Academics & Faculty

Disease that stunts infants' growth traced to same gene that makes kids grow too fast

Discovery ends UCLA scientist's 20-year quest for cause of IMAGe syndrome

The Caterpillar got down off the mushroom ... remarking as it went, 'One side will make you grow taller, and the other side will make you grow shorter.'
—Lewis Carroll, "Alice's Adventures in Wonderland"
UCLA geneticists have identified the mutation responsible for IMAGe syndrome, a rare disorder that stunts infants' growth. The twist? The mutation occurs on the same gene that causes Beckwith–Wiedemann syndrome, which makes cells grow too fast, leading to very large children.
Published in the May 27 edition of the journal Nature Genetics, the UCLA findings could lead to new ways of blocking the rapid cell division that allows tumors to grow unchecked. The discovery also offers a new tool for diagnosing children with IMAGe syndrome, which until now has been difficult to identify accurately. 
Nearly 20 years ago, as a medical resident in his native France, Vilain cared for two boys, ages 3 and 6, who were dramatically short for their ages. Though unrelated, the children shared a mysterious malady marked by minimal fetal development, stunted bone growth, sluggish adrenal glands, and undersized organs and genitals. 
"I never found a reason to explain these patients' unusual set of symptoms," said Vilain, who also directs the UCLA Institute for Society and Genetics. "I've been searching for the cause of their disease since 1993."
When Vilain joined UCLA as a genetics fellow, the two cases continued to intrigue him. His UCLA mentor at the time, geneticist Dr. Edward McCabe, recalled a similar case from his previous post at Baylor College of Medicine. The two of them obtained blood samples from the three cases and analyzed the patients' DNA for mutations in suspect genes but uncovered nothing.
Vilain and McCabe approached the Journal of Clinical Endocrinology and Metabolism and in 1999 published the first description of the syndrome, which they dubbed IMAGe, an acronym of sorts for the condition's symptoms: intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia and genital anomalies. 
The UCLA Clinical Genomics Center performed next-generation sequencing, a powerful new technique that enabled the scientists to scour the enormous area in just two weeks and tease out a slender stretch that held the culprit mutation. The team also uncovered the same mutation in the original three cases described by Vilain and McCabe in 1999.
"We discovered a mutation in a tiny sliver of the chromosome that appeared in every family member affected by IMAGe syndrome," Vilain said. "This was a big step forward. Now we can use gene sequencing as a tool to screen for the disease and diagnose children early enough for them to benefit from medical intervention. 
"We were a little surprised, because the mutation was located on a famous gene recognized for causing Beckwith–Wiedemann syndrome," he added. "The two diseases are polar opposites of each other."
Children born with Beckwith–Wiedemann syndrome — named for the two doctors who discovered it — grow very large, with big adrenal glands, elongated bones and oversized internal organs. Because their cells grow so fast, up to one in five children with the disorder develop cancer at a young age. The disease appears in approximately one out of 15,000 births. 
"Finding opposite functions in the same gene is a rare biological phenomenon," Vilain emphasized. "When the mutation appeared in the slim section we identified, the infant developed IMAGe syndrome. If the mutation fell anywhere else in the gene, the child was born with Beckwith–Wiedemann. That's really quite remarkable."
IMAGe syndrome patients also tend to die young, due to poor adrenal activity, which physicians treat with hormone-replacement therapy.
Vilain's co-authors included first author Valerie Arboleda, Hane Lee, Alice Fleming, Abhik Banerjee, Emmanuele Delot, Imilce Rodriguez-Fernandez, Esteban Dell'Angelica, Stanley Nelson and Julian Martinez-Agosto, all of UCLA; Bruno Ferraz-de-Souza of the University of San Paulo in Brazil; Ignacio Bergada of Hospital de Ninos Ricardo Gutierrez in Argentina; and John Achermann of the University College London Institute of Child Health.
The study was funded by the Doris Duke Charitable Foundation, the Wellcome Trust and the National Institute of Child Health and Human Development (grants RO1HD068 and 1F31HD068136).
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