At first, pediatricians were confused: The newborn patient wouldn’t eat, didn’t cry to be fed, and wouldn’t grow. She had been through an odyssey of tests and treatments, from feeding therapy to swallow studies to tonsillectomies, with no definite explanation for her failure to thrive. Her parents wondered if perhaps they were doing something wrong.
When scientists at Children’s Hospital of Philadelphia looked at the patient’s chromosomes by a SNP array test, however, it clicked: The unusual pattern on her chromosomes matched those of three or four other children with growth failure who had been identified by the Genomics Diagnostic Laboratory at CHOP, and soon, a dozen patients with the same genetic growth condition would be recognized across the globe.
More than eight years and 13,000 genetic tests later, three scientists at CHOP had enough material to pen a paper published in Genetics in Medicine. Better yet, they had a clear, definable disorder complete with phenotype and genetic etiology. Earlier this month, the authority on genetic diseases, Online Mendelian Inheritance in Man, gave the disorder a name: Mulchandani-Bhoj-Conlin Syndrome (MBCS), named after the scientists themselves: Surabhi Mulchandani, MS, genetic counselor and manager of the Genomic Diagnostics Laboratory; Elizabeth Bhoj, MD, PhD, clinician-researcher in the division of Human Genetics; and Laura Conlin, PhD, director in the Genomic Diagnostics Laboratory. The classification would bring much relief to many parents.
“It is rare, but very likely under-diagnosed,” Mulchandani said.
Chromosomes in Common
MBCS is characterized by mild prenatal growth deficiency, slow growth, and the lack of desire to eat. At its heart, MBCS is an imprinting disorder. Normally, people inherit one copy of each chromosome from each parent. However, children with MBCS have both copies of chromosome 20 from their mother, and none from their father. While the exact cause of MBCS is unknown, the researchers predict that the disorder is caused by the lack of paternally inherited genes on chromosome 20.
“Going to the literature, there’s some really well-described syndromes caused by inheriting either both of mom’s or both of dad’s chromosomes, but no one had really looked into what inheriting both copies of your mom’s chromosome 20 did,” Dr. Bhoj said. “This very unique chromosomal difference also truly brought [the children] together because there’s many things, genetic and non-genetic, that make babies have trouble gaining weight — a baby could have congenital heart disease, acid reflux, muscular problems. But this genetic change is very specific.”
For Dr. Bhoj and her colleagues, the next step was to find clinicians from institutions across the world who had seen patients with the same unusual chromosome pattern and weren’t sure how it related to that patient’s medical problems. Eight children between the ages of 4 and 12 were studied who shared a very similar phenotype: All were born at a smaller-than-normal size, experienced difficulty feeding in their first years of life, and grew extremely slowly. Six of the children needed a gastric feeding tube. Most stood at a shorter stature than normal.
While these aspects of MBCS slightly set the children back in their first few months or years of life, the study also found that the disorder came with hope: Four of the children had been put on growth hormones and gained growth velocity. None experienced developmental delays, and all currently attended mainstream schools at age-appropriate grade levels. If a parent worried that MBCS might affect their child’s later development, they could be assured that their child would likely mature well.
“It’s pretty empowering to have a diagnosis of what’s going on, but also to know that there is very little recurrence risk in the family, and to know that if you do give growth hormone, patients can catch up,” Mulchandani said. “There aren’t really long-term major structural issues that the families have to be prepared for.”
The Power of a Name
While it may seem like a simple thing, naming a set of symptoms can have many far-reaching implications. For physicians, Dr. Bhoj explained, the classification will hopefully eliminate treatments that doctors might prescribe because of the vague nature of the patient’s prognosis.
“I think the most important thing is that patients won’t get unnecessary medical interventions to fix this because they weren’t sure what was causing it,” Dr. Bhoj said. “Now we know the natural history, and we know that if you just help them through the initial period, either by using a gastric tube or intense feeding therapies, then they’ll outgrow it, and there are no lasting effects as far as we can see.”
Mulchandani and Dr. Conlin added that the classification has increased awareness of the disorder, and they hope that knowledge will continue to spread to more doctors, most especially endocrinologists.
“Often the genetic testing we do in the laboratory, the SNP array, isn’t the first test that an endocrinologist might order for patients presenting with growth deficiency,” said Dr. Conlin, who also is an assistant professor of pathology and laboratory medicine at the Perelman School of Medicine at the University of Pennsylvania. “But now, if they know that there’s this syndrome out there, maybe they can try to test for it.”
For families, the classification changes lives.
“It relieves the guilt that’s put on parents for why they can’t appropriately feed their child,” Dr. Bhoj said. “[Feeding] is the most basic thing you do when you have a baby, and parents have a lot of emotional distress around not being able to have their children gain weight.”
Dr. Bhoj told the story of an infant in California who had been under the supervision of Child Protective Services because he was believed to be malnourished. When the parents learned of MBCS and had a SNP array done, however, the baby was found to have MBCS, returned to the parents, and received proper treatment.
“It wasn’t because the parents were at fault,” Dr. Bhoj said. “He had this intrinsic lack of desire to eat.”
Already, other families are approaching the scientists at the Genomics Diagnostics Laboratory at CHOP to take a look at genetic tests done at other labs to see if their children might have the imprinting disorder, Mulchandani said. As for the parents of the eight children reported on in Genetics in Medicine, the study conducted by CHOP scientists has brought them together in more obvious and everyday ways: Those who live locally have planned a picnic to discuss their experiences struggling to find the right diagnosis, work through the consequent emotional issues, and reflect on how far they have all come.