text:
Adventist Youth Honors Answer Book/Vocational/Bookbinding

1. Be able to identify the following terms

 * 1) Foredge: the fore edge of a book, that is, the edge opposite the spine.
 * 2) Gutter: the inner margin of a pair of facing pages.  This would be the right margin of an even-numbered page (which is always found on the left side) and the left margin of an odd-numbered page (which is always found on the right).
 * 3) Endsheet: a piece of often decorative paper glued to the inside cover of a book.  Its purpose is to hide the raw edge of the cloth covering.
 * 4) Flysheet: the pages at the beginning and end of a book, not glued to the covers.
 * 5) Signature: a large sheet printed with several pages, intended to form four or more leaves in the finished book. The pages are arranged on the sheet so that all of the pages orient the same way and are in proper sequence after the sheet is folded.
 * 6) Mull: a coarse fabric used for lining the spine of a book.
 * 7) Backbone: the spine of a book.  This is the edge of a book that shows when a book is placed on a shelf.
 * 8) Head: the top margin of a page.
 * 9) Foot: the bottom margin of a page.
 * 10) Deckle edge: the uncut and slightly irregular edge of a piece of paper.
 * 11) Guarding sheets: pieces of paper placed in a book in front of a plate (picture) to prevent ink from the picture from bleeding onto the facing page.
 * 12) Headbanding: a strip of material between a book's spine and the pages.  It usually protrudes slightly above the top edge of the spine.
 * 13) Casing-in: the process of attaching the bound pages of a book to the cover by gluing the endsheets to the inside covers.
 * 14) Buchram: the cloth used on the outside of a book cover.

2. Describe the difference between the following binding methods

 * 1) Perfect binding A paperback or soft cover book consists of a number of signatures or individual leaves between covers of much heavier paper, glued together at the spine with a strong flexible glue; this is sometimes called perfect binding. Mass market paperbacks and pulp paperbacks are small (16mo size), cheaply made and often fall apart after much handling or several years.
 * 2) Hard bound A hardbound or hard cover book has rigid covers and is stitched in the spine. Looking from the top of the spine, the book can be seen to consist of a number of signatures bound together. When the book is opened in the middle of a signature, the binding threads are visible. Modern hardcover books are typically of octavo size, though they are often smaller or larger.
 * 3) Single signature A single signature binding is one in which only one signature and the cover are sewn together at the spine.
 * 4) Spiral (metal and plastic) A spiral-bound book is made of individual sheets, each with a line of holes punched near the bound edge. A metal or plastic spiral wire is fed through the holes to hold the sheets together. Spiral binding allows a book to be disassembled and reassembled by hand without damage.
 * 5) Saddle stitch Stapling through the center fold, also called saddle-stitching, joins a set of nested folios into a single magazine issue.  Most American comic books fall into this category.

a. Bind a single signature hand binding "manuscript".
A manuscript is an original copy of an author's work. Manuscripts are often submitted in the form of typewritten (or computer printed) sheets of paper. Sometimes the manuscripts are two-sided, and sometimes they are single-sided.

In order to bind a manuscript, it must be converted into a form suitable for folio binding - that is, the binder needs at least two leaves per sheet. So instead of 8.5" x 11" sheets of paper, the binder needs 11" x 17" sheets. This is accomplished by pasting the sheets together in what will form the gutter. Once the sheets are pasted together, they can be sewn though the overlapping section and bound normally.

In binding a 16-sheet single-sided manuscript, the right edge of sheet 1 is pasted to the left edge of sheet 16. Similarly, sheets 2 and 15 are pasted together, 3 and 14, 4 and 13, etc. An even sheet number is always pasted to an odd so that the middle sheet is not left standing alone. If there are an odd number of sheets, the first sheet should be pasted to a blank sheet.

When a book is opened, the page on the left side always has an even page number, and the page on the right has an odd page number. Care should be taken to observe this convention when pasting double-sided sheet together. Again, for a 16-sheet, 32-page manuscript, page 1 should be laid on the table face down. Page 32 should be laid face down to the right of it, and the bookbinder should then see pages 2 and 31. These are then pasted together.

Once the paste has dried, each sheet is carefully folded along the center of the overlapping sections. The manuscript will resist folding at this seam because the paper is double-thick there. Nonetheless, this is where the fold should be made. A bone folder makes this task easier. The folded sheets are then nested together to form a signature, and the signature is then ready to sew to a cover made of a single sheet of heavier paper.

b. Bind a blank book using at least four signatures and a permanent cloth hard board binding, using a "case" method.
Follow the steps outlined and illustrated in requirement 7, using four signatures of blank pages.

c. The proper way to "break-in" a new binding.
A new book should be opened first a few pages from the front cover and the pages should be pressed down. Then it should be opened near the back cover and again, the pages should be pressed down. Finally, it should be opened in a few places near the center. If it is opened near the center first, the book's spine may be broken, and if this happens, the book will always want to open to that page.

d. Make a "slip case" for your blank book of at least four signatures.
A slip case can be made from a piece of poster board. The first step is to measure the book and then draw the layout on the poster board as shown in the illustration:

You will want to make the slip case slightly larger than the book's dimensions so that it can be easily inserted and removed. Once the layout has been drawn on the poster board, cut it as shown in the drawing. Then carefully make creases where the dotted lines are drawn. You may use a bone folder to help in doing this, or you may use a ruler. The folds must be crisp and accurate.

The design shown here calls for an extra fold-in which makes the slipcase walls double thick. Apply a thin coat of glue to the inside surface of the fold-in, then fold it on top of the slipcase wall. You may wish to let the glue dry at this point.

Next, apply a light coat of white glue to the back side of tab 1, and another thin layer of glue to the back side of tab 3. Do the same for the bottom tabs. Then assemble the slip case by gluing tab 3 to tab 1, and then gluing tabs 1 and 3 to tab 2. Clamp the tabs with clothes pins while the glue drys. Do not insert your book into the slip case until the glue is completely dry, or you may transfer glue to your book!

Once the glue dries, the slip case is finished. You may decorate the slip case using decoupage (see the decoupage chapter for instructions) if you like, or some other method as you see fit.

4. Identify and describe the uses for the following binder's tools

 * 1) A Bone folder is a tool for folding and creasing paper.  They are traditionally made from the leg bone of a cow or deer, but synthetic bone folders are also available.  Bone folders resemble letter openers.
 * 2) Kick press: a foot operated device used for tightly holding and compressing objects upon which work is being performed.  Presses have many uses in bookbinding.  A text block (that is, the bound pages that have yet to be attached to a cover), is held in a press when the spine is glued up.  It is returned to the press when the cover is attached, and the spine is shaped.
 * 3) Folding needle: a steel needle with a wooden handle sometimes used for working in tight spaces on book covers, such as on decorative corners made of metal (miters).  It is sometimes also used for scoring.
 * 4) Awls are tools with a sharp point at the end of a long shaft mounted in a handle.  They are used for making holes in various materials such as leather (used for book covers) and multiple layers of paper (as in a signature).
 * 5) Sewing frame: a structure upon which books are held while they are being hand-sewn.
 * 6) Squared card: a sheet of heavy stock with two cut edges which together make a 90° angle.  These are used in the same way a carpenter's square is used, that is, in making right angles.
 * 7) Punch: a device for punching holes in material.  These are like sharp tubes driven into the material and removing a usually circular portion.  The waste material goes inside the tube and is sometimes ejected out the top when completely filled.

5. Define the difference of paper weight in relationship to a ream of paper.
In countries that use United States paper sizes, a less direct measure known as basis weight is used in addition to or instead of grammage. The basis weight of paper is the density of paper expressed in terms of the mass of a ream of given dimensions and a sheet count. In the US system, the weight is specified in avoirdupois pounds and the sheet count of a paper ream is usually 500 sheets. However, the mass specified is not the mass of the ream that is sold to the customer. Instead, it is the mass of the uncut "basis ream" in which the sheets have some larger size. Often, this is a size used during the manufacturing process before the paper was cut to the dimensions in which it is sold. So, to compute the mass per area, one must know

 * the mass of the basis ream,
 * the number of sheets in that ream, and
 * the dimensions of an "uncut" sheet in that ream.

The standard dimensions and sheet count of a ream vary according to the type of paper. These "uncut" basis sizes are not normally labeled on the product, are not formally standardized, and therefore have to be guessed or inferred somehow from trading practice. Historically, this convention is the product of pragmatic considerations such as the size of a sheet mold.

By using the same basis sheet size for the same type of paper, consumers can easily compare papers of differing brands. 20 pound bond paper is always lighter and thinner than 32 pound bond, no matter what its cut size. And 20 pound bond letter size and 20 pound bond legal size papers are the same weight paper having different cut size.

However, a sheet of common copy paper that has a basis weight of 20 pounds does not have the same mass as the same size sheet of coarse paper (newsprint). In the former case, the standard ream is 500 sheets of 17 by 22 inch paper, and in the latter, 500 sheets of 24 by 36 inch paper. Here are some basic ream sizes for various types of paper. Units are inches except where noted.

 * {| class="wikitable"

 * Paper Type
 * colspan="2"|Paper Size
 * - Number of sheets
 * Bond, writing, ledger       ||17   ||× 22  ||- 500 sheets
 * Manuscript cover            ||18   ||× 31  ||- 500 sheets
 * Blotting                    ||19   ||× 24  ||- 500 sheets
 * Box cover                   ||20   ||× 24  ||- 500 sheets
 * Cover                       ||20   ||× 26  ||- 500 or 1000 sheets
 * Bristol and tag             ||22½  ||× 28½ ||- 500 sheets
 * Tissue                      ||24   ||× 36  ||- 480 sheets
 * Newsprint                   ||24   ||× 36  ||- 500 sheets
 * Hanging, waxing, bag, etc.  ||24   ||× 36  ||- 500 sheets
 * Book, Text, Offset          ||25   ||× 38  ||- 500 sheets
 * Index bristol               ||25½  ||× 30½ ||- 500 sheets
 * Paperboard (all types)      ||12   ||× 12  ||- 1000 sheets (1,000 square feet per ream)
 * }
 * Tissue                      ||24   ||× 36  ||- 480 sheets
 * Newsprint                   ||24   ||× 36  ||- 500 sheets
 * Hanging, waxing, bag, etc.  ||24   ||× 36  ||- 500 sheets
 * Book, Text, Offset          ||25   ||× 38  ||- 500 sheets
 * Index bristol               ||25½  ||× 30½ ||- 500 sheets
 * Paperboard (all types)      ||12   ||× 12  ||- 1000 sheets (1,000 square feet per ream)
 * }
 * Book, Text, Offset          ||25   ||× 38  ||- 500 sheets
 * Index bristol               ||25½  ||× 30½ ||- 500 sheets
 * Paperboard (all types)      ||12   ||× 12  ||- 1000 sheets (1,000 square feet per ream)
 * }
 * Paperboard (all types)      ||12   ||× 12  ||- 1000 sheets (1,000 square feet per ream)
 * }

Sheets 17 by 22 inches can be cut into four 8½ by 11 inch sheets, a standard for business stationery known conventionally as letter sized paper. So, the 17 by 22 inch ream became commonly used. The 25 by 38 inch book-paper ream developed because such a size can easily be cut into sixteen 6 by 9 inch book-sized sheets without significant waste.

Early newsprint presses printed sheets 2 by 3 feet in size, and so the ream dimensions for newsprint became 24 by 36 inches, with 500 sheets to a ream. Newsprint was made from ground wood pulp, and ground wood hanging paper (wallpaper) was made on newsprint machines. Newsprint was used as wrapping paper, and the first paper bags were made from newsprint. The newsprint ream standard also became the standard for packaging papers, even though in packaging papers kraft pulp rather than ground wood was used for greater strength.

Paper weight is sometimes stated using the "#" symbol. For example, "20#" means "20 pounds per basis ream of 500 sheets".

When the density of a ream of paper is given in pounds, it is often accompanied by its "M weight". The M weight is the weight (in pounds) of 1000 cut sheets. Paper suppliers will often charge by M weight, since it is always consistent within a specific paper size, and because it allows a simple weight calculation for shipping charges.

For example, a 500-sheet ream of 20# copy paper may specify "10 M". Therefore, 1000 sheets (or two reams) will weigh 10 lb (≈4.54 kg).

6. Describe the color and properties of three types of adhesives using in the binding process and where they are used

 * 1) Hot melt animal glue has a brown to amber color range.  It is made from animal hide or bones and is often sold as crystallized flakes.  These flakes must be dissolved in hot water before they can be used.  The mixture must be heated to about 140 °F, and will cool quickly.  Once the glue is removed from the heat source, it will become unworkable in about one minute.  However, animal glue can be reheated even years after its initial application and it will return to a workable state.  Thus, a book bound with animal glue can be repaired or rebound years later, as is often done with antique books.  Animal glues are often used in gluing up a book's spine.
 * 2) Casing-in paste is also known as PVA, white glue (such as Elmers), or carpenters glue (which is yellow).  These glues have a much longer working time than animal glues, but they also have disadvantages as well.  If a surface needs to be reglued, PVA must be completely removed from the surface first, because this type of glue will not stick to itself.  This type of glue is used to bond a text block to its cover.
 * 3) Resin glues also range from dark brown to amber, and are more commonly known as epoxies.  Epoxy is a two-part glue consisting of a resin and a hardener.  When mixed together in the proper proportions, the two compounds react chemically to form an incredibly strong bond.  This bond is often stronger than the materials being glued, and thus the saying, "an epoxy joint is forever."  Resin glues can be used to finish the grain side of leather or impregnated in buckram covering materials.

Preparing the Signatures
To begin, make up the signatures. This is done by folding the pages into halves, quarters, eighths, or sixteenths. Folding standard 8.5"x11" pages into quarters works well, as does folding 11"x17" into eighths.

If making a non-blank book, you need to print the pages in a certain way so that they appear in the proper order and right-side up. Folding a sheet of paper into quarters will produce eight pages. Try this on a blank sheet of paper first, number the pages, unfold, and look at how the pages orient themselves on the unfolded paper. When making a blank book, this step can obviously be skipped. You can also use the pictures below as a guide. Note that with the quarto folding scheme, some of the pages need to be printed upside-down.

Once the folding is done, the bone folder or a knife can be used to cut the folds apart at the top, bottom, and outer edge of the pages. Do not cut the fold along the spine! The signatures are then ready to be sewn, and the sewing will bind them to a cloth tape. An even number of signatures will place the final stitch on the same end of the book as the initial stitch, and this will help when it comes to tying it off.

Prepare the Tapes
Make three to five cloth strips about a half inch wide. The length of these cloth strips should be a bit less than twice the width of the pages. The cloth itself should be a fine cotton or linen. An old pillowcase has been suggested, but any thin cloth will work. These strips of cloth are called tapes. Fewer tapes will make the sewing process go faster, but more tapes will yield a better book.

Stitching
Mark one of the outside signatures to indicate where the tapes will lie as shown in the photograph.

Note that the photographs show a very dark thread being used. This was done to make the thread easier to see for the purpose of illustrating the techniques. When binding your book, you will want to use white thread so that it won't be easy to see in the finished book. Begin stitching by passing the needle and thread through the fold from the outside to the inside. It will be easier to make the hole from the inside of the fold with either an awl or the needle, but the thread should pass from the outside to the inside. This stitch should be made near the edge of the page, but not too near the edge. Leave a couple of inches of thread so you can tie it off when all the sewing is done. Then pass the needle back through the fold so that it comes out on the other side of the cloth tape. Do not run the thread through the tape. Pass the thread over the tape and back into the fold again. Repeat this process until all the tapes are sewn to the signature. Then slip the next signature between the tape and the first signature. Catch the previous stitch as shown in the photograph, and begin stitching the second signature.

Use the same technique for it as for the first signature. Stitch in the rest of the signatures, tighten the thread, and tie it off.

Gluing up the Back
Once the signatures have been sewn together, pull the tapes tight and apply a thin layer of glue to the spine. You can use a small artist's paint brush for this. Work the glue into the cracks between the signatures, but do not let it go too deep or the pages will stick together when you try to open the finished book. The book is then placed in a press, but you can use a heavy weight, two wooden boards and a few C-clamps, or a shop vise to get the same effect.

If you use weights to compress the signatures, be careful not to glue the weights to the book's pages. The idea is to squeeze the pages together as tight as possible while the glue sets.

If you use wooden boards and C-clamps, sandwich the pages between the two boards and clamp them together with the C-clamps.

If using a shop vise, be sure to pad the vise's jaws so you do not damage the pages. The glue will strengthen the spine and adhere the threads to the pages.

The finished product from this stage is called a text block.

Make the Boards
The "boards" are the book's covers. Use either a very stiff non-corrugated cardboard or eighth-inch mason board (available at most lumber yards). Guide Magazine is usually shipped with cardboard liners, so if your church subscribes to it, ask your Junior Sabbath School teacher to save them for you. Cut the boards such that they are slightly larger (about an eighth inch) than the text block on three sides. Make sure the boards are square.

Next, get some heavy cloth or heavy paper - whatever you want to use as the outside surface of the book cover. The remainder of this discussion assumes a cloth cover. Lay the boards on the cloth with a gap between them. The width of this gap should be equal to the width of the text block's spine plus triple the thickness of the boards (three eighths of an inch). Mark the cloth around the boards leaving about a one-inch border. Cut the cloth, and then clip the corners to within a quarter inch of the corners of the boards:

Coat the outside surface of the boards with a thin, even layer of glue, lay them on the cloth, and stretch the cloth smooth. Be sure the gap between the boards is as wide as the text block's spine plus three times the thickness of the boards. Glue a strip of cloth across the spine, bridging the two boards. You may also glue a piece of card stock on top of this strip of cloth to further strengthen the spine. If you do not have card stock, a manila folder or an index card can be pressed into service instead. This strip of card stock should be as long as the text block's spine. Be careful not to glue the cover to your worktable. Ideally, you do not want any of the glue to penetrate the cloth cover, but just in case, you may wish to place a large piece of plastic beneath the cloth when doing this (use the lid from a large plastic storage tub, a plastic bag, or cellophane wrap). Now place as much weight on the boards as you can muster and leave it there until the glue dries.

Attach the Covers
When the glue dries from the previous step, remove it from the press (or remove the weights from the cover) and apply another thin layer of glue to the inside of the book cover. Then fold the top of the cloth cover over and glue it in place. Do the same for the bottom, and then fold over the left and right sides.

Get some wax paper or some plastic and insert two layers of it beneath the first page of the text block. Apply a thin layer of glue around the edge of the paper using a small paint brush. It's OK to brush the glue onto the wax paper. Cover all four edges of the text block, and then add a little more glue to hold down the tapes. Spread out some more wax paper and turn the text block over onto it. Repeat the processes for the back of the book, adding glue to the edges of the page. When you have coated the edges of the back page with glue, remove the layer of waxpaper that the glue was brushed onto, but leave the first layer of waxpaper in place. This layer will prevent the glue from bonding to the next page and keep moisture out of the rest of the book.

Now carefully lift the text block and place it on the back cover. Be sure to center it well. If you misalign it, carefully lift it off and make another attempt. Now fold the front cover closed onto the front page and make sure the text block is well centered. Finally, place the book back in the press again (or under a heavy weight) and shape the spine as best you can. Then let the glue dry. Don't be impatient at this point. If the book still smells like glue when you're ready to remove it, it is still too soon, and removing it will cause the pages to wrinkle and curl.

Finishing
The "finishing" step in bookbinding pertains to books with leather covers. The first step in finishing a leather-bound book is to go over the covers with a polishing tool to smooth out any irregularities. The book can then be placed in a finishing press with a set of embossing plates which will embed a pattern in the cover. (Alternately, the cover can be tooled by hand in the same way that a leather worker decorates leather.) When the book comes out of the finishing press, it may be gilded - that is, have a design tooled into it with gold leaf. Finally, the leather may be varnished.

Historical Notes
The Bookbinding honor was introduced in 1935, and discontinued in 1951. It was reintroduced as an Antique Honor in 1986. It was revised and returned to the Vocational category in 2002.


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Handbook of Genetic Counseling/Acrofacial Dysostosis Syndrome

Acrofacial Dysostosis Syndrome

Definition

 * A condition resulting from problems in the development of the first & second branchial arches. The first arches produce the nerves and muscles for chewing, the lower jaw, 2 middle ear bones, and a small part of the ears. The second arches produce the nerves & muscles of facial expression, 1 middle ear bone, most of the external ears, and parts of the bone above the larynx.

Characteristics

 * underdevelopment of the cheek and jaw area (micrognathnia and malar hypoplasia)
 * feeding and breathing problems in infancy
 * down-sloping palpebral fissures
 * absence of the lower eyelashes
 * lack of development of the internal & external ear with temporary or long-term hearing loss
 * possible cleft palate
 * underdevelopment or absence of the thumb
 * shortened forearms & poor movement in the elbow/limited range of arm motion
 * stomach & kidney reflux
 * normal intellect
 * possible missing, overlapping, or webbing of the toes, clubfeet, hip dislocation, or underdeveloped ribs may occur

Incidence

 * very rare

Etiology

 * Unknown - may represent new mutations of an autosomal dominant trait or variable expression
 * Genetic testing is highly recommended

Genetics

 * located on chromosome 9q32

Prognosis

 * may be lethal is there is lung hypoplasia

Management

 * Possible need for a tracheostomy to help with breathing
 * Possible need for a gastrostomy tube to assure proper nutrition
 * craniofacial surgery to the jaw, cleft palate, & ears
 * plastic surgery for eye, jaw, ears
 * orthopedic surgery for arms, hands, feet, or toes
 * hearing screens
 * speech therapy for proper development
 * physical therapy to improve use of hands and feet

Differential Diagnosis

 * Miller Syndrome
 * Genee-Wiedemann Syndrome
 * Treacher Collins Syndrome
 * Pierre Robin Sequence
 * Franschetti-Klein Syndrome
 * Goldenhar-Gorlin Syndrome
 * Oral-Facial-Digital Syndrome
 * Juberg-Hayward Syndrome (Orocraniodigital Syndrome)
 * Hemifacial Microsomia (HFM)
 * Trisomy 18 (micrognathnia & distal ectromelia)

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


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Handbook of Genetic Counseling/Neural Tube Defects

Neural Tube Defects

(History of)

Introduction

 * Discuss the reason for referral
 * Elicit prior knowledge about neural tube defects/spina bifida
 * Discuss severity of affected sibling & elicit feelings toward sibling's NTD
 * Assess concerns and set goals for the session.
 * Provide overview of topics for counseling session
 * Pregnancy & family history
 * Address risk for NTD for this pregnancy
 * Introduce testing options for NTDs

Client & Partner Information

 * Discuss why it's important to get pregnancy, personal, and family history.
 * Explain that it is a way to identify other potential risk factors
 * Use examples: seizure medication, diabetes, >1 family member with NTD, etc.
 * Go over pregnancy history:
 * How has the pregnancy been going?
 * G1P0? Any stillbirths? Spontaneous or elective abortions?
 * Was the pregnancy planned? If so, how long did it take to become pregnant?
 * LMP? EDC?
 * Any bleeding?
 * Any illnesses during the pregnancy?
 * Infection, cold, rash, fever?
 * Any chronic illnesses?
 * Any exposures during the pregnancy?
 * X-rays, smoking, alcohol, recreational drugs?
 * Medications:
 * Currently?
 * Earlier in the pregnancy?
 * Personal background:
 * Occupation?
 * Do you have a religious preference?
 * Psychosocial assessment
 * Financial, insurance concerns?
 * Support system?
 * Information about the father:
 * Name, age, occupation?
 * Any exposures?
 * Any chronic illnesses?

Elicit History

 * Construct pedigree:
 * Abnormal # miscarriages, stillbirths, infant deaths?
 * Previous children with chromosome abnormality, Down syndrome, birth defects, mental retardation?
 * Obtain detailed information about sister's NTD
 * Any other people in family affected with NTD?
 * Consanguinity? Ethnicity? Other concerns/risk factors?

What are Neural Tube Defects?

 * NTDs are serious birth defects that involve incomplete development of the brain, spinal cord, and/or protective coverings for these organs
 * The cause of NTDs is not completely understood, but involves both environmental and genetic factors (multifactorial inheritance)
 * Sometimes NTDs can occur as part of a larger chromosomal or malformation syndrome (like Meckel syndrome where other malformations such as cleft lip, cleft palate, polydactyly, renal cystic disease and eye defects may be seen)
 * There are three types of NTDs:
 * Anencephaly
 * Infants born with anencephaly have underdeveloped brains, incomplete skulls, and usually survive only a few hours after birth
 * Encephalocele
 * Infants have a hole in the skull through which brain tissue protrudes; most affected infants do not survive or are severely mentally retarded.
 * Spina bifida
 * This is the most common NTD affecting approximately 1/1000 newborns in the U.S.
 * It results from the failure of the spine to close properly during the first month of pregnancy. The precise cause of this defect is not completely understood.
 * There are three types of spina bifida. In order of increasing severity, they are:
 * Spina bifida occulta
 * Includes individuals with a spinal defect associated with a pigmented or hairy patch of skin as well as individuals with absence of one or two vertebral arches.
 * The first group shows an increased incidence of NTDs in offspring and siblings, but the second group (which is about 5% of the population) shows no evidence of any increased risk.
 * This form of spina bifida usually has no symptoms.
 * Meningocele
 * This is the rarest form of spina bifida in which a cyst or lump consisting of membranes surrounding the spinal cord pokes through the open part of the spine.
 * The cyst can be removed by surgery, allowing for normal development.
 * Myelomenigocele
 * This is the most severe form of spina bifida where the protruding cyst contains membranes surrounding the spinal canal, nerve roots of the spinal cord, and often the spinal cord itself.
 * Or there may be no cyst, but a fully exposed section of the spinal cord and nerves.
 * Surgery to close the back is generally performed within 24 hours after birth to reduce the risk for infection and to preserve the existing function in the spinal cord.
 * Individuals with more severe spina bifida usually have paralysis and need surgeries and other extensive medical care.
 * The severity of the paralysis is determined by the spinal nerves that are involved. In general, the higher the cyst on the back, the more severe the paralysis.
 * Often, children need to use crutches, braces, or wheelchairs due to mobility deficits.
 * The condition can also cause bowel and bladder complications.
 * Some children with spina bifida have learning problems. They may have difficulty paying attention, expressing or understanding language, organizing, and grasping reading and mathematical concepts.
 * Hydrocephalus can accompany severe spina bifida
 * This is an accumulation of fluid in the brain
 * Is it controlled by a surgical procedure called "shunting" where the fluid that builds up in the brain is redirected into the abdominal cavity
 * Children with spina bifida may be more prone to developing latex allergies
 * Recent studies show that folic acid, a water-soluble B vitamin, is one factor that may reduce the risk of having a baby with a NTD.
 * A vitamin with 400 micrograms (mcg) of folic acid every day is recommended for most women. This is the same as 0.4 milligrams (mg).
 * If a woman is at an increased risk of having a baby with a NTD, it is recommended that she take a higher dose of folic acid. This should be 4000 mcg of folic acid for 1-3 months before becoming pregnant. This is the same as 4.0 mg.
 * Taking folic acid will not guarantee a healthy baby.
 * Birth defects such as NTDs can occur in any family.
 * Be aware that the patient may feel guilty if she did not take folic acid before her pregnancy.

Quote Risks

 * Spina bifida is usually an isolated birth defect.
 * 95% of babies with NTDs are born to parents with no family history of the disorder.
 * The incidence of a NTD in the population is 1/200 - 1/1000 (This is 0.1% - 0.5%).
 * When NTDs do appear to run in the family, it does not follow any particular pattern of inheritance.
 * Women with certain chronic health problems like diabetes and seizure disorders (treated with certain anticonvulsant medications have an increased risk of having a baby with a NTD. This risk is approximately 1/100 (MOD)
 * If one sibling is affected, the recurrence risk is approximately 2-5% based on the population incidence (Harper).
 * State the risk in both ways (2% risk of abnormality = 98% chance of healthy baby)

Discuss the Screening Options for NTDs

 * Maternal Serum Screening, level II ultrasound, & amniocentesis are three testing options that may tell you if your baby is at an increased risk for a NTD.

Maternal Serum Screening

 * What is it?
 * A blood test that measures three different substances in the mother's blood
 * Alpha-fetoprotein (AFP)
 * Human chorionic gonadotropin (hCG)
 * Unconjugated estriol (uE3)
 * It is routinely offered between 14 and 22 weeks of pregnancy
 * Most accurate when done between 16-18 weeks
 * It is NOT a diagnostic test; it is a screening test
 * It is a way to identify pregnancies at increased risk of certain abnormalities
 * It is NOT an absolute diagnosis of a problem
 * Women who are shown to be at a higher risk are then offered diagnostic testing
 * Level II Ultrasound
 * Amniocentesis
 * What can it tell me?
 * Triple screen suggests an increased risk for certain abnormalities in the fetus such as ONTDs.
 * It also can indicate if there's an increase risk for Down Syndrome or Trisomy 18
 * We have no reasons to suspect these may be an issue in the pregnancy, but the test will provide this information.
 * What can it NOT tell me?
 * Triple screen cannot confirm that your baby has a NTD or other defect
 * It also cannot predict an increased risk for all birth defects
 * Other trisomies, mental retardation, cleft lip, etc. are not included in screen.
 * What does the procedure involve?
 * The screening test is done with a routine maternal blood draw.
 * How do the markers work?
 * Alpha-fetoprotein (AFP):
 * This is the marker primarily used to detect ONTDs
 * It is a protein made by the fetal liver
 * AFP is excreted into the fetal urine and amniotic fluid from where it is transferred across the placenta into the maternal blood.
 * It is not known what AFP does
 * It is present in higher concentrations when there is an ONTD because more AFP leads out into the amniotic fluid
 * It is present in lower concentrations with Down syndrome for unknown reasons.
 * Human chorionic gonadotropin (hCG):
 * This is the "pregnancy hormone" used in pregnancy tests
 * Is it produced by the placenta
 * The concentration is higher in Down syndrome for unknown reasons.
 * Unconjugated estriol (uE3):
 * UE3 is the most sensitive marker for Trisomy 18 (lower with Trisomy 18)
 * It is a steroid produced by the fetus and placenta
 * May be lower in Down syndrome for unknown reasons.
 * MoM (Multiple of the Median):
 * This is the ratio of the marker level in the client to the median marker level
 * It allows us to compare your marker levels to the general population of pregnant women
 * A computer program takes into account all of your specific circumstances and calculates your MoM
 * 1.0 MoM is the expected value
 * If 2.0 MoM, then your concentrations are twice as high as expected
 * No one has a perfect 1.0 MoM
 * What does a "Screen Positive" test result mean?
 * The test results are analyzed for patterns
 * There are specific patterns of the three marker levels associated with an ONTD, Down Syndrome, or Trisomy 18
 * ONTD = High AFP
 * Down Syndrome = Low AFP, High hCG, Low uE3
 * Trisomy 18 = Low AFP, Low hCG, Low uE3
 * 5-10% of women who undergo Triple Screen get abnormal results
 * Only 3-5% of them will have an affected baby
 * For ONTDs:
 * Only the AFP marker is used
 * If the concentration is >2.5 MoM, the result is screen positive for ONTD
 * The incidence of ONTD is 1-2 in 1000 fetuses
 * For Down syndrome:
 * If the risk figure is over 1 in 270, the result is screen positive for DS
 * HCG is the most sensitive marker for DS
 * The incidence of DS is 1 in 660 newborns
 * For Trisomy 18:
 * If the risk figure is over 1 in 100, the result is screen positive for TRI 18
 * UE3 is the most sensitive marker for Trisomy 18
 * The incidence of Trisomy 18 is 3 in 1,000 newborns
 * Why might I have a "Screen Positive" result?
 * The fetus has either an ONTD, DS, or Trisomy 18
 * The fetus has a different chromosome abnormality or birth defect
 * The variation in the level of the marker or markers is normal
 * The gestational age is incorrect
 * Underestimated in ONTDs (She is farther than she thought)
 * Overestimated in DS (She is not as far along as she thought)
 * There are multiple pregnancies (affects NTDs and DS results)
 * Fetal demise (for NTD and Tri 18)
 * Other causes of (+) for NTD:
 * Abdominal wall defect
 * Feto-maternal bleeding
 * Finnish nephrosis (kidney disease)
 * Other causes of (+) for Trisomy 18:
 * X-linked icthyosis (scale-like skin due to steroid sulfatase deficiency)
 * What does a "Screen Negative" test result mean?
 * The pregnancy does not appear to be at an increased risk for ONTD, DS, or TRI 18
 * This does NOT guarantee that the child will not have a birth defect
 * How Accurate is this test?
 * The detection rate is a measure of how sensitive the test is
 * This is the chance of getting a screen (+) when the fetus is actually affected
 * There is a 60% overall detection rate
 * This means that 60 out of 100 affected pregnancies will be found by this test
 * The false (+) rate is the chance of getting a (+) when the pregnancy is unaffected
 * There is a 5% overall false (+) rate
 * 5 out of 100 unaffected pregnancies will screen (+)
 * Of 100 women with normal babies, 5 will screen (+)
 * More specifically:
 * For ONTD:
 * Detection rate is 85%
 * False (+) rate is 1-3%
 * For DS:
 * Detection rate is 60-65%
 * False (+) rate is 5%
 * Higher detection rate and false (+) rate for women over age 35
 * For Trisomy 18:
 * Detection rate is 60-80%
 * False (+) rate is ~0.5%
 * How do I follow up on a "Screen Positive" result?
 * For NTD:
 * Confirm gestational age with ultrasound
 * Offer genetic counseling, ultrasound, and amniocentesis (to measure AFP)
 * If AFP is <3.0 MoM and client is <22 weeks, may repeat triple screen
 * If AFP is >3.0 MoM or client is >22 weeks, offer level II ultrasound and/or amniocentesis
 * For Down Syndrome or Trisomy 18:
 * Confirm gestational age with ultrasound
 * Offer genetic counseling, ultrasound, and amniocentesis
 * DO NOT repeat screen unless initial screen was done before 14 weeks
 * Unexplained screen (+) results may be associated with an increased risk for 3rd trimester complications
 * These pregnancies should be monitored more closely

Level II Ultrasound

 * At 18-20 weeks, a high resolution, targeted ultrasound examination can be done to carefully and specifically examine the baby's spine.
 * This is noninvasive and may provide reassurance but cannot be used as a diagnostic tool.
 * If no evidence of a NTD is seen, it cannot be guaranteed that the baby does not have a NTD.

Amniocentesis

 * If the triple screen results indicate an increased risk for a NTD, one may choose to have an amniocentesis, which is a more invasive, but more diagnostic test.
 * What is it?
 * Procedure used to obtain a small sample of fluid from the fluid-filled sac that surrounds the fetus
 * Performed at 15 weeks gestation or later
 * 15-18 weeks is optimal because it leaves the patient with options
 * 22 weeks is probably the latest it can be done leaving the option of elective abortion
 * Amniotic fluid contains the fetus's urine as well as other cells from the skin, throat, and digestive tract
 * Fluid is studied in the lab for abnormalities
 * What can it tell me?
 * Amnio can detect certain abnormalities in the fetus.
 * Chromosome abnormalities
 * NTDs (Spina Bifida)
 * It can determine the sex of the baby.
 * What can it NOT tell me?
 * Amnio cannot detect all birth defects or mental retardation.
 * For example, congenital heart defects, cleft lip & palate cannot be seen.
 * Also the severity of the defect cannot be known from amnio.
 * Exactly what does the procedure involve?
 * Show figure of amniocentesis.
 * You will lie down on your back with hands behind your head.
 * Your abdomen will be cleaned with alcohol or iodine.
 * A local anesthetic may be applied to your stomach.
 * Ultrasound will be used to locate the position of the baby and the placenta and to find a safe spot for the needle.
 * A long, thin needle will be inserted through the skin, into the uterus.
 * The first few cc's of fluid will be discarded because they probably contain contamination from your cells.
 * Then a small amount (about 1-2 tablespoons) of fluid is removed and the needle is withdrawn.
 * The procedure itself usually takes ~5 minutes.
 * The baby will quickly replace the fluid that is removed.
 * The baby's heartbeat will be monitored by ultrasound.
 * Fluid will be sent to the lab and results are available in 1-2 weeks.
 * There is a small possibility of lab error or lack of cell growth
 * In this case, the procedure would have to be done again.
 * What will it feel like?
 * If an anesthetic is used, you may not feel the needle enter the skin, but you will still feel it enter the uterus.
 * This is described as a sharp pain, like a menstrual cramp that usually lasts a few seconds.
 * You may also feel some cramping after the procedure.
 * You should avoid strenuous activity for 24 hours after the procedure.
 * Call your doctor immediately if you experience abdominal pain or cramps, vaginal bleeding, leakage of clear fluid from the vagina, fever, or anything else unusual.
 * Approximately 2% of women experience light bleeding or spotting.
 * What are the risks?
 * The risk of miscarriage is between 1/400 and 1/200.
 * This means that the added risk for pregnancy loss attributable to the procedure is 0.5% or less.
 * There is a risk of uterine infection but this is less than 1 in 1,000
 * There is a remote chance that birth defects can be caused by the amnio (0.1%).
 * There are special considerations for mothers who are Rh negative. They need to take RhoGam after the amnio procedure.

Offer Resources

 * Spina Bifida Association of America
 * www.sbaa.org
 * 1-800-621-3141

 * March of Dimes information on Spina Bifida, Amniocentesis, Folic Acid, and Maternal blood screening
 * www.modimes.org
 * 1-888-MODIMES

Reporting of the Results

 * If they are having a procedure, discuss how they would like to receive the results
 * Appointment, phone call, etc.
 * Who will contact them?
 * Discuss the options: elective abortion, adoption, etc.


text:
Handbook of Genetic Counseling/Neurofibromatosis - Type 1

Neurofibromatosis - Type 1

Contracting/Introduction

 * What is your understanding about why you were referred to genetics?
 * What are your main concerns or questions?
 * Outline session
 * I will first ask you some questions about your family history and _____'s medical history
 * Then Dr. _____ will examine ______
 * We will discuss what we know at that point about whether or not a diagnosis can be made and we will answer any questions you might have.

Elicit Family History

 * Family history can be helpful in determining if there is something in the family that might be inherited
 * Some of the things I'm looking for in your family history include:
 * Birth defects
 * History of pregnancy losses
 * learning difficulties or MR
 * chronic health problems
 * unusual skin findings or birth marks
 * hearing loss
 * underarm freckling
 * scoliosis
 * seizures
 * vision loss
 * anyone who died at a young age or unexpectedly
 * Anything else that you think might be running in your family

Incidence of NF1

 * NF1 is estimated to affect 1/3,500 people in the population
 * Affects both sexes and all racial and ethnic groups equally

Clinical Features

 * Clinical features are extremely variable both between and within families
 * Not all of the features are present in individuals with NF1
 * Skin:
 * Café-au-lait spots in ~94% of patients
 * Axillary or inguinal freckling- common after 3 years of age
 * Xanthogranulomas (2-5%)
 * Hemangiomas (5-10%)
 * Eye:
 * Optic glioma (often present at birth; occurs in 10-15% of patients)
 * Lisch nodules- pigmented iris hamartomas (100% after the age of 20)
 * Tumors
 * Neurofibromas- benign tumors arising from nerve cells that can occur anywhere in the body and are often associated with the skin.
 * Plexiform neurofibromas- tumors along nerve bundle tracts, can be large and usually appear at birth or early in childhood (occur in ~25%)
 * Malignant peripheral nerve sheath tumors arise in ~2-4% of individuals
 * Pheocromocytoma, rhabdomyoma, neuroblastoma (rare)
 * Myelogenous leukemia (rare)
 * Neurological:
 * Headaches occur in >10% of patients
 * Seizures and/or EEG abnormalities occur in ~20%
 * Seizures 6-7%
 * Hydrocephalus occurs in ~5% of individuals
 * Sensorineural hearing loss occurs in ~5% of patients
 * Precocious puberty (2-5%)
 * Orthopedic:
 * Scoliosis
 * Hypoplastic bowing of lower legs, with pseudoarthrosis at birth
 * Short stature
 * Macrocephaly
 * Cardiovascular:
 * Hypertension (2-5%)
 * Congenital heart defect (2%)
 * Cognitive:
 * Developmental delay
 * Learning disabilities- hyperactivity and/or speech problems occur in 50%
 * Mental retardation (8% of patients)
 * Other-occasional:
 * Syndactyly
 * Glaucoma
 * Ptosis
 * Pruritis

Diagnostic Criteria
(clinical diagnosis based on a number of clinical findings)
 * NF1 is present in an individual who has two or more of the following signs:
 * Six or more café au lait macules >5 mm in prepubertal individuals or >15 mm after puberty
 * Two or more neurofibromas of any type, or one+ plexiform neurofibromas
 * Freckling in the axilla or inguinal regions
 * A tumor of the optic pathway (optic glioma)
 * Two or more Lisch nodules
 * Long bone bowing (w/ or w/o pseudarthrosis)
 * A first-degree relative with NF1 by the above criteria

Natural History and Life Span: NF1

 * Although the medical literature and the internet tend to show the most severe cases, approximately 2/3 have only mild or moderate involvement throughout their lifespan
 * Lifespan is dependent on severity and types of symptoms, but it has been shown in one study that the average life expectancy of patients with NF1 can be reduced by at least 15 years overall
 * Decreased lifespan has been associated with the following features:
 * Malignant peripheral sheath tumors
 * Acute hydrocephalus
 * Severe seizure
 * Progressive spinal plexiform neurofibromas
 * Frequency of more serious complications increases with age
 * Various manifestations of NF1 have different characteristic times of appearance
 * Since characteristic features often develop with age, if NF1 is suspected it is often necessary to continue to follow them for a while before the diagnosis can be ruled out completely
 * Infancy:
 * Café-au-lait spots
 * Long bone bowing
 * Developmental delay
 * Optic glioma
 * Plexiform neurofibroma
 * Childhood:
 * Neurofibromas
 * Freckling patterns
 * Learning disabilities
 * Scoliosis
 * Hypertension
 * Adolescence:
 * Worsening of existing condition
 * Rarely malignant peripheral nerve sheath tumors develop
 * Adulthood:
 * Increase in neurofibromas
 * Hypertension
 * If other symptoms have not developed, they may do so at this time
 * Pregnancy:
 * most pregnancies in women with NF1 are normal but serious complications can occur
 * Many women with NF1 experience a rapid increase in the number and size of neurofibromas during pregnancy
 * Hypertension may first become symptomatic or, if pre-existing, may become worse
 * Large pelvic or genital neurofibromas can complicate delivery
 * cesarean section appears to be necessary more often in pregnant women with NF1 than in other women.

Counseling

 * NF1 gene located on long arm of chromosome 17q11.2
 * NF1 gene is classified as a tumor suppressor gene, however the gene has other functions that are not as well defined
 * In about 50% of individuals with NF 1 it was inherited from an affected parent and the other half are due to a new mutation not already present in the family
 * If a person has this gene they will almost certainly show some signs or characteristics, but these may not be obvious and it is possible for a person to go undiagnosed (nearly 100% penetrant, but variable expressivity)
 * The gene is very large which is consistent with the number of patients with NF1 that were due to a new mutation
 * Gene encodes for a protein called neurofibromin (believed to act as tumor suppressor, but probably also has other functions)
 * Autosomal Dominant inheritance
 * Autosomal means it is on a chromosome other than sex chromosome
 * Dominant means only one altered copy of this gene is necessary to develop symptoms and characteristics
 * Risk assessment:
 * For affected individuals 50% risk for each pregnancy to be affected, although clinical expression is variable
 * For unaffected parents the recurrence risk is (<1%) (germline mosaicism in one man reported)

Testing

 * Families with two or more affected individuals can use linkage analysis to identify carriers of the disease causing NF1 gene
 * Sporadic cases require direct mutational analysis of the gene, if presymptomatic testing is desired
 * DNA testing by protein truncation is available but rarely used for diagnosis (reported to detect 70% of mutations, but not firmly established)
 * Mutation may be missed due to large size of gene and many mutations possible
 * FISH can be used to detect microdeletions of chromosome 17q11.2
 * Individuals with large deletions tend to have mental retardation and an increased tumor burden (approximately 5% of individuals with NF1 have whole gene deletions)

Prenatal testing

 * Possible if there is a known mutation or via linkage studies if enough affected family members
 * It is not often used

Genotype/phenotype correlation

 * Differences seen even in members of same family suggest some randomness to some of features.
 * Two-hit hypothesis supports these findings
 * However, there are some similarities of phenotype seen in

Management and Treatment Options

 * Individuals should be placed on surveillance programs
 * Annual physical examination by a physician who is familiar with NF1
 * Annual ophthalmological examination in childhood, less frequent examination in adults
 * Regular developmental assessment by screening questionnaire
 * Regular blood pressure monitoring
 * Other studies only as indicated on the basis of clinically apparent signs or symptoms (HOWEVER, some centers do MRI on newly diagnosed patients though)
 * Treatment includes treating the symptoms as they occur
 * Learning difficulties: appropriate school placement, IEP
 * Dermal neurofibromas: surgically remove if they are symptomatic
 * Early recognition of long bone bowing can be accompanied with braces (which may help prevent fractures)
 * MRI's should be scheduled to screen for optic gliomas
 * Ophthalmologic exam to look for Lisch nodules
 * Bracing for scoliosis
 * Meds for seizures and headaches

Differential Diagnosis

 * Overlap primarily lies in cutaneous features, especially café-au-lait spots
 * Neurofibromatosis 2 (bilateral acoustic neuromas, tumors of cranial nerves and spinal roots, skin manifestations less frequent than in NF1)
 * Multiple café-au-lait spots (an autosomal dominant trait without other features of neurofibromatosis)
 * LEOPARD syndrome (multiple lentigines, ocular hypertelorism, deafness, congenital heart disease)
 * McCune-Albright syndrome (large café-au-lait spots with irregular margins, polyostotic fibrous dysplasia)
 * Noonan syndrome (short stature, unusual facies, pulmonic stenosis)
 * A Noonan syndrome phenotype occurs in about 12% of patients with NF1 and features may include ocular hypertelorism, down-slanting palpebral fissures, low-set ears, webbed neck, and pulmonic stenosis
 * Multiple endocrine neoplasia type 2B (mucosal neuromas, conjunctival neuromas, pheochromocytoma, medullary carcinoma of the thyroid, marfanoid habitus)
 * Multiple lipomatosis (multiple cutaneous lipomas)
 * Bannayan-Ruvalcaba-Riley syndrome (multiple lipomas and hemangiomas, macrocephaly, spotted pigmentation of the glans penis).
 * Juvenile hyaline fibromatosis (multiple subcutaneous tumors, gingival fibromatosis)
 * Congenital generalized fibromatosis (multiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, and viscera) Multiple intradermal nevi (multiple cutaneous tumors)
 * Klippel-Trenaunay-Weber syndrome (cutaneous hemangiomas, varicose veins, aterio-venous fistulas, and hemi-hypertrophy
 * Proteus syndrome (regional overgrowth, hyperpigmentation, multiple lipomas)

Patient resources

 * National Neurofibromatosis Foundation
 * 95 Pine Street, 16th Floor
 * New York, New York 10005
 * Phone: 212-344-NNFF; 800-323-7938
 * Fax: 212-747-0004
 * Email: NNFF@aol.com
 * Web: www.nf.org

 * Neurofibromatosis, Inc
 * 8855 Annapolis Road, Suite 110
 * Lanham, MD 20706-2924
 * Phone: TDD 410-461-5213
 * Fax: 301-577-0016
 * Email: nfinc1@aol.com
 * Web: www.nfinc.org


text:
Handbook of Genetic Counseling/Neurofibromatosis - Type 1-2

Neurofibromatosis Type 1

Contracting/Introduction

 * Establish rapport with small talk and introduce myself
 * What have you been told about Neurofibromatosis?
 * Acknowledge that the diagnosis was made by the pediatrician when the girls were 6 months old, no NF education provided other than a brochure
 * What concerns do you have? What questions would you like to have answered today?

Elicit Medical History

 * Prenatal and birth history
 * Perinatal complications
 * Immunizations up to date?
 * Any illnesses, hospitalizations, surgeries?
 * Any recent doctor appointments other than ophthalmologist and MRI?
 * Acknowledge that the findings from both of the above were insignificant
 * Review of systems
 * Any vision problems? Hearing? Any heart problems? Any breathing problems? Constipation/Diarrhea? UTI's? Have you noticed any bowing of her legs or curvature of her spine? Do they have any freckles under their arms or in the groin area? Have either of the girls ever had a seizure?
 * Current Medications
 * Developmental Assessment:
 * Are the twins walking? Walking backwards? Running? Scribbling with a crayon? Follow one-step commands? How many words do they know? Do they know any body parts? Colors?
 * Do the girls receive any early intervention services? If yes, what type of services do they receive? How often?
 * What are the feelings of the family in relation to the services? Do you feel that she is getting adequate services?

Elicit Family History

 * Generate a targeted family history
 * Specifically ask about findings of NF type 1
 * Does anyone in the family have: learning problems, DD, MR? Vision problems/loss? Café-au-lait spots? Small raised areas on the skin? Groin or underarm freckling? Bowing of the legs? Scoliosis? Seizure problems?
 * Also ask about:
 * Depression or other psychological problems
 * Any miscarriages or Stillbirths?
 * Anyone born with any birth defects?
 * Anyone die at a young age or unexpectantly?
 * Anyone in leg/back braces or confined to a wheelchair?

Psychosocial Assessment

 * Who is living in your home?
 * Do you have family in this area? Friends?
 * Does anyone help you with your children?
 * How are the childcare needs being met?
 * How has the diagnosis affected your home life?
 * Have you felt anxious while waiting to see genetics?
 * How is the family coping?
 * Do you have insurance?
 * Are you (parents) employed outside of the home? If so, what is your occupation?

Counseling

 * Genes and chromosomes
 * De novo mutation? 50% of cases
 * NF1 gene is classified as a tumor suppressor gene, however the gene has other functions that are not as well defined.
 * Autosomal Dominant inheritance
 * Risk assessment:
 * For affected parents/patient=50%, although clinical expression is variable
 * For unaffected parents the recurrence risk is small (<1%)

Resources

 * Support groups, NF clinic, BCMH services???
 * Most people with NF1 live long and productive lives and do not develop life-threatening complications.
 * Although the medical literature and the internet tend to show the most severe cases, approximately 2/3 have only mild or moderte involvement throughout their lifespan.
 * Provide the patient with resources/literature


text:
Handbook of Genetic Counseling/Neurofibromatosis - Type 1-3

Neurofibromatosis Type 1

Genetic Etiology

 * Mode of inheritance:
 * Autosomal dominant
 * 50% of cases represent a new mutation
 * Chromosome location:
 * The gene for NF1 is located at chromosome 17q11.2
 * The gene is very large, which is consistent with the large mutation rate
 * Penetrance:
 * High- but wide variability in expression

Incidence

 * NF1 is estimated to affect 1/3,500 people in the population

Diagnostic Criteria

 * NF1 is present in an individual who has two or more of the following signs:
 * Six or more café au lait macules >5 mm in prepubertal individuals or >15 mm after puberty
 * Two or more neurofibromas of any type, or one+ plexiform neurofibromas
 * Freckling in the axilla or inguinal regions
 * A tumor of the optic pathway (optic glioma)
 * Two or more Lisch nodules
 * Long bone bowing (w/ or w/o pseudarthrosis)
 * A first-degree relative with NF1 by the above criteria

Clinical Features

 * Clinical features are extremely variable both between and within families
 * Skin:
 * Café-au-lait spots in ~94% of patients
 * Axillary or inguinal freckling- common after 3 years of age
 * Xanthogranulomas (2-5%)
 * Eye:
 * Optic glioma (often present at birth; occurs in 10-15% of patients)
 * Lisch nodules- pigmented iris hamartomas (100% after the age of 20)
 * Neurological:
 * Neurofibromas- benign tumors arising from nerve cells that can occur anywhere in the body and are often associated with the skin.
 * Plexiform neurofibromas- tumors along nerve bundle tracts, can be large and usually appear at birth or early in childhood (occur in ~25%)
 * Malignant peripheral nerve sheath tumors arise in ~2-4% of individuals
 * Headaches occur in >10% of patients
 * Seizures and/or EEG abnormalities occur in ~20%
 * Hydrocephalus occurs in ~5% of individuals
 * Sensorineural hearing loss occurs in ~5% of patients
 * Precocious puberty (2-5%)
 * Orthopedic:
 * Scoliosis
 * Hypoplastic bowing of lower legs, with pseudoarthrosis at birth
 * Short stature
 * Macrocephaly
 * Cognitive:
 * Developmental delay
 * Learning disabilities- hyperactivity and/or speech problems occur in 50%
 * Mental retardation (8% of patients)
 * Other-occasional:
 * Syndactyly
 * Glaucoma
 * Ptosis
 * Pruritis

Risk of Occurrence/Recurrence

 * The risk for an affected individual to have a child with NF1 is 50%
 * The risk for each additional pregnancy is also 50%

Natural History and Life Span

 * Infancy:
 * Café-au-lait spots
 * Long bone bowing
 * Developmental delay
 * Optic glioma
 * Plexiform neurofibroma
 * Childhood:
 * Neurofibromas
 * Freckling patterns
 * Learning disabilities
 * Scoliosis
 * Hypertension
 * Adolescence:
 * Worsening of existing condition
 * Rarely malignant peripheral nerve sheath tumors develop
 * Adulthood:
 * Increase in neurofibromas
 * Hypertension
 * If other symptoms have not developed, they may do so at this time
 * Decreased lifespan has been associated with the following features:
 * Malignant peripheral sheath tumors
 * Acute hydrocephalus
 * Severe seizure
 * Progressive spinal plexiform neurofibromas

Testing

 * Families with two or more affected individuals can use linkage analysis to identify carriers of the abnormal gene NF1
 * Sporadic cases require direct mutational analysis of the gene, if presymptomatic testing is desired
 * FISH can be used to detect microdeletions of chromosome 17q11.2
 * Individuals with large deletions tend to have mental retardation and an increased tumor burden (approximately 5% of individuals with NF1 have whole gene deletions)

Management and Treatment Options

 * Individuals should be placed on surveillance programs
 * Treatment includes treating the symptoms as they occur
 * Learning difficulties: appropriate school placement, IEP
 * Dermal neurofibromas: surgically remove if they are symptomatic
 * Early recognition of long bone bowing can be accompanied with braces (which may help prevent fractures)
 * MRI's should be scheduled to screen for optic gliomas
 * Ophthalmologic exam to look for Lisch nodules
 * Bracing for scoliosis
 * Meds for seizures and headaches

Differential Diagnosis

 * Overlap primarily lies in cutaneous features, especially café-au-lait spots
 * Consider: Russell-Silver, Bloom, Noonan, and Watson syndromes.
 * For neurofibromas, consider:
 * Bannayan-Riley-Ruvalcaba syndrome, Carney syndrome, Proteus syndrome etc.

Additional Psychosocial Issues

 * Risk for increased emotional and social problems
 * Self-esteem issues associated with cosmetic concerns
 * Reproductive concerns
 * For parents, guilt issues as well as blame issues


text:
Handbook of Genetic Counseling/Neurofibromatosis - Type 2

Neurofibromatosis - Type 2

Contracting

 * How have things been since your last visit?
 * What questions or concerns would you like us to address today?

Etiology

 * Disease characteristics
 * Genetic disorder that causes tumors to grow on various nerves
 * Also affects other tissues such as bones and skin
 * Two distinct types: NF-1 and NF-2
 * Inheritance
 * Autosomal dominant
 * Affected individuals have 50% chance of passing on mutation to each of their children
 * Half of affected individuals have de novo mutations
 * If neither parent has NF2, recurrence risk is very low - only one case of germline mosaicism reported
 * Uniform age of onset within families
 * Molecular genetics
 * Caused by mutation in the NF2 gene
 * Located at 22q12
 * Normal gene product is schwannomin or merlin
 * Homology to 4.1 family of cytoskeletal associated proteins
 * Has role in prevention of schwannoma formation
 * Tumor suppressor gene
 * Incidence is 1 in 40,000 people

Clinical Features and Natural History

 * Some variability in clinical manifestations
 * Variability within families is low
 * Suggests strong genotype-phenotype correlation
 * Average age of onset of symptoms is 18-24
 * Some people don't develop signs until their 40's or 50's
 * Considered adult-onset so may be underdiagnosed in children
 * Nonsense and frame shift mutations more severe
 * Bilateral vestibular schwannoma (acoustic neuroma)
 * Affect almost all patients with NF2
 * Tumor that arises from Schwann cells that support and protect nerves with insulation needed to conduct information on 8th cranial nerve
 * Initial symptoms include tinnitus (ringing in ears), hearing loss, and balance dysfunction
 * May result in hearing loss in one or both ears
 * Spinal tumors (>66%)
 * Include schwannomas that may cause numbness in part of body
 * Intramedullary tumors such as astrocytoma and ependymoma (5-33%)
 * Most individuals with spinal cord tumors have more than one
 * Meningiomas (50%)
 * Tumor that grows from cells that line the brain and spinal cord in protective sheets called meninges
 * May be intracranial or spinal
 * Cause different neurological symptoms depending on location
 * Ocular involvement (33%)
 * Cataracts
 * Known as juvenile posterior sublenticular opacity
 * May impair vision if not removed
 * Optic gliomas
 * Tumors on vision nerve
 * May lead to blindness
 * Other features
 * Other types of central nervous system tumors
 * Atypical café-au-lait spots
 * Cutaneous neurofibromas
 * Somatic mosaicism
 * Suspected in individuals with unilateral vestibular schwannoma and multiple other tumors on one side
 * More difficult to diagnose
 * Considerably shortened lifespan
 * Average age of death is 36 years
 * With improvements in diagnosis, monitoring, and surgery this is changing

Diagnosis/Testing Options
OR OR
 * Clinical diagnosis
 * Bilateral VIII nerve mass on CT or MRI (vestibular schwannomas)
 * First degree relative with NF2 and either
 * Unilateral 8th nerve mass
 * Two of the following
 * Meningioma
 * Glioma
 * Schwannoma
 * Juvenile posterior subcapsular lenticular opacity
 * Mutation analysis
 * Mutations identified in 65-80% of patients with clinical diagnosis
 * Testing provided by Athena Diagnostics/Mass Gen
 * Includes SSCP (single stranded conformational polymorphism)
 * May take up to 6 months for results
 * Costs about $2700
 * Considered appropriate to test unaffected at risk children and adults
 * Linkage analysis
 * Appropriate if more than one affected family member
 * Doesn't work for 50% of patients with de novo mutations
 * High accuracy because markers are very closely linked
 * Prenatal testing
 * Available for fetuses at 50% risk or greater
 * Can be performed if mutation identified in affected family member
 * Requires cells obtained from CVS or amniocentesis

Management

 * Currently is no cure or treatment
 * Early recognition allows for earlier intervention and improved outcome
 * Begin screening in early teens
 * ABR and MRI exams for vestibular schwannomas
 * Surgery generally successfully preserves hearing is tumors small
 * Should begin learning sign language before hearing is lost
 * Hearing aids may help preserve hearing early on
 * Routine complete eye examinations
 * Routine neurological examinations
 * Intracranial, cranial nerve, and spinal tumors often slow growing

Differential Diagnosis

 * NF1
 * Has Lisch nodules, axillary and inguinal freckling, and plexiform neurofibromas not seen in NF2
 * Patients with NF2 do not have mental retardation or learning problems
 * Unilateral vestibular schwannoma
 * Accounts for 5-10% of intracranial tumors
 * Less than 5% are bilateral and associated with NF-2
 * Schwannomatosis
 * Multiple schwannomas without vestibular schwannomas
 * Develop intracranial, spinal nerve root, or peripheral nerve tumors
 * Multiple meningiomas
 * Without vestibular schwannomas
 * Typically occur in older adults

Psychosocial Issues

 * Feelings of fear, anger, shock, denial over new diagnosis
 * Difficulty adjusting to loss of hearing
 * Burden of condition requiring extensive surveillance
 * Anxiety about possibility of shortened life span
 * Survivor guilt, transmitter guilt
 * Support system to help cope with diagnosis

Support Resources

 * National Neurofibromatosis Foundation
 * 95 Pine Street, 16th Floor
 * New York, NY 10005
 * Phone: 800-323-7938
 * Web: www.nf.org

 * Neurofibromatosis, Inc
 * 8855 Annapolis Road, Suite 110
 * Lanham, MD 20706-2924
 * Phone: 410-461-5213
 * Web: www.nfinc.org

 * The Acoustic Neuroma Association
 * PO Box 12402
 * Atlanta, GA 30355
 * Phone: 404-237-2704
 * Web: ANAUSA@aol.com


text:
Handbook of Genetic Counseling/Niemann-Pick Disease

Niemann-Pick Disease

Introduction

 * Acknowledge any prior phone contact
 * Assess their knowledge and understanding about Niemann-Pick disease
 * Assess their concerns and ask what they want to discuss today

Intake

 * Elicit medical history
 * Elicit family history
 * Construct pedigree

What is Niemann-Pick disease?

 * A group of rare inherited disorders of fat metabolism (three main types with subdivisions)
 * Type A (acute infantile form) and Type B (chronic, non-neurological form): caused by excessive amounts of a fatty substance (sphingomyelin) that accumulates in the brain, central nervous system, and several visceral organs (liver, spleen, lungs). This is due to a deficiency of the enzyme sphingomyelinase, which breaks down the fat from the cell membrane products created by the normal turnover of cell death.
 * Type C (biochemical form): is a lipid storage disorder that results in the accumulation of excessive amounts of cholesterol within the cells of the liver, spleen, and brain. This is due to the cell's inability to transport the cholesterol properly during esterification reactions. It causes progressive deterioration of the nervous system.

What are the symptoms?

 * Type A: this is the most common form of the disease (80%). Most of the infants appear normal at birth, and then develop symptoms by 6-12 months. There is a gradual decline of motor and intellectual function resulting in a degenerative muscle weakness and floppiness. The severity of the symptoms increases rapidly and life-threatening complications may occur early in childhood. The fat accumulation is so severe that it may represent 2-5% of the body weight.
 * the fat accumulation in various parts of the body occurs in the developing fetus
 * hepatosplenomegaly
 * lymphadenopathy
 * abnormalities of the nervous system (profound MR)
 * poor feeding
 * edema and distention - abdominal swelling
 * vomiting and diarrhea
 * failure to thrive
 * pyrexia - fever
 * macula - bright red spots in the eyes (50%)
 * jaundice
 * Type B: begins in infancy or early childhood. These symptoms progress more slowly and there is minimal nervous system *involvement
 * hepatosplenomegaly
 * bright red spots in the eyes
 * increased susceptibility to lung infections
 * slow growth rate
 * Type C: the disease may strike anytime from early infancy to adulthood, but usually affects school-age children
 * fetal ascites or neonatal liver disease
 * jaundice at birth
 * infantile hypotonia
 * developmental delay
 * hepatosplenomegaly
 * vertical supranuclear gaze palsy (VSGP) - difficulty with upward or downward eye movements
 * ataxia - unsteady gait, clumsiness, difficulty walking
 * dystonia - difficulty in the posturing of limbs
 * dysarthria - slurred, irregular speech {these two eventually become disabling,
 * dysphagia - difficulty swallowing making oral feeding impossible}
 * dementia - learning disorders and progressive intellectual decline
 * cataplexy - sudden loss of muscle tone, causing abrupt falls
 * seizures and tremors accompanying movement

What is the prognosis?

 * Type A: death usually occurs by 4 years of age
 * Type B: the earliest diagnosed patients are now middle-aged without neurological impairment
 * Type C: death usually occurs in the late 2nd or 3rd decade (aspiration pneumonia is often the cause)

Mode of Inheritance

 * autosomal recessive
 * both parents carriers: ¼ affected, 2/4 carriers, ¼ unaffected
 * males and females affected in equal numbers
 * this means that no family history of the disease is the norm

Chromosome location

 * Type A and Type B: SMPD1 (ASM) gene on locus 11p15.1-15.4
 * Type C: NPC1 gene is on locus 18q11-q12
 * NPC2 gene is on locus 14q24.333

Molecular genetics

 * Type A: in non-Jewish populations, many different mutations have been detected in Jewish populations, 1/3 of the people have a R496L point mutation
 * Type B: in non-Jewish populations, many different mutations have been detected in Jewish populations, a 3 base pair deletion ΔR608 is either homozygous or heterozygous with R496L
 * it's not possible to predict the severity by enzyme testing
 * Type C: 95% of patients have mutations in the NPC1 gene (clinical tests available)
 * 5% of patients have mutations in the NPC2 gene (research basis only)
 * the exact gene defect is not known, as mutation scanning has identified most patients as compound heterozygotes with mutations unique to their family (over 100 mutations so far)
 * the individuals with Nova Scotia ancestry (Type D) almost uniformly have a G992W mutation on NPC1

Expression

 * The phenotype (age of onset and severity of symptoms) usually runs true in families
 * Type C: "classic" patients have zero or very low esterification levels with a positive staining pattern, while "variant" patients (about 15%) have intermediate levels of cholesterol esterification and a less distinctive staining pattern

Incidence and Carrier Frequency

 * Type A: identified in people of all races
 * higher incidence in: Ashkenazi Jew ancestry (between 1:20,000 and 1:30,000)
 * carrier frequency: 1:90 to 1:100
 * Type C: rare, with 300 reported cases in the United States and 1 in a million worldwide
 * affects all populations with a prevalence 1:150,000 (est. in western Europe)
 * no accurate info. on true incidence or carrier frequency
 * higher incidence in: French Canadians in Nova Scotia (Type D)
 * Hispanic ancestry in NM and CO (Rio Grande River)
 * Bedouin group in Israel {Founder Effect}

Diagnostic
biochemical testing is used to diagnose; molecular genetic testing is primarily used to confirm diagnosis in "variant" patients
 * Type A and Type B: blood testing - enzyme assay confirms a deficiency of the enzyme sphingomyelinase in the leukocytes (and a biopsy of the bone marrow will show abnormal foam cells)
 * Type C: biochemical test - skin biopsy taken and the fibroblasts are tested for their ability to handle cholesterol (esterification studies to test impaired cell transport and filipin fluorescent staining studies to test cell storage)
 * {Note: The diagnosis of often delayed because many clinicians do not realize that the absence of organomegaly doesn't rule out storage diseases and because "routine" tests for metabolic disease, such as urine screens and lysosomal enzyme panels, are normal in NPC.}

Carrier

 * Type A: partial deficiency in sphingomyelinase activity in cultured fibroblasts indicates the heterozygote state
 * Type C: carrier detection is not yet reliable using standard biochemical tests molecular analysis of the NPC1 gene may be used if proband mutations have been identified

Prenatal

 * Type A and Type B: available by amnio or CVS to measure the enzyme activity
 * Type C: prenatal diagnosis available through amniocentesis or CVS for pregnancies at 25% risk
 * biochemical testing is the proband has a "classical" biochemical phenotype, but not if the proband has a "variant" *biochemical phenotype
 * molecular genetic testing if the proband as identified mutations in the NPC1 gene

Laboratories
adult - 14 cc; child - 6 cc; infant - 2-3 cc
 * Type A: Genzyme Genetics: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/niemann-pick-disease-type-a-testing.aspx
 * Carrier testing for Ashkenazi Jewish individuals
 * Prenatal diagnosis for carrier couples with identified mutations
 * Genzyme's Niemann-Pick disease type A mutation analysis tests for 3 mutations for a 95% carrier detection rate in the Ashkenazi Jewish population.
 * Specimen Requirements:
 * 1. Blood: ACD-A (yellow-top) or EDTA (lavender-top) tube. Adult: 10 ml whole blood; 30 ml whole blood if ordering multiple tests. Turnaround Time: 10-14 days.
 * 2. Mouthwash: Please Note: Patient should not eat, drink, smoke or chew gum for at least one hour prior to collection. (See specimen kit for detailed instructions). Mouthwash samples can be sent when ordering up to two tests. When ordering more than two tests, blood samples are required. 10 ml of Scope® mouthwash that has been swished vigorously for at least 1 minute. Collect in orange-top 50 ml polypropylene tube. Turnaround Time: 10-14 days.
 * 3. Prenatal: Please Note: Call a laboratory genetic coordinator prior to obtaining any prenatal specimens. Prenatal testing is recommended only for carrier couples with identified mutations. In some circumstances, specimens from other family members may be required. All prenatal specimens (including cord blood) must be accompanied by a maternal blood or mouthwash specimen for analysis of possible maternal cell contamination. Discard first 2 ml; then 10 ml amniotic fluid in 15 ml orange-top polypropylene tube, 10-15 mg chorionic villi in laboratory-provided screw-top tubes with sterile transport medium or one T-25 flask of confluent fetal cells. Additional specimen must be obtained for back-up culture at one of our cytogenetics laboratories or another facility. If additional testing is desired, more amniotic fluid is needed. For example, chromosome analysis requires an additional 15-25 ml (see Cytogenetics – Amniotic Fluid Chromosome Analysis test page: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/amniotic-fluid-testing.aspx) and AFAFP requires an additional 2 ml (see Amniotic Fluid Alpha-Fetoprotein - AFAFP test page: http://www.genzymegenetics.com/Our-Services/Reproductive-Testing/afafp-test.aspx). Turnaround Time: 10-14 days (when cell culture required, add ~2 weeks).
 * Baylor DNA Diagnostic Laboratory
 * Ashkenazi Jewish background only (a negative test lowers the carrier risk from 1:100 to 1:1240)
 * diagnosis confirmation
 * carrier identification
 * prenatal diagnosis
 * direct DNA analysis: 3 mutations (R496L, L302P, fsP330)
 * $200 per sample
 * 92% detection accuracy
 * prenatal specimen: 30 cc amniotic fluid >15 weeks gestation
 * >5 mg chorionic villi with 2 T25 flasks
 * postnatal specimen: whole blood in EDTA (purple top) tube
 * Type A and Type B: Dr. Wenger's Lysosomal Diseases Testing Lab, Philadelphia
 * carrier testing
 * 8-10 cc heparinized whole blood at room temp.
 * clinical history and pedigree included
 * $150
 * Type C: Dr. Wenger's Lysosomal Diseases Testing Lab, Philadelphia
 * cholesterol esterification studies
 * $1000
 * Adelaide Women's and Children's Hospital, Australia
 * cholesterol esterification in fibroblasts
 * $305
 * Mayo Clinic
 * biochemical testing only, no mutation

Surveillance, Management, and Treatment

 * Treatment is symptomatic and supportive
 * Type A: bone marrow transplantation is being tested
 * Type B: a splenectomy may relieve pressure in the abdomen; clinical trials are being done for enzyme replacement therapy
 * Type C: clinical studies are being done to determine if a reduction of cholesterol in cells through diet and drugs will help delay the neurological progression; liver transplantation corrects hepatic dysfunction, but doesn't help the neurological disease

Differential Diagnoses

 * neonatal/infantile presentations: biliary atresia, congenital infections, alpha-1-antitrypsin deficiency, tyrosinemia, malignancies, Gaucher disease, infections (TORCH)
 * childhood presentations: pineal region or midbrain tumors, hydrocephalus, GM2 gangliosidosis, mitochondrial disease, maple syrup urine disease, ADD, LD, absence seizures, idiopathic torsion dystonia, Wilson disease, amino acidurias, pseudodementia, HIV encephalopathy
 * adolescent/adult presentations: Alzheimer disease, Pick disease, frontotemporal dementias, Steele-Richardson-Olzewski syndrome, syphilis, HIV dementia, psychiatric illnesses

Psychosocial Issues

 * adjusting to a child with significant medical problems
 * death of a child
 * pregnancy termination
 * guilt of "giving" this to their child
 * sibling survivor guilt
 * emotional support system/respite care for primary caregivers

Patient Resources and Support Groups

 * National Niemann-Pick Disease Foundation
 * North 1590 Fairview Lane
 * Ft. Atkinson, WI 53538
 * 1-877-CURE-NPC
 * www.nnpdf.org

 * Just For The Kids of N.P.C. Inc.
 * 1990 JE-TO Lake E. Drive
 * Danville, Indiana 46122
 * 317-745-2738

 * Genetic Alliance
 * 35 Wisconsin Circle, Suite 440
 * Chevy Chase, MD 20815
 * 800-336-4363
 * http://geneticalliance.org/


text:
Drugs:Fact and Fiction

Disclaimer Notice: Recreational and enhancement drug use can be dangerous and is often illegal. Before reading this book, make sure you understand Wikibooks' medical, legal and risk disclaimers. Information gathered in these pages is for informational purposes only.

Table of contents

 * 1) /Introduction/
 * 2) General Drug Information
 * 3) /Hallucinogens/
 * 4) /Stimulants/
 * 5) /Depressants/

title: Drugs:Fact and Fiction


text:
Handbook of Genetic Counseling/Niemann-Pick Disease-2

Niemann-Pick Disease

(Type A)

Background

 * Niemann-Pick disease is a neurodegenerative disease caused by a lysosomal storage disorder. A deficiency in acid sphingomyelinase (ASM) activity results in the accumulation of sphingomyelin.

Genetics

 * Caused by mutation in ASM gene
 * Chromosomal location 11p15.1-p15.4
 * 18 causal mutations mapped
 * 3 mutations account for 92% of Ashkenazi Jewish (R496L, L302P, and fsP330)

Incidence

 * Within Ashkenazi Jewish population:
 * Incidence: 1 in 40,000
 * Carrier frequency: 1 in 90

Diagnosis

 * Clinical-
 * Hepatosplenomegaly
 * Developmental delay and loss of milestones
 * Presence of "Niemann-Pick" foam cells in bone marrow aspirates
 * Enzymatic-
 * ASM activity below 5% or normal
 * Molecular-
 * Mutation found in ASM gene

Natural History

 * Perinatal:
 * Generally unremarkable:
 * Prolonged jaundice in neonatal period occasionally
 * Early infancy:
 * Around 3 Months:
 * Hepatosplenomegaly noted by physical exam
 * "Niemann-pick" foam cells present in bone marrow aspirates
 * Moderate anemia may be present
 * Hypotonia and muscular weakness, feeding difficulties
 * By 6 months:
 * Psychomotor retardation evident
 * Loss of developmental milestones
 * Cherry-red maculae noted in ophthalmologic exam (50%)
 * Loss of deep tendon reflexes
 * Progression:
 * Continued loss of motor function
 * Deterioration of intellectual capabilities
 * Emaciation, spasticity, and rigidity
 * Death occurs by 2-3 years of age

Inheritance

 * Autosomal recessive

Testing

 * Ashkenazi Jewish panel is available clinically:
 * Carrier and prenatal also available for known family mutations

Management & Treatment

 * There is currently no treatment for Niemann-Pick disease
 * Differential Diagnosis
 * Niemann-Pick disease Type C and D
 * Gaucher Disease
 * Other storage disorders

Psychosocial Issues

 * Early death of child
 * Loss of developmental milestones

Patient Resources

 * National Niemann-Pick Disease Foundation
 * PO Box 49
 * 415 Madison Ave
 * Ft. Atkinson, WI 53538
 * (877)-287-3672
 * (920)-563-0930
 * Email: nnpdf @idcnet.com


text:
Handbook of Genetic Counseling/Noonan Syndrome

Noonan Syndrome

Introduction and contracting

 * What is your primary concern
 * Do you have any questions for us today
 * What are your expectations for your visit today

Outline the session

 * We will be taking medical history information
 * Dr. ___ will come in to perform a physical examination
 * We will be discussing if we think there is a diagnosis that can be made at this time
 * If a diagnosis is made we will explain the inheritance and information we know about the cause

Medical history
(follow form)

Overview of Noonan Syndrome

 * Common autosomal dominant, single gene
 * Mistakenly called male Turner syndrome due to similar characteristics
 * Occurs in both males and females equally

Characteristics of Noonan Syndrome

 * Short stature
 * Congenital heart defects
 * Broad or webbed neck
 * Unusual chest shape (low set nipples, superior pectus carinatum, inferior pectus excavatum)
 * Developmental delay
 * Cryptorchidism
 * Characteristic physical appearance changes over time

Features irrespective of age

 * Low set posteriorly rotated ears with thick helix (90%)
 * Vivid blue or blue-green eyes (lighter than expected for background)
 * thickened or ptotic eyelids
 * hypertelorism

Neonate and Infancy
(age features are most striking)
 * tall forehead
 * hypertelorism with downslant palpebral fissures (95%)
 * prominent eyes
 * Nose has depressed root, wide base, bulbous tip
 * Deeply grooved philtrum
 * High wide peaks to vermillion border of upper lip
 * Excess nuchal skin and low posterior hairline

Children

 * Facial appearance lacks expression (resembles individual with myopathy)

Adolescence

 * Facial shape inverted triangle, wide forehead tapered chin
 * Pinched nasal root and thin bridge
 * Neck lengthens accentuates skin webbing or trapezius muscle
 * Eyes less prominent
 * Curly or wooly hair in older child

Adult

 * Nasolabial folds prominent
 * Skin appears transparent and wrinkled
 * Genetics of Noonan syndrome
 * missense mutations in gene PTPN11 at 12q24.1 identified in 50% of patients
 * gene identified in 2001 (normal gene encodes protein-tyrosine phosphatase, non-receptor type 11 seems to be essential in several intracellular signal transduction pathways controlling diverse developmental processes
 * absence of this mutation in some families suggests heterogeneity
 * AD single gene
 * 50% chance to pass on if affected
 * if parents not affected chance is low <1% (gene clinics)
 * direct transmission reported 30-75% of time rest are de novo
 * predominantly mothers not fathers transmit gene (3:1 ratio) (likely due to cryptorchidism and reduced fertility in males)

Prevalence

 * 1/1000-1/2,500

Diagnostic testing

 * Testing for PTPN11 mutations available on research basis
 * Diagnosis based on clinical findings though
 * High-resolution ultrasound only prenatal test available

Differential Diagnosis

 * Turner syndrome in females should be ruled out through karyotype
 * Trisomy 8p, trisomy 22 mosaicism, sex chromosome rearrangement, in utero exposure to alcohol or primidone
 * Williams, Aarskog, Baraitser-Winter, Costello syndromes share some features
 * Multiple lentigines/LEOPARD syndrome can also have pulmonary valve dysplasia, cardiomyopathy, short stature, hypertelorism, pectus deformity, hearing loss, developmental delay
 * Watson syndrome shares pulmonary valve stenosis, short stature, mild intellectual handicap, café-au-lait patches
 * Cardio-facio-cutaneous syndrome lot of overlap and debate about whether same condition, but MR more severe, skin findings hyperkeratosis, ichthyosis, absent eyebrows, sparse hair, gastrointestinal problems more severe, eyes rarely characteristically light blue/ blue-green

Cause of characteristics

 * Hypothesized to be consequences of lymphatic obstruction

Growth and feeding

 * B.W. usually normal
 * 15% have poor suck, 38% poor suck and vomiting, 24% require tube feeding 2 weeks or more
 * length at birth normal usually then follows 3% ile
 * final height lower end of normal in adults
 * some endocrinologists choose to treat with growth hormone even if deficiency not seen

Development and behavior

 * Delayed milestones
 * Mean age sitting 10 mth, walking 21 mth, two-word sentence 31 mth
 * 10-15 % require special ed
 * IQ usually within normal range, but mild MR seen in 1/3
 * Verbal lower than nonverbal performance
 * Usually good peer, social interactions and self-esteem, but one study suggests that less socially competent and more behavior problems than sibs (not clinically significant)

Ears and hearing

 * May cause delayed speech
 * Reported in >1/3 usually secondary to ottitis media
 * Sensorineural loss in 3%

Cardiovascular

 * Potential bias in frequency due to requirement for diagnosis by many (50-80%)
 * Stenotic or dysplastic pulmonary valve most common (20-50%)
 * 7% of all children with pulmonary stenosis have Noonan
 * hypertrophic cardiomyopathy (20-30%) found at birth, infancy or childhood
 * ASD (10-20%)
 * VSD (5-15%)
 * Coarctation of aorta (9%)
 * Others
 * ECG abnormality found in 87-90%

Eye Problems (occur in up to 95%)

 * Strabismus (48-63%)
 * Refractive errors (60-70%)
 * Amblyopia (33%)
 * Nystagmus (9%)
 * Other problems common

Blood/ liver spleen

 * 1/3 have coagulation problems
 * 2/3 give history of abnormal bleeding or mild-severe bruising
 * hepatosplenomegaly occurs reason unknown(clinically evident 25% ultrasound 51%)
 * should avoid aspirin

Genitourinary

 * Renal abnormalities (generally mild 11%)
 * Cryptorchidism in 60-80% of males may cause deficient spermatogenesis
 * Fertility is rule in females

Skin

 * Follicular keratosis
 * Scalp hair curly, thick and wooly, or sparse with easy breakage
 * Café-au-lait spots and lentigines more frequent than general population

Management if suspected

 * Physical and neuro exam
 * Plot growth on NS charts
 * Cardiology eval
 * Ophthalmology
 * Hearing
 * Coagulation screen
 * Renal ultrasound
 * Clinical and x-ray of spine and rib cage
 * Develop eval
 * Genetics consult

Psychosocial considerations

 * Diagnosis may not be certain
 * Difficulty and stress of having child with health concerns or learning issues
 * Guilt if passed on the gene

Support resources

 * The Noonan Syndrome Support Group
 * PO box 145
 * Upperco, MD 21155
 * Phone: 410-374-5345
 * Email: info@noonansyndrome.org
 * Website:www.noonansyndrome.org

 * MAGIC Foundation for Children's Growth
 * 1327 North Harlem Ave
 * Oak Park, IL 60302
 * Phone: 708-383-0899
 * Email: mary@magicfoundation.org
 * www.magicfoundation.org


text:
Handbook of Genetic Counseling/Oculo-Auriculo-Vertebral Spectrum

Oculo-Auriculo-Vertebral Spectrum

(a.k.a. Goldenhar Syndrome, Oculoauriculovertebral Dysplasia, OAV Syndrome, Facio-Auriculo-Vertebral Spectrum, First & Second Branchial Arch Syndrome)

Overview

 * a condition that affects the growth of the face
 * predominantly unilateral and involves the ear, mouth, and mandible (jaw)
 * about 15% have bilateral involvement though
 * extremely variable with many transitional forms affecting different systems
 * term Goldenhar syndrome used when the spine and the eye (epibulbar dermoids which are benign tumors located just inside the opening of the eye or the eyeballs and can cause vision problems) are involved

Etiology

 * unknown etiology, but is usually sporadic
 * However, a few cases have had a positive family history suggesting autosomal dominant, autosomal recessive, or multifactorial inheritance
 * thought to be caused by abnormal changes in blood vessels and the disruption of the blood supply during embryonic development (early vascular disruption) at about 30-45 days of gestation
 * results in the destruction of differentiating tissue in the first and second branchial arches, from which certain ligaments and bones of the face, parts of the skull, and the middle ear develop
 * amount of damage depends on timing of vascular disruption and degree of tissue destruction
 * No DNA abnormality has been identified
 * However, it has also been noted that certain teratogens (Thalidomide, Primidone, and Accutane) have produced birth defect patterns that are similar to the HFM spectrum.
 * rate of Goldenhar Syndrome found in the children of Gulf War veterans was 4 X's as high as in general population (ABDC collected data) 15 cases when 4 were expected (http://www.widesmiles.org/syndrom/hmsgold/gulfwar.html)

Recurrance Risks
(Unless autosomal dominant pattern found which can be in Goldenhar)
 * chances of having another child with Hemifacial Microsomia or Goldenhar are less than 1%
 * affected person has an approximately 3% chance of passing it on to their children

Incidence

 * The frequency of occurrence is estimated to be 1 in 3000 to 1 in 5000, and there is a slight male predominance (3:2).

Clinical Features

 * Key features:
 * Facial - asymmetry (90%). . .right side predominance (62%)
 * hypoplasia of malar, maxillary, and/or mandibular region
 * macrostomia (lateral cleft-like extension of the corner of the mouth)
 * hypoplasia of the facial musculature
 * frontal bossing
 * Ear - microtia (malformation of the external ear from complete aplasia to a crumpled, distorted
 * pinna which is displaced anteriorly and inferiorly) (65%)
 * accessory preauricular tags and/or pits
 * middle ear anomaly with variable deafness
 * Eye - palpebral fissure is somewhat lowered on the affected side
 * Oral - diminished to absent parotid secretion
 * anomalies in function or structure of the tongue
 * malfunction of the soft palate
 * Associated findings:
 * prenatal growth deficiency, feeding difficulties
 * Vertebral - hemivertebrae or hypoplasia of vertebrae, usually cervical (40-60%)
 * Eye - epibulbar dermoid and/or lipodermoid
 * strabismus
 * unilateral coloboma of the superior lid
 * microphthalmia
 * Oral - cleft lip, cleft palate (7%)
 * Cardiac - various forms of heart disease (45-55%)
 * ventricular septal defect
 * patent ductus arteriosus
 * tetralogy of Fallot
 * coarctation of the descending aorta
 * Lung - pulmonary agenesis or hypoplasia of the lung
 * Renal - ectopic and/or fused kidneys
 * renal agenesis
 * double ureter
 * Nervous - mental retardation (10%)
 * occipital encephalocele
 * hydrocephalus
 * agensis of corpus callosum

Natural History

 * Hemifacial Microsomia is congenital and most of the physical characteristics are apparent at birth.
 * However, the facial asymmetry may not become apparent until the child grows (usually by four years of age).

Potential Medical Concerns

 * lack of the development of the upper and lower jaws can cause breathing problems as well as a dental malocclusion which will need to be addressed surgically and orthodontically

Testing

 * Diagnosis is clinical due to lack of understanding exact cause and probably usually more due to environmental factors
 * Prenatal diagnosis by ultrasound may be possible if there is severe hypoplasia of the mandible or severe abnormality of the ear

Development and Learning

 * Most of these patients have normal intelligence

Management

 * Deafness should be tested for at an early age, and speech therapy is often necessary
 * Help may be required for feeding problems and encouraging weight gain in early infancy
 * Any congenital heart defects may require surgery
 * Plastic surgery may be used to reconstruct the ear, and bone distraction techniques are available to artificially lengthen the jaw bone to improve growth on the face.
 * Children may also need ongoing orthodontic treatment.

Differential Diagnoses

 * Treacher-Collins Syndrome-AD inheritance characterized by facial cleft, hypoplasia of the cheeks and mandible bilaterally, colobomas (or congenital scar) of the eyelids, downward-sloping palpebral fissures, poorly developed supraorbital rims and cheek, receding chin, malformation of the ear
 * CHARGE Association
 * VACTERL Association
 * Townes-Brocks Syndrome
 * Branchio-Oto-Renal (BOR) Syndrome
 * Chromosomal disorders (including Trisomy 9 Mosaicism, Trisomy 18, Ring 21 Chromosome, and Trisomy 22)
 * Teratogen exposure

Psychosocial Issues

 * Assess development.
 * Feeding problems?
 * Are they seeking a diagnosis?
 * Why would a diagnosis be helpful to them?
 * How do other people react is there any teasing by others?
 * How do they feel about the public's response to the facial abnormalities?
 * Would they like to talk with other families going through the same thing?
 * How can we be helpful to them?

Resources

 * Hemifacial Microsomia/Goldenhar Syndrome Family Support Network
 * c/o Kayci Rush
 * 3619 Chicago Avenue
 * Minneapolis, MN 55407-2603
 * (612) 823-3529
 * http://www.widesmiles.org/syndrom/hmsgold/ contains patient information

 * Association of Birth Defect Children (ABDC)
 * 1-800-313-2232
 * http://www.birthdefects.org