Taking a closer look at the family tree
by Nancy Fliesler
Fifteen-day-old Stacy Peace whimpers softly as the nurse tends to her. She is recovering from heart surgery to correct a congenital narrowing in her aorta, the major vessel leaving her heart. She's not yet seen her home, 12 hours north in Maine, a stone's throw from the Canadian border.
The doctors at Northern Maine Medical Center induced her mother's labor early because Stacy had stopped moving. She emerged blue, making barely a sound. She was transported first to Bangor, then ambulanced to Children's Hospital Boston, where cardiac surgeon Frank Pigula, MD, fixed her aorta.
The narrowed aorta is only one of Stacy's problems. She also has an atrioventricular septal defect, or a lack of separation between the two atria and the two ventricles of her heart. In addition, instead of two valves controlling blood flow between the heart's chambers, Stacy has only one. As a result, blood flows in Stacy's heart in ways it shouldn't.
While Stacy rests in the ICU, geneticist Amy Roberts, MD, interviews Stacy's parents, Angela and Scott Peace. Roberts' job is two-fold. First, as a geneticist with expertise in cardiology, she needs to explore whether Stacy's heart problem might be part of a genetic syndrome that could affect future siblings, if the Peaces have more children, or affect other aspects of Stacy's health. If she can diagnose a specific syndrome, she must then ensure that Stacy gets the full range of tests and interventions she needs—not just cardiac follow-up. In essence, Roberts will act as a primary-care pediatrician—one who is expert in her tiny heart patient's rare disorder.
"My husband has pretty much the same problem," Angela tells Roberts. "Holes in his heart."
"Were any other problems noted for Stacy?" Roberts asks.
"Well, she has the bent thumb," Angela says. Indeed, Stacy's thumbs, like her father's, have an extra joint, giving them a finger-like appearance.
Roberts starts sketching a family tree, beginning with Stacy's half-brother, who Angela had with another partner. "Is he healthy?"
"Oh, yes," Angela says.
"Any problems in school? Is he learning OK?" No problems.
"Has anyone ever listened to his heart and heard a murmur?" Roberts continues. "Any birthmarks on his skin?" No, and no.
Angela's brother and half-brother are healthy, but little is known about her half-sisters, who were adopted out of the family. As for Angela's parents, nothing in their medical history seems related to Stacy's problem.
Scott is questioned next. The records note that he's had heart surgery and that a pacemaker was placed to regulate his heart beats.
"Do you know if it was ever activated to correct an arrhythmia?" Roberts asks. No, but the pacemaker has stopped functioning and hasn't been replaced.
"Any problems with your wrists?" Roberts continues.
"This one I can bend back, but this one is as far as it can go. In the wintertime, I lost strength in my hand," Scott adds. "I couldn't even hold a glass."
Roberts checks his hands, wrists and elbows, noting that he can't fully straighten his right arm.
"Have you ever had any eye surgery?" No. "Learning problems?" Yes: Scott required special education through high school.
Scott has a son and daughter from another partner, but both, he says, are healthy. Scott's mother, Roberts learns, had a history of heart attacks. She adds this information to Scott's family tree.
"Anyone else in the family with thumb or heart problems?" No, Scott says. Roberts also checks the family's ethnicity: Albanian, German and Irish on Angela's side; French Canadian, English, and Irish on Scott's.
Upstairs in the ICU, Roberts examines Stacy, noting her three-part thumb and loud heart murmur. A slight fold of skin across the inside corner of Stacy's eyes (near the tear ducts) is probably normal but can also occur in certain genetic syndromes. Similarly, the top of Stacy's nose is somewhat wide and the tops of her ears have extra folds.
"She is beautiful," Roberts tells the Peaces. "Congratulations. Other than the thumbs and the heart murmur, I don't see anything unusual."
Similar to journalists "embedded" with American troops in Iraq, Roberts is part of a trend at Children's to put geneticists in different clinical departments—a convenience for families that also allows geneticists to hone their expertise and clinicians to benefit from their knowledge.
"When you have 30 cardiologists funneling patients to one or two geneticists with a special interest in cardiac disease, you can start recognizing rare conditions, because you've seen them before," says Mira Irons, MD, chief of Clinical Genetics. "And when you funnel rare conditions to one geneticist who knows how to take care of them, you improve patient care."
Roberts is fairly sure that Stacy has Holt-Oram syndrome, also called hand-heart syndrome because of its major features: malformations of the heart and hand bones. The Peaces agree to have Stacy's blood drawn so she can be genetically tested for this condition.
"It's a dominant disorder," Roberts tells them, "So each time Mr. Peace has a child, and later on when Stacy has children of her own, there's a 50/50 chance it will be passed on."
Roberts also recommends evaluation of Scott's other two apparently healthy children. Hand X-rays could reveal subtle bone defects that might signal Holt-Oram disease, and echocardiograms might pick up heart malformations that could cause problems later.
Stacy will also be tested for a 22q11 deletion, a chromosomal defect causing heart malformations and cognitive problems. "I wanted to check this because Stacy's dad had significant learning prob-
lems, and that's not seen in Holt-Oram," Roberts explains later.
If Holt-Oram syndrome is confirmed, Stacy will need to be monitored for cardiac arrhythmias throughout her life. "Her prognosis is good as long as she continues to have a relationship with a cardiologist," Roberts says.
When Liam Tobin was born, his eyes remained closed for about a month because his eyelids were too weak to open. And that was only the beginning. "His eyes were literally like pinballs—they bounced around, quivered and shook," recalls Liam's mother, Elizabeth Hoskins. "Every time we brought him to the doctor, they'd say 'this is amazing' and call everyone in to see it."
Liam had trouble moving his eyes both vertically and horizontally. When he tried to look down, his eyes would drift outward. When he opened his mouth, his left eye also opened, a phenomenon call jaw-winking.
In Minneapolis, where Liam was born, ophthalmologists said he would probably need at least 12 operations, and even then his eyes probably wouldn't be quite right. "He had every eye problem in their brochure—about six different things," says Hoskins. "But there was no overarching explanation."
When they moved to New Orleans, a doctor at Tulane University thought Liam might have a brain tumor. He did an MRI on Liam's brain and found nothing. Then he tested Liam for herpes, on the theory that herpes can cause eye problems; this too came back negative. He did two operations that improved Liam's eye alignment, but then admitted, "We really don't know what else we can do."
At Louisiana State University, Liam was diagnosed with Duane syndrome and underwent another operation. In Houston, an ophthalmologist at Baylor College of Medicine disagreed, but did not have a definite diagnosis for Liam. And at nearby Texas Children's Hospital, an ophthalmologist thought that Liam could have a degenerative condition and lose his eyesight altogether. When his parents asked about surgery, a group of ophthalmologists convened to examine Liam and ended up in a heated argument. That's when Hoskins took to the Internet and found David Hunter, MD, chief of Ophthalmology at Children's Hospital Boston.
"Dr. Hunter said, 'Absolutely, something more can be done for Liam,'" says Hoskins. "It was a completely different experience from what we'd had."
Hunter specializes in strabismus, or misalignment of the eyes, the broad term for Liam's condition. He collaborates closely with neurologist Elizabeth Engle, MD, who has devoted her career to identifying rare, complex types of congenital strabismus, finding their causative genes, and figuring out what these genes do. She has an ongoing genetic study of strabismus, and Liam was promptly enrolled.
Strabismus is caused by a failure of one or more of the six muscles that move the eyeball. Engle has identified several gene mutations that affect these muscles or one of the three cranial nerves that control them. Through her research, Children's has become a diagnostic center for strabismus, and operates a lab that does DNA testing on patients from around the world.
When Liam's family flew up from Texas to see Hunter, Engle was studying a type of complex strabismus called congenital fibrosis of the extraocular muscles. In its most common form, called CFEOM1, a branch of the third cranial nerve—controlling the muscles that lift the eyelid and pull the eyeball upwards—is missing or very small. People with CFEOM1 must hold their head in odd positions to see: they have droopy eyelids, cannot raise their eyes vertically and sometimes have difficulty moving them horizontally.
In the 1990s, Engle identified 60 large families with this pattern of symptoms and mapped the gene for CFEOM1 to chromosome 12 using linkage analysis. This technique looks for a stretch of DNA shared by all family members with the disease, but not by unaffected family members. In 2003, Engle's lab pinpointed the precise mutated gene, called KIF21A.
Examining Liam, then 7 1/2, Hunter felt he might have CFEOM1, but was puzzled that neither of Liam's parents was affected. Plus, Liam's other symptoms—particularly the jaw-winking—weren't typical. In July 2003, he performed surgery on Liam, pulling back his tight outer eye muscles to release the tension. This allowed the inner muscles to pull Liam's out-turning eyes back inward. However, after a few months, his eyes slipped outward again.
Meanwhile, Engle's genetic testing confirmed the CFEOM1 diagnosis, but with a twist: Liam had a unique, previously unidentified KIF21A mutation. His case was recently published in an ophthalmology journal. At the cellular level, Liam's mutation disables a protein, called a kinesin, that is believed to transport essential materials from the cell body of the third cranial nerve, located in the brainstem, down to the nerve endings that meet the eye muscles.
"Kinesins are basically little machines that run up the nerve fibers," Engle says. "Each one carries something from the nerve cell body that's needed at the other end." Because Liam's mutation somehow blocks the transport of this still-unknown cargo, his eye muscles did not receive appropriate nerve stimulation during development and, as a result, are "hooked up" in anomalous ways.
In December 2003, Hunter performed a second operation. This time, he took a chance and overcorrected the outward drift of Liam's eyes, deliberately leaving him cross-eyed. As hoped, this strategy eventually normalized the alignment of Liam's eyes—but only temporarily. So Hunter turned to Botox, injecting tiny doses of the paralytic agent into selected eye muscles. Liam has had three treatments to date, each improving his eye position a bit more.
As Hunter and Engle see more patients with complex strabismus, Hunter's knowledge of the genetics may come to inform his treatment approach. "Over time, I might be able to say something like, 'Oh, a KIF21A mutation—you should skip surgery and go straight to Botox,'" he says. "Or I may feel more comfortable overcorrecting an eye misalignment if I know the genetic diagnosis."
Liam, now 9, now has a 50/50 chance of passing CFEOM1 to his own children. After six operations (including two at Children's), his eyes look close to normal, but he's had to contend with comments from his peers, and may have one more operation to pull up his drooping lids. "Everyone asks me why my eyes are like this,"
Liam says. "Sometimes the surgery is pretty painful, but I think it's worth it."
Children's craniofacial clinic is in full swing when Shannon Denton arrives with her family for a postoperative checkup. Her surgeon, John Mulliken, MD, has suggested she also see a geneticist. The Dentons meet first with genetic counselor Chantal Kelly, and show off photos from Shannon's recent Sweet 16 party.
A photo montage created for the event shows Shannon through the years. It also documents her medical history: Shannon was born with craniosynostosis, a premature fusion of the bony plates of her skull. Normally, through infancy, nature leaves gaps between these plates—including that soft spot at the top of a newborn's head—to give the developing brain room to grow. The plates then gradually fuse together.
But in craniosynostosis, some or all of the plates fuse too early, impeding the brain's growth and distorting the head. This can lead to a dangerous pressure buildup in the brain and cause mental retardation.
Shannon's craniosynostosis was especially severe, giving her head a three-lobed, cloverleaf shape. She underwent two operations as a baby, but when she saw Mulliken last December, her head was still tall and broad with a very high forehead. Mulliken surgically narrowed her skull on both sides and brought her forehead forward, and today her head shape is close to normal.
Craniosynostosis can be part of many genetic syndromes. Shannon had a genetic evaluation years ago, but the field makes new discoveries all the time, and her parents want an update as Shannon approaches her childbearing years.
Shannon's mom, Diane, prepared with diaries and photo albums, tells Kelly that her pregnancy was healthy, except for first-trimester bleeding, and that Shannon was born by C-section. "They realized at delivery that her head was misshapen and way too big," she explains.
Shannon's first operation was dramatic. "They cut across the top of her head and took all the bone out," says Diane. "Everything was soft and exposed, like a jelly. We had to be very careful picking her up."
"That's disgusting!" says Shannon.
Shannon had a shunt placed in her brain in infancy to drain excess fluid. Surprising her doctors, she met her developmental milestones on time. "They thought she would never walk or talk," Diane says proudly.
Small at age 3, Shannon began treatment with growth hormone, which ended only recently. She went to a special-needs preschool, receiving speech and occupational therapy, but after that attended regular schools.
Virginia Kimonis, MD, the craniofacial program's designated geneticist, arrives and quickly reviews Shannon's file. "There are about 150 different craniosynostosis syndromes," she tells the Dentons, "and some genes and tests were not discovered when Shannon was tested previously."
She begins examining Shannon, calling out her observations for Kelly to record. Kimonis notes a single palm crease on Shannon's left hand and a mild incurving of the pinky.
"Now let me take a look at that pretty face," Kimonis says, taking it in her hands. They chat about Shannon's boyfriend, who appears in the Sweet 16 photos.
"She has a low hairline," Kimonis announces. "Let's see if anyone else in the family has a low hairline." The Dentons bend their heads for inspection.
Shannon also has a high-arched palate, or roof of the mouth. (Diane has it too, but claims it's because they're English.) Kimonis notes Shannon's large tonsils and adds, "She doesn't have a cleft palate, that's good news."
Examining Shannon's arms, she finds a dislocated right elbow, which the Dentons attribute to an injury. But the other elbow has limited rotation, suggesting that this feature may be related to a craniosynostosis syndrome.
Kimonis notes Shannon's marked scoliosis, or curvature of the spine. She next performs a variety of head measurements, checks Shannon's vision and asks about heart problems. Examining Shannon's feet, she observes minor webbing of the toes, found in certain genetic conditions.
"Anything unusual about her walk?" she asks the Dentons.
"It's a teenage walk," says Diane dryly. "A saunter."
Kimonis powers up her laptop and goes to a database called London Dysmorphology, which catalogues over 3,000 congenital anomaly syndromes and can aid in diagnosis. She begins plugging in features of Shannon's condition: cloverleaf craniosynostosis, hydrocephalus (fluid in the brain), short stature, elbow dislocation, high-arched palate, palmar crease. She also checks a database called POSSUM with information on more 2,800 syndromes.
The consultation has lasted two hours. "Geneticists can't always make a diagnosis by looking at a child for five minutes," says Kimonis. "We take a complete family history and examine our patients from top to toe. Things a parent might not notice, like palm creases, nails or length of the arms, can be clues."
A refined computer search comes up with a list of 56 possible syndromes, but no readily apparent genetic diagnosis for Shannon. Diane had multiple miscarriages, signaling a possible chromosomal problem, so Kimonis suggests Shannon have a chromosome analysis in addition to DNA testing. But Shannon refuses to have blood drawn, so these tests will have to wait. Kimonis also recommends imaging of Shannon's bones to look for subtle abnormalities that might aid in diagnosis.
"Parents sometimes scour the earth to find a specific diagnosis," Kimonis says. "As a geneticist, I often feel like Sherlock Holmes, putting the pieces together. Then parents can move on and find support groups and literature. We can't predict the future, but we can identify possible complications that need to be looked at."
Working side by side at a world center for craniosynostosis, Kimonis and Mulliken have a unique research opportunity to better understand their patient population and the role genetics plays. They will soon begin recruiting children and their families for a comprehensive clinical study including radiologic, surgical, medical and visual evaluations; family histories going back three generations; and testing for genes that are known or suspected to cause craniosynostosis or are involved with skull development. Kimonis, Mulliken and colleagues also hope to define new genetic syndromes to explain the more than half of craniosynostosis cases with unknown origins.
This study, they hope, will suggest ways of preventing craniosynostosis, and may guide treatment and surgical technique. "Many plastic surgeons know little about the cause of the condition they're operating on," Mulliken says. "Knowing the syndrome, you can predict how the face will grow and do the appropriate surgical correction."
Geneticists are closely allied with a number of other departments throughout Children's, where they give clinical specialists access to a unique expertise and perspective that isn't available using solely traditional diagnostic tools.
Their work helps spur collaboration between different, seemingly unrelated specialties, and improves the care given to patients. In fact, some day, it may be possible to correct genetic conditions by replacing or repairing defective genes.
"Medicine is now down to the molecular level," says Mulliken. "We need a full-time geneticist in every specialty unit."
To learn more about supporting Genetics at Children's Hospital Boston, contact Sarah Roth in the Children's Hospital Trust at (617) 355-4008 or sarah.roth@chtrust.org.
