Rapid Whole Genome Sequencing continues to provide answers and hope for parents of critically ill children with rare diseases

If a Major League Baseball player were to step up to the plate 150 times and get a hit 76 times, his batting average would be an unthinkably torrid .507. 

When it comes to identifying genetic causes for some of the rarest and serious diseases in children, CHOC has put up numbers that even Mike Trout couldn’t dream of achieving. 

Since July 2017, CHOC has ordered the comprehensive and cutting-edge test of rapid whole genome sequencing (rWGS) on 150 patients, with 76 of them getting a precise diagnosis that, in many cases, has resulted in life-changing care. 

“We took what could have been a diagnostic odyssey for these patients and families and cut it down from weeks, months, and sometimes years to, in some cases, only three days,” says CHOC pediatric intensive care unit medical director Dr. Jason Knight, part of an informal leadership team that oversees treatment of critically ill kids with rare diseases in the NICUPICU and CVICU. Other ICU physician team leaders include Dr. Adam SchwarzDr. Juliette Hunt and Dr. John Cleary

CHOC’s rWGS research program was championed by the late Dr. Nick Anas, CHOC’s former pediatrician-in-chief who was director of pediatric intensive care and a beloved figure at the hospital. Dr. Anas, who started at CHOC in 1984, died on April 3, 2018. 

Dr. Anas’ vision for the rWGS research program continues to be realized with successful patient outcomes, from the 2019 diagnosis of an infant girl with the extremely rare cardiac condition Timothy Syndrome to, more recently, a baby boy – Oliver Marley – with a genetic disorder that has been detected in only 10 children worldwide. 

“The CHOC team believed in Oliver – they loved him and took care of him and saw worth in him,” says Caroline Marley of her son, who turns 10 months old this May and was cared for by CHOC clinical teams during two stays, once in the NICU and the second time in the PICU. 

“They told me, ‘We want you to take your baby home,’” Caroline says. 

Testing began in 2017 

Each of us has some 22,000 genes in our bodies that dictate things ranging from the color of our hair to whether we are tall or short. Genes also produce the proteins that run everything in our bodies. Although individually rare, there are more than 6,200 single-gene diseases. RWGS is the technology that, with just a teaspoon of our blood, allows us to look at all the genes in our cells.  

At CHOC, rWGS testing became prominent with the launch of Project Baby Bear in fall 2018. CHOC was among five hospitals to participate in that program, led by Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego. RCIGM has a lab that runs sequencing. 

“To have (the RCIGM) close by and to be a close partner with them has been great,” Dr. Knight says. “We are way ahead of many other pediatric hospitals in this area. It’s a great success story, and something I’m really glad to be a part of.” 

A total of 45 CHOC patients got tested through Project Baby Bear, a $2-million state program for critically ill infants age 1 or younger who were enrolled in Medi-Cal. Of those 45 patients, 55.6 percent – 25 children – were able to have their rare diseases properly diagnosed, says Dr. Neda Zadeh, a CHOC medical geneticist who was involved with setting up CHOC’s rWGS program with Dr. Anas and who has seen most of the 150 kids tested thus far. 

CHOC actually began ordering rWGS testing on patients the year before in a partnership with RCIGM and Illumina, a leading developer and manufacturer of life science tools and integrated systems for large-scale analysis of genetic variation and function. In that 2017 program, 82 CHOC patients were tested with a 47.6 percent positive diagnosis rate, says Ofelia Vargas-Shiraishi, a senior clinical research coordinator in critical care/neonatology research at CHOC. 

CHOC has paid for an additional 23 children to undergo rWGS testing outside of the now-completed Ilumina and Project Baby Bear programs, and continues to have funding on a case-by-case basis, says Dr. Schwarz. 

“In the long run,” Dr. Schwarz says, “we’re saving money by avoiding expensive workups.” 

Adds Dr. Knight: “For a lot of these families, having an answer – even one they might not want to hear – is extremely important.” 

For parents like Caroline Marley, the results have been priceless. 

‘Wouldn’t place money on your son’ 

Oliver was born at 33 weeks after a complicated pregnancy for Caroline, who had a partial placental abruption when she was 14 weeks pregnant. Caroline and her husband, Ted, have another son, Charlie, 4, who is healthy. 

Oliver Marley with his older brother, 4-year-old Charlie

Born weighing 5 pounds and 4 ounces, Oliver had bruises over much of his body and had to be intubated a day after birth when he went into respiratory failure. Doctors detected a small brain bleed and noticed that, at 6 days old, both of his middle fingers were contracted. 

“I’ve never seen this before,” a neurologist at another hospital where Oliver was being treated told the Marleys. 

Oliver also had difficulty swallowing. He could move his arms and legs a bit, but he couldn’t open his eyes. 

Doctors suspected he might have muscular dystrophy. 

After other complications, doctors told the Marleys that Oliver’s outlook looked grim and that he may have to be sent to an acute-care facility. 

“We can’t help him,” one doctor told Caroline. “I don’t believe he will ever come home. If I were going to Vegas, I wouldn’t place money on your son.”  

It got to the point where the Marleys felt Oliver wasn’t getting the best care, so they decided to transfer him to CHOC. A nurse at another hospital whom the Marleys knew recommended CHOC.  

“We will absolutely take him,” a CHOC nurse told the Marleys. 

Oliver transferred to CHOC on Aug. 11, 2020. 

At 8 weeks old, Oliver underwent a tracheotomy and was attached to a ventilator. 

“He literally started thriving,” Caroline recalls. “He started growing because he was not working so hard to breathe. You could just see he was doing better.” 

Still without a diagnosis, Oliver went home on Oct. 19, 2020 with a tracheostomy tube and a ventilator.  

He returned to CHOC after he contracted a viral infection. 

Not convinced Oliver had muscular dystrophy, Dr. Schwarz suggested him as a candidate for rWGS.  

Three days later, in mid-November 2020, the Marleys received an answer: Oliver had two extremely rare genetic changes in his AHCY gene that potentially resulted in S-AdenosylHomocysteine Hydrolase (SAHH) deficiency.  

It is an extremely rare condition with less than 30 patients reported in the world and CHOC’s Dr. Richard Chang, a metabolic disorders specialist and  biochemical geneticist, was consulted to confirm the diagnosis. The disease, which affects brain, muscle and liver development, is associated with high blood levels of methionine and extremely high levels of toxic S-AdenosylHomocysteine (SAH) that interferes with vital cellular growth. 

Oliver was put on a delicate protein-restricted diet to limit the production of SAH without causing protein malnutrition, and his condition immediately improved. Other medications were added subsequently to provide nutrients that deficient due to the toxicity of SAH. He has a condition that is identical to a girl in Pennsylvania who was diagnosed at age 3 and later underwent a liver transplant. That girl is now 9. 

Oliver is scheduled to receive a liver transplant soon, Caroline says. 

Expanding access to rWGS testing 

A lawmaker in San Diego, in partnership with Rady Children’s Hospital and Health Center, is pushing for a new law that would expand access to rWGS testing by qualifying it as a Medi-Cal covered benefit for babies hospitalized in intensive care. 

Assembly Bill 114, The Rare Disease Sequencing for Critically Ill Infants Act, not only would expand availability of such testing to more families, but also would reduce state spending by eliminating many unneeded procedures, treatments and longer hospital stays, State Assemblyman Brian Maienschein wrote in a recent op-ed piece.  

“For critically ill infants hospitalized with unexplained rare diseases,” Maienschein wrote, “the opportunity to benefit from a medical miracle has arrived.” 

Caroline Marley sees that miracle daily with Oliver, who now is up to 20 pounds and moving around more. 

“We at CHOC are slowly building a case for early introduction of rWGS into the clinical management of these difficult cases in high-acuity settings to improve lifelong clinical outcomes and quality of life,” says Brent Dethlefs, executive director of the CHOC Research Institute. 

“There’s growing evidence that early introduction of this technology results in overall cost savings,” Brent adds. “It’s important to get more insurance carriers to cover the cost of this testing over time, which will make rapid whole genome sequencing more available to vulnerable and underserved populations. CHOC always has been an advocate for social justice in health care, which includes greater access to genomic testing.” 

Caroline Marley praises the entire collaborative team at CHOC and the entire CHOC Specialists Metabolic Disorders division, including Dr. Chang, who is in charge of maintaining Oliver’s health until transplant; Erum Naeem, clinical research coordinator, NICU; and Cathy Flores, clinical research nurse coordinator, critical care. 

“It was a team effort involving the critical care, neonatology, metabolic and genetics teams, just to name a few, and a very strong partnership with RCIGM,” says Ofelia Vargas-Shiraishi, a clinical research coordinator at CHOC. 

“We had everyone by our side every step of the way,” Caroline adds. “Child life was amazing, and so is the spiritual care team. If you’re willing to learn, they’re willing to teach you.” 

Dr. Zadeh says the success of CHOC’s rWGS program – with its whopping .507 batting average – is a result of “a very unique blend of the right people coming together at the right time and the right institution with the right set-up.” 

She adds, “I don’t think it would have worked necessarily at every hospital. I think CHOC is unique. We have the right group of kids we are testing. And we have the right group of specialists involved. 

“We love our families. We get to have really great relationships with them. This program just shows that CHOC is all about the whole care of the child and the family.” 

Rapid genome testing for infants saves lives, costs

Its name conjures up images of a familiar fairy tale, but Project Baby Bear has produced some very impressive real-world results that could save the lives of thousands of seriously ill infants.

The recently completed two-year pilot program at five clinical sites in California – including CHOC – helped doctors target a baby’s specific genetic disease in a matter of days, instead of the four to six weeks required for standard genetic tests.

That means quicker diagnoses leading to quicker treatments, less time in the hospital and more answers for anxious parents.

“It can be a real game changer,” said Dr. Jason Knight, a pediatric critical care physician and medical director of CHOC’s pediatric intensive care unit and one of the physician leads on the project. “It’s a tool we didn’t have a few years ago.”

Changing the game

By employing rapid whole genome sequencing (rWGS), doctors could gather vital information that changed the decisions families and clinicians made, and ultimately saved lives and resources. The procedure has historically been used only as a last resort.

By pinpointing the cause of rare disease with rWGS, physicians can customize treatment. And having a genetic diagnosis can eliminate the need for further tests, improve outcomes, reduce hospital stay length and improve the experience of care for families – all while also reducing costs.

In addition, substantial reductions in healthcare spending — $2.5 million — accrued largely because rWGS permitted doctors to discharge babies sooner and reduce the number of procedures that may have been performed in the absence of a precise diagnosis.

Avoided procedures included 11 major surgeries and 16 fewer diagnostic tests such as  open muscle, liver and other biopsies that are performed under general anesthesia.

Success story

In one case, a newborn baby girl with a life-threatening irregular heartbeat was admitted to CHOC Hospital. Instead of undergoing an arduous battery of tests, the child was diagnosed within two days with Timothy Syndrome, an extremely rare cardiac condition that put her at risk for sudden death.

With the genetic diagnosis in hand, CHOC physicians were able to treat the infant with the appropriate medication  for her condition. Her heartbeat was restored to normal, significantly reducing the risk of sudden cardiac death. Her physicians, secure in her diagnosis, implanted a pacemaker, dramatically improving her chances for a happy and healthy childhood.

She recently celebrated her first birthday.

“Without the results of her rapid whole genome sequence, she would have gone home on a different medication and been at a much higher risk for sudden death,” Dr. Knight said. “She got the right diagnosis and we gave her a pacemaker so her risk of sudden death went to zero.”

In all, Project Baby Bear provided diagnoses for 76 of the 178 babies who completed rWGS. This led to a change in the care of 66 babies. It diagnosed 35 rare conditions that occur in less than one in 1 million births. About 150,000 children could benefit from rWGS.

Turning every stone

Even if the test doesn’t diagnose a problem, it can help comfort families, Dr. Knight said.

“Even a negative test can be helpful for some families to know we’re not missing something,” he said. “It gives them assurance that we’ve turned over every stone.”

With the success of the study, Dr. Knight hopes to see the service expand to reach more patients.

“Should we be doing this with all newborns?” he asked. “Based on our experience with Project Baby Bear, it would seem feasible that for newborns and children in intensive care units without clear diagnoses, this should be part of our diagnostic process and the earlier the better.”

Multidisciplinary, multi-site effort

CHOC’s role in Project Baby Bear is a collaborative, multi-disciplinary effort involving many clinicians and staff, including research coordinators Cathy Flores, Erum Naeem and Ofelia Vargas-Shiraishi, and physician leads Drs. John Cleary, Juliette Hunt, Adam Schwarz and Neda Zadeh, in addition to Dr. Knight.

Led by Rady Children’s Hospital-San Diego, Project Baby Bear helps infants who are undergoing intensive care and covered by Medi-Cal. The other participating hospitals include UCSF Benioff Children’s Hospital Oakland, UC Davis Children’s Hospital in Sacramento, and Valley Children’s Healthcare in Madera.

The $2 million Project Baby Bear was funded by the State of California. In-kind contributions of $400,000 from Rady Children’s Hospital ensured more than 90 percent of the state funds were used to support the care and management of critically ill babies.

Learn more about the CHOC Research Institute.

Journey to a rare diagnosis: Colten’s story

Christine Schweer knew early on that her son, Colten, faced some health complications.

Christine, a pediatric intensive care nurse living in the Midwest with her husband, Todd, and then 3-year-old daughter, Chloe, recalls feeling different during her pregnancy with Colten. Once Colten was born, little things started popping up, she says.

Over the next few months, Colten developed several symptoms: cold hands and feet, a sleepy demeanor, strange breathing and chronic, involuntary eye movements – a condition called nystagmus.

At this point, Colten had already gone through several emergency department visits, including an admission to the hospital for respiratory syncytial virus (RSV) and eventually unexplained heart failure. But after genetic testing and screening for cystic fibrosis, cancer and blood clots all came back negative, Colten and his parents and doctors were left confused.

Searching for an answer

Colten was 6 months old when two new symptoms arose. An occupational therapist thought Colten’s vision and hearing were waning, and an ophthalmologist confirmed the therapist’s suspicion.

Then, around 9 months old, Colten’s weight mysteriously began to skyrocket.

Meanwhile, the Schweers decided to relocate to California to be near family. Christine, who now works in the PICU at CHOC at Mission Hospital, transferred all of Colten’s records to CHOC. She began to schedule visits to a team of CHOC providers, including pediatrician Dr. Lauren Dwinell and pediatric cardiologist Dr. Anthony Chang.

Armed with her signature beach bag full of Colten’s records, Christine continued the search for a diagnosis with Colten’s new care team, led by Dr. Chang.

“We hit it off right away,” Christine says of Dr. Chang. “He admired me for my dedication and advocacy for Colten, and I respected him for his thoroughness, for trusting my parental instincts and for his commitment to innovative treatment. We developed a good rapport and a lot of trust. He would listen to me and recommend next steps for us both; then we would meet and compare results.”

But the Schweers and Dr. Chang were still puzzled by Colten’s symptoms, and Colten was now 2 years old.

“Nothing was adding up,” Christine says. Colten’s heart function would worsen if off his medication, and his weight continued to climb. “He was eating healthy and walking, swimming and exercising a lot, but his weight was not budging.”

A few years passed while they continued to search for an answer.

An answer at last

Dr. Chang suggested they revisit genetic testing, despite Colten having received genetic testing a few years prior.

“We trusted Dr. Chang’s instinct,” Christine says. “He pointed out that tests can change even in a short time, and he wanted to be sure we covered our bases.”

He sent them to Dr. Neda Zadeh, a CHOC pediatric geneticist and Associate Director of the Molecular Diagnostic Laboratory.

A thorough walkthrough of Colten’s history and several questions later, Dr. Zadeh had an idea. Recalling a case she encountered during her fellowship at Stanford University, she brought up a rare condition called Alström Syndrome and suggested they test for it.

While they waited, Christine got to work researching Alström Syndrome symptoms and immediately knew they had figured it out.

“Alström checked all the boxes: heart failure, flat and wide feet, nystagmus, obesity and delayed developmental milestones – it completely fit,” Christine says.

Six months later, a genetic sequencing test paid for by the foundation Alström Syndrome International confirmed what Christine and Dr. Zadeh suspected – Colten had Alström Syndrome. He was the 972nd person in the world to receive the rare diagnosis. By this point, he was 8 years old.

The Schweers were immediately welcomed into the Alström family, Christine says. They got involved with the foundation that covered Colten’s genetic testing, and families around the country and globe reached out to them. Colten even met one of his current best friends, a boy with Alström from Canada.

Despite the relief of a diagnosis after years of searching, Alström came with some difficulties. The diagnosis meant that Colten’s vision was weak and that his hearing would decline, too. The disease also affects his lungs, kidneys, liver and weight.

“It of course felt horrible at first to me and my husband to learn that Colten has a rare disease, but it was also a relief to know that we had an answer now; there wouldn’t be so many surprises anymore,” Christine recalls.

The Schweers continued to work with Colten’s specialists, finally certain they knew the cause of his symptoms.

Collaboration is key

Christine reflects on the years of searching for answers and, despite the difficult moments, feels thankful for their collaborative care team at CHOC.

“If it weren’t for Dr. Chang suggesting more genetic testing, if he hadn’t advised we see Dr. Zadeh and if it weren’t for the Alström case Dr. Zadeh remembered from years before, we probably wouldn’t have figured it out,” she says.

Christine thanks Dr. Chang for always keeping innovation in mind.

“It would be easy to think inside the box and rely on past test results,” Christine says, “but Dr. Chang always stayed up-to-date with tests and looked at things creatively. It’s a multidisciplinary team approach at CHOC.”

Most importantly, Christine admires the way Colten’s care team relates with him.

“Doctors at CHOC are very personal with Colten,” she says. “They get on his level and take time to get to know him and what he’s been up to. Colten trusts them and wants to make them happy, so it’s always a positive experience for him to see them.”

The approach has resulted in a fruitful partnership between Colten, his parents and his providers.

“We’re all such a good team now. We feel confident we’re doing everything we can possibly be doing for Colten.”

Learning about rare disease at Peds2040

The experience getting Colten’s diagnosis sparked in Christine a connection to the rare disease community. She heard about a rare disease panel planned for the Pediatrics 2040 Conference, an annual conference on innovation in pediatrics spearheaded by Dr. Chang, who had since been appointed CHOC’s Chief Innovation Officer and head of CHOC’s Sharon Disney Lund Medical Intelligence and Innovation Institute (MI3). Christine expressed interest in attending right away, so MI3 sponsored her to attend. The experience was invaluable.

“It was a great learning opportunity,” Christine says. “I had lunch with a speaker whose son had a rare cancer, spoke with other families and shared Colten’s story with providers, interns and residents.”

She also learned about CHOC’s partnership with Rady Children’s Hospital to offer microarray testing – a more thorough chromosomal test that can detect rare genetic conditions in kids like Colten during infancy.

Thinking back to Colten’s journey to a diagnosis, Christine felt grateful they had MI3 and Dr. Chang on their side. Peds2040 highlights the importance of medical innovation to those with rare diseases.

Colten visits with Dr. Anthony Chang at the Pediatrics 2040 Conference.

One of the most memorable moments of the conference for Christine was Colten arriving toward the end of the day, when he was able to catch up with Dr. Chang.

Colten today

Today, Colten is a loving, strong-willed, intelligent 13-year-old with a deep love of cars and an amazing memory. These days, he and his family are grateful to be able to go several months between specialist appointments.

Even so, Christine notes, he faces some difficulties.

He is short for his age, so they’re seeing endocrinologist Dr. Himala Kashmiri to monitor his hormone levels. Additionally, like his vision, Colten’s hearing has waned and will continue to weaken during his teenage years. But, Christine reports, he has learned braille and thriving at it. And, because Alström can affect multiple organs, they continue to watch his heart, liver and kidney function with the help of medication and several specialists.

Colten continues to see Drs. Dwinell and Chang, along with nephrologist Dr. Shoba Narayan, pulmonologist Dr. Chana Chin, gastroenterologist Ellen Schoenfield, NP, registered dietitian Vanessa Chrisman, audiologist Dr. Kristi Panek and a pediatric ophthalmologist.

Nevertheless, the Schweers ensure Colten is empowered to do what he wants.

“We’ve never held him back from doing something,” Christine says. “If he wants to do something, we’re going to make it happen.”

Colten joined a Challenger baseball team for kids with special needs, now one of his favorite activities.

And, despite vision loss, his love of cars is as strong as ever.

“Before, he could instantly tell you what a car was when he saw it” Christine says. “Now, he can identify them by sound.”

Some of Colten’s favorite memories so far include joining his baseball team, going horseback riding and ziplining, and he has plenty more adventures planned.

“Despite his challenges, he’s very determined and has a don’t-baby-me, I-can-do-this attitude that impresses me – and makes me a nervous wreck,” Christine adds.

“When Colten was little, his doctors said he might not be able to talk. Now we joke that we have to beg him for five minutes of quiet. He doesn’t stop talking when he’s around his loved ones.”

Advice for other families

Christine looks back at the difficult road to a diagnosis and is now grateful for the community that Alström has brought her family.

“Let yourself grieve after a difficult diagnosis,” she says, “but also try to recognize you’re part of a new family. You’re not alone in this. Know that there are other parents out there who know what this feels like, so don’t try to take it on all by yourself. Despite how it can feel at first, every day is not going to be a bad day.”

Learn more about Medical Intelligence and Innovation at CHOC

CHOC-HOSTED INAUGURAL PACIFIC COAST FETAL CARDIOLOGY SYMPOSIUM PROVIDES VITAL EDUCATION

CHOC leads the way in fetal cardiology and fetal echocardiography, and recently shared its expertise at its first “Pacific Coast Fetal Cardiology 2017: An Interactive and Case-based Education Symposium.” Held at the Marriott Hotel, Newport Beach, the conference brought together nurses, sonographers, physicians, trainees and health care professionals from 50 different organizations across the country.

Led by Dr. Wyman Lai, medical director of echocardiography and co-medical director of the CHOC Heart Institute, and Anita Moon-Grady, from University of California, San Francisco, the event provided vital education on how to detect serious heart defects during pregnancy, and how to discern when to refer to a fetal cardiology specialist for further testing, counseling and intervention. Additionally, education was provided on  the current International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and American Society of Echocardiography (ASE) guidelines, including: how to improve screening efficacy; acquire the ability to rule out or assess for selected complex anomalies during fetal cardiology screening; diagnose obstructive left heart lesions and counsel families on treatment options and prognoses; use key features reviewed to diagnose heterotaxy syndrome; counsel patients on the benefits and limitations of early fetal echocardiography; and diagnose tetralogy of Fallot, its variants and when to refer to a pediatric cardiologist for treatment.

More than a dozen cases were presented by various speakers and featured obstructive left heart lesions, Heterotaxy syndromes, early fetal echocardiography and variants of tetralogy of Fallot. Keynote speakers included Dr. Wayne Tworetzky from Boston Children’s and Dr. Lynn Simpson from Columbia.

Dr. Neda Zadeh, CHOC geneticist, presented, “Understanding Fetal Screening for Chromosomal Abnormalities.” No screening test can detect all birth defects, she explained; however, diagnostic testing is the “gold standard”for prenatal diagnosis of a chromosomal abnormality. CHOC pediatric cardiologist, Dr. Pierangelo Renella, provided an in-depth clinical presentation, “Coarctation of the Aorta versus Interrupted Aortic Arch.”

A major highlight of the conference was a live demonstration of a fetal echocardiogram performed by Dr. Wyman Lai on a pregnant patient with a fetus who presented with tetralogy of Fallot. As he demonstrated the procedure on the large screen, attendees were enthralled with Dr. Lai’s presentation and diagnosis.

Learn more about CHOC’s Heart Institute and fetal echocardiography program

Find upcoming conferences and events: CHOC’s Continuing Medical Education

CHOC Conference Addresses Medical Complexities

With the number of children with complex medical needs expected to double in the next decade, an upcoming CHOC conference will provide important information for medical providers who are diagnosing and treating this patient population.

The Dec. 3 “Connecting the Dots … Diagnosing and Treating Children and Adolescents with Medical Complexity” will focus on commonly overlooked and under-diagnosed connective tissue disorders such as Ehlers-Danlos syndrome (EDS); chronic pain syndromes; postural orthostatic tachycardia syndrome (POTS); dysautonomia; and mast cell activation disorder.

The conference is recommended for community pediatricians, family practice physicians, and internal medicine physicians, as well as a variety of specialists, including gastroenterologists, cardiologists, neurologists, rheumatologists and pain specialists.

“These are multisystemic disorders with a variety of symptoms. If patients and physicians are not aware of some of these underlying diagnoses, patients may be experiencing diagnostic odysseys for years prior to an actual diagnosis being made,” says Dr. Neda Zadeh, a CHOC geneticist who will moderate the conference. “Earlier diagnosis is always better.”

Following the conference, attendees will gain new skills related to these conditions:

  • Recognizing the symptoms for some of the more common connective tissue disorders including EDS and hypermobility type, and referring accordingly to appropriate subspecialty.
  • Understanding the symptoms for POTS and how to assess for this in the outpatient medical setting;
  • Recognizing features of mast cell activation disorder, and understanding how this relates to certain forms of EDS;
  • Improving knowledge of chronic pain and connective tissue conditions in children and adolescents;
  • Recognizing the signs and symptoms of a possible underlying connective tissue disorders, as well as the resources and referrals available; and
  • Improving knowledge and treatment of chronic pain in children and adolescents.

Register for the conference on CHOC’s website.

A complementary conference Dec. 3 and 4 is dedicated to teen patients with connective tissue disorders and their parents. If you have a patient who would benefit from the conference, they can also find registration information on CHOC’s website.

CHOC Provides Comprehensive Care for Children with Neurofibromatosis Type 1

CHOC Neurofibromatosis Program – a recently nationally recognized program by the Children’s Tumor Foundation as a Neurofibromatosis Affiliate Clinic – provides comprehensive care to even the most rare medical issues in association with Neurofibromatosis type 1 (NF1).

Dr. Neda Zadeh
Dr. Neda Zadeh

NF1 is a common genetic condition that primarily affects the skin and the nervous system and is caused by a change or mutation in a single gene called NF1.  This condition occurs in approximately one in every 3,000 children. The majority of these children do very well, have happy and healthy lives and may not have major skin issues, developmental disabilities or other neurological issues, says Dr. Neda Zadeh a CHOC medical geneticist and associate director of the Molecular Diagnostic Laboratory at Genetics Center.  However, due to the known complications that can accompany this condition, comprehensive multidisciplinary care is strongly recommended.

“Half of the time, NF1 can occur for the first time in a child due to a spontaneous mutation in the NF1 gene at the time of conception, and is not inherited from a parent,” explains Dr. Zadeh. “It is important for parents to realize that this condition is not the result of anything an expectant mother did or did not do during her pregnancy. In the other 50 percent of patients, we often will see that one of the parents also has NF1 and may not even realize it.”

In order to meet criteria for an NF1 diagnosis, patients must meet two of the following criteria established in 1988 by the National Institutes of Health (NIH), summarized below:

  • Six or more café-au-lait macules of a specific measured diameter depending on the age of the individual (over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals).
  • Two or more neurofibromas of any type or one plexiform neurofibroma.
  • Freckling in the axillary or inguinal regions.
  • Optic glioma.
  • Two or more iris Lisch nodules (iris hamartomas) observed on dilated eye exam.
  • A distinctive bony lesion (sphenoid dysplasia or tibial pseudarthrosis).
  • A first-degree relative (parent, sibling, or offspring) with a known diagnosis of NF1 as defined by the above criteria.

These NIH diagnostic criteria are extremely accurate in adults and children over the age of 5 years. A diagnosis of NF1 should be suspected in individuals who have any one of the above findings. Often if children are younger than 5 at the first evaluation, he or she may not yet have met the above criteria, but may do so after they reach school age. For this reason, visiting a geneticist on a regular basis is important in order to monitor and care for the patient.  Also, in certain cases in which a diagnosis is not completely clear, or there is concern for a different diagnosis, genetic testing via sequencing and deletion/duplication analysis of the NF1 gene is available and usually coordinated after genetic counseling occurs.

Neurofibromatosis type 2 (NF2), a completely separate disorder, is even more rare than NF1.  A patient with NF1 is not at an increased risk compared to the general population to have NF2, especially if there is a negative family history.

Children with NF1 require care from multiple specialists including neurosurgery, neurology, oncology and orthopaedics, and at CHOC is seen at least annually by a geneticist, who aids in coordinating care and management of the condition. CHOC’s  multidisciplinary NF clinic involves all of the above specialists in the routine care of children with NF1 and other related disorders.

“We also can provide information to a patient and their families regarding the possibility to have further children in the family with NF1,” says Dr. Zadeh.

CHOC’s Neurofibromatosis Program has been treating children with NF1 for more than 30 years and annually cares for at least 150 children with NF1. The special program includes CHOC specialists currently involved in cutting edge clinical trials that are not available at many pediatric centers.

Learn more about the genetics program at CHOC.