Since there are more unaffected pregnancies than affected pregnancies it may seem like there is a large absolute # of false positives
 * If their fetus is unaffected it doesn't meant that the triple screen was wrong because all it is supposed to do is pick out women at increased risk for NTDs, Down syndrome, and trisomy 18.

ONTDs

 * 85% detection rate - means that out of 100 pregnancies where the fetus has an ONTD 85 of them are picked up by this screening (it does not pick up closed neural tube defects)
 * 80% of cases of open spina bifida
 * 90% of cases of anencephaly

Trisomy 18

 * 60-80% detection rate - means that out of 100 pregnancies where the fetus has trisomy 18, 60 or 80 of them will be picked up as a positive screen
 * .5% false positive rate - means that out of 200 women who are not carrying a fetus with trisomy 18 1 of those 200 would receive a positive screen

UNDER 35

 * 60-65% detection rate - means that out of 100 pregnancies where the fetus has Down syndrome about 65 will be picked out by this screening
 * 5% false positive rate - means that out of 100 women that do not have a child with Down syndrome 5 of them will receive a positive screen

OVER 35

 * 85-90% detection rate
 * 25% false positive rate

Review

 * Assess if there are any questions or if there is anything that she would like me to explain again
 * Assess how she feels about further testing options
 * Check for understanding by having her explain how she feels about her risk


text:
Handbook of Genetic Counseling/Maternal Serum Triple Screen-2

Maternal Serum Triple Marker Screening (Triple Screen)

Contracting

 * What do you know about why you have been referred for genetic counseling?
 * What have you been told about the triple screen? What is your understanding of your test results?
 * What questions or concerns would you like to address?

Overview of maternal serum screening

 * Background
 * Screening test
 * Not a diagnostic test
 * Used to identify women who are at increased risk for certain birth defects
 * These women then offered diagnostic testing
 * Negative or "normal" result does not mean that a child will not have a birth defect
 * Positive result is not a diagnosis of an abnormality
 * Can identify women at increased risk for Trisomy 21, Trisomy 18, or open neural tube defects
 * Blood test
 * Fetal and placental products can be detected in mother's blood serum during pregnancy
 * Can be offered from 14-22 weeks but most accurate at 16-18 weeks
 * Indirect measure of levels of three substances in mother's blood
 * Alpha-fetoprotein (AFP)
 * Produced by liver of fetus and excreted into amniotic fluid
 * Passes into mother's bloodstream and concentration rises gradually throughout pregnancy
 * Human chorionic gonadotropin (HCG)
 * Pregnancy hormone made by the placenta
 * Level peaks at 10 weeks and declines throughout pregnancy
 * Unconjugated estriol (uE3)
 * Pregnancy hormone made by fetus and placenta
 * Level increases throughout pregnancy
 * Some laboratories also measure levels of inhibin-A
 * Product of placenta
 * Quadruple-marker screening may increase detection rate for Down Syndrome
 * Risk assessment
 * Markers are expressed as multiples of the median (MoM) in report
 * MoM determined by examining results from a large number of women and establishing an "average"
 * The median for all markers is 1.0 MoM
 * An individual's values expressed as marker level in patient/median marker level
 * Laboratory calculates a woman's risks based on levels of three substance plus other factors
 * Multiple gestations would cause levels to be elevated
 * Gestational age
 * Marker levels change throughout pregnancy
 * Inaccurate dates are common reason for false positive
 * Gestational age can be confirmed by ultrasound
 * Maternal weight
 * Increased weight means increased blood volume
 * Markers will be diluted in serum and their concentration lower
 * Maternal race
 * Maternal age
 * Increased risk for having child with chromosomal abnormality as maternal age increases
 * Women over age 35 have higher detection rate and false positive rate
 * Diabetic status
 * Insulin-dependent diabetics have increased risk for neural tube defects
 * Tend to have lower AFP levels, so use lower AFP cutoff
 * Evaluation of screening performance
 * Up to 100 of every 1,000 women who take test will have abnormal result
 * Only 3 of those 100 women will have a baby with a birth defect
 * Most abnormal test results indicate dates are wrong or another factor above has not been accurately accounted for
 * Abnormal result could also be normal variation
 * Pattern of variation in levels may indicate that a woman is at increased risk for a particular birth defect
 * Evaluation of abnormal results
 * Elevated MSAFP
 * Greater than 2.5 MoM
 * Conditions possibly causing elevated MSAFP
 * Normal variant
 * Underestimation of gestational age
 * Multiple pregnancies
 * Open neural tube defects
 * Abdominal wall defects
 * Feto-maternal bleeding
 * Fetal demise
 * Finnish nephrosis
 * Some other birth defects
 * Increased risk for 3rd trimester complications
 * Follow-up strategies:
 * Repeat MSAFP
 * If patient's gestational age is within testable range
 * If only mild elevation (2.5-3.0 MoM)
 * Confirm gestational age by ultrasound
 * Offer ultrasound and amniocentesis
 * Serial ultrasounds and antenatal testing
 * If AFP greater than 3.0 MoM
 * When cause of elevation is not identified
 * Neural tube defects
 * Includes spina bifida, anencephaly most commonly
 * Also includes such conditions as encephalocele and hydrocephalus
 * Neural tube is part of developing embryo that brain and spine develop from
 * Neural tube defects due to failure of this tube to close properly
 * About 2,500 babies born each year in US with neural tube defect
 * Spina bifida
 * Backbone does not form properly
 * Often spinal cord is malformed and protrudes from back
 * Can cause leg paralysis and bladder and bowel problems
 * Anencephaly
 * Upper end of neural tube fails to close
 * Brain and skull severely malformed
 * Babies usually don't survive
 * Multifactorial inheritance
 * Both genetic and environmental factors interact to cause this condition
 * About 90-95% of babies with NTDs born into families with no prior history
 * Screen positive for Down Syndrome
 * Positive if calculated risk is greater than 1 in 270
 * Occurs when AFP is decreased, hCG elevated, and uE3 decreased
 * Conditions possibly associated with screen positive for Down Syndrome
 * Normal variant
 * Overestimation of gestational age
 * Multiple pregnancies (uncommon)
 * Down syndrome
 * Another chromosome abnormality
 * Triploidy
 * Increased risk for 3rd trimester complications
 * Follow-up recommendations
 * Confirm gestational age with ultrasound
 * Repeat test only if patient was at too early a gestational age for the screen to be performed
 * Offer diagnostic ultrasound and amniocentesis
 * Ultrasound for growth and monitoring for preeclampsia in 3rd trimester if hCG greater than 2.5 MoM for unknown reason
 * Down Syndrome
 * Explain chromosomes and nondisjunction
 * Discuss age-related risk and adjusted risk for Down syndrome
 * Clinical features and prognosis
 * Due to extra copy of chromosome 21
 * May cause characteristic facial features, mental retardation, heart defects, and other health problems
 * Cannot predict severity
 * Screen positive for Trisomy 18
 * When calculated risk is greater than 1 in 100
 * Occurs when AFP, hCG, and uE3 are all decreased
 * Conditions associated with positive screen
 * Normal variant
 * Gestational age inaccurate
 * Trisomy 18
 * Another chromosome abnormality
 * Fetal demise
 * Steroid sulfatase deficiency (X-linked ichthyosis)
 * Follow-up recommendations
 * Confirm gestational age by ultrasound
 * Repeat only is gestational age at time of screen found to be too early
 * Offer diagnostic ultrasound and amniocentesis
 * Monitor for preeclampsia and offer ultrasound in 3rd trimester if hCG above 2.5 MoM and no cause identified
 * Trisomy 18
 * Explain chromosomes and nondisjunction
 * Discuss age related and adjusted rates for trisomy 18
 * Clinical features and prognosis
 * Caused by extra copy of chromosome 18
 * Causes severe mental retardation and health problems
 * Usually fatal within first year of life
 * Capabilities and limitations of screening
 * Benefits
 * May provide reassurance that fetus does not appear to have certain birth defects
 * Can help woman manage pregnancy better
 * When problems detected, woman can prepare for delivery or treatment needed right after birth
 * Prepare mentally, emotionally, and socially for birth of child with birth defect
 * May help women over age 35 determine whether to have more invasive procedure
 * Negative screen may actually lower risk for chromosome abnormality
 * Women with negative screen may choose to avoid more risky procedure
 * Monitoring of women with abnormal test result may prevent 3rd trimester complications
 * Limitations
 * Not diagnostic test
 * False positive may produce unnecessary anxiety
 * Negative test does not mean fetus does not have birth defect, only that not at increased risk for conditions mentioned
 * May be no explanation for abnormal result
 * Abnormal results may be associated with pregnancy problems like placental abruption, preterm labor, and low birth weight
 * May cause maternal anxiety
 * Can't identify all birth defects
 * Down syndrome and Trisomy 18 are only chromosomal abnormalities that can be detected with this test
 * Amniocentesis is only way to diagnose or rule out chromosome problems

Other testing options

 * Ultrasound
 * May be offered to confirm gestational age or identify multiple fetuses to help interpret triple screen results
 * Can detect many major birth defects
 * Can rule out 95% of NTDs if visualization is not limited
 * Can't diagnose chromosomal abnormalities
 * Amniocentesis
 * Performed after 15 weeks
 * Risks/Benefits
 * 99.7% accuracy for fetal chromosome analysis
 * Detects 96% of open neural tube defects by testing AFAFP
 * Cannot detect all birth defects or mental retardation
 * Risk of miscarriage due to procedure is 0.5%


text:
Handbook of Genetic Counseling/McCune Albright Syndrome

McCune Albright Syndrome

Introduction

 * Establish rapport with small talk and introduce myself
 * Briefly discuss the topics to be covered during the appointment
 * Assess the concerns of the family and ask if they have any questions today

Elicit Family History Update

 * Any changes in family history?
 * Any new births or plans for pregnancy?

Definition

 * McCune Albright syndrome is a disorder characterized by polyostotic fibrous dysplasia accompanied by café au lait spots and endocrine disorders esp. precocious puberty in girls. The patient is fracture prone, and deformity and shortening of the bones may develop.

Genetic Etiology

 * Mode of inheritance:
 * Thought to be sporadic although there have been a few familial occurrences.
 * Believed to be a somatic mutation disorder
 * Molecular Genetics:
 * Identification of activating mutations in the GNAS1 gene
 * G proteins are involved in signal transduction pathways that affect the production of cAMP
 * An overactive cAMP pathway stimulates growth and function of the gonads, adrenal cortex, specific pituitary cells, osteoblasts, and melanocytes
 * Mutations in the gene render it functionally constitutive.
 * Proposal that this a disorder of mosaicism (nonmocaicism is thought to be a lethal condition)
 * Chromosome location
 * Chromosome 20

Incidence

 * Described in 1936-1937 by McCune and Albright respectively- since then >100 cases have been reported
 * The frequency of diagnosis in females vs. males is 3:2

Clinical Features

 * Endocrine Abnormalities:
 * Precocious puberty occurs in over 50% of the female cases and has been reported for males as well
 * Menstruation, breast development, and pubic hair growth can occur during the first months of life
 * Usually caused by ovarian cysts that secrete estrogen into the blood stream
 * Many women with MAS are fertile in adulthood
 * Hyperthyroidism:
 * 50% of patients with MAS have thyroid gland abnormalities
 * Enlargement=goiter
 * Pituitary thyroid-stimulating hormone (TSH) levels are low in these patients, while thyroid hormone levels may be normal or elevated
 * Excessive secretion of growth hormone has been seen in a few patients
 * Most develop course facies, enlarged hands/feet, and arthritis characteristic of acromegaly
 * Associated with gigantism and gynecomastia
 * Adrenal Enlargement:
 * Rarely seen
 * Excessive secretion of the adrenal hormone cortisol caused by the hyperfunction of the anterior pituitary
 * Results in cushing syndrome
 * Weight gain, obesity of the face and trunk, skin fragility and cessation of growth in children
 * Treatment: removal of adrenal glands or use of drugs that block cortisol synthesis
 * Bone Disease (polyostotic fibrous dysplasia):
 * Abnormal fibrous tissue growth in many bones
 * In affected areas, normal bone is replaced by irregular masses of fibroblast cells leads to deformity and/or thickening of the bones
 * When this occurs in weight bearing bones such as the femur, limping, deformity, and fractures can result
 * Many children have unequal arm/leg length even in the absence of fractures
 * Regions of fibrous dysplasia are also common in the skull and jaw bones
 * May result in facial asymmetry
 * Severity of bone involvement varies
 * Know known hormonal or medical treatment has been proven effective.
 * Some surgical procedures such as grafting, pinning, and casting have been used to correct fracture and deformity (skull and jaw changes are often corrected surgically to improve appearance)
 * Skin abnormalities:
 * Flat areas of increased pigment may be found = café au lait spots
 * These spots are usually present at birth, and they usually do not become more extensive
 * The pattern of pigmentation is unique
 * Starts or ends abruptly at the midline on the abdomen in front or at the spine in the back
 * A few have spots confined to small areas such as the nape of the neck or crease of the buttocks

Natural history

 * Pigmentation is usually evident in infancy
 * Bone dysplasia may progress throughout childhood
 * The sexual precocity is often unusual, with menstruation occurring before breast and pubic hair development.
 * Precocious puberty may lead to short stature

Testing

 * Currently, testing for a mutation in the GNAS1 gene is done for research purposes.
 * It is not a routine test that can be ordered.

Differential Diagnosis

 * Hemihypertrophy, a sporadic condition, has as its most significant feature- limb length asymmetry and sometimes, facial asymmetry. Between 5-8% of these children will develop an intra-abdominal tumor, either Wilms tumor of the kidney or hepatoblastoma.

Psychosocial Assessment

 * How are things at home?
 * Does mom work outside of the home?
 * Financial concerns?
 * How is the family adjusting?

Support Groups

 * The Paget Foundation
 * 120 Wall Street
 * New York NY 10005
 * 2125095335
 * 8002372438
 * e-mail: pagetfdn@aol.com
 * Home Page: http://www.paget.org

 * MAGIC Foundation for Children's Growth
 * 1327 North Harlem Avenue
 * Oak Park IL 60302
 * 7083830808
 * 8003624423
 * e-mail: mary@magicfoundation.org
 * Home Page: http://www.magicfoundation.org

 * NIH/National Institute of Child Health and Human Development
 * 31 Center Dr
 * Bethesda MD 20892
 * 3014965133


text:
Handbook of Genetic Counseling/Medium-chain acyl-coenzyme A dehydrogenase Deficiency

Medium-chain acyl-coenzyme A dehydrogenase Deficiency

Overview

 * Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is an enzyme involved in mitochondrial fatty acid b-oxidation (FAO). Fatty acid oxidation provides energy for peripheral tissues when glycogen is depleted through hepatic ketogenesis. A defect in the MCAD enzyme causes accumulation of medium-chain fatty acids, metabolized to glycine- and carnitine-esters and dicarboxylic acids, and hypoketonia.

Genetics

 * MCAD deficiency is caused by a mutation in the ACADM gene
 * Chromosomal locus 1p31
 * 31 known disease causing mutations
 * 1 common mutation, K304E, accounts for 76% of alleles

Incidence

 * Common in Caucasians, especially with Northern European ancestry
 * Disease incidence 1:4,900 to 1:17,000
 * Carrier frequency 1:40 to 1:100
 * Less common among Hispanics
 * Rare in African-American, and Native-American populations

Diagnosis

 * Metabolic testing
 * Symptomatic individuals should have plasma acylcarnitines, plasma fatty acids, urine organic acids, and urine acylclycines analyzed and interpreted.
 * Enzymatic testing
 * MCAD enzyme activity should be measured in fibroblasts or other tissues to confirm diagnosis
 * Molecular testing
 * Molecular genetic testing by mutation analysis (for K204E) or sequence analysis of the ACADM gene can confirm diagnosis
 * Newborn screening
 * MCAD is part of the newborn screening panel in 9 states (IA, ME, MA, NC, OH, SC, SD, WI, WY).
 * Prenatal testing
 * Enzymatic or molecular testing can be performed prenatally; however, there is limited benefit to prenatal vs. newborn testing.
 * Carrier testing
 * Only molecular testing can determine carrier status.

Clinical Features
seizures, and coma precipitated by prolonged fasting or common illness.
 * Typical presentation includes hypoketotic hypoglycemia, vomiting, lethargy,
 * Hepatomegaly and acute liver disease may also be present.
 * Sudden, unexplained death may be first symptom (18%).

Natural History

 * Typically normal at birth following uneventful pregnancy
 * Most present with symptoms between 3 and 24 months in response to prolonged fasting or infection
 * Initial presentation in adulthood also possible
 * Affected individuals may lose developmental milestones or acquire aphasia or ADD as a result of acute metabolic event
 * Individuals identified as newborns typically develop normally under treatment

Inheritance

 * MCAD deficiency is an autosomal recessive disorder.

Testing

 * Enzymatic and Molecular testing can confirm diagnosis.
 * Both mutation and sequence analysis are available on a clinical basis.

Management & Treatment

 * MCAD is a highly treatable condition- good prognosis when managed
 * Avoidance of fasting is key-
 * Infants should be fed frequently
 * Toddlers should be given 2 g/kg uncooked cornstarch before bed
 * Low-fat diet and carnitine supplementation may be beneficial

Differential Diagnosis

 * Other disorders of acyl-CoA dehydrogenase (ACAD) gene family
 * Other disorders of fatty acid b-oxidation

Psychosocial Issues

 * Parental guilt over allowing too long of time between feedings which triggered onset of symptoms
 * Parental guilt over passing gene to child
 * When presenting symptom is sudden death, loss of seemingly healthy child can be devastating
 * Parent or sibling may be identified as a homozygote during carrier testing
 * Family planning- risk for future offspring/siblings of affected individual

Patient Resources

 * FOD (Fatty Oxidation Disorder) Family Support Group
 * 805 Montrose Drive
 * Greensboro, NC 27410
 * Phone: (336) 547-8682
 * Email: deb@fodsupport.org
 * Web: www.fodsupport.org

 * Organic Acidemia Association
 * 13210 35th Avenue North
 * Plymouth, MN 55441
 * Phone; (763) 556-1797
 * Email: OAANews@aol.com
 * Web: www.oaanews.org

 * United Mitochondrial Disease Foundation
 * 8085 Saltsburg Road, Suite 201
 * Pittsburgh, PA 15239
 * Phone: (412) 793-8077
 * Email: info@umdf.org
 * Web: www.umdf.org


text:
Handbook of Genetic Counseling/Microcephaly

Microcephaly

Contracting

 * Acknowledge prior phone contact
 * Review main concerns of family
 * What do they hope to gain from the session?
 * Overview of today's session, explaining what we will do to try and figure out the cause of ____'s small head.

Family and medical history

 * Obtain information about maternal and neonatal infections, pregnancy exposures to drugs, birth complications, head circumference at birth, head sizes of other family members, seizures, MR, LD, birth defects, unusual physical features, chronic health problems, anyone with a genetic condition, what type of tests have been done

Overview

 * Definitions vary somewhat
 * A congenital anomaly of the central nervous system (CNS) where the head circumference is > 2 or 3 standard deviations below the mean for age and sex
 * most often occurs as a result failure of normal brain growth but may also be due to a poorly growing skull (i.e., craniosynostosis)
 * may be present at birth or occur in first 2 years of life
 * if insult to brain occurs beyond 2 years of age less likely to produce severe microcephaly
 * Clinically and genetically heterogeneous condition
 * Genetic and environmental causes
 * Generally associated with MR, but not in all cases
 * Cognitive effects can vary significantly (normal development or mild developmental delay to severe MR)
 * May be associated with seizures
 * May also occur with other symptoms as in the case of a genetic syndrome

Genetic Causes

 * Autosomal Recessive (Familial) RR 25%
 * Autosomal Dominant RR 50%
 * Syndromes (have other characteristics and often have some degree of MR or learning difficulties)
 * Gross chromosomal abnormalities
 * Trisomy 18
 * Trisomy 13
 * Wolf-Hirschhorn syndrome
 * Cri du Chat syndrome
 * Partial deletion of long arm of 13
 * Contigous gene syndromes
 * Miller-Dieker syndrome
 * Langer-Giedion syndrome
 * Prader-Willi syndrome
 * Aniridia-Wilms tumour syndrome
 * Autosomal recessive disorder
 * Johanson-Blizzard syndrome
 * Seckel syndrome
 * Smith-Lemli-OPitz syndrome
 * Coffin-Siris syndrome (?)

Nongenetic causes

 * Congenital CNS Anomalies
 * Agenesis of the Cerebellar Vermis
 * Agenesis of the Corpus Callosum
 * Craniosynostosis
 * Encephalocele
 * Holoprosencephaly
 * Lissencephaly
 * Macrogyria
 * Porencephaly
 * Schizencephaly
 * Congenital Infections
 * CMV
 * Rubella
 * Toxoplasmosis
 * Varicella
 * Drugs
 * Alcohol
 * Aminopterin
 * Dilantin
 * Methyl Mercury
 * Infections
 * Encephalitis
 * Meningitis
 * Metabolic
 * Maternal Diabetes Mellitus
 * Maternal PKU
 * Inborn Errors of Metabolism
 * Neuronal Ceroid Lipofuscinoses

Testing
CT/MRI -- for structural anomalies: cerebral/cerebellar atrophy, hydrocephaly, calcification, craniosynostosis
 * Imaging Studies
 * Serum
 * karyotype
 * plasma for amino acids
 * serum ammonia
 * TORCH screen (toxo, rubella, CMV, HSV)
 * maternal blood for PKU
 * Urine
 * amino acids and organic acids
 * CMV

References and resources

 * OMIM
 * Mochida GH, Walsh CA. Molecular genetics of human microcephaly. Curr Opin Neurol 2001 Apr;14(2):151-6
 * PedBase.org: http://pedbase.org
 * PedBase: http://pedbase.org/m/microcephaly
 * There is a microcephaly online support group, but I don't know how good it is http://groups.yahoo.com/group/microcephaly/
 * Definition and types of microcephaly: http://www.ayles.demon.co.uk/microcep.htm
 * Teaching Files:Microcephaly
 * Division of Neonatology, Cedars-Sinai Medical Center, Los Angeles, California.


text:
Handbook of Genetic Counseling/Miller Syndrome

Miller Syndrome

Also known as

 * Post axial acrofacial dysostosis
 * Acrofacial Dysostosis, Postaxial Type
 * Acrofacial Dysostosis, Type Genee-Wiedep
 * Genee-Wiedemann Syndrome

Clinical Features

 * Distinctive craniofacial malformations
 * Underdeveloped cheekbones
 * Abnormally small jaw (micrognathia)
 * Cleft palate
 * Small, protruding "cup-shaped" ears
 * Drooping of the lower eyelids
 * Limb Anomalies
 * Incomplete limb development
 * Webbing of fingers or toes
 * Absence of certain fingers and /or toes
 * Underdevelopment of the ulna (bones on the "pinkie" side) and the radius (bones on the thumb side) causing the forearms to appear unusually short
 * Intelligence is normal

Diagnosis

 * Made on clinical features

Management & Treatment

 * Surgeries
 * Tracheostomy to help with breathing
 * Gastrostomy tube to assure proper nutrition
 * Craniofacial surgery to the jaw, ears, and eyes

Genes & Chromosomes

 * Possible AR inheritance

Resources

 * FACES: The National Craniofacial Association
 * P. O. Box 11082
 * Chattanooga, TN 37401
 * (800) 332-2373
 * email: faces@faces-cranio.org
 * Provides financial support for non-medical expenses to patients traveling to a craniofacial center for treatment. Eligibility is based on financial and medical need. Resources include newsletters, information about craniofacial conditions, and networking opportunities.

 * The Foundation for Nager and Miller Syndromes
 * Margaret Ieronimo
 * 1827 #2 Grove Street
 * Glenview, IL 60025
 * (800) 507-FNMS
 * email: fnms@interaccess.com
 * web site: http://www.nagerormillersynd.com/new
 * Excellent resource!! This is an international support group that serves as an information clearinghouse that links families together. They have an extensive library of resources and medical reports and are involved in a genetic research project working to locate the genes responsible for Miller Syndrome. Twice a year, they publish a very informative newsletter.

 * National Health Law Program
 * 1101 14th Street, NW, Suite 405
 * Washington, DC 20005
 * (202) 289-7661
 * Website: http://www.healthlaw.org
 * Provides extensive information on health care law affecting families with children who have special health care needs.

 * Children with Facial Difference: A Parent's Guide.
 * Written by Hope Charkins, MSW. Published by Woodbine House, 1996. 1-800-843-7323.
 * Excellent resource for parents to help them cope with medical, emotional, social, educational, legal, and financial challenges presented by facial differences of their children

Conclusions

 * Overview session
 * Give client resources
 * Give contact info


text:
Handbook of Genetic Counseling/Mosaic trisomy 21 - Transient Myeloproliferative Syndrome

Mosaic trisomy 21 - Transient Myeloproliferative Syndrome

Introduction/Contracting

 * How has everything been going since your last visit in April?
 * Do you have any concerns or questions at this time?
 * We wanted to follow T in genetics because there is such a wide variability in characteristics, cognitive abilities and health concerns in children with mosaic trisomy 21 and we want to make certain that any special services or health care needs are being met.
 * I am going to first ask questions about his medical and developmental hx. since his last visit in April.
 * Dr. Doktour will want to take a look at him
 * We can answer questions you might have and discuss what our impression is now at this time.

Medical History

 * Any new medical problems?
 * How is he eating? What does he eat? How much?
 * Is he still being followed by oncology? What are their expectations for T?
 * Any surgeries or hospitalizations?
 * Medications
 * Review systems briefly to check if any concerns with heart, hearing, eyes, bowel movements or stool, bladder problems, muscle or bone problems (broken bones, muscle weakness), seizures, breathing difficulties or snoring loudly at night, any birth marks or unusual skin findings, allergies.

Developmental History

 * I noted that you feel his development is appropriate for his age.
 * I just want to get documentation of when he achieved certain milestones
 * Ask about milestones
 * Ask what he is currently doing?
 * Typical two-year old can
 * Put on clothes, but not button
 * Use spoon little spilling
 * How does he pick up small objects can he use fingers in pincer grasp
 * About how many words is he saying
 * Is he combining words, how many?
 * Following two step directions
 * Does he have a tricycle? How does he do on that?
 * Is he still receiving services through Baby Watch?

Psychosocial Considerations and Counseling

 * Are you considering having more children?
 * I know Counselor1 and Dr. Doktour have gone over this, but do you have any questions about recurrence risks or how mosaic trisomy 21 occurs.
 * Acknowledge that it has been a lot to go through
 * Childhood illness may increase parents worry and/or overprotective behavior concerning their child
 * Assess how their support has been and whether they are getting all the help they need
 * Assess whether they are worried about cancer recurrence risks

Mosaic Trisomy 21

 * Occurs in 1-2% of liveborn infants with Down syndrome
 * Wide variability in (characteristics) phenotype (ranging from completely normal to full DS phenotype)
 * Intellectual development varies also (near normal to severe mental retardation)
 * How affected an individual is depends on the tissues involved and the proportion of trisomic cells
 * Children with DS have 10-20 fold increase in incidence of leukemia
 * Most common is a transient leukemia known as transient myeloproliferative disorder (TMD)
 * 7 of 8 families with mosaic trisomy 21 studied it appeared that nondisjunction occurred after fertilization then the cell line with extra copy developed and in 1 there was the presence of a third type of chromosome 21 suggesting it was trisomic embryo that lost one copy in one of cell lines subsequently

TMD (Transient Myeloproliferative Disorder)

 * Clinically indistinguishable from congenital leukemia
 * Unique due to spontaneous remission (no chemo)
 * Complete clinical recovery in many cases
 * often associated with trisomy 21 cell line, but not always associated with clinical signs of Down syndrome
 * case report of newborn boy (Bhatt, et al., 1995)
 * high white blood count, undifferentiated
 * initially thought to be congenital leukemia a form that is usually fatal
 * 14 other cases with no phenotypic evidence of trisomy 21
 * clinical course ranged from relatively benign to serious ending up in death
 * all survivors showed complete resolution without chemo
 * extent of mosaicism variable, but there was at least a decrease in percent of trisomy 21 cells and some had complete resolution
 * some had constitutional presence of trisomy 21 (4/15) others only 10 had analysis of skin fibroblasts and they showed normal karyotype

Recurrence Risks Mosaic Trisomy 21

 * Parents not likely to be at any higher risk than general population because nondisjunction probably occurred in the developing embryo and not the egg or sperm.
 * Their risk may be as high as 1% based on empiric risks for parents with a child with full trisomy 21 (this includes risks for other chromosomal abnormalities such as trisomies 18 and 13 and Klinefelter)
 * Uncertainty about whether there will be increased risks to the offspring of individuals with TMD. It is possible for them to have germ cell mosaicism for trisomy 21, which would increase risks for their offspring.

Risks of Recurrence in Cancer

 * Although complete resolution of TMD occurs in most patients with DS, 25% end up developing AMKL within 3 years
 * No patient with normal phenotype and trisomy 21 cell line has been described to develop AMKL
 * Those with constitutional mosaicism speculated to be at higher risk than those without

Resources

 * Bhatt, S. et al. Transient Leukemia With Trisomy 21: Description of a Case and review of the Literature. Amer. Journal of Med. Gen. 58:310-314 (1995).
 * Pangalos, C; Avramopoulos, D; Blouin, J L; Raoul, O; deBlois, M C; Prieur, M; Schinzel, A A; Gika, M; Abazis, D; Antonarakis, S E. Understanding the mechanism(s) of mosaic trisomy 21 by using DNA polymorphism analysis.
 * American Journal of Human Genetics. vol. 54, no. 3 (1994 Mar): 473-81.


text:
Handbook of Genetic Counseling/Mucopolysacharidosis (MPS)

Mucopolysacharidosis (MPS)

Contracting

 * Can you explain to me your main purpose in visiting genetics?
 * What are your main concerns about the diagnosis?
 * Outline session
 * First I will update the medical and family history
 * Doctor will then probably want to perform physical exam
 * Then we will address any concerns or questions

Medical history

 * Follow interim history form and focus on potential health problems/ symptoms described later in outline

Update Pedigree

 * Any other brothers or sisters
 * Full biological?
 * Any other family members with:
 * Genetic conditions
 * Multiple miscarriages
 * Birth defects
 * Chronic illnesses
 * MR learning difficulties
 * Any chance that you and his father related by blood
 * Country where relatives are from originally

Overview

 * Group of inherited metabolic disorders
 * Caused by a deficiency of the specific lysosomal enzymes needed to break down mucopolysaccharides
 * Mucopolysaccharides are long chains of sugar molecules used to build connective tissues and organs in the body
 * When mutations occur in the genes for the enzymes that break down mucopolysaccharides, excess amounts of them are stored in the body
 * This causes progressive damage to organs and tissues
 * Eight clinical types and numerous subtypes have been identified
 * Although each type differs clinically, generally, people with mucopolysaccharidoses experience a period of normal development followed by a decline in physical and/or mental function
 * Some of the excess mucopolysaccharides are excreted through the urine and diagnosis often can be made through clinical examination and urine tests

Incidence

 * Estimated 1 in 25,000 births in U.S. have some form of MPS:

Treatment

 * No simple cure for the mucopolysaccharidoses
 * Treatment is symptomatic and supportive
 * In several individuals, bone marrow transplants have been attempted with varying degrees of success
 * Enzyme replacement trials (ERT) are under investigation for MPS I and MPS II
 * Kakkis et al. (2001) treated 10 patients with MPS I (aged 5 to 22 years) with recombinant human alpha-L-iduronidase at a dose of 125,000 U per kg of body weight given intravenously once weekly for 52 weeks.
 * Hepatosplenomegaly decreased significantly in all patients, and the size of the liver was normal for body weight and age in 8 patients by 26 weeks.
 * The rate of growth in height and weight increased by a mean of 85 and 131%, respectively, at 52 weeks in the 6 prepubertal patients.
 * The mean maximum range of motion of shoulder flexion and elbow extension increased significantly.
 * The number of episodes of apnea and hypopnea during sleep decreased by 61%.
 * New York Heart Association functional class improved by 1 or 2 classes in all patients.
 * Urinary glycosaminoglycan excretion decreased after 3 to 4 weeks of treatment; the mean reduction at 52 weeks was 63% of baseline values.
 * Five patients had transient urticaria during infusions. Serum antibodies to alpha-L-iduronidase were detected in 4 patients

ERT

 * treatment consists of a modified form of the alpha-L-iduronidase enzyme given intravenously
 * takes approximately two hours for a person to receive the treatment, and the treatment is usually given every two weeks
 * Enzyme replacement therapy can stop and often reverse the symptoms of the disorder
 * Disadvantages of the enzyme replacement therapy are its high cost and the fact that it is a lifelong process
 * Potential adverse reactions including "allergic type reaction"
 * Initial evidence of potential treatment for Hurler syndrome (Keeling KM et al., 2001)
 * Gentamicin-mediated suppression of Hurler syndrome stop mutations restored a low level of alpha-L-iduronidase activity and reduced lysosomal glycosaminoglycan accumulation
 * results suggest that the suppression of premature stop mutations may provide an effective treatment for Hurler syndrome patients with premature stop mutations in the IDUA gene

Types of MPS

 * MPS type I
 * Hurler, Scheie, and Hurler/Sheie syndromes also known respectively as MPS-IH, MPS-IS, and MPS-IH/S
 * Hurler syndrome takes its name from Gertrud Hurler, the doctor who described a boy and girl with the condition in 1919
 * In 1962, Dr. Scheie, a consultant ophthalmologist, wrote about some of his patients who were more mildly affected
 * Patients who seem not to fit clearly in either the severe or the mild end of the disorder are said to have *Hurler/Scheie syndrome
 * All are caused by missing enzyme - alpha-L-iduronidase
 * Alpha-L-iduronidase breaks down (mucopolysaccharides) heparan sulfate and dermatan
 * Found at locus 4p16.3
 * No reliable way of telling from biochemical tests how severe the disorder will be
 * residual alpha-L-iduronidase activity in Hurler fibroblasts is heat-stable whereas that in Scheie fibroblasts is heat-labile
 * Progression and severity of disease are highly variable within the spectrum of MPS)

General symptoms

 * multiple organ and tissue involvement
 * Joint stiffness
 * Skeletal deformities
 * Enlarged liver
 * Obstructive airway disease; respiratory infection and cardiac complications are the most common direct causes of death
 * Ophthalmologic manifestations and hearing disorders

Three subgroups of MPSI according to severity

 * Sheie syndrome
 * corneal opacities
 * aortic valve disease
 * normal stature
 * mild or absent intellectual impairment
 * nearly normal life span
 * seldom recognized during infancy or early childhood
 * No neurologic involvement
 * Joint stiffness, carpet tunnel syndrome
 * Mild hepatosplenomegaly
 * Hurler/Sheie
 * Onset of symptoms between 3 and 8 years of age
 * death in 2nd or 3rd decade normal or near normal intelligence
 * more severe physical symptoms than those with Scheie syndrome
 * short stature
 * dysostosis multiplex
 * hepatosplenomegaly
 * corneal clouding
 * umbilical or inguinal hernia
 * psychotic symptoms may appear later in life
 * Hurler syndrome
 * Most severe form
 * Occurs in infancy
 * Macrocephaly (*may appear early in infancy while complete clinical picture develops during second year of life)
 * Respiratory infections*
 * Limited hip abduction*
 * Apnea or difficulty breathing
 * Coarse (gargyloid) facies
 * accelerated growth from infancy followed by progressive decline in the rate of development
 * progressive physical disability
 * progressive mental retardation
 * dysostosis multiplex
 * corneal clouding
 * death usually before the age of 10 years usually result of pneumonia and heart failure

Inheritance and risks

 * AR inheritance, panethnic
 * Parents of affected child have ¼ chance of each pregnancy being affected
 * Unaffected sibs of patient have 2/3 chance of being carrier
 * Combined frequency: approximately 1 in 50,000
 * Hurler: 1 in 100,000
 * Hurler-Scheie: 1 in 115,000
 * Scheie: 1 in 500,000

Diagnosis

 * can be diagnosed with a blood looking at levels of alpha-L-iduronidase
 * low level of this enzyme in a person's white blood cells is characteristic of the disease
 * confirmed by this absence of alpha-L-iduronidase in the white blood cells, the excretion of dermatan sulfate and heparan sulfate in the urine, and by physical appearance
 * Molecular (DNA) analysis can also be used to verify the diagnosis

Genetic Testing

 * Prenatal diagnosis
 * possible once a diagnosis has been made in the family and a genetic alteration identified (CVS and
 * amount of alpha-L-iduronidase can be measured in the amniotic cells or chorionic villi Molecular (DNA) analysis can be used to verify the diagnosis prenatally, by looking for the same genetic alteration that is present in the family member
 * Carrier testing
 * Enzyme analysis using white blood cells is not effective or reliable in identifying carriers of these disorders
 * However, a study in 2002 (Mandelli J et al.) showed that leukocyte IDUA from MPS I heterozygotes differed from the normal enzyme in terms of optimum pH, Km, and Vmax of the reaction and thermostability at 50 degrees C. They claimed these parameters provide a simple and reliable tool for the detection of carriers for MPS I.
 * molecular (DNA) analysis is used to identify carriers
 * first test someone in the family who has already been diagnosed with the disorder, so that the laboratory can identify the genetic alteration present in that individual and look for that same alteration in at-risk family members

Overview

 * named after Charles Hunter, the professor of medicine in Manitoba, Canada, who first described two brothers with the disorder in 1917
 * Hunter syndrome is less common than MPS I and has no corneal clouding and pursues a slower course than MPS I
 * Some think there are two distinct types of the condition, the mild and the severe
 * Others believe there is just one disorder with a wide range in the severity of the problems it causes

Risks and inheritance

 * X-linked recessive
 * Rarely girls have been diagnosed
 * Mother of affected boy is carrier
 * 50% risk to future boys
 * maternal aunts and sisters at risk of being carrier
 * carrier testing available

Description of symptoms

 * Severe form:
 * Joint stiffness
 * Mental deterioration
 * Dwarfing
 * Progressive deafness
 * Death by age 15
 * Mild form:
 * Short stature
 * Limitation of motion
 * Enlarged forehead, tongue and lips
 * Life span may be normal

Other Differentials

 * MPS III,or Sanfilippo syndrome
 * experience progressive dementia and mental deterioration in childhood
 * Death usually occurs in the late teens
 * MPS IV,or Morquio syndrome
 * Symptoms usually appear in infancy and may include severe dwarfing and corneal clouding
 * Intelligence is normal
 * Cardiac or respiratory disease may cause death in the third or fourth decade of life
 * MPS VI,or Maroteauz-Lamy syndrome
 * resembles Hurler syndrome
 * Onset is in infancy
 * intelligence is normal
 * Individuals may live into the second or third decade
 * MPS VII, Sly disease
 * experience corneal clouding, skeletal irregularities, and enlargement of the liver and spleen
 * Intellectual impairments vary for this type of MPS

Drug-induced lysosomal storage disease

 * example of phenocopy
 * thought that drugs of widely differing pharmacologic activity can interact with polar lipids within the lysosomes to yield lipid-drug complexes resistant to enzymatic digestion

Psychosocial considerations

 * Assess how this disease is viewed by patient and family members
 * Probably difficult to watch progression of disease may feel helpless
 * May seek out every possible therapy (including alternative med. tx)
 * Difficulty accepting that life-span may be shortened
 * May have been overprotected by parents
 * May struggle with feelings of dependence on others
 * Discuss support group

Support and Information Organizations

 * National MPS Society, Inc.
 * 102 Aspen Drive
 * Downingtown, PA 19335
 * info@mpssociety.org
 * http://www.mpssociety.org
 * Tel: 610-942-0100
 * Fax: 610-942-7188

 * National Organization for Rare Disorders (NORD)
 * P.O. Box 1968
 * (55 Kenosia Avenue)
 * Danbury, CT 06813-1968
 * orphan@rarediseases.org
 * http://www.rarediseases.org
 * Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)
 * Fax: 203-798-2291

 * National Tay-Sachs and Allied Diseases Association
 * 2001 Beacon Street
 * Suite 204
 * Boston, MA 02135
 * NTSAD-boston@worldnet.att.net
 * http://www.ntsad.org
 * Tel: 617-277-4463 800-90-NTSAD (906-8723)
 * Fax: 617-277-0134
 * http://www.ninds.nih.gov/health_and_medical/disorders/mucopolysaccharidoses.htm --National Institute of Neurological :Disorders and Stroke


text:
Handbook of Genetic Counseling/Multiple Pregnancy Loss

Multiple Pregnancy Loss

Introduction and contracting

 * Acknowledge prior phone contact
 * Did you come up with any questions you would like us to discuss?
 * What do you hope to get from the visit?
 * What is your main concern?
 * Explain that we will be taking a detailed pregnancy and family history to try to help us provide some answers concerning your pregnancy losses
 * We will then have Dr. _________, one of our medical geneticists, come in and we will talk to you and try to answer your questions and explain what we know

Medical History

 * Why were you referred to genetic counseling?
 * Who referred you?
 * Who is your current doctor?
 * How many pregnancies have you had?
 * Confirm when the losses were and what the suspected causes are
 * What were you told you about the pregnancy losses?
 * What types of testing have they done to try to find a reason for the miscarriages?
 * Were you sick at all during the pregnancies?
 * Did you drink, smoke or use drugs?
 * Any medications during the pregnancies
 * Did you take prenatal vitamins?
 * Any concerns about anything you might have been exposed to during any of your pregnancies?
 * Why do you believe you have had the miscarriages?
 * Have you had problems with infertility?
 * What type of infertility work up have you had?
 * What is the next step in the process for you?

Family History

 * Take a family history to see if there are any hereditary diseases that may run in your family that may or may not be related to your history of pregnancy losses
 * Pedigree (ask specifically about)
 * Miscarriages in other family members
 * Infertility
 * Mental retardation/learning difficulties
 * Birth defects
 * Chronic illnesses such as diabetes or heart disease
 * Consanguinity
 * Country where your ancestors came from

Psychosocial assessment

 * How are you handling the pregnancy losses?
 * Have family members or friends been supportive?
 * What do your plans for the future look like?
 * Are you currently working outside the home?
 * What is your occupation?
 * Your husband's occupation?
 * Do you have a religious preference?
 * Are you in touch with a perinatal loss support group?
 * Would you like to be in touch with a support group?
 * Is your insurance covering the testing that has been performed?
 * Are there any other concerns or questions?

Trisomy 16

 * one of most common chromosomal abnormalities
 * affected embryos or fetuses never survive past first trimester
 * is the cause of may first trimester losses
 * explain chromosomes
 * explain nondisjunction
 * reassure her that it is not do to anything she did or did not do
 * once a woman has a child with an identified trisomy the risk of having another child with a trisomy is about 1% (is this what you would quote here) this is usually quoted for Down syndrome and trisomy 18 or 13 because they are viable??????

AMA counseling

 * as women get older their risk of having a fetus or child with a trisomy increases gradually
 * there is no magic age at which the risks become high, but at age 35 the risks of having a child with a chromosomal abnormality become high enough that it makes sense to offer diagnostic testing such as amnio (after 15 wks and CVS 10-12 wks)

Early Pregnancy Loss

 * establishing pregnancy is more difficult than many people realize
 * clinically recognized pregnancy loss occurs in ~15% of pregnancies
 * 40-60% of all conceptions may be lost, but most of these (3/4) are estimated to be lost before it is recognized clinically
 * most miscarriages occur between 6-8 weeks and expulsion between 10-12 weeks
 * after 3 consecutive clinical abortions the risk of aborting next pregnancy is 20-55%

Causes of pregnancy losses
(only chromosome abnormalities and uterine abnormalities are definitively implicated in pregnancy loss)
 * chromosomal abnormalities (most common 70% of first trimester loss)
 * balanced translocation carrier (2.7-4.8% of couples with recurrent losses)
 * trisomies and other chromosomal anomalies
 * Hormonal causes
 * Inadequate luteal phase
 * Deficient progesterone
 * Endometrial factors (endometrial protein expression)
 * Uterine abnormalities
 * septate uterus
 * bicornate uterus
 * uterine myomas or fibroids
 * DES exposure in utero
 * Environmental exposures
 * Alcohol (women who drink 2X's week had sig. higher SA than other women but drinkers also tend to smoke also - possible confounding?)
 * tobacco ( if ½ pack a day or greater and appears to be dose dependent)
 * heavy caffeine intake (moderate intake is not associated with SA)
 * chemical solvent exposure in either sex may increase risk
 * Immune Causes
 * autoimmune problems -- estimated to be cause of multiple SA's in up to 30% of women (woman makes antibodies that will attack her own proteins and those that she has in common with the fetus)
 * anticardiolipin antibodies -- type of a group of antiphospholipid antibodies that may be associated with miscarriage
 * circulating antibodies to cardiolipin and/or inappropriate coagulation parameters, plus poor reproductive outcome, SLE, or spontaneous thrombosis (the antibodies can react with phospholipids that are required for coagulation)
 * SLE - an autoimmune disease thought to be related to SA's (Antichromatin IgG is useful in diagnosing SLE antinuclear antibody testing can indicate many at risk for SLE or some other autoimmune diseases)
 * alloimmune causes -- (response to tissues from another individual of the same species)
 * theory that must recognize fetus as foreign by the HLA and produce blocking antibodies for pregnancy to progress
 * only one of four studies found benefit to leukocyte immunization via paternal leukocyte transfusions
 * Diabetes (controlled or unsuspected is not thought to cause SA)
 * Infection
 * chlamydia trachomatous causes acute and chronic infection of the endometrium which could interfere with implantation (more chlamydia antibodies in women with recurrent SA's but not all studies confirmed this)
 * Mycoplasma hominis and ureaplasma urealyticum (controversy over importance in losses)
 * CMV but suggests this is rare and causation not proven
 * Herpes simplex virus (importance in SA's debated)
 * HIV does not increase rates of loss in asymptomatic women
 * Psychological factors-two studies showed significant reduction in SA among women who have 3 or more SA's when undergoing counseling once per week during pregnancy


text:
Handbook of Genetic Counseling/Nager Syndrome

Nager Syndrome

Also known as

 * Acrofacial Dysostosis, Nager Type
 * AFD
 * Nager Acrofacial Dysostosis Syndrome
 * Split Hand Deformity-Mandibulofacial Dysostosis

Inheritance

 * Unknown but…
 * Mild type family histories indicate AD inheritance
 * Severe type family histories indicate AR inheritance

SF4 Gene

Clinical Features

 * Downward slanting eyelids
 * Absence or underdeveloped cheekbones
 * Severe underdevelopment of the lower jaw
 * Malformed outer and middle ears
 * Cleft palate
 * Absence of lower eyelashes
 * Scalp hair extending onto the cheek
 * Underdeveloped or missing thumbs
 * Occasional absence of the radial limb
 * Preaxial limb anomalies

Other Problems

 * Stomach reflux
 * Kidney reflux
 * Hearing loss
 * Possible limitations in arm motion
 * Heart problems

Diagnosis

 * Made on clinical features

Management & Treatment

 * Surgeries
 * Tracheostomy to help with breathing
 * Gastrostomy tube to assure proper nutrition
 * Craniofacial surgery for the jaw and ears
 * Identify and manage hearing loss
 * Thorough work-up to identify any heart & kidney problems

Resources

 * FACES: The National Craniofacial Association
 * P. O. Box 11082
 * Chattanooga, TN 37401
 * (800) 332-2373
 * email: faces@faces-cranio.org
 * Provides financial support for non-medical expenses to patients traveling to a craniofacial center for treatment. Eligibility is based on financial and medical need. Resources include newsletters, information about craniofacial conditions, and networking opportunities.

 * The Foundation for Nager and Miller Syndromes
 * Margaret Ieronimo
 * 1827 #2 Grove Street
 * Glenview, IL 60025
 * (800) 507-FNMS
 * email: fnms@interaccess.com
 * web site: http://www.nagerormillersynd.com/new
 * This is an international support group that serves as an information clearinghouse that links families together. They have an extensive library of resources and medical reports and are involved in a genetic research project working to locate the genes responsible for Nager Syndrome. Twice a year, they publish a very informative newsletter.

 * National Health Law Program
 * 1101 14th Street, NW, Suite 405
 * Washington, DC 20005
 * (202) 289-7661
 * Website: http://www.healthlaw.org
 * Provides extensive information on health care law affecting families with children who have special health care needs.

 * Children with Facial Difference: A Parent's Guide.
 * Written by Hope Charkins, MSW. Published by Woodbine House, 1996.
 * 1-800-843-7323.
 * Excellent resource for parents to help them cope with medical, emotional, social, educational, legal, and financial challenges presented by facial differences of their children.

Conclusion

 * Overview of session
 * Give resource list
 * Give contact info