I watched "Miracle On 34th Street" last night, like I try to do every year. And every year, even though I know what is going to happen with each scene in the movie, I find myself crying. Especially during the scene where a mother of a deaf little girl (Sammy) takes her daughter to see Santa and Santa uses sign language to communicate with the little girl.
Before Timmy was born, I could sit through movies like this and not shed a tear. No, wasn't and am not a cold hearted person. I believe it was because I never realized just how uncaring and cruel this World is to the disabled. Until a person is walking in the same shoes of a person, who is having to deal with and face the day-to-day care and struggles of a loved one, it is sometimes hard for those on the outside looking in to understand the cruelity and difficulties that the disabled individuals and their families face.
I was watching "Good Morning America" this morning and this news story really got to me as well.
Disabled Musicians Make Up Band 'Flame' - ABC News
Even though I'm the type of person, who perfers the original singers/bands to preform the original version of my favorite songs. These disabled individuals are pretty good.
I just hope that one day that their dreams of Making It To The Top comes True.
Friday, November 27, 2009
Wednesday, November 25, 2009
Things That I'm Thankful For.....
Thanksgiving is my favorite time of the year. Even though my hips and waist scream at me at this time every year, I look forward to my dad cooking the turkey stuffed with his yummy homemade oyster stuffing, the candied yams, the cranberry sauce and I can't forget the collards. YUMMMMMY!!!!
This year there is a lot that I have to be Thankful for. I'm Thankful For.....
1. Finding a Cornea Specialist, despite my genetic eye disorder, was willing to preform a Boston Keratoprosthesis, which has restored my vision to the point where I can now read the 2nd line of an eye chart.
2. Timmy not having any major complications following surgery to remove his tonsils and adnoids.
3. Timmy continuing to do so WONDERFULLY following the removal of his trach in July!
4. Timmy's starting Kindergarten and having the WORLD'S GREATEST teacher! Who has many, many, many years of experience of working with children who have multiple and varying degrees of disabilities.
5. Timmy's physical, mental, oral and cognitive inchstone development since school started.
6. Emily's developmental growth and maturity. Her loving and caring nature toward Timmy.
7. For all of my 7 children. Gwendolynn 24 years, Tamarah 22 years, Linwood Jr. 18 years, Zachary 13 years, Timothy 6 years, Emily 4 years and our ^Angel^ Josiah who graced our life for 1 short month almost 3 years ago. Each of my children have touched my life in their own special way. Filling my Heart and Life with Lots of Love and Memories that I will Cherish Forever!
8. For Floyd. Even though he has caused me some grief during the year, he has been My rock. My support and he has showered me with Lots of Love!
9. For Timmy's Home Health Nurses, Merry, Dottie, Julie and Amy. Thank You, so much for your support, dedication, love, care, time and patience with having to put up with not just Timmy's needs, but those of Emily, Zachary, myself and Floyd.
HAPPY THANKSGIVING EVERYONE!!!!!
Tuesday, November 24, 2009
Tuesday Cuteness
This is Emily's Fall of 2009 JPre-K picture. Isn't she just the cutest? Ya gotta love her big bright smile and her curly red hair. Just think, she was blessed with the $200 hair doo that most women would die for!
These pictures were taken last Wednesday, November 18th, during Emily's class "Being Thankful" Feast at school. We were unable to attend, due to the fact that I had a Doc appointment that I needed to keep. Thank goodness Emily's teacher was nice enough to have taken some pictures and printed them off for those of us parents who were unable to attend. Don't all of the children look adorable in their pilgrim costumes that they made?
All of the kiddos in Timmy's class got a really fun treat last week. Cory, one of the student teachers from UNCW, our local college, brought his motorcycle to school for the kids to see and explore. Timmy had a blast! In the picture, Timmy appears to be very serious. He is intently listening to Cory discribe all of the aspects of the motorcycle to him. The BIGGEST thrill for Timmy was when Cory actually started up the motorcycle while Timmy was sitting on it!
Monday, November 23, 2009
A Change of Heart
This morning Timmy's CAP-C case manager stopped by to drop off a belated birthday gift for Timmy, before she headed off to the hospital to undergo surgery to repair a torn rotator cuff in her shoulder.
This was such a wonderful gesture, being that buying gifts for her clients isn't something that she typically does. Because she feels that if for some reason (finances, illness), she is unable to purchase something for one of her clients it would be unfair to that person.
I guess like the majority of people in which Timmy has come in contact with, he has stolen her heart strings and wrapped them tightly around his little finger.
Timmy's amazing strength and willingness to fight and overcome illnesses and obstacles in his life, his ability to give love without a single spoken word or gesture, his personality, his bright smile that will light up any room and his contageous laughter is sure to steal the hearts of anyone.
Once Timmy's CAP-C case manager had left, Emily immediately volunteered to help Timmy open his present. By this time, it was time to put Emily on the school bus. So we promised that Timmy would wait til this afternoon to open his present, so that she could be there to help.
On Mondays and Wednesdays, Timmy and Emily arrive home from school about the same time (1:30-1:45PM). Today Timmy arrived home about 30 minute before Emily. Once Emily got home she immediately wanted to sing Happy Birthday To Timmy and help him to open his present.
Emily insisted that everyone participate in singing Happy Birthday. If she caught someone not singing, if someone sneezed or coughed, or spoke to another person, she would start singing the Birthday Song from the beginning. After 4 attempts, we FINALLY got the song sang to her satisfaction.
Once the present was opened, As an adult, I'm ashamed to admit, my very 1st thought was a very ungrateful one. "What in the world is a non verbal special needs child going to do with a set of Walkie Talkies?" I can't explain why I had such an ungrateful thought. Honestly, I'm not typically an ungrateful person. I can usually find the best in anything and anyone. I knew that the gift was bought with a lot of thought, by a mom who understands disabilities. Timmy's CAP-C case manager has a son, who has a visual impairment, developmental delays and other special needs.
It was at that moment that I had a virtual slap in the face or a bump on my noggin. Of course, Walkie Talkies are a perfect gift for a non verbal special needs child. How? Well, with the help from an adult or a sibling, the vocalizations that Timmy makes, even though they aren't words, CAN be taken as conversation. And the holder of the 2nd Walkie Talkie can carry on a conversation with Timmy. Which hopefully will help him to understand the pattern to a meaningful conversation and possibly pick up new words.
At about this same time, I guess it was the force of the virtual slap or bump on my noggin that gave me two ideas for uses of the Walkie Talkies. We have a baby monitor in Timmy's room, Unfortunately his monitor doesn;'t have intercom capabilities. So if one of us happens to be downstairs with Timmy while the other parent is upstairs, one of us has to come to the bottom of the stairs and yell up stairs to have questions answered. The same goes if both of us happens to be upstairs and one of Timmy's nurses has a question or concern that needs addressing.
Timmy's monitor is always on if one or both of us is upstairs. So we could use the Walkie Talkies to talk to each other while still being able to tend to Timmy's needs and not having to run to the stairs and yell up to have questions answered.
The moral of this story is; When someone does something nice for you or someone that you love, instead of being ungrateful and finding faught in the gift; Look closely at the gift and try to find something positive within it. If you look long and hard enough, you will surely find something positive that will truely turn our ungrateful frown upside down. SMILE!
This was such a wonderful gesture, being that buying gifts for her clients isn't something that she typically does. Because she feels that if for some reason (finances, illness), she is unable to purchase something for one of her clients it would be unfair to that person.
I guess like the majority of people in which Timmy has come in contact with, he has stolen her heart strings and wrapped them tightly around his little finger.
Timmy's amazing strength and willingness to fight and overcome illnesses and obstacles in his life, his ability to give love without a single spoken word or gesture, his personality, his bright smile that will light up any room and his contageous laughter is sure to steal the hearts of anyone.
Once Timmy's CAP-C case manager had left, Emily immediately volunteered to help Timmy open his present. By this time, it was time to put Emily on the school bus. So we promised that Timmy would wait til this afternoon to open his present, so that she could be there to help.
On Mondays and Wednesdays, Timmy and Emily arrive home from school about the same time (1:30-1:45PM). Today Timmy arrived home about 30 minute before Emily. Once Emily got home she immediately wanted to sing Happy Birthday To Timmy and help him to open his present.
Emily insisted that everyone participate in singing Happy Birthday. If she caught someone not singing, if someone sneezed or coughed, or spoke to another person, she would start singing the Birthday Song from the beginning. After 4 attempts, we FINALLY got the song sang to her satisfaction.
Once the present was opened, As an adult, I'm ashamed to admit, my very 1st thought was a very ungrateful one. "What in the world is a non verbal special needs child going to do with a set of Walkie Talkies?" I can't explain why I had such an ungrateful thought. Honestly, I'm not typically an ungrateful person. I can usually find the best in anything and anyone. I knew that the gift was bought with a lot of thought, by a mom who understands disabilities. Timmy's CAP-C case manager has a son, who has a visual impairment, developmental delays and other special needs.
It was at that moment that I had a virtual slap in the face or a bump on my noggin. Of course, Walkie Talkies are a perfect gift for a non verbal special needs child. How? Well, with the help from an adult or a sibling, the vocalizations that Timmy makes, even though they aren't words, CAN be taken as conversation. And the holder of the 2nd Walkie Talkie can carry on a conversation with Timmy. Which hopefully will help him to understand the pattern to a meaningful conversation and possibly pick up new words.
At about this same time, I guess it was the force of the virtual slap or bump on my noggin that gave me two ideas for uses of the Walkie Talkies. We have a baby monitor in Timmy's room, Unfortunately his monitor doesn;'t have intercom capabilities. So if one of us happens to be downstairs with Timmy while the other parent is upstairs, one of us has to come to the bottom of the stairs and yell up stairs to have questions answered. The same goes if both of us happens to be upstairs and one of Timmy's nurses has a question or concern that needs addressing.
Timmy's monitor is always on if one or both of us is upstairs. So we could use the Walkie Talkies to talk to each other while still being able to tend to Timmy's needs and not having to run to the stairs and yell up to have questions answered.
The moral of this story is; When someone does something nice for you or someone that you love, instead of being ungrateful and finding faught in the gift; Look closely at the gift and try to find something positive within it. If you look long and hard enough, you will surely find something positive that will truely turn our ungrateful frown upside down. SMILE!
Tuesday, November 10, 2009
Developmental Gains
I would like to take a few minutes to answer a couple of questions that I have been asked recently. What do you attriubte to Timmy's developmental bursts that he has had? Do you think removing the trach helped?
Let me answer the second question first, only because its answer is more simple. Timmy has only had his trach out for almost 3 1/2 months (YAY!), so I don't feel that it has recently attributed to Timmy's developmental bursts. But in the scheme of things to come, I do feel that by having the trach out, it is going to help Timmy tremendously. How? Well, first off, it gives him less on his body to explore and focus on. Not that him exploring his body is a bad thing, but Timmy was at times obsessed with playing with his trach, pulling out the trach and removing his Passy-Muir (speaking valve) that we were unable to get him to focus on anything else.
Now to help you better understand "How and Why" I feel that over the past year or so Timmy has made such great developmental gains, I will have to go back quite a ways. When Timmy was born he was very critical. Timmy's initial diagnosis at birth was respiratory failure, pneumothorax (hole in his lung), sepsis, congenital anomilities (brain and eyes), insulin dependant diabetes, and kidney failure. Immediately following his birth Timmy was placed on an osculator to help him breathe, where he spent the first few weeks of his life before being switched over to a ventilator. It wasn't until Timmy was 2 1/2 months old before it was discovered that both of his nasal passages were blocked, hence the reason he couldn't be weaned off the ventilator and subsequently had to have a tracheostomy placed.
At about 6 months of age Timmy started receiving PT (physical therapy) and OT (occupational therapy) once a week at home. We didn't let the therapist "push" Timmy to his fullest potential, because we felt that by over stimulating him and stressing him would lessen our time with him. So when the therapist would come for their visit, if Timmy was asleep we requested that the therapist just let him sleep. And if Timmy seemed to be having a "bad" day we would cancel therapy. Also during the months leading up to Timmy's 1st year of life, after being discharged from the hospital, Timmy had a lot of Doc appointments, so this too prevented him from having weekly therapy sessions on a regular basis.
9 1/2 Months Old
By a year of age Timmy had some small developmental gains. He could roll over in both directions and could hold his head up very well when lying on his tummy. But even though we were seeing these small gains, we let our fear of losing Timmy stop us from pushing him. When I look back, I now realize that at the first sign of development we should have really pushed Timmy to his fullest potential. I feel by not doing so, we have somehow, even in a small way, hindered his brain from developing neurons necessary for him to be able to preform certain task. \
Let me answer the second question first, only because its answer is more simple. Timmy has only had his trach out for almost 3 1/2 months (YAY!), so I don't feel that it has recently attributed to Timmy's developmental bursts. But in the scheme of things to come, I do feel that by having the trach out, it is going to help Timmy tremendously. How? Well, first off, it gives him less on his body to explore and focus on. Not that him exploring his body is a bad thing, but Timmy was at times obsessed with playing with his trach, pulling out the trach and removing his Passy-Muir (speaking valve) that we were unable to get him to focus on anything else.
Now to help you better understand "How and Why" I feel that over the past year or so Timmy has made such great developmental gains, I will have to go back quite a ways. When Timmy was born he was very critical. Timmy's initial diagnosis at birth was respiratory failure, pneumothorax (hole in his lung), sepsis, congenital anomilities (brain and eyes), insulin dependant diabetes, and kidney failure. Immediately following his birth Timmy was placed on an osculator to help him breathe, where he spent the first few weeks of his life before being switched over to a ventilator. It wasn't until Timmy was 2 1/2 months old before it was discovered that both of his nasal passages were blocked, hence the reason he couldn't be weaned off the ventilator and subsequently had to have a tracheostomy placed.
4 Months Old
Even before Timmy's birth we were told "Don't expect him to live longer than a few hours, due to all of his medical complications." After seeing him in such critical shape following his birth and being told that we only had a short time with him, when we brought him home from the NICU at 4 1/2 months of age, he was on continuous oxygen, continuous pulse oximeter and apnea monitoring. Still we felt very blessed to finally have him home with us.
At about 6 months of age Timmy started receiving PT (physical therapy) and OT (occupational therapy) once a week at home. We didn't let the therapist "push" Timmy to his fullest potential, because we felt that by over stimulating him and stressing him would lessen our time with him. So when the therapist would come for their visit, if Timmy was asleep we requested that the therapist just let him sleep. And if Timmy seemed to be having a "bad" day we would cancel therapy. Also during the months leading up to Timmy's 1st year of life, after being discharged from the hospital, Timmy had a lot of Doc appointments, so this too prevented him from having weekly therapy sessions on a regular basis.
By a year of age Timmy had some small developmental gains. He could roll over in both directions and could hold his head up very well when lying on his tummy. But even though we were seeing these small gains, we let our fear of losing Timmy stop us from pushing him. When I look back, I now realize that at the first sign of development we should have really pushed Timmy to his fullest potential. I feel by not doing so, we have somehow, even in a small way, hindered his brain from developing neurons necessary for him to be able to preform certain task. \
Timmy had the World's GREATEST Neonatologist! On Timmy's 1st. birthday we took Timmy to see the staff of the NICU, who had become emotionally attached to Timmy the 4 1/2 months that he was in the NICU. I had a looong heart felt conversation with Timmy's Neonatologist, who sternly, but lovingly pointed out, that we were doing more harm to Timmy by not pushing him to his fullest potential by restricting his therapies. He also reminded me that I had once said to him that I would do ANYTHING to prove the medical professionals wrong. That Timmy WOULD go far in life. Following the Holidays and our move in March of 2005, I requested that Timmy start having PT, OT, and ST (speech therapy) 2x a week. From April to July of 2005, Timmy received all of his therapies 2x a week. In mid July Timmy started attending Easter Seals UCP a few hours a day each week. During this time we didn't see much in the way of developmental gains. However he was starting to sit up better while in his highchair. Timmy was still wanting to sleep a lot. I'm not sure if it was due to over stimulation, stress or his nightly sleep patterns at night, or maybe I should say lack thereof.
May 2005
In mid October 2005, Timmy was hospitalized for 2 weeks due to some type of infection. After being sent home with a PIC line and antibotics, we felt that maybe once the illness was behind him, we could start pushing Timmy to his fullest potential in therapy once again. Around this time we had started Timmy on Melatonin and it was helping him to be able to sleep better at night. Within 4 days fo being home, Timmy was back in the hospital with what was later diagnosed as Pseudomonus Pneumonia with possible aspiration pneumonia. Timmy spent 53 days in the PICU. When Timmy finally came home, he was on a ventilator and continuous oxygen. So here again, we had a child who was very frail. So the therapists couldn't do much of any type of therapy with Timmy except for passive range of motion.
By mid March 2006 we had Timmy weaned off of the oxygen and he no longer needed the ventilator. What little gains we and the therapists had made with Timmy before his illness, had been lost. So we had to start back from square one.
August 2006
By August Timmy was able to tolerate being in his stander once again for 20-30 minutes at a time. Timmy had beaten the odds once again, by being able to recover from such a serious bout of pneumonia. Timmy was getting his therapies PT, OT, ST twice a week and we even felt that it in Timmy's best interest so we added vision therapy. We spent alot of time playing with and singing to Timmy. Slowly but surely developmental gains started to emerge. He was starting to tolerate oral stimulation, his muscle tone was improving, his balance was improving and he was a very happy boy.
In late March 2007, Timmy had yet another setback, due to a 3 week hospitalization from having Ecoli pneumonia and yet again the possibility of aspiration pneumonia. I feel that the aspiration wasn't due to the consistancy of food and liquids that he was consuming, but rather from the severe reflux, that at the time, Timmy suffered from. During this hospitalization Timmy had his G-Tube placed and a Nissen Fundoplacation procedure.
In July 2007 we moved to a different part of our state so that we could be closer to Timmy's Specialists. Timmy's new therapists had a different outlook as to what and how we should proceed with Timmy's therapies. They felt that we needed to give up the over use of the stander, positioning seating devices and to use "play therapy" throughout the day to stimulate Timmy. I was very skeptical at this approach at first, but I was willing to give it a try. I had been told for the past almost 4 years that Timmy needed special devices to help with standing, posture and play. So we continued to use the stander and his highchair for support and positioning ONLY while playing, when we needed Timmy to be able to use both of his hands for play.
Mid August 2007
Before August we had tried to work with Timmy to get him to drink from a cup, but didn't have much success. After our move in July, Timmy absolutely refused to drink from his bottle. I was adamant and was not going to relent and let the nurses syringe all of Timmy's liquids in via his Mic-key button. I knew how important it was for Timmy to keep hydrated, but yet on the other hand, Timmy is a stubborn child and one who tends to want to take the easy way out. So we kept offering him his bottle and the cup at each feeding. One day Timmy just decided that he wanted the cup. I could be wrong on my guess, but I attribute Timmy's refusal of his bottle to maturity and him not wanting his new nurses and therapists to view him as a baby.
November 2007
By Timmy's 4th birthday he was able to sit unsupported for a few seconds, even if it was what I call "taco style" sitting. The first of December 2007, we moved back to our old hometown, so that we could be closer to our support team (my parents and our friends). Due to finances when we moved back home, we had to move in with my parents for a while (Dec. 2007- April 2008). Timmy's therapies didn't start back until Mid January 2008, due to having to have all of his services transferred back to the county in which we had moved, the Holidays and our trip to Chicago to visit Grandma. Luckily, we were able to get the same PT and ST that Timmy had before our move, to come back to work with him.
I asked Timmy's PT her thoughts about not using the stander, a positioning device for sitting and incooperating play therapy with his reguolar therapy throughout the day. She agreed that it was worth a try. The PT was amazed that Timmy was able to sit unsupported for only a few seconds, because he wasn't able to do this before our move.
Once we moved into our own place in May 2008, we were better able to implement a therapy regiment that we felt best suitable for Timmy. Throughout the years we have learned that Timmy learns best with routine and repetition. So we set up our daily therapy and play activities along these lines. By using this approach we had to be very attentive to Timmy's communication cues, vocalizations and facial expressions, because in a sense he is the one who was totally in charge of his daily therapy session if it was going to work. We also had to know when his vocalizations and facial expressions we just him trying to get out of doing an activity.
Our experience with the Pre-K program through our local school district last year wasn't a good experience. Timmy was placed into a Special Education Class, but unfortunately he was the ONLY child who was non-ambulatory. In my observation of the other children, most of their problems seemed to be behavioral. All of the other children could walk, run, see, hear and talk. So being that the other children were your typical active 4 year olds, this made time that the teacher could spend with Timmy one-on-one very limited. Even though there was 1 Teacher's Aid in the classroom, most of the time they both were having to tend to a child who was having a behavior issue. The classroom was too small for his KidKart to be manouvered around in. And even though the Teacher supposedly had some Special Education Training, she didn't have ANY training in dealing with a student with as complex learning difficulties that Timmy has.
The three things that I attribute the most to Timmy's developmental burst are....
1. Timmy's Kindergarten teacher this year is the World's GREATEST!!! She has many, many, many years of experience teaching special needs children with varying degrees of disabilities. Mrs. Bishop is very receptive to Timmy's communication gestures, vocalizations and facial expressions. She is a teacher who believes in work BEFORE play. She uses materials, stategies and techniques that center around Timmy's interest to help keep him focused and interested in wanting to learn. And as a Special Education Teacher she realizes that she has to be in charge of each individual student and the class as a whole in order for each child to be able to learn and to reach their full potential. Being that Timmy will remain in this same teacher's class throughout his elementary years, I'm anxious to see just how far this teacher will be able to carry Timmy developmentally.
2. As for physical therapy. Timmy has had the same physical therapist for almost 5 years. I feel that Timmy having the same therapist for so many years and being able to form a trusting relationship with her has played a major part in Timmy's development. The therapist is a very Down to Earth yet serious person. She has learned ALL of Timmy's tricks of the trade for trying to get out of doing his therapy, like pretending to be asleep, crying, having a "Timmy" tantrum, you name it Mr. Timmy has tried it. While working with Timmy fingers/hands in the mouth are a DEFINATE No, No! She tries to make therapy fun by playing music, making up silly rhymes, or singing some of his favorite songs to a silly tune, like her Hip-Hop version of Row, Row, Row Your Boat.
I asked Timmy's PT her thoughts about not using the stander, a positioning device for sitting and incooperating play therapy with his reguolar therapy throughout the day. She agreed that it was worth a try. The PT was amazed that Timmy was able to sit unsupported for only a few seconds, because he wasn't able to do this before our move.
Once we moved into our own place in May 2008, we were better able to implement a therapy regiment that we felt best suitable for Timmy. Throughout the years we have learned that Timmy learns best with routine and repetition. So we set up our daily therapy and play activities along these lines. By using this approach we had to be very attentive to Timmy's communication cues, vocalizations and facial expressions, because in a sense he is the one who was totally in charge of his daily therapy session if it was going to work. We also had to know when his vocalizations and facial expressions we just him trying to get out of doing an activity.
Every waking hour of Timmy's day is spent doing something theraputic and/or educational. Like the picture above, Timmy is playing with small toys in a bowl of cool water. We count the toys, sing songs in relation to the objects i.e. if one of the toys is a rabbit, we might sing Little Bunny FuFu or Do Your Ears Hang Low.
We incooperate many different smells, textures, taste and sounds into play during the day. We sing, count, and say the ABC's over and over during the day. We practice stacking, sorting and putting objects into and taking objects out of a container.
Instead of using a stander we use the couch, Timmy's bed, or Emily and Timmy's play table to have Timmy stand up beside, to aid in weight bearing and to have him to "have" to use the muscles necessary for this skill. In turn this helps to strengthen these muscles.
Instead of having Timmy to spend a majority of his day sitting in his KidKart or another chair that offers support and positioning, we have him to sit on the floor, prop and side sitting. This also helps strengthen muscles necessary for independant sitting and helps with balance.
We use an exercise ball to help with balance and to strengthen neck muscles by having him to lay across the ball while holding up his head.
The unsupported standing, sitting and the use of the exercise ball ALL help in strengthening muscles, gaining better muscle control and balance.
Timmy LOVES to swing. So when he is in the swing we sing songs, ABC's, count, and use the opportunity to teach Stop/Go, Close/far, back/forward, and body parts. We will touch a body part on Timmy as he swings forward toward us and say "I touched you -----." (Fill in the bland.) Then we may ask him "Can you show me where your ----- is?" (Fill in the blank) H
Timmy ABSOLUTELY hates oral stimulation. So instead of using our fingers or a flavored stick, we let Timmy use a lollypop to stimulate himself for a while first. After a few minutes he is more willing to let us stimulate him orally.
Our experience with the Pre-K program through our local school district last year wasn't a good experience. Timmy was placed into a Special Education Class, but unfortunately he was the ONLY child who was non-ambulatory. In my observation of the other children, most of their problems seemed to be behavioral. All of the other children could walk, run, see, hear and talk. So being that the other children were your typical active 4 year olds, this made time that the teacher could spend with Timmy one-on-one very limited. Even though there was 1 Teacher's Aid in the classroom, most of the time they both were having to tend to a child who was having a behavior issue. The classroom was too small for his KidKart to be manouvered around in. And even though the Teacher supposedly had some Special Education Training, she didn't have ANY training in dealing with a student with as complex learning difficulties that Timmy has.
The three things that I attribute the most to Timmy's developmental burst are....
1. Timmy's Kindergarten teacher this year is the World's GREATEST!!! She has many, many, many years of experience teaching special needs children with varying degrees of disabilities. Mrs. Bishop is very receptive to Timmy's communication gestures, vocalizations and facial expressions. She is a teacher who believes in work BEFORE play. She uses materials, stategies and techniques that center around Timmy's interest to help keep him focused and interested in wanting to learn. And as a Special Education Teacher she realizes that she has to be in charge of each individual student and the class as a whole in order for each child to be able to learn and to reach their full potential. Being that Timmy will remain in this same teacher's class throughout his elementary years, I'm anxious to see just how far this teacher will be able to carry Timmy developmentally.
2. As for physical therapy. Timmy has had the same physical therapist for almost 5 years. I feel that Timmy having the same therapist for so many years and being able to form a trusting relationship with her has played a major part in Timmy's development. The therapist is a very Down to Earth yet serious person. She has learned ALL of Timmy's tricks of the trade for trying to get out of doing his therapy, like pretending to be asleep, crying, having a "Timmy" tantrum, you name it Mr. Timmy has tried it. While working with Timmy fingers/hands in the mouth are a DEFINATE No, No! She tries to make therapy fun by playing music, making up silly rhymes, or singing some of his favorite songs to a silly tune, like her Hip-Hop version of Row, Row, Row Your Boat.
3. To get Timmy to where he is developmentally today took ALOT of hard Work, Patience, Persistance, routine, repetitiveness and most definately even MORE Patience. We have done away with his stander, the adaptive walker, the floor sitter. We "have" or better yet "MAKE" Timmy sit up without support as much as possible. We give him every opportunity to stand up. We MAKE him HAVE to use his muscles that are needed to do these activities. By him having to use these muscles he is strengthing the muscles and gaining better control of them. We stopped using an exercise mat while doing therapy with Timmy. An exercise mat is squishy and not the same type of surface that Timmy would be preforming on If/When he learns to crawl, walk, etc. So we chose to make the therapy surface as natural for him as possible.
Also, Timmy's overall good health, except for a couple of very minor setbacks, a reaction to Baclofen in the Spring of last year and recovery time from having his tonsils and adnoids removed earlier this year, has played a BIG role in his developmental gains.
As the old saying goes "With Age Comes Maturity." Let's just hope that this statement is true as well in Timmy's overall developmental gains.
Monday, November 9, 2009
American Journal Of Medical Genetics
Here is an article that was written and published following our visit to NIH, in December 2008. It briefly describes the PAX6 gene mutation that Timmy inherited from both his dad and myself. And how this mutation affects each of us. In the article it states that Timmy's brother "possibly" inherited both mutated copies of the PAX6 gene. I would like to clarify that Josiah passed away due to a ruptured bowel and NOT because of the "possibility" of him having inherited 2 copies of the mutated gene. My glucose level that was evaluated was not a fasting glucose level. I had forgotten that I had eaten just before the blood draw. (A busy day, stress and age all played a part in my memory lapse!) :0) During my visit to NIH in August 2009, I have been daignosed with Type 2 diabetes. My blood glucose levels are currently being controlled by exercise and a Metformin tablet 3x a day.
NOTE: Two additional MRI pictures can be viewed on previous post dated Nov 8th.
AMERICAN JOURNAL OF MEDICAL GENETICS
CLINICAL REPORT
Compound Heterozygosity for Mutations in PAX6 in a Patient With Complex Brain Anomaly, Neonatal Diabetes Mellitus, and Microophthalmia
Benjamin D. Solomon,1 Daniel E. Pineda-Alvarez,1 Joan Z. Balog,1 Donald Hadley,1 Andrea L. Gropman,1,2 Radha Nandagopal,3 Joan C. Han,3 Jin S. Hahn,4 Delphine Blain,5,6 Brian Brooks,5 and Maximilian Muenke1*
1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
2Children’s National Medical Center, Washington, District of Columbia
3Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
4Stanford University, Palo Alto, California
5National Eye Institute, National Institutes of Health, Bethesda, Maryland
6MedStar Research Institute, Hyattsville, Maryland
Received 22 July 2009; Accepted 2 August 2009
We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals. Published 2009 Wiley-Liss, Inc.
Key words: PAX6; microophthalmia; aniridia; neonatal diabetes mellitus
How to Cite this Article: Solomon BD, Pineda-Alvarez DE, Balog JZ, Hadley D, Gropman AL, Nandagopal R, Han JC, Hahn JS, Blain D, Brooks B, Muenke M. 2009. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet Part A 149A:2543–2546.
INTRODUCTION
PAX6, located on chromosome 11p13, is a highly evolutionarily conserved transcription factor involved in ocular and neural development [Hanson et al., 1999; Simpson and Price, 2002].
Heterozygous deletions or loss-of-function mutations in PAX6 can result in ocular anomalies [Jordan et al., 1992; Robinson et al., 2008]. Truncating mutations in the open-reading frame are more commonly associated with aniridia; missense mutations occur with variable eye anomalies including keratopathy, congenital optic nerve defects, cataracts, isolated foveal hypoplasia, iris hypoplasia, and (rarely) microophthalmia [Tzoulaki et al., 2005].
PAX6 is expressed in the pancreas, and mutations in PAX6 may result in abnormal glucose metabolism and defective processing of proinsulin [Wen et al., 2009]. In the human embryo, PAX6 is expressed in the pituitary gland, and in mice, appears to play a role in pituitary development and function [Bentley et al., 1999; Kioussi et al., 1999; Terzic and Saraga-Babic, 1999]. Finally, heterozygous mutations in PAX6 may also result in auditory processing deficits related to corpus callosum anomalies [Bamiou et al., 2007].
One individual has previously been described with compound heterozygous nonsense mutations in PAX6 [Glaser et al., 1994]. That patient, who died at 1 week of age, had anophthalmia with fused eyelids, choanal atresia, microcephaly, and a complex brain anomaly described as a large midline cavity with an absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria. Facial dysmorphisms included a small, malformed nose, a high-arched palate, and micrognathia. No other organ anomalies were noted on full autopsy, and endocrinologic abnormalities were not described.
We describe a 4-year-old male who additionally had trisomy 21 and who is the second reported patient (and the only to survive the neonatal period) with mutations in both PAX6 alleles. We also depict a four-generation pedigree in which there was clinical and molecular evidence that numerous relatives were PAX6 mutation heterozygotes. This family provides evidence for the wide phenotypic spectrum associated with mutations in PAX6. The father’s missense mutation resulted in much milder ophthalmologic anomalies than the mother’s nonsense mutation, while the presence of both mutations in the propositus (and likely, his deceased brother) resulted in severe ophthalmologic, neurologic, and endocrinologic manifestations, the last of which has not previously been described in a human with two PAX6 mutations.
Published 2009 Wiley-Liss, Inc. {This article is a US Government work and, as such, is in the public domain in the United States of America.
Grant sponsor: National Human Genome Research Institute, National Institutes of Health.
*Correspondence To:
Prof. Maximilian Muenke, National Institutes of Health, Building 35,
Room 1B-203, MSC 3717, Bethesda, MD 20892.
E-mail: mamuenke@mail.nih.gov
Published online 26 October 2009 in Wiley InterScience (www.interscience.wiley.com)
METHODS
The patient and his parents participated in our comprehensive clinical study on holoprosencephaly and related neurological disorders at the National Human Genome Research Institute, National Institutes of Health. Appropriate consent was obtained for all participants, including for photo publication. Sequence analysis for SHH, ZIC2, SIX3, and TGIF, the four most common holoprosencephaly-associated genes, was performed by methods previously described [Roessler et al., 1996; Brown et al., 1998; Wallis et al., 1999; Gripp et al., 2000]. Sequence analysis of PAX6 was performed commercially (GeneDx, Gaithersburg, MD).
CLINICAL REPORT
When evaluated by us, the propositus was a 4-year-old Caucasian male with prenatally diagnosed trisomy 21. He was initially diagnosed as having lobar holoprosencephaly. His complex medical history additionally included bilateral microophthalmia, choanal atresia, severe developmental delay, and renal dysplasia with recurrent urinary tract infections. Evidence for hypopituitaris included central hypothyroidism, secondary adrenal insufficiency, and a history of cryptorchidism and micropenis (now status—post-testosterone treatment) making gonadotropin deficiency likely. He had neonatal-onset insulin-dependent diabetes mellitus which was very difficult to control, but abdominal MRI revealed no pancreatic anomalies.
Review of the propositus’s brain MRI showed structural abnormalities not consistent with holoprosencephaly because of the lack of hemispheric fusion, but included multiple anomalies including agenesis of the corpus callosum, midline interhemispheric cyst, hypoplastic pons, and vermis (absent inferiorly), possible Dandy–Walker malformation, dysplastic tectum, pituitary and hypothalamic hypoplasia, and a globular (though not fused) basal ganglia. The thalamic nuclei were well separated by a large third ventricle. Microcephaly and asymmetric microophthalmia were also evident (Fig. 1).
On physical examination, the child displayed physical features consistent with his diagnosis of trisomy 21, as well as bilateral severe microophthalmia, extreme microcephaly (head circumference 50th centile for a 1-month-old with Down syndrome), and a smooth philtrum (Fig. 1).
Propositus with compound heterozygosity for mutations in PAX6. Facial features were consistent with trisomy 21 and were also notable for extreme microcephaly, microophthalmia, and a smooth philtrum. Axial, coronal, and sagittal (from top) brain MRI demonstrates complex structural brain anomaly in propositus. (SEE ABOVE MRI PHOTO).
The propositus’s mother had a history of aniridia, but reported no other medical problems. She had an extensive family history of autosomal-dominant aniridia, though no previous genetic study had been initiated. On physical examination, no extraocular anomalies were appreciated. Ophthalmological examination showed bilateral aniridia, glaucoma, and corneal opacifications, as well as a dense cataract in the right eye. While she had not been previously diagnosed with diabetes, she had an elevated fasting glucose on our evaluation.
The propositus’s father reported a history of cataracts in early childhood and eventual blindness, as well as hearing loss. He also had an extensive family history of similar visual problems and hearing loss. On examination, he had a high palate and dental crowding in addition to ocular anomalies. Ophthalmological examination showed bilateral microcornea, a right eye cataract, and left aphakia (absent lens). He also had subtle iris hypoplasia and corectopia.
The propositus’s brother, on whom DNA was not available for testing, was described as having very similar structural brain anomalies to the propositus. He additionally had neonatal diabetes mellitus and anophthalmia, and died in infancy.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
MOLECULAR TESTING
Sequence analysis for mutations in the four most common holoprosencephaly-associated genes (SHH, ZIC2, SIX3, and TGIF) was negative.
The patient’s father had a nonconservative missense mutation (c.112C>T, resulting in p.R38W) in the paired box domain of PAX6. This mutation has previously been reported in a patient with microphthalmia and aniridia [Henderson et al., 2007]. This is a highly evolutionarily conserved residue which mediates sequence specific DNA binding [Hanson et al., 1999; Xu et al., 1999].
The patient’s mother had a nonsense mutation (c.718C>T, resulting in p.R240X) in the homeobox domain of PAX6. This mutation has previously been reported in a patient with aniridia. The premature insertion of a stop codon in the homeobox domain is predicted to result in nonsense-mediated decay and a consequently functionally null allele [Wilson et al., 1995; Tzoulaki et al., 2005].
The propositus inherited both the maternal and paternal mutations in PAX6.
DISCUSSION
This is the second reported and the only known surviving patient with mutations in both PAX6 alleles. Analysis of the findings provides a unique example of the phenotypic effects of compound heterozygosity of mutations of PAX6. The propositus’s hypopituitarism, diabetes mellitus, and brain and ophthalmologic anomalies can all be explained by the PAX6 mutations. The mutations also explain the ophthalmologic phenotype in his parents, and additionally may explain impaired glucose tolerance in the propositus’s mother.
The previously reported patient, who had a nonsense mutation in each PAX6 allele, survived to the eighth day of life [Glaser et al.,1994]. The propositus’s brother, who was described as having near identical brain and ophthalmologic anomalies as the propositus, died in early infancy and was not available for genetic testing. However, given the similar phenotypes and the 25% chance that the parents would give birth to a child with both mutations, it is likely that the deceased sibling inherited both mutant alleles. The morbidity associated with inheriting two mutations and the fact that the propositus additionally had trisomy 21 make his survival and relative good health an especially rare event.
Finally, this case highlights the importance of a multidisciplinary approach which includes the evaluation of multiple family members in the diagnosis of unusual and complex patients.
ACKNOWLEDGMENTS
We are extremely grateful to the family presented in this report. This research was supported by the Intramural Research Program of the National HumanGenome Research Institute, National Institutes of Health.
REFERENCES
Bamiou DE, Free SL, Sisodiya SM, Chong WK, Musiek F, Williamson KA, van Heyningen V, Moore AT, Gadian D, Luxon LM. 2007. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med 161:463---469
Bentley CA, Zidehsarai MP, Grindley JC, Parlow AF, Barth-Hall S, Roberts VJ. 1999. Pax6 is implicated in murine pituitary endocrine function. Endocrine 10:171–177.
Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M. 1998. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 20:180–183.
Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL. 1994. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463–471.
Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai EH, Massague J, Muenke M, Elledge SJ. 2000. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 25:205–208.
Hanson I, Churchill A, Love J, Axton R, Moore T, Clarke M, Meire F, van Heyningen V. 1999. Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations. Hum Mol Genet 8:165–172.
Henderson RA, Williamson K, Cumming S, Clarke MP, Lynch SA, Hanson IM, FitzPatrick DR, Sisodiya S, van Heyningen V. 2007. Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia. Eur J Hum Genet 15:898–901.
Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A, Hastie N, van Heyningen V. 1992. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet 1:328–332.
Kioussi C, O’Connell S, St-Onge L, Treier M, Gleiberman AS, Gruss P, Rosenfeld MG. 1999. Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci USA 96:14378–14382.
Robinson DO, Howarth RJ, Williamson KA, van Heyningen V, Beal SJ, Crolla JA. 2008. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia.AmJ Med Genet Part A 146A:558–569.
Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. 1996. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357–360.
Simpson TI, Price DJ. 2002. Pax6; a pleiotropic player in development. Bioessays 24:1041–1051.
Terzic J, Saraga-Babic M. 1999. Expression pattern of PAX3 and PAX6 genes during human embryogenesis. Int J Dev Biol 43:501–508.
Tzoulaki I, White IM, Hanson IM. 2005. PAX6 mutations: Genotypephenotype correlations. BMC Genet 6:27.
Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. 1999. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22:196–198.
Wen JH, Chen YY, Song SJ, Ding J, Gao Y, Hu QK, Feng RP, Liu YZ, Ren GC, Zhang CY, Hong TP, Gao X, Li LS. 2009. Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia 52:504–513.
Wilson DS, Guenther B, Desplan C, Kuriyan J. 1995. High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA. Cell 82:709–719.
Xu HE, Rould MA, Xu W, Epstein JA, Maas RL, Pabo CO. 1999. Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding. Genes Dev 13:1263–1275.
NOTE: Two additional MRI pictures can be viewed on previous post dated Nov 8th.
AMERICAN JOURNAL OF MEDICAL GENETICS
CLINICAL REPORT
Compound Heterozygosity for Mutations in PAX6 in a Patient With Complex Brain Anomaly, Neonatal Diabetes Mellitus, and Microophthalmia
Benjamin D. Solomon,1 Daniel E. Pineda-Alvarez,1 Joan Z. Balog,1 Donald Hadley,1 Andrea L. Gropman,1,2 Radha Nandagopal,3 Joan C. Han,3 Jin S. Hahn,4 Delphine Blain,5,6 Brian Brooks,5 and Maximilian Muenke1*
1National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
2Children’s National Medical Center, Washington, District of Columbia
3Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
4Stanford University, Palo Alto, California
5National Eye Institute, National Institutes of Health, Bethesda, Maryland
6MedStar Research Institute, Hyattsville, Maryland
Received 22 July 2009; Accepted 2 August 2009
We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals. Published 2009 Wiley-Liss, Inc.
Key words: PAX6; microophthalmia; aniridia; neonatal diabetes mellitus
How to Cite this Article: Solomon BD, Pineda-Alvarez DE, Balog JZ, Hadley D, Gropman AL, Nandagopal R, Han JC, Hahn JS, Blain D, Brooks B, Muenke M. 2009. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia. Am J Med Genet Part A 149A:2543–2546.
INTRODUCTION
PAX6, located on chromosome 11p13, is a highly evolutionarily conserved transcription factor involved in ocular and neural development [Hanson et al., 1999; Simpson and Price, 2002].
Heterozygous deletions or loss-of-function mutations in PAX6 can result in ocular anomalies [Jordan et al., 1992; Robinson et al., 2008]. Truncating mutations in the open-reading frame are more commonly associated with aniridia; missense mutations occur with variable eye anomalies including keratopathy, congenital optic nerve defects, cataracts, isolated foveal hypoplasia, iris hypoplasia, and (rarely) microophthalmia [Tzoulaki et al., 2005].
PAX6 is expressed in the pancreas, and mutations in PAX6 may result in abnormal glucose metabolism and defective processing of proinsulin [Wen et al., 2009]. In the human embryo, PAX6 is expressed in the pituitary gland, and in mice, appears to play a role in pituitary development and function [Bentley et al., 1999; Kioussi et al., 1999; Terzic and Saraga-Babic, 1999]. Finally, heterozygous mutations in PAX6 may also result in auditory processing deficits related to corpus callosum anomalies [Bamiou et al., 2007].
One individual has previously been described with compound heterozygous nonsense mutations in PAX6 [Glaser et al., 1994]. That patient, who died at 1 week of age, had anophthalmia with fused eyelids, choanal atresia, microcephaly, and a complex brain anomaly described as a large midline cavity with an absent corpus callosum, hypoplastic brainstem, near-absent olfactory bulbs, and polymicrogyria. Facial dysmorphisms included a small, malformed nose, a high-arched palate, and micrognathia. No other organ anomalies were noted on full autopsy, and endocrinologic abnormalities were not described.
We describe a 4-year-old male who additionally had trisomy 21 and who is the second reported patient (and the only to survive the neonatal period) with mutations in both PAX6 alleles. We also depict a four-generation pedigree in which there was clinical and molecular evidence that numerous relatives were PAX6 mutation heterozygotes. This family provides evidence for the wide phenotypic spectrum associated with mutations in PAX6. The father’s missense mutation resulted in much milder ophthalmologic anomalies than the mother’s nonsense mutation, while the presence of both mutations in the propositus (and likely, his deceased brother) resulted in severe ophthalmologic, neurologic, and endocrinologic manifestations, the last of which has not previously been described in a human with two PAX6 mutations.
Published 2009 Wiley-Liss, Inc. {This article is a US Government work and, as such, is in the public domain in the United States of America.
Grant sponsor: National Human Genome Research Institute, National Institutes of Health.
*Correspondence To:
Prof. Maximilian Muenke, National Institutes of Health, Building 35,
Room 1B-203, MSC 3717, Bethesda, MD 20892.
E-mail: mamuenke@mail.nih.gov
Published online 26 October 2009 in Wiley InterScience (www.interscience.wiley.com)
METHODS
The patient and his parents participated in our comprehensive clinical study on holoprosencephaly and related neurological disorders at the National Human Genome Research Institute, National Institutes of Health. Appropriate consent was obtained for all participants, including for photo publication. Sequence analysis for SHH, ZIC2, SIX3, and TGIF, the four most common holoprosencephaly-associated genes, was performed by methods previously described [Roessler et al., 1996; Brown et al., 1998; Wallis et al., 1999; Gripp et al., 2000]. Sequence analysis of PAX6 was performed commercially (GeneDx, Gaithersburg, MD).
CLINICAL REPORT
When evaluated by us, the propositus was a 4-year-old Caucasian male with prenatally diagnosed trisomy 21. He was initially diagnosed as having lobar holoprosencephaly. His complex medical history additionally included bilateral microophthalmia, choanal atresia, severe developmental delay, and renal dysplasia with recurrent urinary tract infections. Evidence for hypopituitaris included central hypothyroidism, secondary adrenal insufficiency, and a history of cryptorchidism and micropenis (now status—post-testosterone treatment) making gonadotropin deficiency likely. He had neonatal-onset insulin-dependent diabetes mellitus which was very difficult to control, but abdominal MRI revealed no pancreatic anomalies.
Review of the propositus’s brain MRI showed structural abnormalities not consistent with holoprosencephaly because of the lack of hemispheric fusion, but included multiple anomalies including agenesis of the corpus callosum, midline interhemispheric cyst, hypoplastic pons, and vermis (absent inferiorly), possible Dandy–Walker malformation, dysplastic tectum, pituitary and hypothalamic hypoplasia, and a globular (though not fused) basal ganglia. The thalamic nuclei were well separated by a large third ventricle. Microcephaly and asymmetric microophthalmia were also evident (Fig. 1).
On physical examination, the child displayed physical features consistent with his diagnosis of trisomy 21, as well as bilateral severe microophthalmia, extreme microcephaly (head circumference 50th centile for a 1-month-old with Down syndrome), and a smooth philtrum (Fig. 1).
Propositus with compound heterozygosity for mutations in PAX6. Facial features were consistent with trisomy 21 and were also notable for extreme microcephaly, microophthalmia, and a smooth philtrum. Axial, coronal, and sagittal (from top) brain MRI demonstrates complex structural brain anomaly in propositus. (SEE ABOVE MRI PHOTO).
The propositus’s mother had a history of aniridia, but reported no other medical problems. She had an extensive family history of autosomal-dominant aniridia, though no previous genetic study had been initiated. On physical examination, no extraocular anomalies were appreciated. Ophthalmological examination showed bilateral aniridia, glaucoma, and corneal opacifications, as well as a dense cataract in the right eye. While she had not been previously diagnosed with diabetes, she had an elevated fasting glucose on our evaluation.
The propositus’s father reported a history of cataracts in early childhood and eventual blindness, as well as hearing loss. He also had an extensive family history of similar visual problems and hearing loss. On examination, he had a high palate and dental crowding in addition to ocular anomalies. Ophthalmological examination showed bilateral microcornea, a right eye cataract, and left aphakia (absent lens). He also had subtle iris hypoplasia and corectopia.
The propositus’s brother, on whom DNA was not available for testing, was described as having very similar structural brain anomalies to the propositus. He additionally had neonatal diabetes mellitus and anophthalmia, and died in infancy.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
MOLECULAR TESTING
Sequence analysis for mutations in the four most common holoprosencephaly-associated genes (SHH, ZIC2, SIX3, and TGIF) was negative.
The patient’s father had a nonconservative missense mutation (c.112C>T, resulting in p.R38W) in the paired box domain of PAX6. This mutation has previously been reported in a patient with microphthalmia and aniridia [Henderson et al., 2007]. This is a highly evolutionarily conserved residue which mediates sequence specific DNA binding [Hanson et al., 1999; Xu et al., 1999].
The patient’s mother had a nonsense mutation (c.718C>T, resulting in p.R240X) in the homeobox domain of PAX6. This mutation has previously been reported in a patient with aniridia. The premature insertion of a stop codon in the homeobox domain is predicted to result in nonsense-mediated decay and a consequently functionally null allele [Wilson et al., 1995; Tzoulaki et al., 2005].
The propositus inherited both the maternal and paternal mutations in PAX6.
DISCUSSION
This is the second reported and the only known surviving patient with mutations in both PAX6 alleles. Analysis of the findings provides a unique example of the phenotypic effects of compound heterozygosity of mutations of PAX6. The propositus’s hypopituitarism, diabetes mellitus, and brain and ophthalmologic anomalies can all be explained by the PAX6 mutations. The mutations also explain the ophthalmologic phenotype in his parents, and additionally may explain impaired glucose tolerance in the propositus’s mother.
The previously reported patient, who had a nonsense mutation in each PAX6 allele, survived to the eighth day of life [Glaser et al.,1994]. The propositus’s brother, who was described as having near identical brain and ophthalmologic anomalies as the propositus, died in early infancy and was not available for genetic testing. However, given the similar phenotypes and the 25% chance that the parents would give birth to a child with both mutations, it is likely that the deceased sibling inherited both mutant alleles. The morbidity associated with inheriting two mutations and the fact that the propositus additionally had trisomy 21 make his survival and relative good health an especially rare event.
Finally, this case highlights the importance of a multidisciplinary approach which includes the evaluation of multiple family members in the diagnosis of unusual and complex patients.
ACKNOWLEDGMENTS
We are extremely grateful to the family presented in this report. This research was supported by the Intramural Research Program of the National HumanGenome Research Institute, National Institutes of Health.
REFERENCES
Bamiou DE, Free SL, Sisodiya SM, Chong WK, Musiek F, Williamson KA, van Heyningen V, Moore AT, Gadian D, Luxon LM. 2007. Auditory interhemispheric transfer deficits, hearing difficulties, and brain magnetic resonance imaging abnormalities in children with congenital aniridia due to PAX6 mutations. Arch Pediatr Adolesc Med 161:463---469
Bentley CA, Zidehsarai MP, Grindley JC, Parlow AF, Barth-Hall S, Roberts VJ. 1999. Pax6 is implicated in murine pituitary endocrine function. Endocrine 10:171–177.
Brown SA, Warburton D, Brown LY, Yu CY, Roeder ER, Stengel-Rutkowski S, Hennekam RC, Muenke M. 1998. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 20:180–183.
Glaser T, Jepeal L, Edwards JG, Young SR, Favor J, Maas RL. 1994. PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet 7:463–471.
Gripp KW, Wotton D, Edwards MC, Roessler E, Ades L, Meinecke P, Richieri-Costa A, Zackai EH, Massague J, Muenke M, Elledge SJ. 2000. Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet 25:205–208.
Hanson I, Churchill A, Love J, Axton R, Moore T, Clarke M, Meire F, van Heyningen V. 1999. Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations. Hum Mol Genet 8:165–172.
Henderson RA, Williamson K, Cumming S, Clarke MP, Lynch SA, Hanson IM, FitzPatrick DR, Sisodiya S, van Heyningen V. 2007. Inherited PAX6, NF1 and OTX2 mutations in a child with microphthalmia and aniridia. Eur J Hum Genet 15:898–901.
Jordan T, Hanson I, Zaletayev D, Hodgson S, Prosser J, Seawright A, Hastie N, van Heyningen V. 1992. The human PAX6 gene is mutated in two patients with aniridia. Nat Genet 1:328–332.
Kioussi C, O’Connell S, St-Onge L, Treier M, Gleiberman AS, Gruss P, Rosenfeld MG. 1999. Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci USA 96:14378–14382.
Robinson DO, Howarth RJ, Williamson KA, van Heyningen V, Beal SJ, Crolla JA. 2008. Genetic analysis of chromosome 11p13 and the PAX6 gene in a series of 125 cases referred with aniridia.AmJ Med Genet Part A 146A:558–569.
Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. 1996. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14:357–360.
Simpson TI, Price DJ. 2002. Pax6; a pleiotropic player in development. Bioessays 24:1041–1051.
Terzic J, Saraga-Babic M. 1999. Expression pattern of PAX3 and PAX6 genes during human embryogenesis. Int J Dev Biol 43:501–508.
Tzoulaki I, White IM, Hanson IM. 2005. PAX6 mutations: Genotypephenotype correlations. BMC Genet 6:27.
Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. 1999. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet 22:196–198.
Wen JH, Chen YY, Song SJ, Ding J, Gao Y, Hu QK, Feng RP, Liu YZ, Ren GC, Zhang CY, Hong TP, Gao X, Li LS. 2009. Paired box 6 (PAX6) regulates glucose metabolism via proinsulin processing mediated by prohormone convertase 1/3 (PC1/3). Diabetologia 52:504–513.
Wilson DS, Guenther B, Desplan C, Kuriyan J. 1995. High resolution crystal structure of a paired (Pax) class cooperative homeodomain dimer on DNA. Cell 82:709–719.
Xu HE, Rould MA, Xu W, Epstein JA, Maas RL, Pabo CO. 1999. Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding. Genes Dev 13:1263–1275.
Sunday, November 8, 2009
Timmy's MRI Report
In December 2008, when we were at NIH, they sent Timmy's MRI to the Carter Center for review. Below is the finding from the Carter Center, that we just recently obtained from NIH. I don't know what any of this really means. Timmy has a Neurology appointment on Nov. 13th and at this time, I'm hoping that the Neurologist can explain some if not all of this to us. Maybe some of you can understand what is being described here.
CC Neuroradiology Report
Exam Type Exam Media Referral Source (CC)
MRI DICOM CD/DVD Other
Image Diagnosis
Other
Comments
Not HPE. Multiple anomalies including agenesis corpus callosum, hypoplastic pons, vermis (absent inferiorly), possible Dandy-Walker. Tectum dysplastic. Hypoplastic pituitary and hypothal.
Microcephalics. Asymmetric microophthalmia. Basal ganglia abnormal, globular (but not fused). Given eye, cortical malformation, post fossa anomalies, raises question of CMD/MEB spectrum.
Detailed Findings (For Internal Research Use Only )
Caudate Mesencephalon
0 (seperated) 0 (Normal)
Lentiform Thalmi
0 (separated) 0 (seperated)
Hemispheric Fusion Hemisph Fused Portions
Absent Not HPE, therefore
*Anterior Falx Present *Posterior Falx Present
Ant CC/Genu Present Ant. Body CC Present
Post Body CC Present Post CC/Splenium Present
- CC Comment -
Complete ACC
Cortical Malformation Optic Chiasm
Present Dysgenetic
Orbits Olfactory Bulb
Absent
Olfactory Sulci
Absent IHC-
Present w/comm - type 1
Dorsal Cyst
Absent VP Shunt
Absent
Myelination
Age Appropriate Vessels
0 (Normal)
Aquaduct
Patent
Ventricular System and Cyst Comments
Midline interhemispheric fissure vs cyst is enlarged. Thalami are separated by enlarged 3rd vent with posterior commissure connecting the two thalami. Asymmetric large temporal horns, R>L.
Stanford School of Medicine & Lucile Packard Children’s Hospital
Stanford, California, 94305-5235
Tel: (650) 723-6841. Email hpe@stanford.edu
CC Neuroradiology Report
Date of Exam Age at Exam (yr) Date of Review
7/14/2008 4.7 1/23/2009
Exam Type Exam Media Referral Source (CC)
MRI DICOM CD/DVD Other
Image Diagnosis
Other
Comments
Not HPE. Multiple anomalies including agenesis corpus callosum, hypoplastic pons, vermis (absent inferiorly), possible Dandy-Walker. Tectum dysplastic. Hypoplastic pituitary and hypothal.
Microcephalics. Asymmetric microophthalmia. Basal ganglia abnormal, globular (but not fused). Given eye, cortical malformation, post fossa anomalies, raises question of CMD/MEB spectrum.
Detailed Findings (For Internal Research Use Only )
Pituitary Hypothalamus
1 (partial) DysgeneticCaudate Mesencephalon
0 (seperated) 0 (Normal)
Lentiform Thalmi
0 (separated) 0 (seperated)
Hemispheric Fusion Hemisph Fused Portions
Absent Not HPE, therefore
*Anterior Falx Present *Posterior Falx Present
Ant CC/Genu Present Ant. Body CC Present
Post Body CC Present Post CC/Splenium Present
- CC Comment -
Complete ACC
Cortical Malformation Optic Chiasm
Present Dysgenetic
Orbits Olfactory Bulb
Absent
Olfactory Sulci
Absent IHC-
Present w/comm - type 1
Dorsal Cyst
Absent VP Shunt
Absent
Myelination
Age Appropriate Vessels
0 (Normal)
Aquaduct
Patent
Ventricular System and Cyst Comments
Midline interhemispheric fissure vs cyst is enlarged. Thalami are separated by enlarged 3rd vent with posterior commissure connecting the two thalami. Asymmetric large temporal horns, R>L.
Interpreted By:
Patrick Barnes, M.D., Professor of Radiology-Diagnostic Radiology
Jin Hahn, M.D., Professor of Neurology and PediatricsStanford School of Medicine & Lucile Packard Children’s Hospital
Stanford, California, 94305-5235
Tel: (650) 723-6841. Email hpe@stanford.edu
Friday, November 6, 2009
Birthday Party
We had Timmy's 6th birthday party at school today. Even though the Circus Theme that I had planned on using had to be replaced by SpongeBob, the party was a success! The kids really had fun with the Fishing Game, the Tatoos and bouncing in the Bounce House! I didn't get as many pictures as I had hoped. One reason was because Dad's digital camera was having mechanical problems. (Saaanta, I want a Digital Camera For Christmas. Pleeeease!) And also because Dad was behind the camera taking the pictures. For some reason the men in my life, just don't know how to take a variety of pictures. Maybe for this reason, that is why I haven't seen too many male photographers in my lifetime? Anyway I hope that you enjoy the pictures.....
Thursday, November 5, 2009
Pulmonology Visit
Timmy had a Pulmonology visit today at UNC with Dr. Jessica Pittman. She was very pleased with just how well Timmy is doing, since the removal of his trach. Dr. Pittman took Timmy off of his Pulmocort nebulizer treatments. YAY!! No more daily breathing treatments. We are still able to give Xopenex and saline nebs as needed. She put Timmy on an antibotic "just because" Timmy has had some yellowish to tannish secretions coming out of his trach stoma. he antibotic is just a precaution, in case some kind of bug is trying to rear its ugly head. This way we can possibly stop it before it hits Timmy too hard. We discussed Timmy's sleep study results from the test in August. Timmy had a couple of centeral apnea episodes and a desaturation of less than 90% for a minute. Dr. Pittman doesn't feel that this is a big issue at this time, being that we aren't seeing any problems with sleep or breathing at home during the night. She looked into Timmy's ear (left). She removed the TONS of ear wax that had built up. And was able to then confirm that YES Timmy's left ear tube had most definately come out the night before. Soooo, we have a call into Dr. Z (ENT) to see what if anything he feels should be done. All in all, this was a great visit. Timmy measured 37+ inches tall and was roughly 36lbs. Timmy's next Pulmonology visit is in 6 months, unless he should get sick and need to be seen sooner.
Wednesday, November 4, 2009
Physical Therapy
I've been a good girl this year, I just hope that Santa agrees. I REALLY would like a Digital camera for Christmas. Right now all I have for taking pictures is my cell phone. So I apologize that my pictures are a bit blurry.
Here are a few pictures of Timmy during his physical therapy session yesterday. He really wasn't into therapy yesterday. Well, not with the therapist who comes to the house. The therapist who comes to the house to see Timmy is an "all play aside" serious and time for hard work type of therapist. She has been working with Timmy for almost 4 years. So she doesn't buy the complaining, the pretending to be waaaay too tired for therapy or the pretending to fall asleep routine that Timmy likes to sometimes "try" to get away with. And fingers/hands in the mouth are DEFINATELY a NO, NO!
Here are a few pictures of Timmy during his physical therapy session yesterday. He really wasn't into therapy yesterday. Well, not with the therapist who comes to the house. The therapist who comes to the house to see Timmy is an "all play aside" serious and time for hard work type of therapist. She has been working with Timmy for almost 4 years. So she doesn't buy the complaining, the pretending to be waaaay too tired for therapy or the pretending to fall asleep routine that Timmy likes to sometimes "try" to get away with. And fingers/hands in the mouth are DEFINATELY a NO, NO!
Tuesday, November 3, 2009
Birthday Pictures
Happy 6th Birthday Timmy!
The six things about you that make me smile. (In no particular order)
1. Your award winning personality.
2. Your photo-genic smile.
2. Your contageous laughter.
4. Hearing you call me MaMa. (Even though I can't get you to say "I Love You!")
5. Your upbeat nature in the mornings.
6. Your willingness and eagerness to learn and to please others with what you have learned.
We still have a long tough road ahead of us, but together we will make it through.
MsMa Loves You!
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