Abnormal growth in noonan syndrome: the challenge of optimal therapy. 

Savage MO, Padidela R, Kirk JM, Malaquias AC, Jorge AA.

Department of Endocrinology, Barts and the London School of Medicine and Dentistry, London, UK. m.o.savage@qmul.ac.uk

Noonan syndrome (NS) is a phenotypically heterogeneous condition frequently associated with short stature. Genetic investigations have identified mutations in several genes, e.g.PTPN11, KRAS, RAF and SOS1 in patients with the NS phenotype and related disorders such as LEOPARD, Costello and Cardiofacio- cutaneous syndromes. In NS, PTPN11 mutations are present in 29-60% of cases. The degree of short stature does not associate closely with the presence of a mutation; however, some PTPN11-positive patients have decreased growth hormone (GH)-dependent growth factors consistent with mild GH insensitivity. GH therapy induces short-term increases in height velocity over 1-3 years, and is likely to improve adult height.

PMID: 19550387 [PubMed - indexed for MEDLINE]

Successful fertility treatment for Klinefelter’s syndrome.

J Urol. 2009 Sep

Ramasamy R, Ricci JA, Palermo GD, Gosden LV, Rosenwaks Z, Schlegel PN.
Center for Reproductive Medicine and Infertility, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York.

PURPOSE: We examined preoperative factors that could predict successful microdissection testicular sperm extraction in men with azoospermia and nonmosaic Klinefelter’s syndrome. We also analyzed the influence of preoperative hormonal therapy on the sperm retrieval rate.

MATERIALS AND METHODS: A total of 91 microdissection testicular sperm extraction attempts were done in 68 men with nonmosaic Klinefelter’s syndrome. Men with serum testosterone less than 300 ng/dl received medical therapy with aromatase inhibitors, clomiphene or human chorionic gonadotropin before microdissection testicular sperm extraction. Preoperative factors of patient age and endocrinological data were compared in those in whom the procedure was and was not successful. The sperm retrieval rate was the main outcome. Clinical pregnancy (pregnancy with heartbeat) and the live birth rate were also calculated.

RESULTS: Testicular spermatozoa were successfully retrieved in 45 men (66%), representing 62 (68%) attempts. Increasing male age was associated with a trend toward a lower sperm retrieval rate (p = 0.05). The various types of preoperative hormonal therapies did not have different sperm retrieval rates but men with normal baseline testosterone had the best sperm retrieval rate of 86%. Patients who required medical therapy and responded to that treatment with a resultant testosterone of 250 ng/dl or higher had a higher sperm retrieval rate than men in whom posttreatment testosterone was less than 250 ng/dl (77% vs 55%). For in vitro fertilization attempts in which sperm were retrieved the clinical pregnancy and live birth rates were 57% and 45%, respectively.

CONCLUSIONS: Microdissection testicular sperm extraction is an effective sperm retrieval technique in men with Klinefelter’s syndrome. Men with hypogonadism who respond to medical therapy may have a better chance of sperm retrieval.

ScienceDirect

Herron: Down syndrome an oft misunderstood disorder
By Mason Herron / Columnist
published: Tue, 15 Sep, 2009

When we reflect upon the progress humanity has made, we often reach two conclusions: praise for the progress and the heroes that brought it and the realization of how much more progress must be made. Historically speaking, there are a plethora of examples to this law: colonialism, religious tolerance, civil rights, gender equality, etc.

You get the idea. Perhaps, then, we might consider these reflections and apply them to an issue of today that might not be as eminent but is nonetheless in dire need of grave reflection and consideration, and that is the way we perceive the nature of Down syndrome.

Down syndrome — also referred to as trisomy 21 — is a disorder brought on by the presence of an additional chromosome in an individual’s genes. People who have the disorder are typically developmentally disabled and display below-average cognitive ability. Physical characteristics include low muscle tone, almond-shaped eyes, a flat nasal bridge, a protruding tongue and a number of other features. Each individual might experience these characteristics with different intensities and variability.Down syndrome occurs in one of every 800 births, and the risk of conceiving a child with Down syndrome increases as women grow older, with women older than 35 having 80 percent of Down syndrome births.
 Our understanding of Down syndrome — and the way it was portrayed — was, until recently, simple at best and cruel at worst. The disorder was popularly referred to as “mongolism” (in reference to a Mongoloid race), and the term still creeps its way into modern medical texts. Worse, however, was the implementation of a policy in the early 20th century by 33 of 48 states that mandated that individuals with Down syndrome be forced to undergo involuntary sterilization, and many were murdered by Nazi Germany’s “Action T4” euthanasia program.

This history reveals not only a lack of ethics in regard to the mentally disabled, but also a severe underestimation of the capabilities of those who are born with Down syndrome. A generation after many of those with Down syndrome would have been institutionalized, many are able to happily live and work independently. Many are also perfectly literate, and I hope I need not point out the remarkable athletic talent and leadership displayed at Special Olympics events across the country.

But then one reads this: “It is crucial to reaffirm the morality of aborting a fetus diagnosed with Down syndrome … Because a person afflicted with Down syndrome is only capable of being marginally productive (if at all),” Nicholas Provenzo, founder of the Center for the Advancement of Capitalism, said.

Perhaps no one has said it better than online blogger, Diana Hsieh. “[Christians] would regard abortion as a moral way to prevent the infliction of a miserable, degraded life on the person that will emerge from the womb. Instead, they want to create more mentally defective and perpetually dependent children by outlawing abortion.”

A 2002 study revealed that 91 to 93 percent of Down syndrome pregnancies were intentionally terminated. Many potential parents are unwilling to take on the burdens and uncertainties of raising a disabled child. However, these fears are often exacerbated by a misunderstanding of Down syndrome. According to a congressional testimony by Dr. Brian Skotko, mothers included in his study that had been diagnosed as having a Down syndrome pregnancy “reported that doctors did not tell them about the positive potential of people with Down syndrome, nor did they feel like they received enough up-to-date information or contact information for parent support groups.”

Efforts have been made to rectify this concern. The bi-partisan Prenatally and Postnatally Diagnosed Conditions Awareness Act, signed by President Bush in October 2008, is a bill that seeks to inform and educate the public about Down syndrome and other prenatally or postnatally diagnosed disorders. Fortunately, government has not been the only instrument used toward the proliferation of information regarding Down syndrome. Many organizations, including the National Association for Down Syndrome, the National Down Syndrome Society and the Down Syndrome Association of Pittsburgh, have done work to educate others about this condition, as well.

It seems our immediate impressions of people often get the best of us. In the eyes of some, those with Down syndrome live an incomplete life, an unfair life. Yet we must realize this is not always the case and that those with Down syndrome shouldn’t be defined by their disorder. By willfully changing our perceptions on this particular issue, we take a step toward contributing to the progress of humanity as a whole.

E-mail Mason at mph20@pitt.edu.

PittNews

Molecular genetic analysis of Down syndrome.

Hum Genet. 2009 Jul

Patterson D.
Eleanor Roosevelt Institute, University of Denver, 2101 E. Wesley Avenue, Denver, CO 80208-6600, USA. dpatter2@du.edu

Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer’s disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex.

Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

SpringerLink

Triple-marker prenatal screening program for chromosomal defects.

Obstet Gynecol. 2009 Jul

Kazerouni NN, Currier B, Malm L, Riggle S, Hodgkinson C, Smith S, Tempelis C, Lorey F, Davis A, Jelliffe-Pawlowski L, Walton-Haynes L, Roberson M.
Genetic Disease Screening Program, California Department of Public Health, Richmond, California, USA. neely.kazerouni@cdph.ca.gov

OBJECTIVE: To examine screening performance of California’s triple-marker screening program, using data from a statewide registry for chromosomal defects.

METHODS: This study included 752,686 women who received a screening risk and had an expected date of delivery between July 2005 and the end of June 2007. Follow-up diagnostic services for screen-positive women were performed at state-approved centers. Data on diagnostic outcomes from these visits were entered into the California Chromosomal Defect Registry (CCDR). Other CCDR sources include mandatory reporting by all cytogenetic laboratories and hospitals and outcome data forms submitted by prenatal care providers. RESULTS: The observed detection rate for Down syndrome (N=1,217) was 77.4%. It varied significantly by gestational dating method and maternal age. The rates for women aged younger than 35 years and 35 years and older were 62.4% and 94.0%, respectively. The detection rates were 81.3% for ultrasound-dated pregnancies and 67.5% for last menstrual period-dated pregnancies. For Turner syndrome, trisomy 18, triploidy, and trisomy 13, the detection rates were 79.4%, 82.5%, 98.1%, and 36.0%, respectively. The positive rate for Down syndrome was 5.4%. Of women with a Down syndrome fetus who were screen positive, only 49.5% opted for amniocentesis. Of women who obtained results from amniocentesis indicating a Down syndrome fetus, 61.4% had an elective termination, 26.2% had a live birth, 4.5% had a death or miscarriage, and 7.9% had an unknown outcome.

CONCLUSION: The observed performance of this large triple-marker screening program exceeds generally predicted detection rates for Down syndrome. This study methodology will be used to measure the performance of subsequent screening enhancements.

Lippincott, Wilkins & Williams

Language development impairment and trisomy 8 mosaicism
 

Klinik und Poliklinik für Phoniatrie und Pädaudiologie, Medizinische Hochschule Hannover, Hannover, Germany. Ptok.Martin@mh-hannover.de

Constitutional trisomy 8 mosaicism (46,XX/47,XX,+8 or 46,XY/47,XY,+8) is characterized by trisomic distribution of chromosomes in some but not all cells of the body. The full condition presents with physical stigmata, skeletal abnormalities and a mild to moderate cognitive impairment.Here we present a boy aged 3 years 10 months with partial trisomy 8 who was referred because of a language impairment. Because of known anomalies (corpus callous agenesis, deformities of the spine) a chromosomal analysis was initiated.This case highlights the necessity for an interdisciplinary diagnostic approach in children with language impairment and other constitutional disorders

Springer Link

Congenital gastrointestinal defects in Down syndrome: a report from the Atlanta and National Down Syndrome Projects.

Clin Genet. 2008 Nov 17

Freeman SB, Torfs CP, Romitti PA, Royle MH, Druschel C, Hobbs CA, Sherman SL.
Department of Human Genetics, Emory University, Atlanta, GA, USA.

We report Down syndrome (DS)-associated congenital gastrointestinal (GI) defects identified during a 15 year, population-based study of the etiology and phenotypic consequences of trisomy 21. Between 1989 and 2004, six sites collected DNA, clinical and epidemiological information on live-born infants with standard trisomy 21 and their parents. We used chi-squared test and logistic regression to explore relationships between congenital GI defects and infant sex, race, maternal age, origin of the extra chromosome 21, and presence of a congenital heart defect. Congenital GI defects were present in 6.7% of 1892 eligible infants in this large, ethnically diverse, population-based study of DS. Defects included esophageal atresia/tracheoesophageal fistula (0.4%), pyloric stenosis (0.3%), duodenal stenosis/atresia (3.9%), Hirschsprung disease (0.8%), and anal stenosis/atresia (1.0%). We found no statistically significant associations between these defects and the factors examined. Although not significant, esophageal atresia was observed more often in infants of younger mothers and Hispanics, Hirschsprung disease was more frequent in males and in infants of younger mothers and blacks, and anal stenosis/atresia was found more often among females and Asians.

PubMed

Congenital heart disease in children with Down’s syndrome: Turkish experience of 13 years.

Acta Cardiol. 2008 Oct

Nisli K, Oner N, Candan S, Kayserili H, Tansel T, Tireli E, Karaman B, Omeroglu RE, Dindar A, Aydogan U, Başaran S, Ertugrul T.
Paediatric Cardiology Division, Paediatrics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey. kemalnisli@yahoo.com

BACKGROUND: Down’s syndrome (DS) is the most common chromosomal abnormality due to a trisomy of chromosome 21 commonly associated with congenital heart defects (CHDs). This study aimed to evaluate the frequency and types of CHD patterns in Turkish children with DS.

METHOD: The data relate to paediatric patients with DS who underwent cardiologic screening between 1994 and 2007 and were reviewed in our Paediatric Cardiology unit.

RESULTS: Four hundred and twenty-one out of the 1042 paediatric patients with DS studied over a 13-year period had associated CHD. Of these, 320 (77.6%) had a single cardiac lesion, while the remaining 92 patients (22.4%) had multiple defects. The most common single defect was an atrioventricular septal defect (AVSD) found in 141 patients (34.2%), followed by 69 patients (16.7%) showing secundum type atrial septal defect, and ventricular septal defect in 68 patients (16.5%). AVSDs were the leading type, isolated or combined with other cardiac anomalies with an overall occurrence of 19.8% of paediatric patients with DS, and 49.2% of paediatric patients with both DS and CHD.

CONCLUSION: This is the first study concerning the frequency and type of CHD observed in Turkish children with DS. The high frequency ofAVSD in Turkish children with DS implied that early screening for CHDs by echocardiography is crucial. The correction of AVSDs in paediatric patients with DS should be performed in the first 6 months of life to avoid irreversible haemodynamic consequences of the defect.

PMID: 19014001 [PubMed - in process]

Trisomy 22pter-q12.3 presenting with hepatic dysfunction variability of cat-eye syndrome.

Clin Dysmorphol. 2009 Jan

Jezela-Stanek A, Dobrzańska A, Maksym-Gasiorek D, Trzeciakowski W, Gutkowska A, Olczak-Kowalczyk D, Gajdulewicz M, Spodar K, Czech-Kowalska J, Krajewska-Walasek M.
Department of Medical Genetics, Children’s Memorial Health Institute, Warsaw, Poland. jezela@gmail.com

We describe the clinical characteristics of two patients with cat-eye syndrome (CES, MIM #115470) resulting from a supernumerary marker chromosome that includes 22pter-q12.3. They both presented a constellation of features typical of CES, including coloboma, auricular malformations, heart and renal anomalies, as well as hepatic dysfunction, which led to severe effects. In one case Pierre Robin sequence was diagnosed which has not been described earlier in this trisomy. Although CES is a well known, but infrequently diagnosed disorder, we draw attention both to its clinical overlaps with other disorders and, in view of the clinical variability being identified within the 22q11 region, to the importance of careful molecular examination of proximal 22q in patients with suggestive clinical signs.

PMID: 18955897 [PubMed - in process]

Miracle Children Survive Against the Odds

OPRAH.com) — A baby who never uttered a word touched the hearts of nearly a million people.

A second-grader with so much courage, people around the world called him a hero.

A 6-year-old boy who was never supposed to walk — and now won’t stop running.

The stories of these miracle children can make you believe that anything is possible.

Kendra and Maliyah

Oprah met her first two little miracle guests when they were just 4 years old. Conjoined twins Kendra and Maliyah Herrin were born sharing a large intestine, bladder, liver and single kidney. Each sister had two arms, but just one leg. The survival rate for conjoined twins is extremely low, but the girls exceeded all expectations and even learned to crawl — something doctors said might never happen.

As the twins grew older, their parents, Jake and Erin, faced an agonizing decision. If Kendra and Maliyah continued their lives conjoined, their shared kidney could eventually fail. But doctors had never performed surgery to separate two bodies sharing the same kidney, and there was a chance the twins might not survive.

Erin and Jake made the decision to let doctors separate their conjoined twin daughters when they were 4 years old. After a 26-hour surgery, Erin and Jake got the good news — the doctors had successfully separated their daughters.

Kendra and Maliyah are now adorable 6-year-olds. They have started first grade and say their favorite part of the day is — of course — recess!

Erin says things are going really well for the girls. Each girl has one kidney — Kendra has the one she once shared with her sister, and Maliyah was given a kidney from her mother. “Especially after Maliyah got her kidney from me, things went a lot better,” Erin says.

However, both girls still face a long road ahead and will need back surgery to straighten their spines. Three weeks later they will be fitted for prosthetic legs. “That’s a big milestone,” Erin says. Oprah.com: Learn more about these miracle twins

Lin

The world jumped to its feet when basketball giant Yao Ming walked side by side with 9-year-old Lin Hao at the Beijing Olympics opening ceremony. But who was the little hero waving the Chinese flag?

Lin survived the devastating earthquake in Sichuan on May 12, 2008, that claimed the lives of 20 of his schoolmates. After freeing himself from the debris, Lin risked his own life by going back into the rubble and carrying two of his unconscious friends to safety.

When asked why he took such a dangerous risk, Lin simply replied that he was the hall monitor and it was his job.

Cody

Cody also dreams of walking in the opening Olympic ceremonies — but as a star athlete. It’s an ambitious goal for a 6-year-old who wasn’t expected to live past his first day, but Cody is used to defying the odds.

When Cody was born, his parents, Tina and Mike, immediately knew something wasn’t right. “The doctors got very quiet. The nurses got very quiet,” Mike says. “I did notice that his legs looked different — they didn’t straighten out.” Mike was told their baby boy had an incurable disease and wouldn’t make it through the day. “That’s when Mike had told me that we needed to mourn the loss of our son,” Tina says.

Miraculously, Cody survived, but he still had a difficult journey ahead. When he was just 15 months old, both of Cody’s legs needed to be amputated. “He was fitted with his first prosthesis when he was 18 months old,” Tina says. “They did not think that he was going to walk in his first prosthetics right away, and on his second day, I think, or first day of therapy, he started walking.”

Those weren’t the only expectations Cody surpassed. “Cody has really done everything that they said he wouldn’t do,” Mike says. “He wasn’t supposed to be able to walk. Well, he walks — he runs. He wasn’t supposed to be able to talk, [because] he only has one vocal cord. He just goes on forever.”

Cody’s love for running gave his parents the idea to put a team together to raise money for the hospital that gave him his prosthetic legs. “These are my running legs, and I run very fast in them and I bounce in them,” Cody says. “Since I have different legs, I can do anything.”

Cody truly can do whatever he sets his mind to — and now that he’s on a swim team, a certain Olympic superstar better watch out! “Michael Phelps, I’m coming,” Cody says. “I’m gonna race you!”

Other than his athletic abilities, there is one thing Cody wants the world to know. “That I’m special,” he says.

Tina says her son has always had the drive to exceed expectations, and she and her husband, Mike, are right there to encourage Cody whenever he needs a boost. “When he says, ‘I can’t,’ we say, ‘That’s not a word allowed in this household,’” she says. “We find a way for him to do it. It might be different than someone else, but we work together and we get through it.”

Mike says Cody’s spirit is contagious to everyone he meets. “He’s always had that about him,” he says. “He just walks into a room and absolutely takes over somehow with his personality.” Cody even brightens the day of the disabled veterans he’s met with who have lost their limbs. “He’s never had his limbs, and he’s just smiling, bouncing through the room, and just wants to race everybody.”

Milagros

When Oprah first met Milagros, the little girl had already become a symbol of hope for people around the world.

Milagros was born with a rare genetic disorder called sirenomelia, also known as “mermaid syndrome.” Her legs were born fused together and she had no external genitalia. Most babies with this condition die during birth or before they are born.

When her parents, Ricardo and Sara, first saw their newborn, they were afraid they had been cursed. “When I finally saw her and saw her little legs, I was shaking and crying,” Sara says. “All I could do was cry.”

Ricardo and Sara refused to give up hope for their daughter and even named her Milagros, meaning “miracles” in Spanish. Despite the odds against her, Milagros lived to see her first birthday. But without surgery to separate her legs, doctors said she wouldn’t live much longer. After a five-hour surgery, Ricardo and Sara, along with the rest of the world watching on live TV, received the miraculous news — Milagros survived the rare and dangerous operation.

There is another miracle for Milagros. Even though doctors weren’t sure she would ever walk, she’s here today … and she’s ready to dance!

Megastar singer Celine Dion met Milagros and 11 other special children as part of the book “An Incredible Journey with Celine Dion: 12 Heroes Among Us.” The children’s stories were compiled by correspondents from Readers Digest, and the proceeds will benefit children all over the world.

“It’s an amazing project because you can read and learn about those miracles and heroes — babies, children — you can learn about those stories, and all the proceeds go for needy children and sick children,” she says. “It was a blessing.”

Donald

When he was 12 years old, Donald lived through one of the most destructive disasters in American history, Hurricane Katrina. As the water filled up his house, Donald climbed on top of the refrigerator, and his mom got on the counter.

“The more the water rose, the more we panicked,” he says. “The windows shattered from the wind. The water’s getting up high where we can’t touch the floor anymore. My mom didn’t know how to swim, and I didn’t know how to swim.”

Eventually, Donald’s mom lost her grip on a curtain rod and drowned. In that moment, life without his mother seemed so unbearable that Donald decided to end his life. “I completely gave up. I decided to, you know, just sink to the bottom,” he says. “I didn’t hold my breath, because I just wanted it to happen as quick as possible.”

Donald says as water began to fill his lungs, his will to survive took over and he paddled toward the only light he could see — a shattered window. “I think some spiritual force or God shattered that window as a final attempt of escape,” he says.

Donald paddled out, cutting himself on the shards of glass sticking out, and climbed to the roof of his house. For the next 13 hours, he stayed on roofs above the flood line, waiting until help arrived.

Three years after Katrina, Donald is now 15 and living with an aunt. He says the moment when he considered suicide, something told him it wasn’t his time. “I did a lot of thinking to myself in those short few seconds,” he says. “Something, almost a guardian angel, said, ‘Live and move on because you have extraordinary things ahead of you.’”

On the roofs of houses, Donald says he and another young man he met waited for their rescue. They were able to signal for help with the light of the other man’s cell phone.

After their meeting in Montreal, Quebec, for “An Incredible Journey with Celine Dion: 12 Heroes Among Us,” Celine says Donald’s story of survival is an inspiration. “I wish for my son to have the strength that you have,” she tells him.

Eliot

Two months before he was born, Eliot was diagnosed with Trisomy 18 — a genetic disorder with a very low survival rate. His parents, Matt and Ginny, began writing letters to him daily. Oprah.com: Get Matt and Ginny’s heartwarming update

“Dear Eliot: Right now you are two months from being born,” Matt wrote in one letter. “Doctors tell us that you won’t likely make it to birth. Your mom and I are praying against that. We’re praying for healing. We are praying for nothing less than a miracle. You’re our first child, and the day of your birth couldn’t come sooner.”

Against the odds, Eliot survived his birth. “You are already a miracle to us,” Matt wrote that day.

Every day that Eliot lived, he beat the odds. The median life span for children with Trisomy 18 is just five to 15 days — but Eliot just kept on surviving.

Matt and Ginny’s letters to their infant son continued for 99 precious days. They turned their letters and literally thousands of photos of Eliot into a video that has now been seen nearly a million times on YouTube.

Matt and Ginny joined Oprah and Celine from their living room in Fayetteville, Arkansas. And they have some big news — they are expecting another baby!

Matt says their tribute to Eliot started as a blog, which they used to keep friends and family updated on his status even before he was born. “Once he was here, we just took a lot of pictures and took a lot of video, and we knew we wanted to put that together in some way to tell the story of his life.”

“We knew from day to day that we had that day,” Ginny says. “I would tell Matt a lot: ‘I’ll be sad later. I’m going to enjoy every second now.’ So even though his diagnosis never changed, we just decided we were going to enjoy every second that we had.”

Celine is moved by that idea. “Life imposes things on you that you can’t control, but you still have the choice of how you’re going to live through this,” she says. “Once you know the diagnosis and it’s not good, then you make the best of it.”

“We celebrate you,” Oprah says. “What an inspiration your family has been to the world.”

From “The Oprah Winfrey Show”

CNN News